CN112439066A

CN112439066A - Pharmaceutical composition comprising chemical ablation agent and pH adjusting agent and use thereof

Info

Publication number: CN112439066A
Application number: CN201910813387.5A
Authority: CN
Inventors: 邹方霖; 邹礼常; 王建霞; 王艺羲
Original assignee: Chengdu Kuachang Aopu Medical Technology Co ltd
Current assignee: Chengdu Kuachang Aopu Medical Technology Co ltd
Priority date: 2019-08-30
Filing date: 2019-08-30
Publication date: 2021-03-05

Abstract

The present disclosure relates to a pharmaceutical composition comprising a chemoablative agent and a pH adjusting agent, and its use as a topical active ingredient in the preparation of a topical medicament for the treatment of a localized disease condition.

Description

Pharmaceutical composition comprising chemical ablation agent and pH adjusting agent and use thereof

Technical Field

Background

Due to the support of a great deal of research work, solid tumors are often used as research models for locally diseased diseases, especially refractory locally diseased diseases. A solid tumor is a neoplastic disease characterized by a tumor mass, which is a characteristic pathological tissue containing tumor cells. In the case of pancreatic cancer tumor bodies, pancreatic cancer cells account for only about 30% by volume of the tumor bodies. It can be seen that in addition to tumor cells, there are often a greater number of other components in tumor body tissue (sometimes also referred to as the microenvironment of the tumor cells), including other various cells, various intercellular substances, various ducts, etc.

Topical administration has the advantage of physically targeting the drug. It has therefore been thought that topical administration of cytotoxic drugs can increase the intratumoral concentration and thus the efficacy of the drug. However, topical administration of cytotoxic drugs has not shown a significant improvement in efficacy. Merely increasing its intratumoral concentration does not appear to significantly improve its efficiency in targeting cancer cells in intratumoral tissues. In addition to resorting to their sustained release forms, cytotoxic drugs are still almost systemically administered clinically. Chemical ablators (high purity ethanol, high concentration of acids and bases) are not characterized by cell destruction but by tissue destruction. Compared with cytotoxic drugs, it has almost no systemic effect of targeting cancer cells, but often shows higher local effect. However, they are often strong disrupters that do not sufficiently distinguish the target tissue from other tissues. This makes their practical application of intervention volumes (e.g., acid-base doses not exceeding 0.2ml/kg) and intervention sites very limited (e.g., restrictions on the organs in which the tumor resides, limited ablation of the tumor margins, etc.). Thus, chemical ablative agents have been clinically faded out of malignant solid tumors in the last decade. In fact, at present, there are few local drugs with high local safety and local curative effect in clinic.

Thus, there is still a need to develop new drugs, especially topical drugs, for the treatment of localized pathological conditions such as solid tumors to meet various clinical needs that the prior art has not yet been able to meet. In fact, there is an urgent need for the prevention and treatment of other localized conditions, particularly intractable localized conditions.

Disclosure of Invention

The invention aims to provide a local medicament for preventing and treating local pathological changes, in particular refractory local pathological changes. More specifically, it is an object of the present invention to provide a topical medicament that physically targets a localized lesion, but has lower side effects and higher efficacy.

According to one aspect of the present invention, there is provided a topical pharmaceutical composition for the treatment of a topical pathological condition, comprising an acid-base chemoablative agent and a pH adjusting agent, wherein the chemoablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemoablative agent in the pharmaceutical composition is 0.5% or more, preferably 0.75% or more or 2.5% or more, and the amount of the pH adjusting agent is such that the pH of the pharmaceutical composition is more neutral than the pH of the individual drug at the same concentration of the chemoablative agent, and the absolute value of the difference between the pH of the pharmaceutical composition and the pH of the individual drug at the same concentration of the chemoablative agent is 0.25 or more.

According to another aspect of the present invention, there is provided a use of a combination comprising an acid-base chemical ablative agent and a pH adjusting agent as topical active ingredients for the preparation of a topical pharmaceutical composition for the treatment of a topical pathological condition, wherein the chemical ablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemical ablative agent in the pharmaceutical composition is 0.5% or more, preferably 0.75% or 2.5% or more; the pH regulator is used in such an amount that the pH value of the pharmaceutical composition is closer to neutral than the pH value of the chemical ablation agent and the single drug, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent and the single drug is more than or equal to 0.25.

According to a further aspect of the present invention, there is provided a topical pharmaceutical composition for treating a topical pathological condition, comprising an acid-base type chemical ablative agent, a pH adjusting agent, a topical synergistic product thereof, and a suitable solvent, wherein the chemical ablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemical ablative agent in the topical pharmaceutical composition is 0.5% or more, preferably 0.75% or more, or 2.5% or more; the pH regulating agent enables the pH value of the pharmaceutical composition to be closer to neutral than the pH value of the chemical ablation agent with the concentration of the single medicine, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent with the concentration of the single medicine is more than or equal to 0.25.

According to yet another aspect of the present invention, there is provided a method for treating a localized disease condition, comprising administering to a localized disease area of an individual in need thereof a therapeutically effective amount of a topical pharmaceutical composition comprising as a locally active ingredient an acid-base chemoablative agent and a pH adjusting agent, wherein the chemoablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemoablative agent in the topical pharmaceutical composition is 0.5% or more, preferably 0.75% or 2.5% or more; the pH regulating agent enables the pH value of the pharmaceutical composition to be closer to neutral than the pH value of the chemical ablation agent with the concentration of the single medicine, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent with the concentration of the single medicine is more than or equal to 0.25.

In the present invention, the above topical pharmaceutical composition further comprises a topical synergist of the chemical ablative agent and the pH adjusting agent.

Embodiments according to the present invention have the following advantages over the prior art for the treatment of localized disease conditions: compared with the existing cytotoxic drugs, the compound has almost non-toxic systemic safety and obviously higher local lesion curative effect; compared with the existing molecular targeted drugs, the compound has less rigorous screening of indications and great potential for rapidly growing tumor bodies, large tumor bodies and blood-poor tumor donors; compared with the existing chemical ablation agents, the chemical ablation agent has higher effectiveness and obviously lower local irritation and damage to surrounding normal tissues, so that the application range of the chemical ablation agent is wider and the application volume is higher. The applications and compositions of the present invention are also not plagued by the problem of drug resistance encountered with existing cytotoxic drugs and existing molecular targeted drugs. In addition, the application and the composition are convenient to prepare and low in cost, and are particularly beneficial to leading the vast population who is difficult to bear high expense to enjoy safe and effective treatment.

Detailed Description

The inventors of the present invention conducted a study of chemical ablative agents (3% sodium hydroxide) with 7% sodium bicarbonate-3% sodium hydroxide as negative control. It is speculated from the disclosure of the prior art that the efficacy of sodium bicarbonate added to sodium hydroxide solution decreases with decreasing pH (e.g., from pH12 to 10.0). However, surprisingly, the low pH compositions show significantly improved tumor inhibition (e.g., from 43% to 68%) over high pH sodium hydroxide. Accordingly, the inventors of the present invention have studied pharmaceutically acceptable acid-base chemical ablator/pH modifier compositions, and have further studied the acid-base chemical ablator/pH modifier compositions and their local synergists.

Thus, according to one aspect of the present invention, there is provided a topical pharmaceutical composition for the treatment of a topical pathological condition, comprising an acid-base chemoablative agent and a pH adjusting agent, wherein the chemoablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemoablative agent in the pharmaceutical composition is 0.5% or more, preferably 0.75% or 2.5% or more, and the amount of the pH adjusting agent is such that the pH of the pharmaceutical composition is more neutral than the pH of a single drug with the same concentration of the chemoablative agent, and the absolute value of the difference between the pH of the pharmaceutical composition and the pH of a single drug with the same concentration of the chemoablative agent is 0.25 or more

In one embodiment, the topical pharmaceutical composition further comprises a topical synergist of the chemical ablative agent and a pH adjusting agent.

According to another aspect of the present invention, there is provided a topical pharmaceutical composition for treating a topical pathological condition, comprising an acid-base type chemical ablative agent, a pH adjusting agent, a topical synergistic product thereof, and a suitable solvent, wherein the chemical ablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemical ablative agent in the topical pharmaceutical composition is 0.5% or more, preferably 0.75% or 2.5% or more; the pH regulating agent makes the pH value of the pharmaceutical composition approach neutral compared with the pH value of the chemical ablation agent with the concentration of the single medicine, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent with the concentration of the single medicine is more than or equal to 0.25

According to another aspect of the present invention, there is provided a method for treating a localized disease condition, comprising administering to a localized disease area of an individual in need thereof a therapeutically effective amount of a topical pharmaceutical composition comprising as a locally active ingredient an acid-base chemoablative agent and a pH adjusting agent, wherein the chemoablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemoablative agent in the topical pharmaceutical composition is 0.5% or more, preferably 0.75% or more, or 2.5% or more; the pH regulating agent enables the pH value of the pharmaceutical composition to be closer to neutral than the pH value of the chemical ablation agent with the concentration of the single medicine, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent with the concentration of the single medicine is more than or equal to 0.25.

In the context of the present invention, the term "pharmaceutical composition" is used to refer to a mixture of more than one drug uniformly distributed in the same dosage form.

In the context of the present invention, the term "topical active ingredient" is used to refer to an active ingredient in a topical medicament that provides an effective topical effect, typically an effective destructive effect on a topical lesion. The term "local effect" or "local activity" refers to a pharmacological effect or pharmacological activity at a target area that is produced primarily by the drug itself rather than by the drug-bearing blood. The term "topical drug (composition)" refers to a therapeutic drug (composition) that exerts its pharmacological effects primarily through local action. The term "target area" as used herein refers to the target site of administration, e.g., adjacent, interfacial, internal (preferably internal) to a localized lesion, etc.

Within the scope of the present invention, the term "therapeutically effective amount" refers to an amount of a drug that is used to treat a disease (e.g., a tumor) and achieve an effective effect (e.g., reduce or/and alleviate symptoms of the disease).

In the context of the present invention, unless otherwise indicated, the term "concentration" refers to the weight percent concentration (w/w) of the specified component in the topical pharmaceutical composition. The term "local administration concentration" refers to the concentration of a specified component at the time the drug is administered locally, which may be the concentration of the specified component at the site where the drug contacts the target area (e.g., injection needle hole or infusion tube outlet).

Within the scope of the present invention, the pharmaceutical composition is a topical synergistic composition. Within the scope of the present invention, the pH adjusting agent and the chemical ablative agent are locally synergistic in the same solution. Within the scope of the present invention, the local synergist is locally synergistic with the chemical ablative agent and its pH adjusting agent in the same solution.

In the context of the present invention, the term "local synergy" refers to the synergistic effect of the drugs through local effects of local co-usage. The term "synergistic effect" means that the co-use of drugs (e.g., base salt of a polybasic weak acid and acid salt of a polybasic weak acid, strong base and acid salt of a polybasic weak acid) exhibits more therapeutically beneficial pharmaceutical effects than their separate use, including, for example, synergistic efficacy and synergistic safety. The term "synergistic efficacy" means that the active ingredients together exhibit a higher desired efficacy than either ingredient alone and/or that the combination does not exhibit the desired efficacy (e.g., tumor suppression rate) as either ingredient alone. The term "synergistic safety" refers to the desired safety (e.g., irritation, damage to surrounding normal tissue) exhibited by the active ingredients in combination over either ingredient alone, even though the efficacy of the combination is no greater than the maximum efficacy of the individual ingredient, it is efficacious, and the safety of the combination is significantly greater than the safety of the individual ingredient alone (e.g., antagonism of side effects), the combination also produces a synergistic effect.

In one embodiment, the synergistic composition is a synergistic safety composition. In one embodiment, the synergistic composition is a synergistic pharmacodynamic composition.

In the context of the present invention, the term "acid-base chemical ablative agent" (often abbreviated in this application to chemical ablative agents or ablative agents) refers to a substance whose acid-base property alone can produce a tissue-destroying effect, and which is also typically the most basic or acidic substance in the composition. The chemical ablative agent is one or more selected from the group consisting of pharmaceutically acceptable: strong base, weak acid, or strong acid.

In one embodiment, the concentration of the strong base in the pharmaceutical composition is 0.5% or more, preferably 0.75% or more, or 1% or more, or 0.5-10%, preferably 0.75-10% or 1-10%.

In one embodiment, the concentration of the weak base in the pharmaceutical composition is 2.5% or more, preferably 3.0% or 5% or more, or 2.5-35%, preferably 3.0-35% or 5-35%.

In one embodiment, the concentration of the strong acid in the pharmaceutical composition is 0.5% or more, preferably 0.75% or more, or 1% or more, or 0.5 to 10%, preferably 0.75 to 10% or 1 to 10%.

In one embodiment, the concentration of the weak acid in the pharmaceutical composition is ≥ 2.5%, preferably ≥ 3.0% or ≥ 5%, or from 2.5-20%, preferably from 3.0-20% or from 5-20%.

In one embodiment, the pH of the pharmaceutical composition is 7.5 ± 4.5, preferably 10.0 ± 2.0 or 4.0 ± 2.0.

In one embodiment, the chemical ablative agent is selected from a strong base or a weak base, and the pharmaceutical composition has a pH of 10.0 ± 2.0 or 10.5 ± 1.0.

In one embodiment, the chemical ablative agent is selected from a strong base or a weak base, and the pharmaceutical composition has a pH of 8.0 ± 1.0.

In one embodiment, the chemical ablative agent is selected from a strong or weak acid and the pharmaceutical composition has a pH of 4.0 ± 1.0.

In one embodiment, the chemical ablative agent is selected from a strong or weak acid and the pharmaceutical composition has a pH of 3.0 ± 1.0.

In one embodiment, the addition of the pH adjusting agent causes the pH of the pharmaceutical composition to tend to be neutralized and the buffering capacity of the pharmaceutical composition to increase.

In one embodiment, the pharmaceutical composition has a buffer capacity of>0.01mol·L^-1·pH^-1Preferably 0.015 to 0.45 mol. L^-1·pH^-1。

In one embodiment, the buffer capacity of the pharmaceutical composition is preferably ≥ 0.04 mol.L^-1·pH^-1More preferably not less than 0.05 mol/L^-1·pH^-1。

In one embodiment, the pharmaceutical composition has a buffer capacity of 0.04 to 0.45 mol.L^-1·pH^-1More preferably 0.05 to 0.45 mol.L^-1·pH^-1。

In the context of the present invention, the term "buffer capacity" (also known as buffer index) is used to indicate the amount (e.g.xmol) of strong monobasic acid (e.g.hydrochloric acid) or strong monobasic base (e.g.sodium hydroxide) required to be added when the pH of a unit volume (e.g.1L) of the pharmaceutical composition is changed by 1 unit, in mol. L^-1·pH^-1。

In the context of the present invention, the term "pH modifying agent" refers to an agent that changes its pH or pH buffering capacity upon addition of a solution containing a particular acid-base type chemical ablative agent.

Within the scope of the present invention, the pH adjusting agent is one or more selected from the group consisting of the chemical ablative agent and the group of the following which can make the pH of the pharmaceutical composition more neutral: strong base, weak base, strong acid, strong base, inorganic salt, organic weak acid, alkali metal salt, weak acid, strong acid. In the pharmaceutical composition, the concentration of the pH regulator may be 1% or more, preferably 2 to 35%.

Within the scope of the present invention, the tendency of the pH of the chemical ablative agent to be neutralized means that: when the chemical ablation agent is selected from strong alkali or weak alkali, the difference between the pH of the chemical ablation agent and the pH of the composition is more than or equal to 0.25; when the chemical ablation agent is selected from strong acid or weak acid, the difference between the pH of the composition and the pH of the chemical ablation agent is more than or equal to 0.25. The addition of a pH adjusting agent may also allow the buffering capacity of the composition to be increased after the pH is changed.

Within the scope of the present invention, the pH adjusting agent is preferably selected from water-soluble pharmaceutical excipient compounds and/or water-soluble auxiliary pharmaceutical compounds. In one embodiment, the concentration of the pH adjusting agent may be 2% or more or 3% or more, preferably 3 to 35%.

Within the scope of the present invention, the weak base is selected from one or more of the following groups: basic inorganic salt of polybasic weak acid, acidic inorganic salt of polybasic weak acid and nitrogenous weak base.

In the context of the present invention, the term "weak polybasic acid type inorganic salt" refers to weak polybasic acid type inorganic salts capable of ionizing hydrogen ions in water, preferably weak polybasic acid type inorganic salts as chemical ablants which are basic in 0.01M aqueous solution, preferably at pH >8.0 (e.g. disodium hydrogen phosphate, sodium hydrogen carbonate, potassium hydrogen carbonate). The term "polybasic weak acid basic inorganic salt" refers to a polybasic weak acid inorganic salt that is not capable of ionizing hydrogen ions in water, and includes the normal salts of a polybasic weak acid strong base inorganic salt. The term "weak nitrogen-containing base" refers to a weakly basic compound comprising nitrogen elements, wherein the weakly basic compound is preferably selected from weakly basic compounds having a solubility in water (w/w) of 2% or more.

