CN111821257A

CN111821257A - Pharmaceutical preparation, system containing same, preparation method and application thereof

Info

Publication number: CN111821257A
Application number: CN201910299964.3A
Authority: CN
Inventors: 张洁; 唐培克
Original assignee: Huzhou Enowei New Pharmaceutical Preparation Co ltd
Current assignee: Huzhou Enowei New Pharmaceutical Preparation Co ltd
Priority date: 2019-04-15
Filing date: 2019-04-15
Publication date: 2020-10-27
Also published as: WO2020211787A1; CN113573697A

Abstract

The invention discloses a pharmaceutical preparation, a system containing the same, a preparation method and application thereof. The pharmaceutical formulation comprises water, a pH buffer pair and a local anesthetic; the local anesthetic in the pharmaceutical formulation includes dissolved and undissolved local anesthetics; the mass percentage of the local anesthetic in the pharmaceutical preparation is more than 2 percent; the pH buffer solution enables the mass percentage of the dissolved local anesthetic in the pharmaceutical preparation to be less than 1%; the local anesthetic is lidocaine, tetracaine, bupivacaine, articaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, mepivacaine, prilocaine, ropivacaine, tricaine, benzocaine or procaine; the sum of the mass percentages of the components in the pharmaceutical preparation is 100%. In many analgesic applications, the pharmaceutical formulation is capable of achieving a continuous analgesic effect of 6, 12, 18, 24, 36, or even 48 hours or more.

Description

Pharmaceutical preparation, system containing same, preparation method and application thereof

Technical Field

The invention relates to a pharmaceutical preparation, a system containing the same, a preparation method and application thereof.

Background

Local anesthetic formulations are used to prevent or treat pain in the skin or mucosa, for example: a 2% lidocaine hydrochloride gel for reducing pain associated with sunburn; enna (english name EMLA) is an emulsion of low-spot co-melted oil droplets of lidocaine and prilocaine for anesthesia of preoperative intact skin with pain; lidoderm is a solidified gel patch containing 5% lidocaine, which is used to reduce postherpetic neuralgia (the skin itself is intact); pliaglis is a low-spot co-melted oil-drop emulsion containing 7% lidocaine and 7% tetracaine for use in anesthesia of preoperative intact skin with pain. However, each of the above local anesthetic formulations has serious limitations. For example: lidocaine hydrochloride gel does not anesthetize intact skin; prilocaine in EMLA causes methemoglobinemia; tetracaine in Pliaglis causes allergic reactions associated with local anesthetics of the ester type, and tetracaine is hydrolyzed, so Pliaglis must be stored refrigerated to reduce the rate of hydrolysis; lidoderm cannot anesthetize intact skin within 120 minutes, even 4 hours, and Lidoderm cannot exceed 12 hours per use. However, the above-mentioned local anesthetic preparations have a common limitation in that a safe analgesic effect cannot be achieved continuously for a long period of time.

In the treatment of many diseases, it is desirable that the product has a continuous analgesic effect of 6, 12, 18, 24, 36, or even 48 hours or more. Therefore, the need for a safe pharmaceutical preparation with long-term continuous and safe analgesic effect is a problem to be solved.

Furthermore, in order to achieve a long-term analgesic effect of a water-containing pharmaceutical preparation on the affected area, it is important to keep the drug layer applied to the affected area in place and to keep the volatile component (water) therein, because the ability of the pharmaceutical preparation to deliver the active ingredient into the skin may be greatly reduced after a sufficient amount of the volatile component is lost. Therefore, the problem to be solved is to find a drug preparation with anti-flowing property and a system capable of ensuring that the moisture of the drug preparation is not volatilized.