In one embodiment, the composition includes, for example, the compositions listed in table 1 below.

TABLE 1

In one embodiment, the chemical ablative agent is a strong base and the pH adjusting agent is one or more selected from one or more of the following: polybasic weak acid basic inorganic salt, nitrogenous weak base, strong acid strong base inorganic salt, polybasic weak acid acidic inorganic salt, organic weak acid alkali metal salt, weak acid and strong acid, wherein the concentration of the strong base is more than or equal to 0.5 percent, and preferably 0.75 to 10 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong bases, the pH adjusting agent is selected from one or more polybasic weak acid basic inorganic salts, and the concentration of the strong base is 0.75% or more, preferably 1-10%, more preferably 2-7%; the concentration of the polybasic weak acid basic inorganic salt is more than or equal to 2 percent, and preferably 2 to 20 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong bases, the pH adjusting agent is selected from one or more nitrogen-containing weak bases, and the concentration of the strong base is greater than or equal to 0.75%, preferably 1-10%, more preferably 2-7%; the concentration of the weak base containing nitrogen is more than or equal to 2 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong bases, the pH adjusting agent is selected from one or more polybasic weak acid type inorganic salts, and the concentration of the strong base is more than or equal to 0.75%, preferably 1-10%, more preferably 2-7%; the concentration of the polybasic weak acid type inorganic salt is more than or equal to 2 percent, and preferably 2 to 20 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong bases, the pH adjusting agent is selected from one or more alkali salts of organic weak acids, and the concentration of the strong base is 0.75% or more, preferably 1-10%, more preferably 2-7%; the concentration of the organic weak acid alkali metal salt is more than or equal to 2 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong bases, the pH adjusting agent is selected from one or more strong acid and strong base inorganic salts, and the concentration of the strong base is 0.75% or more, preferably 1-10%, more preferably 2-5%; the concentration of the strong acid strong base inorganic salt is more than or equal to 1 percent, and is preferably 1.5 to 10 percent.

In one embodiment, the chemical ablative agent is one or more strong bases and the pH adjusting agent is one or more selected from one or more of the following: polybasic weak acid basic inorganic salt, nitrogenous weak base and polybasic weak acid acidic inorganic salt, wherein the concentration of the strong base is more than or equal to 0.75 percent, preferably 1-10 percent, and more preferably 2-7 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from a weak base and the pH adjusting agent is one or more selected from one or more of the following: the concentration of the weak base is more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 35 percent, preferably 3.0 to 35 percent or 5 to 35 percent, the concentration of the pH regulator is more than or equal to 2 percent, preferably 2 to 35 percent, and the weak base is selected from polybasic weak acid basic inorganic salt, polybasic weak acid acidic inorganic salt or nitrogenous weak base.

In one embodiment, the chemical ablative agent is selected from the group consisting of basic inorganic salts of weak polybasic acids at a concentration of 2.5% or more, preferably 2.5 to 15%.

In one embodiment, the chemical ablative agent is selected from a nitrogen-containing weak base, and the concentration of the nitrogen-containing weak base is greater than or equal to 2.5%, preferably 2.5-35%.

In one embodiment, the chemical ablative agent is selected from the group consisting of weak acid inorganic salts in polybasic form, and the concentration of the weak acid inorganic salts in polybasic form is 2.5% or more, preferably 2.5-15%.

In one embodiment, the chemical ablative agent is one or more polybasic, weak acid basic inorganic salts and the pH adjusting agent is one or more selected from one or more of the following: the pH regulator comprises nitrogen-containing weak base, polybasic weak acid acidic inorganic salt, organic weak acid alkali metal salt, weak acid and strong acid, wherein the concentration of the polybasic weak acid basic inorganic salt is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5-20 percent, preferably 3.0-20 percent or 5-20 percent, and the concentration of the pH regulator is more than or equal to 2 percent, preferably 2-35 percent.

In one embodiment, the chemical ablative agent is selected from one or more basic inorganic salts of weak acid, the pH adjusting agent is selected from one or more basic inorganic salts of weak acid, and the concentration of the basic inorganic salt of weak acid is more than or equal to 2.5%, preferably more than or equal to 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the polybasic weak acid type inorganic salt is more than or equal to 2.5 percent, and preferably 2.5 to 10 percent.

In one embodiment, the chemical ablative agent is selected from one or more basic inorganic salts of weak acid, the pH adjusting agent is selected from one or more nitrogen-containing weak bases, and the concentration of the basic inorganic salt of weak acid is more than or equal to 2.5%, preferably more than or equal to 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the weak base containing nitrogen is more than or equal to 2 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more basic inorganic salts of weak acid, the pH adjusting agent is selected from one or more alkali metal salts of organic weak acid, and the concentration of the basic inorganic salt of weak acid is greater than or equal to 2.5%, preferably greater than or equal to 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the organic weak acid alkali metal salt is more than or equal to 5 percent, and preferably 5 to 35 percent.

In one embodiment, the chemical ablation agent is selected from one or more basic inorganic salts of weak acid, the pH regulator is selected from one or more weak acid or/and strong acid, and the concentration of the basic inorganic salt of weak acid is more than or equal to 2.5%, preferably more than or equal to 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the weak acid or/and the strong acid is more than or equal to 0.5 percent, and is preferably 1 to 15 percent.

In one embodiment, the chemical ablative agent is one or more inorganic salts selected from the group consisting of one or more weak acid salts of polybasic acids, and the pH adjusting agent is one or more selected from one or more of the following groups: the pH regulator comprises a nitrogen-containing weak base, an organic weak acid alkali metal salt, a weak acid and a strong acid, wherein the concentration of the polybasic weak acid inorganic salt is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5-20 percent, preferably 3.0-20 percent or 5-20 percent, and the concentration of the pH regulator is 2 percent, preferably 2-35 percent.

In one embodiment, the chemical ablation agent is selected from one or more weak acid basic inorganic salts, the pH regulator is selected from one or more weak bases containing nitrogen, and the concentration of the weak acid basic inorganic salts is more than or equal to 2.5%, preferably more than or equal to 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the weak base containing nitrogen is more than or equal to 2 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more weak acidic inorganic salts, the pH adjusting agent is selected from one or more organic weak acidic alkali metal salts, and the concentration of the weak acidic basic inorganic salt is more than or equal to 2.5%, preferably more than or equal to 3.0%, or 2.5-10%, preferably 3.0-10%; the concentration of the organic weak acid alkali metal salt is more than or equal to 5 percent, and preferably 5 to 35 percent.

In one embodiment, the chemical ablative agent is selected from a nitrogen containing weak base and the pH adjusting agent is one or more selected from one or more of the following: the concentration of the weak basic inorganic salt containing nitrogen is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 35 percent, preferably 3.0 to 35 percent or 5 to 35 percent, and the concentration of the pH regulator is more than or equal to 2 percent, preferably 2 to 35 percent

In one embodiment, the chemical ablation agent is selected from one or more nitrogen-containing weak bases, the pH regulator is selected from one or more polybasic weak acid type inorganic salts, and the concentration of the nitrogen-containing weak bases is more than or equal to 2.5%, preferably more than or equal to 3.0% or more than or equal to 5%, or 2.5-35%, preferably 3.0-35% or 5-35%; the concentration of the polybasic weak acid type inorganic salt is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the chemical ablation agent is selected from one or more nitrogen-containing weak bases, the pH regulator is selected from one or more polybasic weak acid basic inorganic salts, and the concentration of the nitrogen-containing weak bases is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 35 percent, preferably 3.0 to 35 percent or 5 to 35 percent; the concentration of the polybasic weak acid basic inorganic salt is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the chemical ablation agent is selected from one or more nitrogen-containing weak bases, the pH regulator is selected from one or more organic weak acid alkali metal salts, and the concentration of the nitrogen-containing weak base is more than or equal to 2.5%, preferably more than or equal to 3.0% or more than or equal to 5%, or 2.5-35%, preferably 3.0-35% or 5-35%; the concentration of the organic weak acid alkali metal salt is more than or equal to 2 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablation agent is selected from one or more nitrogen-containing weak bases, the pH regulator is selected from one or more weak acids or/and strong acids, and the concentration of the nitrogen-containing weak bases is more than or equal to 2.5%, preferably more than or equal to 3.0% or more than or equal to 5%, or 2.5-35%, preferably 3.0-35% or 5-35%; the concentration of the weak acid or/and the strong acid is more than or equal to 0.5 percent, and is preferably 1 to 15 percent.

In one embodiment, the chemical ablative agent is selected from an acid ablative agent, wherein the acid ablative agent is selected from one or more of a weak acid or a strong acid, and the concentration of the strong acid is 0.5% or more, preferably 0.75% or more 1% or more, or 0.5-10%, preferably 0.75-10% or 1-10%; or the concentration of the weak acid is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 20 percent, preferably 3.0 to 20 percent or 5 to 20 percent.

In one embodiment, the chemical ablative agent is selected from a weak acid and the pH adjusting agent is one or more selected from one or more of the following: strong base, basic inorganic salt of polybasic weak acid, nitrogenous weak base, acidic inorganic salt of polybasic weak acid and alkali metal salt of organic weak acid, wherein the concentration of the weak acid is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 20 percent, preferably 3.0 to 20 percent or 5 to 20 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more weak acids, the pH adjusting agent is selected from one or more basic inorganic salts of weak acid and/or acidic inorganic salts of weak acid, and the concentration of the weak acid is greater than or equal to 2.5%, preferably greater than or equal to 3.0% or greater than or equal to 5%, or from 2.5% to 20%, preferably from 3.0% to 20% or from 5% to 20%; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 25 percent.

In one embodiment, the chemical ablative agent is selected from one or more weak acids, the pH adjusting agent is selected from one or more weak bases containing nitrogen, and the concentration of the weak acid is greater than or equal to 2.5%, preferably greater than or equal to 3.0% or greater than or equal to 5%, or from 2.5% to 20%, preferably from 3.0% to 20% or from 5% to 20%; the concentration of the weak base containing nitrogen is more than or equal to 1 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more weak acids, the pH adjusting agent is selected from one or more organic weak acid alkali metal salts, and the concentration of the weak acid is greater than or equal to 2.5%, preferably greater than or equal to 3.0% or greater than or equal to 5%, or from 2.5% to 20%, preferably from 3.0% to 20% or from 5% to 20%; the concentration of the organic weak acid alkali metal salt is more than or equal to 2 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is a strong acid and the pH adjusting agent is one or more selected from one or more of the following: polybasic weak acid basic inorganic salt, nitrogenous weak base, polybasic weak acid acidic inorganic salt, organic weak acid alkali metal salt and weak acid, wherein the concentration of the strong acid is more than or equal to 0.5 percent, preferably more than or equal to 0.75 percent or more than or equal to 1 percent, or 0.5 to 10 percent, preferably 0.75 to 10 percent or 1 to 10 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong acids, the pH adjusting agent is selected from one or more basic inorganic salts of weak acid and/or acidic inorganic salts of weak acid, and the concentration of the strong acid is 0.5% or more, preferably 0.75% or more and 1% or more, or 0.5-10%, preferably 0.75-10% or 1-10%; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 25 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong acids, the pH adjusting agent is selected from one or more nitrogen-containing weak bases, and the concentration of the strong acid is 0.5% or more, preferably 0.75% or more and 1% or more, or 0.5-10%, preferably 0.75-10% or 1-10%; the concentration of the weak base containing nitrogen is more than or equal to 1 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong acids, the pH adjusting agent is selected from one or more organic weak acid alkali metal salts, and the concentration of the strong acid is 0.5% or more, preferably 0.75% or more and 1% or more, or 0.5-10%, preferably 0.75-10% or 1-10%; the concentration of the organic weak acid alkali metal salt is more than or equal to 1 percent, and preferably 2 to 35 percent.

In one embodiment, the chemical ablative agent is selected from one or more strong acids, the pH adjusting agent is selected from one or more other weak acids, and the concentration of the strong acid is 0.5% or more, preferably 0.75% or more 1% or more, or 0.5-10%, preferably 0.75-10% or 1-10%; the concentration of the other weak acids is more than or equal to 1 percent, and preferably 2 to 25 percent.

In one embodiment, the total concentration of the chemoablative agent/pH modifier composition is ≧ 1.5%, preferably 2.25-40%.

In one embodiment, the total concentration of the chemical ablative agent/pH adjusting agent composition is also the locally administered concentration of the chemical ablative agent/pH adjusting agent composition.

In one embodiment, the strong base comprises an alkali metal hydroxide, wherein the alkali metal hydroxide comprises, for example: sodium hydroxide, potassium hydroxide, calcium hydroxide.

In one embodiment, the strong base is sodium hydroxide or/and potassium hydroxide, preferably sodium hydroxide.

In one embodiment, the polybasic weak acid basic inorganic salt comprises, for example, sodium phosphate, sodium carbonate, potassium carbonate, borax, preferably sodium carbonate and/or sodium phosphate.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium carbonate, and the concentration of the sodium hydroxide is more than or equal to 0.5%, preferably 0.75-5%; the concentration of the sodium carbonate is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium phosphate, and the concentration of the sodium hydroxide is more than or equal to 0.5%, preferably 0.75-5%; the concentration of the sodium phosphate is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the polybasic weak acid acidic inorganic salt includes, for example, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, sodium hydrogen sulfate.

In one embodiment, the polybasic weak acid acidic inorganic salt is sodium bicarbonate and/or disodium hydrogen phosphate.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium bicarbonate, and the concentration of the sodium hydroxide is more than or equal to 0.5%, preferably 0.75-5%; the concentration of the sodium bicarbonate is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium dihydrogen phosphate, and the concentration of the sodium hydroxide is more than or equal to 0.5 percent, preferably 0.75 to 5 percent; the concentration of the sodium dihydrogen phosphate is more than or equal to 2 percent, and is preferably 2 to 10 percent.

In one embodiment, the chemical ablative agent is sodium carbonate, the pH adjusting agent is sodium bicarbonate, and the concentration of the sodium carbonate is more than or equal to 1.5%, preferably 3-10%; the concentration of the sodium bicarbonate is more than or equal to 2.5 percent, and is preferably 4-15 percent.

In one embodiment, the chemical ablative agent is sodium phosphate dibasic, the pH adjusting agent is sodium phosphate monobasic, and the concentration of the sodium phosphate dibasic is greater than or equal to 1.5%, preferably 2-7%; the concentration of the sodium dihydrogen phosphate is more than or equal to 2 percent, and is preferably 3 to 10 percent.

In one embodiment, the weak base containing nitrogen includes, for example, ammonia water, ammonia chloride, 2-aminoethanol, tromethamine, triethanolamine, tris, 2-aminoethanol, tromethamine, triethanolamine, meglumine, and meglumine.

In one embodiment, the alkali metal salts of organic weak acids include, for example, potassium hydrogen phthalate, sodium acetate, sodium propionate, sodium butyrate, sodium malonate, sodium lactate, sodium citrate, sodium malate, sodium lauryl sulfate.

In one embodiment, the alkali metal salt of an organic weak acid is one or more selected from the group consisting of: sodium acetate, sodium propionate, sodium butyrate, sodium malonate, sodium lactate, sodium citrate and sodium malate.

In one embodiment, the strong acid strong base inorganic salt includes, for example, sodium chloride, potassium chloride, sodium iodide, potassium iodide.

In one embodiment, the chemical ablative agent is sodium hydroxide and the pH adjusting agent is potassium chloride, and wherein the concentration of the sodium hydroxide is 0.5% or more, preferably 0.75-5%; the concentration of the potassium chloride is more than or equal to 1 percent, and is preferably 1.5 to 10 percent.

In one embodiment, the weak acid is selected from one or more of inorganic weak acids such as: phosphoric acid, carbonic acid, boric acid, sulfurous acid; the weak organic acids include 1-3 hydroxy-substituted C1-10 aliphatic carboxylic acids, such as: acetic acid, glycolic acid, propionic acid, malonic acid, butyric acid, succinic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1, 2, 3-tricarballylic acid), malic acid (2-hydroxysuccinic acid), tartaric acid, oxalic acid, gluconic acid.

In one embodiment, the weak acid is preferably selected from one or more of the following: carbonic acid, acetic acid, glycolic acid, propionic acid, malonic acid, butyric acid, succinic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1, 2, 3-tricarballylic acid), malic acid (2-hydroxysuccinic acid), tartaric acid, oxalic acid, gluconic acid; acetic acid is preferred.

In one embodiment, the weak acid comprises acetic acid, and the concentration of acetic acid is ≥ 3.5%, preferably 5-15%.

In one embodiment, the chemical ablative agent is acetic acid, the pH adjusting agent is sodium bicarbonate, and the concentration of the acetic acid is greater than or equal to 5%, preferably 5-15%; the concentration of the sodium bicarbonate is more than or equal to 2 percent, and preferably 2 to 10 percent.

In one embodiment, the chemical ablative agent is acetic acid, the pH adjusting agent is sodium acetate, and the concentration of the acetic acid is greater than or equal to 3.5%, preferably 5-15%; the concentration of the sodium acetate is more than or equal to 5 percent, and preferably 5 to 25 percent.

In one embodiment, the weak acid comprises acetic acid and gluconic acid, preferably gluconic acid.

In one embodiment, the strong acid includes, for example, hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, selenic acid, hydrobromic acid, hydroiodic acid.

In one embodiment, the strong acid is one or more selected from the group consisting of: hydrochloric acid, sulfuric acid, nitric acid, preferably hydrochloric acid.

In one embodiment, the chemical ablative agent is hydrochloric acid and the pH adjusting agent is acetic acid, and wherein the concentration of the acetic acid is 3.5% or more, preferably 5-15%; the concentration of the hydrochloric acid is more than or equal to 0.5 percent, and is preferably 1 to 5 percent.

Within the scope of the present invention, the topical co-agent is selected from one or more of a cytotoxic drug and/or a conventional non-potent drug.

In one embodiment, the pharmaceutical compositions comprising the chemoablative agent, the pH adjusting agent composition, and their topical synergists (exemplified only by amino acid based nutrients) include, for example, the compositions listed in table 2 below.

TABLE 2

In the present disclosure, the term "cytotoxic drug" is used to refer to a drug that is effective in treating a localized disease condition (e.g., a solid tumor) by its cytotoxicity through absorption at a safe dose, and is selected from cytotoxic drugs known in the art, preferably from cytotoxic drugs approved or to be approved by or loaded in chinese, us, or european official administrative departments (e.g., FDA or chinese drug administration) as if they were anti-tumor chemotherapeutic drugs. The term "absorption" as used herein refers to a pharmacological effect resulting from the formation of drug-bearing blood into the target area by blood absorption of the drug; the term "absorbed drug" refers to a therapeutic drug that exerts its pharmacological effect primarily through absorption.

In the context of the present disclosure, the term "conventional ineffective drug" is used in distinction to a conventionally effective drug (e.g., an antitumor drug) and refers to a drug that may exhibit a specific cellular effect (e.g., an antitumor cellular effect) in a cellular experiment, but does not exhibit a more effective inhibitory effect than the conventionally effective compound by absorption in an animal experiment, and thus is not approved by a drug administration (e.g., FDA) as an effective drug for treating a specific localized disease, such as a non-anti-localized disease drug, a nutritional drug, a diagnostic drug, a pharmaceutical adjuvant, and the like.

In one embodiment, the concentration of cytotoxic drug is 50% or more, preferably 50 to 100% of its solubility in the pharmaceutical composition.

In one embodiment, the conventional ineffective drug is 0.35% or more, preferably 0.35% to 20%.

In one embodiment, the cytotoxic drug is selected from one or more of the following groups: drugs that disrupt the structure and function of DNA, drugs that interfere with transcribed RNA embedded in DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis, preferably one or more selected from the group consisting of: alkylating agents such as cyclophosphamide, carmustine; metal platinum complexes such as cisplatin, carboplatin; DNA topoisomerase inhibitors such as doxorubicin, topotecan, irinotecan; anti-tumor antibiotics such as actinomycins, daunorubicin; pyrimidine antagonists such as uracil derivatives 5-fluorouracil, furfluorouracil, bifurcofurouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine; taxanes such as paclitaxel, docetaxel.

In one embodiment, the cytotoxic agent is selected from the group consisting of the alkylating agents (e.g., cyclophosphamide, carmustine, etc.), and the concentration (w/v) of the alkylating antineoplastic drug in the topical pharmaceutical composition is 0.5-6%, preferably 0.75-1.5%.

In one embodiment, the cytotoxic agent is selected from the group consisting of the metal platinum complexes (e.g. cisplatin, carboplatin, etc.) and the concentration (w/v) of the metal platinum complex in the topical pharmaceutical composition is from 0.03 to 0.15%, preferably from 0.05 to 0.15%.

In one embodiment, the cytotoxic agent is selected from the group consisting of the DNA topoisomerase inhibitors (e.g. doxorubicin, topotecan, irinotecan, etc.) and the concentration (w/v) of the DNA topoisomerase inhibitor in the topical pharmaceutical composition is from 0.05 to 0.20%, preferably from 0.075 to 0.15%.

In one embodiment, the cytotoxic agent is selected from the group consisting of the antitumor antibiotics (e.g. actinomycins, daunorubicin, etc.) and the concentration (w/v) of the antitumor antibiotic in the topical pharmaceutical composition is 1-4%, preferably 1-2%.

In one embodiment, the cytotoxic drug is selected from pyrimidine antagonists (e.g. uracil derivatives 5-fluorouracil, furacil, bifacil fluorouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine, etc.) and the concentration (w/v) of the pyrimidine antagonist in the topical pharmaceutical composition is 0.5-2%, preferably 0.75-1.5%.

In one embodiment, the cytotoxic drug is selected from the group consisting of said taxanes (e.g. paclitaxel, docetaxel, etc.) and the concentration (w/v) of said taxanes in said topical pharmaceutical composition is 0.5-2%, preferably 0.75-1.5%.

In one embodiment, the conventional ineffective drug is one or more selected from the group consisting of: amino acid nutrients, carbohydrate nutrients, lipid nutrients, pigment aromatic compounds, salicylic acid compounds and quinine compounds.

In the context of the present invention, the term "amino acid based nutrient" refers to amino acids and small molecule (molecular weight <3000 daltons) derivatives thereof having a nutraceutical effect.

In the context of the present invention, the term "carbohydrate nutrient" is used to indicate a carbohydrate compound having a nutraceutical effect, preferably selected from monosaccharides, carbohydrate polymers and carbohydrate derivatives having a nutraceutical effect, more preferably selected from carbohydrate nutraceuticals and carbohydrate excipients having a nutraceutical effect as carried in the chinese, us or european official pharmacopoeia or guidelines, including for example monosaccharides or their derivatives from the group: glucose, ribose, deoxyribose, xylose, fructose, galactose and fucose.

In the context of the present invention, the term "liponutrient" is used to refer to a lipo-compound having a nutraceutical effect, preferably selected from lipo-compounds having a nutraceutical effect as carried in the chinese, us or european official pharmacopoeia or guidelines, more preferably selected from one or more of the following groups: lipids, fatty acids, fatty milks and lipids.

In the context of the present invention, the term "chromoaromatic compound" refers to a pharmaceutically acceptable aromatic compound capable of selectively absorbing or reflecting light of a specific wavelength at a target region, which may include, for example, vital dyes, photosensitizers, and colored chemotherapeutic agents. The vital dyes may for example comprise one or more of the following organic dyes and derivatives thereof: methylene blue (including its hydrates), patent blue, isothio blue, toluidine blue, trypan blue, basic blue, eosin, basic fuchsin, crystal violet, gentian violet, neutral red, janus green B, safranin, bengal red, and the like. The photosensitizer may include, for example, one or more of the following: mixed porphyrin photosensitizers, porphyrin-based compounds (e.g., porphyrin, porphine, purpurin, endogenous porphyrin) and derivatives thereof, phthalocyanine-based compounds, bacteriochlorin-based compounds, fused ring quinone-based compounds, benzoporphyrin derivatives, 5-aminolevulinic acid, chlorins-based compounds, and the like. The colored chemotherapeutic agent may be, for example, one or more of the following: nitrophenol compounds, flavonoid compounds (e.g., anthocyanins, genistein, etc.), isohexenylnaphthoquinone compounds (e.g., alkannins), and the like. Taking methylene blue as an example, the derivative thereof is also generally a dye, such as 1, 9-dimethylmethylene blue, 1-methylmethylene blue, and the like. Some of the colored aromatic compounds, such as methylene blue, are both vital dyes, photosensitizers, and colored chemotherapeutic agents.

In the context of the present disclosure, the term "salicylic acid-like compounds" is used to refer to salicylic acid and its derivatives. The Salicylic acid (Salicylic acid) has the chemical name of 2-hydroxybenzoic acid. The salicylic acid derivative may be any suitable one known to those skilled in the art, and may be, for example, a salicylic acid derivative including a metal-containing compound and a salicylic acid derivative containing no metal compound. The former may be, for example, sodium salicylate, magnesium salicylate, zinc salicylate, metal element complex (e.g., copper Aspirin), and the like, while the latter may include, for example, acetylsalicylic acid (Aspirin), lysine Aspirin, difluorosalicylic acid, aminosalicylic acid, p-aminosalicylic acid, N-phenylanthranilic acid, salicylanilide, o-ethoxybenzamide, phenyl salicylate, methyl paraben, ethyl paraben, salsalate, dicumarol, and pharmaceutically acceptable derivatives thereof.

In the context of the present disclosure, the term "quinine-like compounds" is used to refer to pharmaceutically acceptable quinines and structural analogs thereof, such as quinine and isomers and pharmaceutically acceptable salts thereof. Examples of the quinine isomer include quinidine, cinchonine and cinchonidine, and examples of the salt thereof include quinine hydrochloride, quinine dihydrochloride, and quinine sulfate.

In one embodiment, the concentration (w/v) of the amino acid based nutrient is not less than 5%, preferably 10-35%.

In one embodiment, the concentration (w/v) of the carbohydrate nutrient is not less than 5%, preferably 5-40%.

In one embodiment, the concentration of the lipid nutrient is greater than 5%, preferably 10-30%.

In one embodiment, the concentration (w/v) of the pigment aroma compound is 0.35% or more, preferably 0.35-10%.

In one embodiment, the concentration (w/v) of the salicylic acid-based compound is not less than 2%, preferably 2-30%.

In one embodiment, the concentration (w/v) of the quinine compound is not less than 2%, preferably 2-10%.

In one embodiment, the amino acid based nutrient is selected from one or more of a basic amino acid and/or a non-basic amino acid based nutrient, wherein the basic amino acid based nutrient is for example arginine, lysine, histidine, preferably arginine; such as one or more of the following groups: neutral amino acids, acidic amino acids, amino acid salts, wherein the neutral amino acids are, for example: glycine, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, alanine, valine, leucine, isoleucine, phenylalanine, proline, such as: aspartic acid, glutamic acid, the amino acid salt including the amino acid and acid salt, such as lysine hydrochloride, histidine hydrochloride, glutamic acid hydrochloride, cysteine hydrochloride, arginine hydrochloride, glycine sulfate, lysine hydrochloride, aspartic acid hydrochloride.

In one embodiment, the amino acid nutrient is preferably one or more amino acids selected from the group consisting of: arginine, lysine, glycine, tryptophan, serine, cysteine, glutamine, proline.

In one embodiment, the concentration of the amino acid based nutrient is preferably ≥ 5%, preferably 7.5-35%.

In one embodiment, the amino acid nutrient comprises arginine. In one embodiment, the amino acid nutrient is arginine, and the concentration of arginine is ≥ 10%, preferably 10-20%.

In one embodiment, the chemical ablative agent is sodium hydroxide, the pH adjusting agent is sodium bicarbonate, the amino acid nutrient is arginine, and wherein the concentration of the sodium hydroxide is 0.5% or more, preferably 0.75-5%; the concentration of the sodium bicarbonate is more than or equal to 2.5 percent, and is preferably 4 to 15 percent; the concentration of the arginine is more than or equal to 10 percent, and preferably 10 to 20 percent.

In one embodiment, the chemical ablative agent is sodium carbonate, the pH adjusting agent is sodium bicarbonate, the amino acid nutrient is arginine, and wherein the concentration of the sodium carbonate is ≥ 1.5%, preferably 2-10%; the concentration of the sodium bicarbonate is more than or equal to 1 percent, and is preferably 1 to 5 percent; the concentration of the arginine is more than or equal to 10 percent, and preferably 10 to 20 percent.

In one embodiment, the amino acid based nutrient comprises glycine. In one embodiment, the amino acid based nutrient is glycine and the concentration of glycine is ≥ 10%, preferably 10-25%.

In one embodiment, the amino acid based nutrient comprises lysine hydrochloride.

In one embodiment, the amino acid nutrient is a mixture of 2 or more amino acid nutrients.

In one embodiment, the carbohydrate nutrient is one or more selected from the group consisting of: glucose, fructose, chitosan oligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, xylo-oligosaccharide, fructo-oligosaccharide, manno-oligosaccharide, xylitol, more preferably selected from one or more of the following: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannooligosaccharide and xylitol, wherein the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is more than or equal to 10 percent, and is preferably 10-40 percent.

In one embodiment, the liponutrient is one or more selected from the group consisting of: vegetable oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat milk, medium-chain fat milk, phospholipids, and the concentration (w/v) of the lipid nutrient in the pharmaceutical composition is not less than 4%, preferably 4-25%.

In one embodiment, the pigment aroma compound is one or more selected from the group consisting of: methylene blue, patent blue, isothio blue, bengal red, and in the pharmaceutical composition the concentration (w/v) of the pigmentary aromatic compound is not less than 0.35%, preferably 0.5-10%.

In one embodiment, the salicylate compound is one or more selected from the group consisting of: salicylic acid, acetylsalicylic acid, aspirin-lysine, and in the topical pharmaceutical composition, the concentration (w/v) of the salicylic acid compound is not less than 5%, preferably 5-10%.

In one embodiment, the quinine compound is one or more selected from the group consisting of: quinine hydrochloride, quinine dihydrochloride and quinine sulfate, and in the topical pharmaceutical composition, the concentration (w/v) of the quinine compound is more than or equal to 3 percent, and is preferably 3-6 percent.

The pharmaceutical composition according to the present disclosure may be any dosage form suitable for topical administration which may comprise the active ingredient (the pharmaceutical composition, and optionally other drugs as described above), preferably the following dosage forms: injections (preferably topical injections), external liquids, and aerosols.

In the context of the present invention, the term "injectable formulation" is used to refer to a sterile formulation containing an active ingredient and a liquid carrier and intended for in vivo administration. The injection is classified into a local injection, an intravenous injection, etc. according to the administration mode, and the intravenous injection can be used as the local injection only after the given local administration concentration. The injection is classified into liquid injection, powder injection for injection, etc. according to its commercial form. The powder injection for injection comprises sterile dry powder and a solvent, wherein the sterile dry powder contains part or all of active ingredients, and the solvent contains all of liquid carriers. The concentration of the active ingredient in an injection is the concentration of the active ingredient in its mixture with the entire liquid carrier, usually in the liquid drug at the end point (e.g. needle hole, catheter outlet, etc.) of a topical administration device (syringe, piercer, infusion catheter, etc.). For injectable powder injections, the concentration of the active ingredient is the concentration of the active ingredient in a mixture of sterile dry powder and vehicle (e.g., a reconstituted solution, or the pharmaceutically acceptable liquid carrier).

In the context of the present invention, the term "topical liquid formulation" refers to a liquid medicament comprising an active ingredient and a liquid carrier and intended for topical administration [ e.g., to the skin, mucous membranes (e.g., ocular, nasal, etc.) or/and oral passages (e.g., oral, rectal, vaginal, urethral, nasal, auditory, etc.) ], and includes, e.g., lotions, liniments, drops, gargles, lotions, and the like. When the liquid medicine is locally administered, the liquid medicine is usually from a washing liquid bottle, a dropping liquid pipe, a washing liquid bottle for a person to be cleaned, a cotton swab and other local administration instruments. The concentration of the active ingredient in the external liquid preparation is the concentration of the active ingredient in the liquid medicine.

In the context of the present invention, the term "nebuliser" refers to a dosage form comprising an active ingredient and a liquid carrier and which, in use, is administered by nebulising under pressure a liquid medicament as described above, for administration to the skin, mucous membranes (e.g. ocular, nasal, etc.) or/and the oral tract (e.g. oral, rectal, vaginal, urethral, nasal, auditory etc.), including for example aerosols, sprays, nebulisers and the like. For topical administration, nebulization of liquid drugs is often accomplished by means of topical administration devices such as aerosols, nebulizers, and the like. After the medicine is atomized and sprayed to the target position, the medicine is accumulated to form liquid medicine. The liquid medicament is substantially identical in composition to the liquid medicament prior to aerosolization. Thus, the concentration of the active ingredient in the nebulant may be expressed in terms of the concentration of the active ingredient in the liquid medicament prior to nebulisation.