Open body surfaces that are not covered by skin or mucous membranes, such as surgical incisions, burned and scalded surfaces, wound surfaces, etc., often have analgesic needs, and are characterized by absorption of foreign substances, such as local anesthetics, without the skin-like barriers. Therefore, if a local anesthetic preparation without sustained release function is placed on an open human body surface, for example, 2% lidocaine hydrochloride commonly used in hospitals is applied on the surface of burns and scalds, the local anesthetic contained in the preparation can be quickly absorbed into the general blood circulation, resulting in high blood concentration and short duration of analgesic effect, which may cause serious side effects, and therefore, the problem to be solved is to find a pharmaceutical preparation capable of realizing sustained release effect.

Post-operative incision analgesia is a common requirement. The currently widely used method is to deliver centrally acting drugs, such as fentanyl and dolantin, into the patient's body using an analgesic pump. The medicines enter brain tissues after passing through a blood brain barrier and are combined with related pain receptors, so that the purpose of analgesia is achieved. However, all of these centrally acting analgesics may cause serious side effects such as respiratory depression and addiction. Therefore, it would be a significant advance to use local anesthetics without central nervous system effects to control post-operative incision pain. However, as described above, the local anesthetic preparation for the surgical incision analgesia must release the contained local anesthetic in a sustained manner. Along this line, Exparel, a product recently introduced in the United states, has received popularity from both physicians and patients to replace or reduce the amount of central analgesic with the specially formulated local anesthetic bupivacaine. However, there are a number of disadvantages associated with Exparel (1) because the liposomes encapsulating bupivacaine in the formulation are unstable and thus Exparel must be stored and transported under refrigeration; (2) exparel requires complex injection procedures of up to 20 needles along the surgical incision, which is inconvenient and time consuming; (3) post-operative analgesia is typically required for at least 2-3 days, but the effective analgesic effect of Exparel is only 24 hours. Therefore, the search for a pharmaceutical preparation that can achieve long-term postoperative incision analgesia, can be conveniently used, and can be transported and stored at room temperature is also a problem to be solved.

Disclosure of Invention

The invention aims to overcome the defect that a local anesthetic preparation in the prior art cannot realize a long-time continuous safe analgesic effect, and provides a novel medicinal preparation, a system containing the same, a preparation method and application of the novel medicinal preparation.

The pharmaceutical preparation and the system containing the same are mainly applied to the surface of a human body (complete skin or open human body surface) needing analgesia, and can obtain continuous and safe analgesia effects for 6, 12, 18, 24, 36, 48 or even longer hours.

The pharmaceutical preparation also has the advantages of room temperature storage, convenient use and the like, and can replace the traditional central nervous anesthetic in the analgesic application, thereby avoiding the serious side effect caused by the central nervous anesthetic.

The invention solves the technical problems through the following technical scheme:

the invention provides a pharmaceutical formulation comprising water, a pH buffering pair, and a local anesthetic; the pH buffered pair is dissolved in water in the pharmaceutical formulation and forms a pH buffered solution; the local anesthetic in the pharmaceutical formulation comprises a dissolved local anesthetic and an undissolved local anesthetic; the mass percentage of the local anesthetic in the medicinal preparation is more than 2% and is not 100%; the pH buffer solution enables the mass percentage of the dissolved local anesthetic in the pharmaceutical preparation to be less than 1% and not 0; the local anesthetic in the pharmaceutical preparation is lidocaine, tetracaine, bupivacaine, articaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, mepivacaine, prilocaine, ropivacaine, tricaine, benzocaine or procaine; the sum of the mass percentages of the components in the pharmaceutical preparation is 100%.

In the above-mentioned pharmaceutical preparation, the pH buffering pair refers to what is commonly referred to as a "pH buffering pair" in the field of biochemistry, that is, two substances of a conjugate acid-base pair constituting a pH buffering solution.

In the pharmaceutical preparation, the pH buffer pair may be, for example, a pH buffer pair commonly used in the field of biochemistry, and the pH of the pH buffer solution formed may be a pH at which the mass percentage of the dissolved local anesthetic in the pharmaceutical preparation is controlled to 1% or less and not 0. The pH buffer pair may be, for example, a pH buffer pair effective against a change in pH of the pharmaceutical preparation in a pH range of 7 to 13, preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate, a pH buffer pair consisting of dipotassium hydrogen phosphate and potassium dihydrogen phosphate, a pH buffer pair consisting of sodium tetraborate and sodium hydroxide or a pH buffer pair consisting of tris and HCl, more preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate or a pH buffer pair consisting of sodium tetraborate and sodium hydroxide, further more preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate. The pH buffer pair forms a pH buffer solution which can resist the change of the pH value caused by the external substance entering the drug preparation. The foreign substance may be introduced into the body fluid or sweat, or may be introduced into the body fluid or sweat after contact with air or another agent used simultaneously.

When the pH buffer pair is a pH buffer pair consisting of disodium hydrogenphosphate and sodium dihydrogenphosphate, the molar concentration of the pH buffer pair in the pharmaceutical preparation is preferably 0.02 to 0.4mol/L, more preferably 0.05 to 0.3mol/L or 0.1 to 0.3mol/L, further more preferably 0.08 to 0.22 mol/L.

Wherein the molar concentration unit mol/L refers to the molar amount of the pH buffer pair per liter of the pharmaceutical preparation.

Wherein, the ratio of the molar concentration of the sodium dihydrogen phosphate to the molar concentration of the disodium hydrogen phosphate in the pharmaceutical preparation is preferably 14:1-19: 1. For example, a pH buffer pair consisting of 0.19mol/L disodium hydrogenphosphate and 0.01mol/L sodium dihydrogenphosphate may be used; wherein 0.19mol/L disodium hydrogen phosphate means that 0.19mol/L disodium hydrogen phosphate is contained in the pharmaceutical preparation, and 0.01mol/L sodium dihydrogen phosphate means that 0.01mol/L sodium dihydrogen phosphate is contained in the pharmaceutical preparation.

In the above pharmaceutical preparation, the pH of the pharmaceutical preparation may be, for example, 7 to 13, preferably 7 to 11 or 7.5 to 9.5.

In the pharmaceutical preparation, the local anesthetic in the pharmaceutical preparation may be 3% or more, 4% or more, 5% or more, 8% or more, or 10% or more, for example, 3% to 15%, 4% to 10%, or 5% to 8% by mass of the pharmaceutical preparation.

In the above pharmaceutical preparation, the dissolved local anesthetic is a local anesthetic dissolved in water in the pharmaceutical preparation.

In the above pharmaceutical preparation, the dissolved local anesthetic may be present in the pharmaceutical preparation in an amount of 0.7% or less, 0.5% to 0.7% or 0.5% or less, by mass.

In the pharmaceutical preparation, the undissolved local anesthetic is a local anesthetic that is not dissolved in water in the pharmaceutical preparation.

In the above pharmaceutical preparation, the local anesthetic in the pharmaceutical preparation is preferably lidocaine, tetracaine, or bupivacaine, more preferably lidocaine or tetracaine, and further more preferably lidocaine.

In the above pharmaceutical preparation, the pharmaceutical preparation preferably comprises a suspending agent, which may be a suspending agent conventionally used in the art, the suspending agent is preferably carbomer, the type of the suspending agent is preferably Pemulen TR-2 or Carbopol 971, and the manufacturer is Lubrizol corporation, USA. The weight percentage of the suspending agent in the pharmaceutical preparation is preferably 0.10-0.50%.

In the above pharmaceutical preparation, the pharmaceutical preparation preferably includes a thickening agent, which is added to increase the viscosity of the pharmaceutical preparation and to reduce the flow of the pharmaceutical preparation applied to the skin away from the target area of the skin or other tissue. The thickener is preferably one or more of xanthan gum, starch, carbomer and cellulose, more preferably one or more of xanthan gum, starch, hydroxyethyl cellulose and hydroxypropyl cellulose. The mass percentage of the thickener in the pharmaceutical preparation is preferably 0.2% to 8%, more preferably 1% to 6%, and even more preferably 2% to 5%.