It will be appreciated by those skilled in the art that according to the present invention, the pharmaceutical composition of the present invention should be formulated for local administration to the target area, preferably as a topical pharmaceutical formulation.

According to the preparation method of the present invention, the preparation of the pharmaceutical composition of the present invention comprises the steps of: a liquid medicament is prepared containing the essential components (e.g. the pharmaceutical composition) and optionally other substances. The liquid drug may be a solution (e.g. a solution in a hydrophilic vehicle, preferably an aqueous solution), a suspension, or an emulsion. When the liquid drug is a suspension, the dispersion medium may be any suitable medium known to those skilled in the art, such as a micro-material or a nano-material. When the liquid drug is an emulsion, the dispersion medium may be any suitable one known to those skilled in the art, such as a vegetable oil, a synthetic oil or a semi-synthetic oil which may be used for injection. Wherein the vegetable oil may be, for example, cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and peanut oil.

According to the preparation method of the present invention, the concentration of the pharmaceutical composition and the other drug is greater than or equal to the concentration thereof in the pharmaceutical composition of the present invention. When the concentration is more than that in the pharmaceutical composition of the present invention, it can be further diluted for use.

According to one embodiment of the preparation method of the present invention, the liquid injection of the pharmaceutical composition of the present invention can be prepared by a method comprising the following steps: 1) the necessary components (e.g. the pharmaceutical composition) and optionally other components in the amounts required in accordance with the concentration for topical administration are added to water to prepare a liquid; 2) adding other optional medicines into the liquid prepared in the step 1) according to the required amount of the local administration concentration, and uniformly mixing to obtain a liquid medicine; 3) sterilizing the liquid medicine prepared in the step 2) and preparing the liquid injection. When in use, the bacteria-removing liquid medicine in the liquid injection can be directly used as a local administration liquid medicine or used as a diluted liquid medicine.

According to one embodiment disclosed herein, the powder injection for injection of the pharmaceutical composition of the present invention may be prepared by a method comprising the steps of: preparing a sterile dry powder containing a desired amount of the pharmaceutical composition according to the topical administration concentration; and preparing a sterile vehicle containing the optional other components in the required amounts according to the concentration for topical administration. The sterile dry powder is preferably sterile freeze-dried powder, and the preparation method comprises the following steps: 1) preparing a solution comprising amino acids as nutrients, poorly water-soluble neutralizing substances and optionally other components; 2) sterilizing, filtering and packaging; 3) freeze drying; 4) and (5) plugging and capping. The freeze-drying process conditions include, for example: the pre-freezing condition is that the temperature is kept at minus 45 ℃ for 4 hours; sublimation drying condition is that the heating rate is 0.1 ℃/min, and the heating is kept for at least 10 hours when the temperature is raised to-15 ℃; the desorption drying conditions were 30 ℃ for 6 hours. When in use, the sterile dry powder of the powder injection for injection is redissolved in a sterile solvent to form a redissolved liquid medicine which can be directly used as a local administration liquid medicine or diluted.

According to one embodiment of the preparation method of the present invention, the external liquid formulation of the pharmaceutical composition of the present invention is prepared by a method comprising the steps of: the liquid medicament is prepared by adding the required amount of the pharmaceutical composition according to the topical administration concentration and optionally other components to the vehicle. In use, the liquid medicine in the liquid preparation for external use may be used as a liquid medicine for topical administration directly or after dilution.

According to one embodiment of the method of preparation of the present invention, the pharmaceutical composition nebulizer of the present invention may be prepared by a method comprising the steps of: 1) adding the required amount of the pharmaceutical composition according to the local administration concentration and the atomization excipient into the solvent to prepare liquid; 2) adding other optional components which are required according to the local administration concentration into the liquid prepared in the step 1) and uniformly mixing to obtain the liquid medicine. Common atomizing excipients include, for example: glycerin, polysorbate-80, benzalkonium chloride, microcrystalline cellulose-sodium carboxymethyl cellulose, and the like. In use, the liquid medicament is applied to an atomiser (e.g. a spray) and is applied topically to a target area in the form of a spray-on stick, under atomisation, which sticks to the target area as liquid medicament.

In accordance with the principles of these methods described above, one skilled in the art can prepare a variety of specific dosage forms comprising the compositions of the present invention by any suitable specific method. For example, variations in the pharmaceutical compositions of the invention include: the composition may contain different kinds and concentrations of the pharmaceutical composition, different kinds and concentrations of other drugs, different kinds and concentrations of other additives (e.g., analgesics, activators, etc.).

In the present disclosure, the pharmaceutical composition is primarily for use in the prevention and treatment of localized disease conditions, especially refractory localized disease conditions, by topical administration.

In the context of the present invention, the term "locally diseased disease" refers to a disease with locally diseased symptoms, whereas the term "locally diseased" refers to structural, morphological or functional abnormalities, native or secondary to a local part of the animal (preferably human) body, which may for example include one or more of the following: tumor body, non-tumor, local inflammation, secretion function disorder of secretory gland, etc. The local site may be any suitable one known to those skilled in the art, and may for example be a local site in an organ comprising one or more of: secretory organs where the secretory system is located, cardiovascular organs where the blood circulatory system is located, skin, and the like.

Local administration requires that the drug composition (local active ingredient, composition ratio and component concentration) be administered by interventional means to the tissue where the local lesion is located and produce the desired therapeutic effect in that tissue. For example, when the lesion is a tumor, the local tissue is the tumor body in which the tumor cells are located; when the lesion is a non-neoplastic mass, the local tissue is an abnormality such as a mass, e.g., a hyperplastic, cyst, nodule, or other lesion mass; when the lesion is local inflammation, the local tissue is an inflamed area, such as a general inflamed mass; when the lesion is abnormal secretion, the local tissue is the source of the abnormality or the secretory gland in which it is located. For another example, when the disease is abnormal insulin secretion, the abnormality is caused in the islets of langerhans, and the local tissue is the islets of langerhans or the pancreas in which the islets of langerhans are located; when the condition is a skin condition, the localized tissue is the diseased skin or an appendage of the diseased skin.

Specifically, in the present disclosure, the local lesions include tumors, non-tumor enlargement, local inflammation, secretory gland dysfunction and skin diseases.

In the context of the present invention, the term "tumor" refers to a mass formed due to abnormal proliferation of cells or mutated cells, which includes solid tumors. The term "solid tumor" refers to a tumor having a tumor body, which may be due to any pathology (malignant and non-malignant) and at any stage of the tumor, including for example the following groups classified by tumor cell type: epithelial cell tumors, sarcomas, lymphomas, germ cell tumors, blastomas; and tumors named as the organ or tissue in which the tumor cell foci are located, including, for example, tumors named as the following organs or tissues: skin, bone, muscle, breast, kidney, liver, lung, gall bladder, pancreas, brain, esophagus, muscle of the shoulder, large intestine, small intestine, spleen, stomach, prostate, emerald, ovary, or uterus.

Specifically, the malignant tumor includes, for example, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, stomach cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer, and the like.

The non-malignant tumor includes, for example, breast tumor, pancreatic tumor, thyroid tumor, prostate tumor, liver tumor, lung tumor, intestinal tumor, oral tumor, esophageal tumor, stomach tumor, nasopharyngeal tumor, laryngeal tumor, testicular tumor, vaginal tumor, uterine tumor, fallopian tube tumor, ovarian tumor, etc.

In one embodiment, the localized disease condition comprises a non-neoplastic enlargement. The term "non-neoplastic enlargement" refers to enlargement other than a tumor, and includes, for example, hyperplasia (e.g., hyperplasia of the breast, pancreas, thyroid, parathyroid, prostate, etc.), cyst (e.g., cyst of the breast, thyroid, parathyroid, etc.), nodule (e.g., nodule of the breast, thyroid, parathyroid, etc.), abnormal vein mass (e.g., hemorrhoid, etc.), localized inflammatory edema, microbial infection edema, etc. The hemorrhoid includes internal hemorrhoid, external hemorrhoid, and mixed hemorrhoid.

In one embodiment, the localized disease condition comprises localized inflammation, particularly refractory inflammation. Within the scope of the present invention, the term "local inflammation" refers to a non-neoplastic inflammation at a local site, including for example, inflammatory inflammation (inflammatory inflammation), exudative inflammation (inflammatory inflammation) and proliferative inflammation, which may be any suitable one known to the skilled person, and may for example include one or more of the following: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, and oophoritis.

In one embodiment, the topical pathological condition includes a skin condition, particularly an intractable skin condition. Within the scope of the present invention, the term "skin disease" refers to a lesion native or secondary to the skin or skin appendages, which may be any suitable one known to a person skilled in the art, and may for example include one or more of the following: skin cancer, non-malignant tumors of the skin, viral skin diseases (e.g., herpes, warts, rubella, hand-foot-and-mouth disease), bacterial skin diseases (e.g., impetigo, furuncle, leprosy), fungal skin diseases (e.g., various ringworm), sexually transmitted diseases (e.g., syphilis, gonorrhea, and condyloma acuminatum), allergic and autoimmune skin diseases (e.g., contact dermatitis, eczema, urticaria), physical skin diseases (e.g., solar skin diseases, chilblain, corns, rhagades of hands and feet, pressure sores), connective tissue diseases (e.g., lupus erythematosus), skin disorders (e.g., freckles, pigmented nevi, various plaques), skin appendages diseases (e.g., acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis, and bromidrosis).

In one embodiment, the localized disease condition comprises secretory dysfunction of a secretory gland. Within the scope of the present invention, the term "secretory gland" refers to a structure composed of gland cells or gland cell groups that performs a secretory function (secretion), which includes exocrine glands and endocrine glands. The secretory gland secretory dysfunction includes secretory gland hyperfunction (for example, hyperthyroidism) and secretory gland hypofunction (for example, hypothyroidism and islet hypofunction (one of diabetes)).

In one embodiment, the localized disease condition comprises cardiovascular disease. Interventional therapy has become an important treatment for cardiovascular diseases. Such cardiovascular diseases include, for example, hemangiomas, hypertrophic obstructive cardiomyopathy, atrial fibrillation, cardiac arrhythmias, arterial emboli, and the like.

The topical drug in the present invention is a therapeutic drug, which, when used for the prevention and treatment of a localized disease, can also be administered in combination with other interventions, systemic chemotherapy, immunotherapy, photodynamic therapy, sonodynamic therapy, surgical intervention or a combination of such therapies to further enhance the therapeutic effect.

In the present disclosure, the pharmaceutical composition is primarily for use in the prevention and treatment of localized disease conditions by topical administration.

In the use and method for topical treatment and prevention of a localized disease condition according to the present disclosure, the one composition comprising a chemoablative agent, a pH adjusting agent, and a topical co-product thereof is administered topically at their concentration or amount ratio in the topical pharmaceutical composition. The concentration or amount provides a synergistic effect on the local response compared to local administration.

Based on the studies described in more detail below, although the specific mechanism remains to be further studied, the pharmaceutical composition of the present invention exhibits a pharmaceutical effect of promoting effective destruction of the relevant structures of the tissues in which the local lesion is located (e.g., the lesion tissue, the lesion cells, and any structure involved in constituting them), while minimizing damage to the normal tissues of the patient, thereby achieving safe and effective treatment of the local lesion disease.

Examples

The present invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention thereto. In the following examples, all experimental animals were performed according to the relevant regulations and industry discipline. Unless otherwise specified, all tests were carried out according to the usual methods.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified. The partial alkalizing agents, water-soluble electrolytes and antitumor agents used in the following examples are listed in Table 3.

TABLE 3

Class (c): 1 is strong base, 2 is strong acid, 3 is polybasic weak acid basic inorganic salt, 4 is other weak base, 5 is organic weak acid alkali metal salt, 6 is polybasic weak acid acidic inorganic salt, 7 is weak acid, 8 is amino acid compound, 9 is strong acid strong base inorganic salt, 10 is other medicine

The experimental animals used in the following examples were all purchased from professional laboratory animals company and were all SPF (Specific Pathogen Free) grade animals. Taking mice as an example, there are 2 species: BALB/c mouse, nude mouse, wherein the nude mouse is mutation line (BALB/c-nu) mouse obtained by introducing nude gene (nu) into BALB/c mouse. The mice are healthy females with the age of 6-8 weeks and the body weight of 17.5-20.5 g.

In the following examples, unless otherwise indicated, subcutaneous transplantation of tumor animals was performed according to the general practice of subcutaneous inoculation of solid tumor cells according to the guidelines issued by the drug administration. Unless otherwise indicated, solid tumors grow to the desired volume (e.g., mice carry tumors 30-500 mm)³) Then for successful modeling, the model was randomly divided into experimental groups of 6 animals each using PEMS 3.2 software (compiled by the national institutes of public health, western, university, Sichuan). Items for experimental observation, measurement and analysis include general state, body weight, food intake, animal graft versus host disease, solid tumor volume, tumor weight, survival time, and the like.

The tumor volume calculation formula is as follows:

tumor volume (V) ═ l/2 × a × b²Wherein a represents the tumor length and b represents the tumor width.

The tumor growth inhibition rate (abbreviated as tumor inhibition rate in the invention) is calculated by the following formula:

tumor inhibition rate Y (%) ═ (CW-TW)/CW × 100%, where TW is the average tumor weight of the study group; CW is the average tumor weight of the negative control group.

In the following examples, experimental results (e.g. tumor weights) are expressed as means ± standard deviation (x ± s), differences between two experimental animal groups and group means are compared by significance test using statistical software SPSS 13.0 or SPSS 19.0, tests are performed using statistic t, test level α is 0.05, P <0.05 indicates that the difference is statistically significant, otherwise it is not statistically significant.

Within the scope of the present invention, the combination of drug A and drug B is designated as B/A. The effect (including efficacy and safety) of the combination of drugs can be theoretically determined according to the judgment of q:

q-actual combined effect/theoretical purely additive expected effect.

When q is 1, the actual combined effect is in accordance with theoretical expectations, showing additive effect; when q is<1, the actual combined effect is weaker than the theoretical expectation, and the antagonism is shown; when q is>1, the actual combined action is over the theoretical expectation, and the synergistic effect is shown. A, B Single use efficacy (denoted respectively as E) unless otherwise indicated_A、E_B) Actual combined drug effects of A and B (denoted as E)_A+B) All are tumor inhibition rates. The q calculation formula has many calculation methods for simply adding the expected drug effect theoretically, and most methods aim at the cell experimental effect.

Improving the drug effect of antitumor drugs is always the biggest medical problem in the world. Even a few percent of efficacy is difficult and difficult to improve, so that the theoretical expectation of drug combination in animal experiments is usually not high, and once the drug combination is realized, the significance is great. A method for judging the drug effect of an anti-tumor combined drug commonly used in animal experimental literature is based on the hypothesis that: the actual combined action is obviously superior to the single-medicine action, which is the super-theoretical expectation. The concrete judgment is as follows: (E)_A+B>E_AAnd E_A+B>E_B) And the tumor weight difference of the composition group and each group has statistical significance (all are p)<0.005)。

Another method for determining the combined effect in animal experiments is the Burgi method (Burgi Y. Pharmacology; Drug actions and reactions. cancer res.1978, 38 (2); 284) 285). The Burgi method is improved by Jinzheng (Jinzheng, the addition of the combined medicines, Chinese pharmacology newspaper 1980; 1(2), 70-76), and q is calculated as:

q＝E_A+B/(E_A+E_B-E_A·E_B)，

wherein (E)_A+E_B-E_A·E_B) Simply adding the A medicine and the B pharmacology theoryPhase effect.

The determination of the effect of the combination of drugs in the following antitumor animal experiments is shown in Table 4:

TABLE 4

Example 1: preparation of pharmaceutical compositions

Numerous different topical pharmaceutical compositions of the present invention can be formulated according to the above-described method of preparing the pharmaceutical composition of the present invention. Several examples of the preparation tests of the pharmaceutical composition of the present invention are listed below.

1. Preparation of liquid injection

The necessary components (such as 3g of sodium hydroxide as a chemical ablation agent and 7g of sodium bicarbonate as a pH regulator), optional other components and a liquid carrier (such as water for injection) which is constant to the total volume (such as 100ml) in the pharmaceutical composition are measured according to the required concentration, slowly mixed uniformly, sterilized, filtered and divided into the required amount (such as 10 ml/bottle) for storage and standby. The preparation (e.g. 7% sodium bicarbonate/3% aqueous sodium hydroxide) can be administered topically as a liquid medicament.