In the above pharmaceutical preparation, the pharmaceutical preparation preferably comprises glycerin and/or propylene glycol, which can be added to reduce the risk of skin irritation. The mass percentage of the glycerol and/or the propylene glycol in the pharmaceutical preparation is preferably 2-25%.

In the above pharmaceutical preparation, the pharmaceutical preparation preferably has a non-flowability that means that the surface thereof does not flow to a horizontal plane in 12 hours of standing after the pharmaceutical preparation in one container is stirred. The pharmaceutical preparation having such non-fluidity can prevent or reduce the loss of the pharmaceutical preparation applied to the skin or the surgical incision from the application site.

In the above pharmaceutical preparation, when the local anesthetic is tetracaine, it is preferable that the tetracaine in the pharmaceutical preparation is 0.5% by mass or more of the pharmaceutical preparation, and the tetracaine dissolved in the pharmaceutical preparation is 0.1% by mass or less of the pharmaceutical preparation.

In the above pharmaceutical preparation, the local anesthetic is preferably lidocaine. Preferably, the mass percentage of lidocaine in the pharmaceutical preparation is more than 2% or more than 3% in the pharmaceutical preparation, and the mass percentage of lidocaine dissolved in the pharmaceutical preparation is less than 1% in the pharmaceutical preparation. Compared with the compound medicinal preparation (a product containing two or more local anesthetic components, such as enna) in the invention and on the market, the medicinal preparation using lidocaine as a single local anesthetic has better advantages: (1) safer, easier to approve, and long-term use (since lidocaine is the most commonly used local anesthetic, its safety is generally known, and can be used for more than three months in a continuous manner); (2) the ability to anaesthetize intact skin within 120 minutes, even within 90 minutes (the ability to anaesthetize intact skin within 90 minutes or within 120 minutes is also very important as timely relief of pain in patients, especially pain like postherpetic neuralgia, is important for the patient).

In the above pharmaceutical preparation, the pharmaceutical preparation may contain no lipid material, and in this case, the pharmaceutical preparation may be referred to as a non-lipid pharmaceutical preparation. Wherein the lipid material refers to the lipid material which is conventional in the art, and generally refers to one or more of animal fat, vegetable fat and other fat materials which are approved by the medical administration and are except for the animal fat and the vegetable fat.

The medicinal preparation can also be a hydrogel medicinal preparation, and is particularly suitable for medicinal preparations placed in incision tissues before surgical incision suturing, the hydrogel medicinal preparation further comprises a gelling agent on the basis of the medicinal preparation, and the gelling agent accounts for 0.2-5% of the mass of the hydrogel medicinal preparation. The hydrogel medicine preparation containing the gelling agent in percentage by mass exists in the form of hydrogel, can be placed into incision tissues before the surgical incision is sutured, and then is sutured into the surgical incision, so that the postoperative incision pain can be well controlled.

In the above hydrogel pharmaceutical preparation, the mass percentage of the gelling agent in the hydrogel pharmaceutical preparation is preferably 0.5% to 4%, more preferably 1.0% to 3.0%.

In the above hydrogel pharmaceutical preparation, the gelling agent may be one that can be safely absorbed by body tissues in the prior art, and may be, for example, one or more of xanthan gum, hyaluronic acid and a salt of a protonic acid. The gelling agent is preferably xanthan gum, hyaluronic acid or a salt of hyaluronic acid. The gelling agent is more preferably a mixture of xanthan gum and hyaluronic acid or a mixture of xanthan gum and sodium alginate.

Wherein, the hyaluronic acid is divided into two types, one type is cross-linked hyaluronic acid, and the other type is non-cross-linked hyaluronic acid. The hyaluronic acid may be a cross-linked hyaluronic acid, a non-cross-linked hyaluronic acid, or a mixture of a cross-linked hyaluronic acid and a non-cross-linked hyaluronic acid.

Wherein, the sodium salt is preferably sodium salt. The sodium humate is divided into two types, one type is crosslinking sodium humate, and the other type is non-crosslinking sodium humate. The sodium salt can be cross-linked sodium salt, non-cross-linked sodium salt or a mixture of cross-linked sodium salt and non-cross-linked sodium salt.

In the above hydrogel pharmaceutical preparation, the concentration of the dissolved local anesthetic in the hydrogel pharmaceutical preparation is preferably 10 mg/ml or less, more preferably 5 mg/ml or less.

In the hydrogel pharmaceutical preparation, the concentration of the local anesthetic in the hydrogel pharmaceutical preparation is preferably 20 mg/ml or more, more preferably 40 mg/ml or more, and further more preferably 60 mg/ml or more.

In the hydrogel pharmaceutical preparation, the undissolved local anesthetic in the hydrogel pharmaceutical preparation accounts for more than 80% of the local anesthetic in the hydrogel pharmaceutical preparation by mass.

In the above hydrogel pharmaceutical preparation, the pH of the hydrogel pharmaceutical preparation is preferably 7.4 to 9.0, more preferably 7.8 to 8.8, and further more preferably 7.9 to 8.4.

In a preferred embodiment of the hydrogel pharmaceutical preparation, the gel forming agent is sodium hyaluronate, the mass percentage of the gel forming agent in the hydrogel pharmaceutical preparation is 0.2% -4%, the pH buffer pair is a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate, the local anesthetic is lidocaine or bupivacaine, and the pH value of the hydrogel pharmaceutical preparation is 7.8-8.8; the concentration of the local anesthetic in the hydrogel pharmaceutical formulation is 20 mg/ml or more or 40 mg/ml or more; the concentration of the dissolved local anesthetic in the hydrogel drug formulation is 5 mg/ml or less.

In a preferred embodiment of a hydrogel drug formulation, said gel-forming agent is a hyaluronic acid or a salt of a hyaluronic acid, said gel-forming agent is present in said hydrogel drug formulation in an amount of 0.2% to 5% by mass, said pH buffer pair is formed such that said hydrogel drug formulation has a pH of 7.8 to 8.8, said dissolved local anesthetic is present in said hydrogel drug formulation at a concentration of 5 mg/ml or less, and said local anesthetic is present in said hydrogel drug formulation at a concentration of 20 mg/ml or more. The mass percentage of the gelling agent in the hydrogel pharmaceutical preparation is preferably 0.3-3%. The pH buffer pair is preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate. The local anesthetic is preferably lidocaine or bupivacaine. The sodium hyaluronate is preferably sodium hyaluronate, and preferably more than 95 wt% of the sodium hyaluronate is non-crosslinked sodium hyaluronate, and more preferably 98-100 wt% of the sodium hyaluronate is non-crosslinked sodium hyaluronate. The pH of the hydrogel pharmaceutical formulation is preferably 7.8 to 8.5. The concentration of the local anesthetic in the hydrogel pharmaceutical formulation is preferably 40 mg/ml or more.

In the above hydrogel pharmaceutical preparation, the hydrogel pharmaceutical preparation may contain no lipid substance, and in this case, the hydrogel pharmaceutical preparation may be referred to as a non-lipid pharmaceutical preparation. Wherein the lipid material refers to the lipid material which is conventional in the art, and generally refers to one or more of animal fat, vegetable fat and other fat materials which are approved by the medical administration and are except for the animal fat and the vegetable fat.

The inventors wish to state that, with regard to the following lidocaine-containing formulations: in making the xanthan gum free formulations of the present invention containing dissolved and undissolved lidocaine, the formulations are heated above the melting point of lidocaine (about 68 degrees celsius) and then stirred rapidly, causing the undissolved lidocaine particles to melt to a liquid state and break up into small "oil droplets" suspended in the formulation, which become small suspended crystal particles after cooling to room temperature. Although the formulations described herein contain suspending agents such as PemulentR-2, hydroxyethyl cellulose, hydroxypropyl cellulose or starch, which serve to suspend undissolved small particles of lidocaine, the inventors have found that the small particles of lidocaine in these suspensions crystallize into relatively large crystals (greater than 1 mm in length) as storage time increases. The presence of lidocaine in the form of large crystals may result in uneven distribution of lidocaine in the formulation, which may affect the anesthetic effect. The inventors have surprisingly found that if xanthan gum is added to the formulation, the lidocaine does not crystallize to visible size crystals.