2. Preparation of powder injection for injection

The necessary components (such as 3g of sodium hydroxide as a chemical ablation agent and 7g of sodium bicarbonate as a pH regulator) and other optional components in the pharmaceutical composition and a liquid carrier (such as water for injection) which is constant to the total volume (such as 100ml) are measured according to the required concentration, slowly and uniformly mixed, sterilized, filtered, subpackaged into the required amount (such as 10 ml/bottle), freeze-dried, corked and rolled to prepare the sterilized dry powder for later use.

The topical administration of the liquid medicament can be effected by reconstituting the required amount of sterile dry powder (e.g. 1 vial of the above-described dry powder) in the required concentration of the respective component in the required reconstitution liquid (e.g. water for injection) to the required reconstitution solution (e.g. 7% sodium bicarbonate/3% sodium hydroxide aqueous solution).

3. Preparation of external liquid preparation

The essential components of the pharmaceutical composition (e.g. 3g of sodium hydroxide as chemical ablator, 7g of sodium bicarbonate as pH adjuster), optional other components and a liquid carrier (e.g. water for injection) are measured to the desired concentration and mixed slowly and homogeneously. The preparation (e.g. 7% sodium bicarbonate/3% aqueous sodium hydroxide) can be directly used as a liquid medicament for topical liquid administration.

4. Preparation of nebulant

The essential components of the pharmaceutical composition (e.g. 3g sodium hydroxide, 7g sodium bicarbonate) and the following adjuvants of the nebuliser were measured at the desired concentrations (as described in table 1): glycerin (2.5g), polysorbate-80 (1.5g), benzalkonium chloride (0.02g), and microcrystalline cellulose-sodium carboxymethyl cellulose (1.5g), then a vehicle (e.g., water for injection) with a constant volume to a total volume (e.g., 100ml) is added, and they are slowly mixed until uniform for use. The preparation (such as 7% sodium bicarbonate/3% sodium hydroxide aqueous solution) can be used as spray stock solution, and can be directly sprayed on target area to form liquid medicine after being added into a sprayer.

Example 2: synergistic study of compositions

In one experiment, successfully modeled test animals (S180-bearing mice, mean tumor volume 314mm³) The groups were randomly divided into 2 negative control groups (01, 02) and 9 drug study groups (1-9). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The negative control and study drug were injected intraperitoneally (groups 02, 6, 9) and intratumorally (other study groups), respectively. Each group was administered once every 3 days for a total of 3 times, with an injection volume of 150 ul/tube. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 4.

30 mice, male and female are not limited, and are randomly divided into 3 groups (1, 3, 4, 7, 8 groups in the following table), and 6 mice are in each group. Each group of experimental animals was injected with 100ul of study drug in the quadriceps muscle of the right leg. After 24h of injection, animals were euthanized and the degree of congestion, edema, degeneration, necrosis, etc. at the injection site was observed and scored for a stimulus response. The scoring criteria were calculated based on the negative control group phenomenon being 0 points and the 3% NaOH group phenomenon being 5 points. The results of the stimulus response scores are shown in table 4.

30 New Zealand white rabbits with the weight of 2.0-2.5kg and unlimited male and female parts. Experimental rabbits were randomly divided into 5 groups (1, 3, 4, 7, 8 groups in the table below), with 6 rabbits per group. The experimental rabbit is anesthetized by intravenous injection of anesthetic at the ear margin, then is fixed on a rabbit frame in a supine position, a small incision on the right side is made under aseptic conditions to open the abdomen and expose the liver, then a PTC (positive temperature coefficient) needle of 22G is punctured into the center of the thickest liver right lobe of the liver, the depth of the needle point from a liver envelope of a puncture point is 1.5cm, and research medicines are slowly injected at a constant speed respectively. One intrahepatic injection was administered to each rabbit, and study drug 1, OmL, as shown in the table below, was injected. After the administration, the rabbits were fed with conventional feed, euthanized 1 week later, and then the necrotic area in the liver was determined after dissection. The liver was dissected along the center of the necrotic area, and the maximal and minimal diameters of the necrotic area were measured on the maximum level. The average diameter of the liver tissue necrosis area is (maximum diameter + minimum diameter)/2. The results of the average diameter of the necrotic area in liver tissue are shown in table 5.

TABLE 5

In the above table, the tumor inhibition rates of the composition study groups 6 and 9 were lower than the conventional effective tumor inhibition standard (40%) in the intraperitoneal injection series, and the tumor weights of each of them were not statistically significant (both p >0.005) from the negative control group (02). Surprisingly, with the same composition, study group 4 had a tumor inhibition rate that was more than 20 times higher than study group 6 (68%: 3%) and study group 9 had a tumor inhibition rate that was more than 40 times higher than study group 12 (87%: 2%). Thus, different modes of administration of the same composition show significantly different targeting and pharmacology through disparate drug effects. After different modes of administration (i.e., intraperitoneal and local), the composition of the same composition may vary completely in the target area (local lesion). The composition injected intraperitoneally enters the blood and reaches the local lesion, where it is administered in a composition that is completely diluted or even dissolved by the blood (e.g., different retention of different compositions in certain organs). While the target composition of a topically administered composition is the same as (at least over a period of time) that it is administered. Conversely, compositions administered in different ways should have different compositional characteristics to achieve synergistic efficacy.

In the prior art, locally administered bases and acids above a certain concentration threshold (e.g. sodium hydroxide, sodium carbonate, sodium bicarbonate, acetic acid, hydrochloric acid) are used as chemoablative agents. The two polarizations of the pH of the chemical ablative agent (toward 0 or toward 14) are considered to be positively correlated factors for its chemical ablative action. Thus, the pH of conventional chemical ablative agents is typically selected to be 2% (e.g., 50% acetic acid, 25% hydrochloric acid), or 11.5% (e.g., 7% sodium hydroxide). Under such extreme pH conditions, strong undifferentiated tissue destruction is considered to be the basis for the pharmacological effects of conventional chemical ablative agents. It is generally believed that the greater the damage to normal tissue by the chemical ablative agent, the greater the damage to diseased tissue. Many chemical ablative agents are screened for damage to normal tissue, such as liver tissue. In the above table, the results of the single drug study groups 1, 2 are consistent with the knowledge of the prior art: the higher the stimulation response score, the larger the necrotic surface diameter of the liver tissue and the higher the tumor suppression effect.

Thus, the addition of a pH adjusting agent that neutralizes the pH of the chemical ablative agent should ideally exhibit an antagonistic, rather than a synergistic, effect on tissue destruction. The addition of 7% sodium bicarbonate (pH6.9) reduced the pH of 3% sodium hydroxide (pH11.8) by 1.6 and the composition was significantly neutralized (7% sodium bicarbonate/3% NaOH, pH 10.2). Study group 4 did show a reduction in the stimulation response score and in the necrotic surface diameter of liver tissue as predicted compared to 1, and the composition group showed local stimulation antagonism and normal tissue disruption antagonism. However, in the above table, the tumor inhibition rate of study group 4 was greater than that of study group 1. Between study groups 4, 3, 1, composition group 4 had q ═ 1.11>1.00, and it was statistically significant (both p <0.05) in the residual tumor weight differences between groups 3 and 1, respectively, thus showing significant synergistic efficacy. These results indicate that the addition of more pH neutral substances may result in compositions that exhibit higher tissue destruction specificity, thereby reducing the risk of local irritation, showing synergistic safety, and may even provide synergistic efficacy at the same time.

The emergence of this less commonly recognized phenomenon (compositions where the pH of the chemical ablative agent tends to be neutral exhibit synergistic, even significant, synergistic effects against diseased tissue) clearly necessitates a less common solution. In the above table, in the topical administration series, although the component amount ratios of the respective compositions were the same, the tumor inhibition rate of the composition study group 5 was only 47% (32%: 68%) of the composition study group 4, and the difference in tumor weights of the two groups was statistically significant (p < 0.005). Between study groups 5 and 2, their tumor inhibition rates did not reach the 40% universal standard and the remaining tumor weight differences were not statistically significant (p >0.05), thus no synergistic efficacy was shown. The compositions used in study groups 5 and 4 had the same composition and ratio of amounts, but different concentrations of chemical ablative agent and its pH adjusting agent, resulting in different shared effects. These results further illustrate that compositions administered in different ways may require entirely different components in order to achieve synergistic efficacy. Compositions for systemic administration usually require component-to-component ratio (which are instead diluted into the blood), whereas compositions for topical administration give no other characteristic (e.g. concentration) than the component-to-component ratio.

In addition, in the above table, the pH of 15% arginine/7% sodium bicarbonate/3% NaOH was slightly increased from that of 7% sodium bicarbonate/3% NaOH, whereas the addition of 15% arginine resulted in a decrease in the stimulation response score and the necrotic surface diameter of liver tissues, showing local stimulation antagonism and normal tissue destruction antagonism. However, between study groups 8, 7, 4, composition group 8 had q ═ 1.15>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between groups 7 and 4, respectively, thus showing significant synergistic efficacy. These results demonstrate that the addition of new topical synergists can allow the compositions to exhibit higher potency, even synergistic potency, by altering the composition properties (perhaps such as increasing the buffer capacity).

In summary, the compositions of the present invention appear to exhibit a pharmacological profile when administered topically that is significantly different from systemic administration. For example, instead of being molecularly distributed in the blood to attack pathogens in diseased tissue (e.g., tumor cells in a tumor), the primary pharmacology is distributed as a drug solution in the interstitial space at the site of administration to attack diseased tissue (e.g., tissue in a tumor)

According to the above studies and more similar studies, it can be concluded that the requirements of the application technical scheme of the composition of the present invention as a topical active ingredient in the preparation of topical medicaments for the treatment of locally diseased diseases are:

the composition of the pharmaceutical composition of the present invention must be such that it can be administered topically and above a certain concentration threshold such that the ratio of the amounts of the components of the pharmaceutical composition produces a synergistic effect. Specifically, in the pharmaceutical composition, the concentration of the chemical ablation agent should be less than or equal to the effective ablation concentration (for example, the tumor inhibition concentration in a tumor-bearing mouse experiment can be more than or equal to 40%) but more than or equal to the synergistic drug effect concentration threshold (for example, the concentration of the strong base or strong acid chemical ablation agent is more than or equal to 0.5%, and the concentration of the weak base or weak acid chemical ablation agent is more than or equal to 2.5%). And the concentration of the pH regulator is such that the pharmaceutical composition is neutralized and the absolute value of the difference between the pH of the pharmaceutical composition and the pH of the individual chemical ablative agent at the same concentration is greater than or equal to 0.25.

In addition, compositions exhibiting synergistic efficacy have been determined to also have a buffer capacity of>0.01mol·L^-1·pH^-1The buffer solution of (1).

In addition, the composition of the invention can further improve the drug effect, even the synergistic drug effect by adding local synergistic substances.

The following examples further study the technical scheme of the composition of the present invention based on the above requirements.

Example 3: the invention discloses a technical scheme research on the synergistic effect of a strong base ablation agent/pH regulator composition

In one experiment, testThe experimental animal is BALB/c mouse, the modeling cell is breast cancer 4T1 cell, 1 × 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 325 mm)³) The groups were randomly divided into 1 negative control group (0) and 11 drug study groups (1-11). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injections were administered in an amount of 150 ul/dose. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 6.

TABLE 6

In the above table, the tumor inhibition rates of the composition group 7 and the study group 1 were not greatly different between the study groups 7, 1, 6, and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), and thus no synergistic efficacy was shown. Between study groups 8, 2, 5, composition group 8 had q 1.04>1.00 and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 5, respectively, thus showing significant synergistic efficacy. Between study groups 9, 3, 4, the tumor inhibition rates of composition group 9 and study group 3 were not significantly different and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), thus showing no synergistic efficacy. Between study groups 11, 3, 10, composition group 11 had q ═ 1.42>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 10, respectively, thus showing significant synergistic efficacy.

In accordance with the above and more similar studies, the preferred conditions for the alkali ablator/pH modifier composition of the present invention are:

the concentration of the strong base is more than or equal to 0.5 percent, and preferably 0.75 to 7.5 percent;

the amount ratio (w: w) of said strong base and said pH adjusting agent is <1, preferably 1/20-1/1.25;

the difference between the pH value of the single medicine with the same concentration of the strong base and the pH value of the composition is more than or equal to 0.25, and preferably 0.5-3.5;

the pH of the composition is 10.0 ± 2.0, preferably 10.0 ± 1.0; and

the pH regulator is selected from one or more of the following groups which meet the conditions: polybasic weak acid basic inorganic salt, organic weak acid alkali metal salt, other weak bases, strong acid strong base inorganic salt, polybasic weak acid acidic inorganic salt, weak acid and strong acid; and

the concentration of the pH regulator is more than or equal to 1 percent, and is preferably 1 to 35 percent.

In addition, as shown in example 2, the alkali ablative agent/pH adjusting agent composition of the present invention can further improve the efficacy, even synergistic efficacy, by adding local synergists.

Example 4: the invention discloses a technical scheme research on the synergistic action of a weak base ablation agent/pH regulator composition

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (average tumor volume 307 mm)³) The groups were randomly divided into 1 negative control group (0) and 13 drug study groups (1-13). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injections were administered in an amount of 150 ul/dose. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 7.

TABLE 7

In the above table, the tumor inhibition rates between the study groups 7, 1, 6 were not greatly different between the composition group 7 and the single drug group 1, and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), so that no synergistic efficacy was exhibited. Between study groups 8, 1, 4, composition group 8 had q ═ 1.43>1.00, and it was statistically significant (both p <0.05) in the residual tumor weight differences between groups 1 and 4, respectively, thus showing significant synergistic efficacy. Between study groups 9, 2, 5, composition group 9 had q ═ 1.43>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 5, respectively, thus showing significant synergistic efficacy. Similarly, composition group 10 also showed significant synergistic efficacy, but its tumor suppression rate was only 60% of that of composition group 9. The tumor suppression rates between the study groups 11, 3, 5 were not very different between the composition group 11 and the single drug group 5, and the remaining tumor weights between the two groups were not statistically significant (p >0.05), thus showing no synergistic efficacy.

In addition, between study groups 13, 12, and 9, composition group 13 had q ═ 1.16>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between 12 and 9 groups, respectively, thus showing significant synergistic efficacy. Again, the results demonstrate that the addition of topical synergists can allow the compositions to exhibit synergistic efficacy by altering the composition properties (perhaps such as increasing the buffer capacity).

In accordance with the above and further similar studies, preferred conditions for the weak base ablative agent/pH adjusting agent compositions of the present invention are, in accordance with the above and further similar studies:

the concentration of the weak base ablation agent is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 20 percent, preferably more than or equal to 3.0 to 20 percent or more than or equal to 5 to 20 percent;

the difference between the pH value of the single weak base with the same concentration and the pH value of the composition is more than or equal to 0.25, preferably 0.5-2.5; and

the pH of the composition is 9.0 ± 2.0, preferably 9.0 ± 1.3;

the pH regulator is selected from one or more of the following groups which meet the conditions: other weak bases, organic weak acid alkali metal salts, weak acids, strong acids. Wherein the other weak base is a weak base different from the weak base as an ablative agent;

When the weak base ablative agent/pH adjuster composition is a weak basic polybasic acid salt/weak acidic polybasic acid salt composition, the ratio of the basic polybasic acid salt to the acidic polybasic acid salt (w: w) is greater than 0.56 and less than 7, preferably 1-2.

In addition, the weak base ablative agent/pH modifier composition of the invention can further improve the drug effect, even the synergistic drug effect, by adding local synergists.

Example 5: the technical scheme research of the synergistic action of the weak acid ablator/pH regulator composition

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 316 mm)³) The groups were divided into 1 negative control group (0) and 12 drug study groups (1-12). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injections were administered in an amount of 150 ul/dose. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 8.

TABLE 8

In the above table, between study groups 7, 1, and 5, q of composition group 7 was 0.85<1.00, and the remaining tumor weight difference between composition group 7 and 1 and 5 groups, respectively, was statistically significant (both p <0.05), thus showing significant antagonistic drug effects. Between study groups 8, 2, 4, composition group 8 had q ═ 1.02>1.00, and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 4, respectively, thus showing significant synergistic efficacy. The tumor inhibition rates between the composition group 9 and the single drug group 4 were not very different between the study groups 9, 3, 4, and the remaining tumor weight difference between the two groups was not statistically significant (p >0.05), thus showing no synergistic efficacy. Between study groups 10, 2, 6, composition group 10 had q 1.04>1.00 and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 6, respectively, thus showing significant synergistic efficacy.

In addition, between study groups 12, 10, 11, composition group 12 had q of 1.05>1.00 and had statistical significance (both p <0.05) to the remaining tumor weight differences between groups 10 and 11, respectively, thus showing significant synergistic efficacy. Again, this result demonstrates that the addition of a topical synergist can allow the composition to exhibit synergistic efficacy by altering the composition properties (perhaps such as increasing the buffer capacity) without a substantial pH shift.