Accordingly, the present invention also provides a pharmaceutical preparation which is a lidocaine-containing preparation containing lidocaine, xanthan gum, and water, and the lidocaine in the lidocaine-containing preparation includes dissolved lidocaine and undissolved lidocaine; the sum of the mass percentages of the components in the preparation containing lidocaine is 100%.

In the lidocaine-containing preparation, preferably, the total mass percentage of dissolved lidocaine and undissolved lidocaine in the lidocaine-containing preparation is 2% or more and is not 100% in the lidocaine-containing preparation; the mass percentage of the dissolved lidocaine in the lidocaine-containing preparation is 1% or less, and is not 0. More preferably, the mass percentage of the dissolved lidocaine in the preparation containing lidocaine is 0.1% -1%.

In the preparation containing lidocaine, the preparation containing lidocaine may further contain a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate. The weight percentage of the disodium hydrogen phosphate in the lidocaine-containing preparation may be 0.1%, and the weight percentage of the sodium dihydrogen phosphate in the lidocaine-containing preparation may be 4%, for example.

In the preparation containing lidocaine, the mass percentage of lidocaine in the preparation containing lidocaine is preferably more than 1.5%, and is not 100%, more preferably 2% to 8%, and may be 5%, for example.

In the lidocaine-containing preparation, the mass percentage of the dissolved lidocaine in the lidocaine-containing preparation is preferably 1% or less or 0.5% or less, and is not 0.

In the preparation containing lidocaine, the mass percentage of the xanthan gum in the preparation containing lidocaine is preferably more than 0.1% and is not 100%; more preferably 0.2% to 10%; even more preferably from 1% to 6%, for example 3%.

The lidocaine-containing preparation may further contain hydroxypropyl cellulose, and the mass percentage of the hydroxypropyl cellulose in the lidocaine-containing preparation is preferably 1% or more and is not 100%; more preferably 1% to 5%, for example 3%.

In the above lidocaine-containing preparation, preferably, the lidocaine-containing preparation includes (or consists of) lidocaine, xanthan gum, and water; the mass percentage of the lidocaine in the preparation containing the lidocaine is 2% -8%; the mass percentage of the dissolved lidocaine in the lidocaine-containing preparation is 1% or less, and is not 0, preferably 0.6% or less or 0.5% or less, and is not 0, and may be 0.1% to 1%, for example; the mass percentage of the xanthan gum in the preparation containing lidocaine is more than 0.1%, preferably 0.2% -10%, and more preferably 1% -6%; the balance of water.

The pharmaceutical preparation (referring to the various pharmaceutical preparations mentioned above, for example, hydrogel pharmaceutical preparation, non-lipid pharmaceutical preparation or lidocaine-containing preparation) of the present invention can be used for pain relief on open human body surface, and is also suitable for pain relief on intact skin (such as skin with postherpetic neuralgia) and near intact skin.

The present invention also provides a system for fixing the aforementioned pharmaceutical preparation on the skin, which comprises the aforementioned pharmaceutical preparation (referring to the aforementioned various pharmaceutical preparations, such as hydrogel pharmaceutical preparation, non-lipid pharmaceutical preparation or lidocaine-containing preparation) and a medical covering film for completely enclosing the pharmaceutical preparation in an enclosed space formed by the medical covering film and the surface of human body tissue.

In the above system, preferably, the medical covering film includes a barrier film layer, an adsorption layer and a mesh adhesive layer, one side of the adsorption layer is combined on the barrier film layer, and the other side of the adsorption layer is combined with the mesh adhesive layer; the area of the non-adhesive area of the reticular adhesive layer accounts for more than 10% of the total area of the reticular adhesive layer and is not 100%; the mesh adhesive layer is used for completely enclosing the pharmaceutical preparation in an enclosed space formed by the medical covering film and the surface of the human body tissue.