In accordance with the above and more similar studies, the preferred conditions for the weak acid ablator/pH adjuster composition of the present invention are:

the concentration of said weak acid is > 3%, preferably 5-25%;

the difference between the pH value of the composition and the pH value of the single medicine with the same concentration of the weak acid is more than or equal to 0.25, and preferably 0.5-2.5; and

the pH of the composition is 4.0 ± 1.5, preferably 4.0 ± 1.0;

the pH regulator is selected from one or more of the following groups which meet the conditions: strong base, polybasic weak acid basic inorganic salt, nitrogenous weak base, polybasic weak acid acidic inorganic salt and organic weak acid alkali metal salt; and

In addition, the weak acid ablator/pH modifier composition of the present invention may further improve the efficacy, even synergistic efficacy, by adding local synergists.

Example 6: research on technical scheme of synergistic effect of strong acid ablative agent/pH regulator composition

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (average tumor volume 324 mm)³) The groups were divided into 1 negative control group (0) and 9 drug study groups (1-9). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injections were administered in an amount of 150 ul/dose. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 9.

TABLE 9

In the above table, between study groups 6, 1, 5, q of composition group 6 was 0.93<1.00, and the remaining tumor weight difference between composition group 6 and 1 and 5 groups, respectively, was statistically significant (both p <0.05), thus showing significant antagonistic drug effects. Between study groups 7, 2, 5, composition group 7 had q ═ 1.05>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 5, respectively, thus showing significant synergistic efficacy. The tumor inhibition rates between the combination group 8 and the single drug group 4 were not very different between the study groups 8, 3, 4, and the remaining tumor weights between the two groups were not statistically significant (p >0.05), thus showing no synergistic efficacy.

In accordance with the above and more similar studies, the preferred conditions for the aqueous solution of the strong acid ablative agent/pH adjusting agent composition of the present invention are:

the concentration of the strong acid is > 0.5%, preferably 0.75-3%;

the amount ratio (w: w) of the strong acid and the pH adjusting agent is <1, preferably 1/20-1/1.25;

the difference between the pH value of the composition and the pH value of the weak acid with the same concentration as the single medicine is more than or equal to 0.25, and preferably 0.5-4.0; and

the pH of the composition is 4.0 ± 1.5, preferably 4.0 ± 1.0;

the pH regulator is selected from one or more of the following groups which meet the conditions: basic inorganic salt of polybasic weak acid, nitrogenous weak base, inorganic salt of polybasic weak acid and alkali metal salt of organic weak acid; and

Example 7: synergistic study of the composition of the chemical ablation agent, pH adjuster, and their local synergists of the present invention

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 317 mm)³) The groups were randomly divided into 2 negative control groups (01, 02) and 20 drug study groups (1-20). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The negative control and study drug were injected intraperitoneally (groups 02, 11, 15) and intratumorally (other study groups), respectively. Each group was administered once every 3 days for a total of 3 times, and intratumoral injections were administered in an amount of 150 ul/dose. On day 5 after the end of the administration, the animals were euthanized, and the tumor weight was measured after dissection, and the tumor inhibition rate was calculated from the negative control group, and the results are shown in table 10.

Watch 10

In the above table, the tumor inhibition rates of the composition study groups 11 and 15 were lower than the conventional effective tumor inhibition standard (40%) in the intraperitoneal injection series, and the difference in tumor weights between study group 11 and the negative control group (02) was not statistically significant (p > 0.005). Surprisingly, with the same composition, study group 10 showed a tumor inhibition rate that was more than 2-fold higher than study group 11 (86%: 36%) and study group 14 showed a tumor inhibition rate that was more than 25-fold higher than study group 14 (83%: 3%). Thus, different modes of administration of the same composition show significantly different targeting and pharmacology through disparate drug effects. After different modes of administration (i.e., intraperitoneal and local), the composition of the same composition may vary completely in the target area (local lesion). The composition injected intraperitoneally enters the blood and reaches the local lesion, where it is administered in a composition that is completely diluted or even dissolved by the blood (e.g., different retention of different compositions in certain organs). While the target composition of a topically administered composition is the same as (at least over a period of time) that it is administered. Conversely, compositions administered in different ways should have different compositional characteristics to achieve synergistic efficacy.

This phenomenon, which is less desirable in general terms (systemic versus topical administration shows a very different effect), obviously necessitates a less common technical solution. In the above table, in the topical administration series, although the component amount ratios of the respective compositions were the same, the tumor inhibition rate of the composition study group 12 was only 38% (33%: 86%) of the composition study group 10, and the difference in tumor weights of the two groups was statistically significant (p < 0.005). The tumor inhibition rate of the composition study group 16 was only 27% (22%: 83%) of the composition study group 14, and the tumor weight difference of the two groups was statistically significant (p < 0.005). In fact, the tumor inhibition rates of the composition research group 12 and the single-drug research group 2 and the tumor weight difference of the composition research group 14 and the single-drug research group 4 are not different greatly, the tumor weight difference is not statistically significant (p is greater than 0.005), and the composition research group does not show a synergistic effect. However, between study groups 10, 1, 5, composition group 10 had q ═ 1.04>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between groups 1 and 5, respectively, thus showing significant synergistic efficacy. Between study groups 14, 3, and 8, composition group 14 had q ═ 1.13>1.00, and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 8, respectively, thus showing significant synergistic efficacy. These results further illustrate that compositions administered in different ways may require entirely different components in order to achieve synergistic efficacy. Compositions for systemic administration usually require component-to-component ratio (which are instead diluted into the blood), whereas compositions for topical administration give no other characteristic (e.g. concentration) than the component-to-component ratio.

Furthermore, between study groups 18, 1, 17, composition group 18 had q ═ 1.19>1.00, and it had statistical significance (both p <0.05) with the remaining tumor weight differences between groups 1 and 17, respectively, thus showing significant synergistic efficacy. Between study groups 20, 3, 19, composition group 14 had q ═ 1.20>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 19, respectively, thus showing significant synergistic efficacy.

In summary, the compositions of the present invention appear to exhibit a pharmacological profile when administered topically that is significantly different from systemic administration. For example, instead of being molecularly distributed in the blood to attack pathogens within the diseased tissue (e.g., tumor cells within a tumor), the primary pharmacology is distributed as a drug solution to the interstitial space of the tissue at the site of administration to attack the diseased tissue (e.g., intratumoral tissue).

From the above studies and further similar studies, it is possible to conclude the requirements for a technical solution for the use of a combination of chemoablative agents, pH-modifying agents, and their local synergists as a topical active ingredient in the preparation of a topical medicament for the treatment of locally varying diseases:

the composition of the pharmaceutical composition of the present invention must be such that it can be administered topically and above a certain concentration threshold such that the ratio of the amounts of the components of the pharmaceutical composition produces a synergistic effect. Specifically, in the pharmaceutical composition, the concentration of the chemical ablation agent should be less than or equal to the effective ablation concentration (for example, the tumor inhibition concentration in a tumor-bearing mouse experiment can be more than or equal to 40%) but more than or equal to the synergistic drug effect concentration threshold (for example, the concentration of the strong base or strong acid chemical ablation agent is more than or equal to 0.5%, and the concentration of the weak base or weak acid chemical ablation agent is more than or equal to 2.5%). Based on the concentration of the chemical ablative agent, the quantity ratio conditions of each of the necessary components are: the chemical ablative agent concentration is as described above; the concentration of the pH regulator is the concentration which can generate synergistic action with the chemical ablation agent (specifically, the concentration which can lead the pharmaceutical composition to be neutral and lead the absolute value of the difference between the pH of the pharmaceutical composition and the pH of the single drug with the same concentration as the chemical ablation agent to be more than or equal to 0.25); the concentration of the local synergist is such that it synergistically acts with the chemical ablative agent and its pH adjusting agent (e.g., is greater than 5% or greater than 25% of the saturation solubility of the local synergist in the composition).

Furthermore, the synergistic combination of the chemoablative agent and the pH adjusting agent appears to be the basis of the synergistic effect of the chemoablative agent/pH adjusting agent/topical synergist pharmaceutical composition of the present invention.

Example 8: further study on the synergistic technical solution of the composition of chemical ablation agent, pH adjuster, and their local synergists of the present invention

In one experiment, the experimental animals were BALB/c mice, and the modeled cells were breast cancer 4T1 cells at 1X 10⁶Individual cells/animal right axillary subcutaneous transplantation tumor modeling. Successfully modeled test animals (tumor volume mean 336 mm)³) The groups were divided into 1 negative control group (0) and 24 drug study groups (1-24). The negative control was physiological saline and study drugs are shown in the table below. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was administered once every 3 days for a total of 3 times, and intratumoral injections were administered in an amount of 150 ul/dose. 5 days after the administration, the animals were euthanized, tumor weights were determined after dissection, and the inhibition was calculated from the negative control groupThe results of the tumor rates are shown in Table 11.

TABLE 11

In the above table, between study groups 15, 1, 5, composition group 15 had q 1.01>1.00 and had statistical significance (both p <0.05) to the remaining tumor weight differences between groups 1 and 5, respectively, thus showing significant synergistic efficacy. Between study groups 16, 2, 6, composition group 16 had q ═ 1.02>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 2 and 6, respectively, thus showing significant synergistic efficacy. The tumor suppression rate was greatest in the composition group 17 among study groups 17, 1, and 7, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 1 and 7, respectively, thus showing synergistic efficacy. The tumor suppression rate was greatest in the composition group 18 among study groups 18, 1, and 8, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 1 and 8, respectively, thus showing synergistic efficacy. Between study groups 19, 1, 9, composition group 19 had q ═ 1.11>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 1 and 9, respectively, thus showing significant synergistic efficacy. Between study groups 20, 1, 10, composition group 20 had q 1.04>1.00 and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 1 and 10, respectively, thus showing significant synergistic efficacy. The tumor suppression rate was greatest in composition group 21 among study groups 21, 1, 11, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 1 and 11, respectively, thus showing synergistic efficacy. The tumor suppression rate was greatest for composition group 22 among study groups 22, 3, 12, and was statistically significant (both p <0.05) from the remaining tumor weight differences between groups 3 and 12, respectively, thus showing synergistic efficacy. Between study groups 23, 3, 13, composition group 23 had q ═ 1.08>1.00, and it was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 13, respectively, thus showing significant synergistic efficacy. Between study groups 24, 3, 14, composition group 24 had q 1.06>1.00 and was statistically significant (both p <0.05) in the difference in residual tumor weights between groups 3 and 14, respectively, thus showing significant synergistic efficacy.

Example 9: the pharmaceutical composition of the invention has more anti-tumor applications

In this series of experiments, the successfully modeled nude mice bearing human cancer cells were randomly divided into 1 negative control group and 6 study groups. The corresponding negative control was normal saline, and the 6 study drugs were: 4% sodium bicarbonate/7% sodium carbonate, 4% sodium bicarbonate/15% acetic acid, 7% sodium carbonate/1% potassium hydroxide, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide, 2% KCl/1% NaOH/20% arginine/20% xylitol, 20% glycine/3% sodium bicarbonate/10% acetic acid. The drugs were all aqueous solutions and were prepared according to the preparation method of example 1. Each group was injected intratumorally, once every 3 days for a total of 3 times, 150. mu.l/patient. On day 5 after the end of the administration, the animals were euthanized, and tumor weights were determined after dissection, and the tumor inhibition rates were calculated from the respective negative control groups.

1) Application of the compound in treating breast tumor

In this study, a successfully modeled nude mouse bearing human breast cancer cells (MDA-MB231) (tumor mean volume 303 mm)³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 79%, 73%, 77%, 92%, 97% and 91% of the total content of the extract meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

2) Application of the compound in lung tumor treatment

In the study, a nude mouse with human lung cancer cells (A549) successfully modeled (average tumor volume 326 mm)³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 71%, 76%, 79%, 92%, 95%, 89%, allMeets the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40 percent).

3) Application of the compound in thyroid tumor treatment

In the study, the nude mouse with human thyroid carcinoma cells (SW579) (mean tumor volume 341 mm) was successfully modeled³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 79%, 75%, 71%, 92%, 97% and 88% of the total content of the extract meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

4) Use in the treatment of prostate tumors

In this study, human prostate cancer cell (LNCaP/AR) bearing nude mice (mean tumor volume 348 mm) were successfully modeled³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 71%, 78%, 76%, 93%, 97%, 92%, all of which meet the commonly recognized effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

5) Application of the compound in liver tumor treatment

In the study, the nude mice (average tumor volume 309 mm) with human hepatoma cells (HepG2) successfully modeled³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 73%, 71%, 76%, 92%, 95%, 89%, all meet the generally recognized effective anti-tumor standard (tumor inhibition rate is more than or equal to 40%).

6) Application of the compound in treating head and neck tumors

In the present study, nude mice with human head and neck cancer cells (F μ da) successfully modeled (mean tumor volume 305 mm)³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 72%, 79%, 75%, 93%, 97%, 86%, all meet the generally recognized effective anti-tumor standard (tumor inhibition rate is more than or equal to 40%).

7) Application of the compound in treatment of nasopharyngeal tumors

In this study experimentSuccessfully modeled nude mice with human nasopharyngeal carcinoma cells (CNE1) (mean tumor volume 327 mm)³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 79%, 73%, 71%, 91%, 95% and 88% of the total content of the extract meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

8) Application of the compound in treating gastric tumor

In the study, nude mice (average tumor volume 314 mm) with human gastric carcinoma cells (BGC823) successfully modeled³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 71%, 73%, 74%, 88%, 91%, 93%, all meet the generally recognized effective anti-tumor standard (tumor inhibition rate is more than or equal to 40%).

9) Application of the compound in ovarian tumor treatment

In the study, nude mice with successfully modeled human ovarian carcinoma cells (PA1) (mean tumor volume 311 mm)³) The groups were randomized into a negative control group and 6 study groups (A, B, C, D, E, F groups). A. The tumor inhibition rates of B, C, D, E, F groups were: 75%, 76%, 71%, 91%, 93% and 85% of the total content of the extract meet the generally considered effective anti-tumor standard (the tumor inhibition rate is more than or equal to 40%).

Similar results were obtained with some other compositions of the invention prepared by the method of example 1 (e.g., synergistic compositions in each example) for use in the treatment of each of the tumors described above.

Locally administered interventions for diseases with locally diseased symptoms, especially intractable diseases, are often modeled as tumors. Among the diseases associated with localized lesions, the mechanisms of tumors are extremely complex and the most difficult to treat. Local administration protocols obtained using tumor models are generally applicable to other diseases associated with local lesions. The following experiments investigated further applications of the compositions of the present invention.

Example 10: application of anti-non-tumor and non-inflammatory local lesion diseases

In one experiment, the non-pregnant female rats (weighing 150-180g) were randomly divided into a blank control group and a molding group. Taking mammary gland hyperplasia as a model, the model group is injected with estradiol benzoate (0.5mg/kg, 1 time/day, continuous for 20 days), and then progesterone (5mg/kg, 1 time/day, continuous for 5 days). Successfully modeled test animals were randomly divided into a negative control group, a positive control group and 3 study groups (1, 2, 3 groups), with 6 animals per group. The administration was started on the day of the group. The negative control was physiological saline, the positive control was tamoxifen (rottendorf phanna GmhH), and the 3 study drugs were: 4% sodium bicarbonate/7% sodium carbonate, 4% sodium bicarbonate/15% acetic acid, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide. The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1. The negative control group and the study group are injected once in the swelling area every 3 days, each time is 100 mu l, and the total dose is 5 times. The positive control group is administrated by gavage with tamoxifen 2 times a day, 0.1mg/kg gavage each time, and administration is carried out for 30 days. The items observed, measured and analyzed in the experiment include nipple enlargement inhibition rate and pathological changes of mammary tissue, in addition to the conventional food intake, body weight, general state. The calculation of pathological changes of mammary tissue and evaluation criteria of drug effect are the same as those in the previous experiment. The nipple enlargement inhibition ratio (R%) was calculated as follows:

R％＝[(△D01-△Dn)/△D01]％＝1-△Dn/△D01

wherein, Delta D01 is the difference (D01-D0) between the nipple diameter (D01) of the negative control group and the nipple diameter (D0) of the blank control group at the 33 th day after the first administration, and Delta Dn is the difference (Dn-D0) between the nipple diameter (Dn) of the study group and the nipple diameter (D0) of the blank control group.

The evaluation criteria of the drug efficacy of the nipple enlargement inhibition rate (R%) are as follows:

(R%) < 40% is invalid and (R%) > 40% is valid.

The results of the teat growth inhibition rate are shown in table 12 below.

TABLE 12

In the above table, the papilla diameters of the 1, 2, 3 and positive control groups were all much smaller than those of the negative control group at day 33 after the first administration, and the differences were statistically significant (all P < 0.05). In this case, the inhibition rates of nipple enlargement in groups 02, 1, 2 and 3 were 62%, 78%, 71% and 86%, respectively, and all were effective drug effects.

On the 33 th day after the first administration, the pathological integrals of the groups 1, 2 and 3 are respectively 0.75 +/-0.21, 0.77 +/-0.26 and 0.46 +/-0.22, which are all less than or equal to 1, are close to the blank control group (0.32 +/-0.15), and are obviously different from the pathological integrals of the negative control group (3.81 +/-0.41) and have statistical significance (all are less than 0.05). While the positive control group had a pathology score greater than 1 (1.86. + -. 0.31). The safety observations of the drugs were essentially the same.

Similar results can be obtained with some other compositions of the present invention prepared using the method of example 1 (e.g., synergistic compositions in each example).

In another experiment, infertile female rats were randomly divided into a placebo group and a molding group. The non-inflammatory goiter is used as a model, the building module is raised for more than 3 months in the environment of low-iodine feed feeding, and urine iodine is obviously reduced, and thyroid gland is obviously enlarged to successfully build the model. Successfully modeled test animals were randomly divided into a negative control group, a positive control group and 3 study groups, each group of 6 animals. The administration was started on the day of the group. The negative control was physiological saline, the positive control was potassium iodate, and the 3 study drugs were: 4% sodium bicarbonate/7% sodium carbonate, 4% sodium bicarbonate/15% acetic acid, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide. The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1.

The negative control group (group 01) and the study groups (groups 1, 2 and 3) were injected once every 3 days into the swollen area, 100. mu.l/body each time, and a total of 5 times. The positive control group (02 group) was administered potassium iodate (KIO3) at 27 times at a daily dose of 0.4. mu.g/kg per dose. Items observed, measured and analyzed in the experiment include thyroid relative weight and thyroid pathology examination, in addition to regular food intake, body weight, general state. The observation of thyroid pathological changes and evaluation criteria of drug efficacy are the same as in the previous experiment. 30 days after the first administration, the rats were euthanized, the thyroid gland was detached, the wet weight was weighed, and the relative thyroid mass was calculated (thyroid relative mass w ═ thyroid mass/rat mass).

calculation formula for the inhibition of increase of adenoid gland (R%) is as follows:

R％＝[(△w₀₁-△w_n)/△w₀₁]％＝1-△w_n/△w₀₁

in the formula, delta w₀₁The difference in relative thyroid mass (w) between the negative control group (01) and the blank control group (0)₀₁-w₀)，△w_nTo investigate the difference (w) between the relative masses of thyroid glands of group (n) and blank control group (0)_n-w₀)。

evaluation criteria for drug efficacy of the increase inhibition rate (R%) of the glandular gland are: (R%) < 40% is invalid and (R%) > 40% is valid. The -like gland increase inhibition rate (R%) obtained in the experiment is shown in Table 13 below.

Watch 13

In the above table, the relative masses of the thyroid glands in groups 1, 2, 3 and 02 were all much smaller than those in the negative control group at day 30 after the first administration, and the differences between the groups and the negative control group were statistically significant (all P < 0.05). In this case, the inhibition rates of increase in -like glands were 78%, 71%, 91% and 67% in groups 1, 2, 3 and 02, respectively, and all were effective.

On day 30 after administration, the difference between groups 1, 2 and 3 and the blank control group in terms of follicular morphology and size, epithelial cells, and inter-leaflet fibrous tissue was less than 15%, and was close to the positive control group. The safety observations for each group of drugs were essentially the same.

Mastoplasia (MGH), also known as mammary dysplasia, is characterized by painful swelling of the breast with lumps. Goiter is one of the most common non-neoplastic, non-inflammatory focal disease states. Given that the compositions of the present invention target diseased tissue beyond the causative agent (e.g., pathogen) itself, goiter can serve as a localized disease model for proliferative lesions that are neither inflammatory nor malignant. Such diseases include: non-malignant tumors, hyperplasia (e.g., hyperplasia of breast, pancreas, thyroid, parathyroid, prostate, etc.), cyst (e.g., cyst of breast, thyroid, parathyroid, etc.), abnormal vein mass (e.g., hemorrhoid, etc.), other nodules (e.g., nodules of breast, thyroid, parathyroid, etc.). The hemorrhoid includes internal hemorrhoid, external hemorrhoid, and mixed hemorrhoid.

Example 11: study of anti-local inflammation

In one experiment, adult male rats (weighing approximately 150-180g) were randomly divided into a blank control group and a building block. Using allergic rhinitis as model, the model group uses Ovalbumin (OVA) sensitizing solution (each milliliter contains 0.5mgOVA and 30mg Al (OH)₃) The allergen was sensitized by intraperitoneal injection (once a day, 7 times total), and then the mixture was subjected to nasal drip (once a day, 7 times total) with ovalbumin molding solution (3% OVA) to mold. Successfully modeled test animals were randomly divided into a negative control group, a positive control group and 3 study groups, each group of 6 animals. The administration was started on the day of the group. The negative control was physiological saline, the positive control was budesonide nasal drops (AstraZeneca Pty Ltd), and the 3 study drugs were sprays containing the following components: 4% sodium bicarbonate/7% sodium carbonate, 4% sodium bicarbonate/15% acetic acid, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide. The liquid stock solutions all contain water and the following auxiliary materials: glycerol (2.5%), polysorbate-80 (1.5%), benzalkonium chloride (0.02%), microcrystalline cellulose-sodium carboxymethylcellulose (1.5%). The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1.

Each group is made into a mould, nasal cavity spraying is carried out once a day, each time is 300 mul/body, and the medicine is taken 7 times. Items observed, measured and analyzed in the experiment included nasal symptom scores in addition to regular food intake, weight, general status. Nasal symptoms were scored the next day after completion of the treatment, using the overlap-add method to score nasal symptoms (nasal scratching, sneezing, watery nasal discharge) observed within 30min after nasal administration with ovalbumin. Scratching the nose: the number of times of scratching the nose is 1 minute, the repeated scratching of the nose surface is more than 2 minutes, and the rubbing of the nose surface is 3 minutes everywhere. Sneezing: 1 to 3 are 1 minute, 4 to 10 are 2 minutes, and more than 11 are 3 minutes. Running nose: until the anterior nares is 1 point, 2 points through the anterior nares, and 3 points full of nasal discharge. Nasal symptom scores obtained from the experiments are shown in table 14 below.

TABLE 14

In the above table, on day 8 after the first administration, except the blank control group, the other groups all showed nasal scratching, sneezing, nasal discharge, etc. after the nasal drip of ovalbumin solution. Compared with the negative control group, nasal symptom scores of 1, 2, 3 and 02 groups are all reduced remarkably, and the difference between each group and the negative control group is statistically significant (P < 0.05).

Allergic rhinitis is one of the most common inflammatory focal diseases. Given that the compositions of the present invention target diseased tissue beyond the causative agent (e.g., pathogen) itself, allergic rhinitis may serve as a model of inflammatory localized disease. Such diseases include: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, and oophoritis.

Example 12: studies on secretion disorders of antisecretory glands

In one experiment, adult male rats (weighing approximately 150-180g) were randomly divided into a blank control group and a building block. Using hyperthyroidism as a model, the modeling module is modeled by levothyroxine (intraperitoneal injection, dosage of 50 mug/100 g body weight, continuous injection for 10 days). The successfully modeled test animals were randomly divided into a negative control group (group 01), a positive control group (group 02) and 3 study groups, 6 animals per group, except for the unmodeled blank control group (group 0). The administration was started on the day of the group. The negative control was physiological saline, the positive control was thioimidazole, and the 3 study drugs were: 4% sodium bicarbonate/7% sodium carbonate, 4% sodium bicarbonate/15% acetic acid, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide. The study drugs were all aqueous solutions and were prepared according to the preparation method of example 1.

The negative control group and the study group are injected once in the swelling area every 3 days, each time is 100 mu l, and the total dose is 7 times. The positive control group is drenched with methyl-lucimidazole 1 time a day, and the medicine is drenched with 10mg/kg stomach every time for 21 days. Items observed, measured and analyzed in the experiment include serological examinations (thyroid hormone levels) in addition to regular food intake, body weight, general state. Thyroid hormone levels were determined as follows: on the 5 th day after the administration, the rats were fasted without water, and blood was collected from the abdominal aorta the next day to centrifuge the serum. T3 and T4 were measured by enzyme-linked immunosorbent assay according to the kit instructions (Beijing northern Biotechnology Co., Ltd.). The results of the measurements are given in Table 15 below.

Watch 15

Group of	Research medicine	T3	T4
				0	(blank control)	0.8±0.1	37.2±4.8
01	Physiological saline	1.9±0.1	121.3±9.2
				02	Methyl-sulfur imidazole	1.1±0.1	70.3±15.9
1	4% sodium bicarbonate/7% sodium carbonate	0.9±0.1	64.1±13.2
				2	4% sodium bicarbonate/15% acetic acid	0.9±0.1	63.5±11.8
3	15% arginine/7% sodium bicarbonate/3% sodium hydroxide	0.9±0.1	49.2±12.4

In the above table, on day 26 after the first administration, the levels of thyroid hormones in groups 1, 2, 3, and 02 were significantly decreased compared to the negative control group, and the difference between each group and the negative control group was statistically significant (all P < 0.05).

Hyperthyroidism is one of the most common local pathological diseases with abnormal secretion of secretory glands. Considering that the composition of the invention targets diseased tissue beyond the causative agent (e.g., pathogen) itself, hyperthyroidism may serve as a model for such localized disease. Such diseases include, for example: hyperthyroidism, hypothyroidism and islet function depression.

Example 13: anti-skin disease study

In this study, 20 volunteers with athlete's foot who participated in the study were divided into 4 groups, including 1 positive control group and 3 study groups (A, B, C groups), with 5 persons each. The positive control was dacron cream (siennan poplar pharmaceutical co., ltd.) and the 3 study drugs were liquid stock solutions of the following compositions as active ingredients: 4% sodium bicarbonate/7% sodium carbonate, 4% sodium bicarbonate/15% acetic acid, 15% arginine/7% sodium bicarbonate/3% sodium hydroxide. The preparation method of the spray is shown in example 1. The liquid stock solution contains the following auxiliary materials besides the active ingredients: glycerol (2.5%), polysorbate-80 (1.5%), benzalkonium chloride (0.02%), microcrystalline cellulose-sodium carboxymethylcellulose (1.5%). The aerosol liquid raw liquid storage device is stored in a container of the aerosol device before use. The positive control group is applied with Daktarin cream on affected part once a day for 7 times. The negative control group and 3 study groups sprayed the affected part with the corresponding spray once a day for 7 times. The therapeutic effect judgment standard is as follows: curing: skin lesions subsided > 90%, effective: regression of skin lesions > 50%, no effect: the skin lesions subsided < 50%.

Significant regression of skin lesions occurred 7 days after dosing in both the positive control group and the 3 study groups. The results 10 days after administration are shown in Table 16 below.

TABLE 16

Group of	Number of cases	Number of healed diseases	Effective number	Number of invalid	Inefficiency (%)
						Positive control group	5	0	3	2	40
Group A	5	1	3	1	20
						Group B	5	0	4	1	20
Group C	5	2	3	0	0

Similar results were obtained using a spray of the same composition as the other compositions of the invention prepared in example 1 (e.g. synergistic compositions in each example).

Tinea pedis is a fungal skin disease, which is one of the most common skin diseases in south China. Given that the compositions of the present invention target diseased tissue beyond the pathogen itself, tinea pedis can be used as a model for skin disease. Such diseases may for example include one or more of the following: skin cancer, non-malignant tumors of the skin, viral skin diseases (e.g., herpes, warts, rubella, hand-foot-and-mouth disease), bacterial skin diseases (e.g., impetigo, furuncle, leprosy), fungal skin diseases (e.g., various ringworm), sexually transmitted diseases (e.g., syphilis, gonorrhea, and condyloma acuminatum), allergic and autoimmune skin diseases (e.g., contact dermatitis, eczema, urticaria), physical skin diseases (e.g., solar skin diseases, chilblain, corns, rhagades of hands and feet, pressure sores), connective tissue diseases (e.g., lupus erythematosus), skin disorders (e.g., freckles, pigmented nevi, various plaques), skin appendages diseases (e.g., acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis, and bromidrosis).

The present disclosure includes the following items:

item 1, a topical pharmaceutical composition for the treatment of a topical pathological condition comprising an acid-base chemoablative agent and a pH adjusting agent, wherein the chemoablative agent is a strong base, a weak acid, or a strong acid, and in the pharmaceutical composition the concentration of the chemoablative agent is 0.5% or more, preferably 0.75% or more or 2.5% or more, and the amount of the pH adjusting agent is such that the pH of the pharmaceutical composition is more neutral than the pH of the chemoablative agent at the same concentration of the single drug, and the absolute value of the difference between the pH of the pharmaceutical composition and the pH of the chemoablative agent at the same concentration of the single drug is 0.25 or more.

Item 2, use of a combination comprising an acid-base chemical ablative agent and a pH adjusting agent as a topical active ingredient for the preparation of a topical pharmaceutical composition for the treatment of a topical pathological condition, wherein the chemical ablative agent is a strong base, a weak acid, or a strong acid, and in the pharmaceutical composition the concentration of the chemical ablative agent is not less than 0.5%, preferably not less than 0.75% or not less than 2.5%; the pH regulator is used in such an amount that the pH value of the pharmaceutical composition is closer to neutral than the pH value of the chemical ablation agent and the single drug, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent and the single drug is more than or equal to 0.25.

Item 3, a topical pharmaceutical composition for the treatment of a topical pathological condition comprising an acid-base chemoablative agent, a pH adjusting agent, a topical co-product thereof, and a suitable solvent, wherein the chemoablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemoablative agent in the topical pharmaceutical composition is 0.5% or more, preferably 0.75% or more, or 2.5% or more; the pH regulating agent enables the pH value of the pharmaceutical composition to be closer to neutral than the pH value of the chemical ablation agent with the concentration of the single medicine, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent with the concentration of the single medicine is more than or equal to 0.25.

Item 4, a method of treating a localized disease comprising administering to a localized diseased area of an individual in need thereof a therapeutically effective amount of a topical pharmaceutical composition comprising an acid-base chemical ablative agent and a pH adjusting agent as locally active ingredients, wherein the chemical ablative agent is a strong base, or a weak base, a weak acid, or a strong acid, and the concentration of the chemical ablative agent in the topical pharmaceutical composition is 0.5% or more, preferably 0.75% or more, or 2.5% or more; the pH regulating agent enables the pH value of the pharmaceutical composition to be closer to neutral than the pH value of the chemical ablation agent with the concentration of the single medicine, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent with the concentration of the single medicine is more than or equal to 0.25.

Item 5, the use or method according to item 2 or 4, wherein the topical pharmaceutical composition further comprises a topical synergist of the chemical ablative agent and a pH adjusting agent.

Item 6, the pharmaceutical composition, the use or the method according to one of items 1 to 5, wherein the chemical ablative agent is a strong base and the concentration of the strong base in the pharmaceutical composition is 0.5% or more, preferably 0.75% or more, 1% or more, 0.5 to 10%, preferably 0.75 to 10% or 1 to 10%; or

The chemical ablation agent is weak base, and in the pharmaceutical composition, the concentration of the weak base is more than or equal to 2.5%, preferably more than or equal to 3.0% or more than or equal to 5%, and is 2.5-35%, preferably 3.0-35% or 5-35%; or

The chemical ablation agent is strong acid, and the concentration of the strong acid in the pharmaceutical composition is more than or equal to 0.5 percent, preferably more than or equal to 0.75 percent or more than or equal to 1 percent, and is 0.5-10 percent, preferably 0.75-10 percent or 1-10 percent; or

The chemical ablation agent is weak acid, and the concentration of the weak acid in the pharmaceutical composition is more than or equal to 2.5%, preferably more than or equal to 3.0% or more than or equal to 5%, or 2.5-20%, preferably 3.0-20% or 5-20%.

Item 7, a pharmaceutical composition, use or method according to one of items 1 to 6, wherein the pH adjusting agent is one or more selected from the group consisting of other than the chemical ablative agent and which can cause the pH of the chemical ablative agent to tend to be neutralized: strong base, weak base, strong acid, strong base, inorganic salt, organic weak acid alkali metal salt, weak acid, strong acid, and in the pharmaceutical composition, the concentration of the pH regulator is not less than 1%, preferably 2-35%.

Item 8, the pharmaceutical composition, the use or the method according to one of items 1 to 7, wherein the weak base comprises a weak basic inorganic salt of a polybasic acid, an inorganic salt of a weak acid of a polybasic acid, a weak base containing nitrogen.

Item 9, a pharmaceutical composition, use or method according to one of items 6 to 8, wherein the chemical ablative agent is one or more strong bases and the pH adjusting agent is one or more selected from the group consisting of: polybasic weak acid basic inorganic salt, strong acid strong base inorganic salt, nitrogen-containing weak base, polybasic weak acid acidic inorganic salt, organic weak acid alkali metal salt, weak acid and strong acid, wherein the concentration of the strong base in the pharmaceutical composition is more than or equal to 0.5 percent, and preferably 0.75 to 10 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

Item 10, a pharmaceutical composition, use or method according to one of items 6 to 8, wherein the chemical ablative agent is one or more weak bases and the pH adjusting agent is one or more selected from the group consisting of: weak base, organic weak acid alkali metal salt, weak acid and strong acid except the chemical ablation agent, and in the pharmaceutical composition, the concentration of the chemical ablation agent is more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 35 percent, preferably 3.0 to 35 percent or 5 to 35 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

Item 11, the pharmaceutical composition, use or method according to one of items 6 to 8, wherein the chemical ablative agent is selected from a weak acid and the pH adjusting agent is selected from one or more of: strong base, basic inorganic salt of polybasic weak acid, weak base containing nitrogen, acidic inorganic salt of polybasic weak acid and alkali metal salt of organic weak acid, wherein in the pharmaceutical composition, the concentration of the weak acid is more than or equal to 2.5 percent, preferably more than or equal to 3.0 percent or more than or equal to 5 percent, or 2.5 to 20 percent, preferably 3.0 to 20 percent or 5 to 20 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

Item 13, the pharmaceutical composition, use or method according to one of items 6 to 8, wherein the chemical ablative agent is selected from a strong acid and the pH adjusting agent is selected from one or more of: polybasic weak acid basic inorganic salt, nitrogenous weak base, polybasic weak acid acidic inorganic salt, organic weak acid alkali metal salt and weak acid, wherein the concentration of the strong acid in the pharmaceutical composition is more than or equal to 0.5 percent, preferably more than or equal to 0.75 percent or more than or equal to 1 percent, or 0.5 to 10 percent, preferably 0.75 to 10 percent or 1 to 10 percent; the concentration of the pH regulator is more than or equal to 1 percent, and preferably 2 to 35 percent.

Item 14, the pharmaceutical composition, use or method according to one of items 6 to 13, wherein the strong base comprises an alkali metal hydroxide, wherein the alkali metal hydroxide comprises sodium hydroxide, potassium hydroxide, calcium hydroxide.

Item 15, the pharmaceutical composition, use, or method according to one of items 8-13, wherein the polybasic weak acid basic inorganic salt comprises sodium phosphate, sodium carbonate, potassium carbonate, borax.

Item 16, a pharmaceutical composition, use or method according to one of items 8 to 13, wherein the polybasic weak acid acidic inorganic salt comprises monobasic sodium phosphate, dibasic sodium phosphate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium hydrogen sulfate.

Item 17, a pharmaceutical composition, use or method according to one of items 8 to 13, wherein the weak base containing nitrogen is selected from the group consisting of ammonia, ammonia chloride, 2-aminoethanol, tromethamine, triethanolamine, tris, 2-aminoethanol, tromethamine, triethanolamine, meglumine.

Item 18, a pharmaceutical composition, use or method according to one of items 6 to 13, wherein the alkali metal salt of an organic weak acid comprises potassium hydrogen phthalate, sodium acetate, sodium propionate, sodium butyrate, sodium malonate, sodium lactate, sodium citrate, sodium malate, sodium lauryl sulfate.

Item 19, a pharmaceutical composition, use or method according to one of items 6 to 13, wherein the strong acid strong base inorganic salt comprises sodium chloride, potassium chloride, sodium iodide, potassium iodide.

Item 20, the pharmaceutical composition, the use or the method according to one of items 6 to 13, wherein the weak acid is selected from one or more of inorganic weak acids or/and organic weak acids, wherein the inorganic weak acids comprise phosphoric acid, carbonic acid, boric acid, sulfurous acid; the weak organic acids include C1-10 aliphatic carboxylic acids substituted with 1-3 hydroxyl groups, such as acetic acid, glycolic acid, propionic acid, malonic acid, butyric acid, succinic acid, lactic acid (2-hydroxypropionic acid), citric acid (2-hydroxy-1, 2, 3-propanetricarboxylic acid), malic acid (2-hydroxysuccinic acid), tartaric acid, oxalic acid, gluconic acid.

Item 21, the pharmaceutical composition, use or method according to one of items 6 to 13, wherein the strong acid comprises hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, selenic acid, hydrobromic acid, hydroiodic acid.

Item 22, a pharmaceutical composition, use or method according to one of items 3 or 5 to 21, wherein the topical co-agent is selected from one or more of a cytotoxic drug and/or a conventional ineffective drug and in the pharmaceutical composition the concentration of the cytotoxic drug is 50 to 100% of its saturation concentration; and/or the concentration of said conventional ineffective drug is 0.35-40%, preferably 1-40%.

Item 23, a pharmaceutical composition, use or method according to item 22, wherein the cytotoxic drug is selected from one or more of the following groups: drugs that disrupt the structure and function of DNA, drugs that interfere with transcribed RNA embedded in DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis, preferably one or more selected from the group consisting of: alkylating agents such as cyclophosphamide, carmustine; metal platinum complexes such as cisplatin, carboplatin; DNA topoisomerase inhibitors such as doxorubicin, topotecan, irinotecan; anti-tumor antibiotics such as actinomycins, daunorubicin; pyrimidine antagonists such as uracil derivatives 5-fluorouracil, furfluorouracil, bifurcofurouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine; taxanes such as paclitaxel, docetaxel.

Item 24, a pharmaceutical composition, use or method according to item 22, wherein the conventional ineffective drug is one or more selected from the group consisting of: amino acid nutrients, carbohydrate nutrients, lipid nutrients, pigment aromatic compounds, salicylic acid compounds and quinine compounds.

Item 25, the pharmaceutical composition, use or method according to item 24, wherein the amino acid based nutrient is selected from one or more of a basic amino acid based nutrient such as arginine, lysine, histidine, preferably arginine, and/or a non-basic amino acid based nutrient; such as one or more of the following groups: neutral amino acids, acidic amino acids, amino acid salts, wherein the neutral amino acids are, for example: glycine, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, alanine, valine, leucine, isoleucine, phenylalanine, proline, such as: aspartic acid, glutamic acid, said amino acid salts including salts of the amino acids with acids as described above, such as lysine hydrochloride, histidine hydrochloride, glutamic acid hydrochloride, cysteine hydrochloride, arginine hydrochloride, glycine sulfate iron, lysine hydrochloride, aspartic acid hydrochloride, and the concentration (w/v) of the amino acid nutrients in the pharmaceutical composition is ≥ 5%, preferably 10-30%.

Item 26, a pharmaceutical composition, use or method according to item 24, wherein the carbohydrate nutrient is selected from one or more of the following: glucose, fructose, chitosan oligosaccharide, glucosamine, lactulose, sorbitol, ribose, sorbose, mannose, galactose, sucrose, lactose, trehalose, xylo-oligosaccharide, fructo-oligosaccharide, manno-oligosaccharide, xylitol, more preferably selected from one or more of the following: glucose, sodium gluconate, chitosan oligosaccharide, glucosamine, lactulose, ribose, mannooligosaccharide and xylitol, wherein the concentration (w/v) of the carbohydrate nutrient in the pharmaceutical composition is more than or equal to 10 percent, and is preferably 10-40 percent.

Item 27, a pharmaceutical composition, use or method according to item 24, wherein the liponutrient is selected from one or more of the following: vegetable oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), long-chain fat milk, medium-chain fat milk, phospholipids, and the concentration (w/v) of the lipid nutrient in the pharmaceutical composition is not less than 4%, preferably 4-25%.

Item 28, the pharmaceutical composition, use or method according to item 24, wherein the pigment aromatic compound is one or more selected from the group consisting of: methylene blue, patent blue, isothio blue, bengal red, and in the pharmaceutical composition the concentration (w/v) of the pigmentary aromatic compound is not less than 0.35%, preferably 0.5-10%.

Item 29, a pharmaceutical composition, use or method according to item 24, wherein the salicylate compound is one or more selected from the group consisting of: salicylic acid, acetylsalicylic acid, aspirin-lysine, and in the topical pharmaceutical composition, the concentration (w/v) of the salicylic acid compound is not less than 5%, preferably 5-10%.

Item 30, the pharmaceutical composition, use or method according to item 24, wherein the quinine compound is selected from one or more of: quinine hydrochloride, quinine dihydrochloride and quinine sulfate, and in the topical pharmaceutical composition, the concentration (w/v) of the quinine compound is more than or equal to 3 percent, and is preferably 3-6 percent.

Item 31, a pharmaceutical composition, use or method according to one of items 1 to 30, wherein the local pathology comprises a tumor, a non-tumorous enlargement, a local inflammation, a secretory gland dysfunction and a skin disease.

Item 32, the pharmaceutical composition, the use or the method according to item 31, wherein the neoplasm comprises a malignant neoplasm and a non-malignant neoplasm.

Item 33, the pharmaceutical composition, use or method of item 32, wherein the malignant tumor comprises breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, prostate cancer, liver cancer, lung cancer, intestinal cancer, oral cancer, esophageal cancer, gastric cancer, laryngeal cancer, testicular cancer, vaginal cancer, uterine cancer, ovarian cancer.

Item 34, the pharmaceutical composition, use or method according to item 32, wherein the non-malignant tumor comprises a breast tumor, a pancreatic tumor, a thyroid tumor, a prostate tumor, a liver tumor, a lung tumor, an intestinal tumor, an oral tumor, an esophageal tumor, a stomach tumor, a nasopharyngeal tumor, a laryngeal tumor, a testicular tumor, a vaginal tumor, a uterine tumor, a fallopian tube tumor, an ovarian tumor.

Item 35, a pharmaceutical composition, use or method according to item 31, wherein the non-neoplastic mass comprises a hyperplasia (e.g. of the breast, pancreas, thyroid, parathyroid, prostate), a cyst (e.g. of the breast, thyroid, parathyroid), a nodule (e.g. of the breast, thyroid, parathyroid), an abnormal venous mass (e.g. a hemorrhoid), a localized inflammatory mass, a microbial infection.

Item 36, the pharmaceutical composition, the use or the method according to item 31, wherein the local inflammation is a non-neoplastic inflammation at a local site, including degenerative, exudative and proliferative inflammation.

Item 37, a pharmaceutical composition, use or method according to item 36, wherein the local inflammation comprises one or more of: arthritis, mastitis, pancreatitis, thyroiditis, prostatitis, hepatitis, pneumonia, enteritis, stomatitis, pharyngitis, periodontitis, esophagitis, gastritis, gastric ulcer, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, vaginitis, metritis, salpingitis, and oophoritis.

Item 38, the pharmaceutical composition, the use or the method according to item 31, wherein the secretory gland dysfunction includes a secretory gland hyperactivity (e.g., hyperthyroidism) and a secretory gland hypofunction (e.g., hypothyroidism, hypoinsulinemia).

Item 39, the pharmaceutical composition, use or method according to item 31, wherein the skin disorder is a lesion native or secondary to the skin or skin appendages, comprising one or more of: skin cancer, non-malignant tumors of the skin, viral skin diseases (e.g., herpes, warts, rubella, hand-foot-and-mouth disease), bacterial skin diseases (e.g., impetigo, furuncle, leprosy), fungal skin diseases (e.g., various ringworm), sexually transmitted diseases (e.g., syphilis, gonorrhea, and condyloma acuminatum), allergic and autoimmune skin diseases (e.g., contact dermatitis, eczema, urticaria), physical skin diseases (e.g., solar skin diseases, chilblain, corns, rhagades of hands and feet, pressure sores), connective tissue diseases (e.g., lupus erythematosus), skin disorders (e.g., freckles, pigmented nevi, various plaques), skin appendages diseases (e.g., acne, rosacea, seborrheic dermatitis, alopecia areata, alopecia, hyperhidrosis, and bromidrosis).

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

1. A topical pharmaceutical composition for the treatment of a topical pathological condition comprising an acid-base chemoablative agent and a pH adjusting agent, wherein the chemoablative agent is a strong base, a weak acid, or a strong acid and the concentration of the chemoablative agent in the pharmaceutical composition is 0.5% or more, preferably 0.75% or 2.5% or more, and the amount of the pH adjusting agent is such that the pH of the pharmaceutical composition is more neutral than the pH of the same concentration of the chemoablative agent per drug and the absolute value of the difference between the pH of the pharmaceutical composition and the pH of the same concentration of the chemoablative agent per drug is 0.25 or more.

2. Use of a combination of an acid-base type chemical ablative agent and a pH adjusting agent as a topical active ingredient in the preparation of a topical pharmaceutical composition for the treatment of a topical pathological condition, wherein the chemical ablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemical ablative agent in the pharmaceutical composition is 0.5% or more, preferably 0.75% or more or 2.5% or more; the pH regulator is used in such an amount that the pH value of the pharmaceutical composition is closer to neutral than the pH value of the chemical ablation agent and the single drug, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent and the single drug is more than or equal to 0.25.

3. A topical pharmaceutical composition for the treatment of a topical pathological condition comprising an acid-base chemical ablative agent, a pH adjusting agent, their topical synergists, and a suitable solvent, wherein the chemical ablative agent is a strong base, a weak acid, or a strong acid, and the concentration of the chemical ablative agent in the topical pharmaceutical composition is 0.5% or more, preferably 0.75% or more, or 2.5% or more; the pH regulating agent enables the pH value of the pharmaceutical composition to be closer to neutral than the pH value of the chemical ablation agent with the concentration of the single medicine, and the absolute value of the difference between the pH value of the pharmaceutical composition and the pH value of the chemical ablation agent with the concentration of the single medicine is more than or equal to 0.25.

4. Use according to claim 2, wherein the topical pharmaceutical composition further comprises a topical co-product of the chemical ablative agent and a pH adjusting agent.

5. The pharmaceutical composition or use according to any one of claims 1 to 4, wherein the chemoablative agent is a strong base and the concentration of the strong base in the pharmaceutical composition is 0.5% or more, preferably 0.75% or more 1%, 0.5 to 10%, preferably 0.75 to 10% or 1 to 10%; or

6. The pharmaceutical composition or use according to any one of claims 1-5, wherein said pH modifying agent is one or more selected from the group consisting of agents other than said chemical ablative agent that tend to neutralize the pH of said chemical ablative agent: strong base, weak base, strong acid, strong base, inorganic salt, organic weak acid alkali metal salt, weak acid, strong acid, and in the pharmaceutical composition, the concentration of the pH regulator is not less than 1%, preferably 2-35%.

7. A pharmaceutical composition or use according to claim 3 or 4, wherein the topical co-agent is selected from one or more of a cytotoxic drug and/or a conventional ineffective drug and in the pharmaceutical composition:

the concentration of the cytotoxic drug is 50-100% of the saturation concentration; and/or

The concentration of the conventional ineffective drug is 0.35 to 40%, preferably 1 to 40%.

8. A pharmaceutical composition or use according to claim 7 wherein the cytotoxic drug is selected from one or more of the following groups: drugs that disrupt the structure and function of DNA, drugs that interfere with transcribed RNA embedded in DNA, drugs that interfere with DNA synthesis, drugs that affect protein synthesis, preferably one or more selected from the group consisting of: alkylating agents such as cyclophosphamide, carmustine; metal platinum complexes such as cisplatin, carboplatin; DNA topoisomerase inhibitors such as doxorubicin, topotecan, irinotecan; anti-tumor antibiotics such as actinomycins, daunorubicin; pyrimidine antagonists such as uracil derivatives 5-fluorouracil, furfluorouracil, bifurcofurouracil, cytosine derivatives cytarabine, cyclocytidine, 5-azacytidine; taxanes such as paclitaxel, docetaxel.

9. The pharmaceutical composition or use according to claim 7, wherein the conventional ineffective drug is one or more selected from one or more of the following groups: amino acid nutrients, carbohydrate nutrients, lipid nutrients, pigment aromatic compounds, salicylic acid compounds and quinine compounds.

10. The pharmaceutical composition or use according to one of claims 1 to 9, wherein the local lesions comprise tumors, non-tumorous enlargement, local inflammation, secretory gland dysfunction and skin diseases.