The barrier film layer is a barrier film conventionally used in the medical field, and the barrier film layer can be a material which is impermeable to water vapor or has a limited water vapor permeability, such as a polyethylene film, an ethylene-vinyl acetate copolymer film (EVA film for short) or a polyurethane film.

The adsorption layer may be a material capable of adsorbing or retaining a pharmaceutical preparation containing water in the prior art, and may be, for example, a nonwoven fabric having high absorbability.

The mesh-shaped adhesive layer only has an adhesive-free area and an adhesive area, and generally, the adhesive-free area and the adhesive area are uniformly distributed. For example, the reticular rubber layer is a rubber net consisting of curves and/or straight lines. Preferably, the reticular rubber layer is a rubber net consisting of a group of parallel warps and a group of parallel wefts. More preferably, the warp and the weft are arranged vertically. More preferably, the distance between two adjacent warps is equal to the distance between two adjacent wefts. Here, the warp threads and the weft threads on the mesh-like adhesive layer constitute adhesive regions, and the other regions of the mesh-like adhesive layer than the warp threads and the weft threads constitute adhesive-free regions.

Wherein, the thickness of the reticular rubber layer is preferably 0.25-0.75 mm.

The adhesive of the mesh adhesive layer can be a medical pressure-sensitive adhesive which is insoluble in water, and is preferably organic silica adhesive and/or acrylic adhesive.

One side of the adsorption layer can be adhered to the barrier film layer through glue, and the other side of the adsorption layer can also be compounded on the barrier film layer through hot pressing.

Wherein, the reticular rubber layer can be adhered to the other surface of the adsorption layer by a spraying mode in the prior art.

Preferably, the area of the adhesive-free region of the mesh-shaped adhesive layer accounts for more than 30% of the total area of the mesh-shaped adhesive layer. More preferably, the area of the non-glue area of the mesh-like glue layer accounts for more than 50% of the total area of the mesh-like glue layer. More preferably, the area of the adhesive-free region of the mesh adhesive layer accounts for more than 70% of the total area of the mesh adhesive layer, and may be, for example, 70% to 90%.

Among them, the length elongation of the medical cover film in all directions is preferably 10% or more, and for example, may be 10% to 30%. The medical cover film having the above stretching ratio is comfortable when used in the joint muscle and the like.

In the above system, preferably, the length of the outer edge of the medical covering film from the outer edge of the preparation layer formed by the pharmaceutical preparation is 5mm or more, for example, 2 to 4 cm.

The invention also provides a preparation method of the pharmaceutical preparation (referring to the various pharmaceutical preparations, such as hydrogel pharmaceutical preparation, non-lipid pharmaceutical preparation or lidocaine-containing preparation), wherein the preparation method comprises the following steps: the components in the medicinal preparation are uniformly mixed.

In the above preparation method, the preparation method preferably comprises the steps of: (1) mixing the other components except the local anesthetic in the medicinal preparation to obtain a mixed solution; (2) and mixing the mixed solution with the local anesthetic, heating, and cooling to room temperature.

In step (2), the heating temperature is preferably 75-85 ℃, for example, 80 ℃.

Wherein, in step (2), the heating is preferably performed under stirring.

The invention also provides application of the pharmaceutical preparation (various pharmaceutical preparations such as hydrogel pharmaceutical preparations, non-lipid pharmaceutical preparations or lidocaine-containing preparations) in preparation of medicines for treating pain in herpes zoster, pain of nerve damage after herpes zoster, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, joint pain, osteoarthritis pain, back pain, pain caused by gout, pain caused by soft tissue injury, postoperative incision pain, burn pain or pain caused by burn scab removal.

The invention also provides the use of the aforementioned system for the manufacture of a medical device for the treatment of pain during herpes zoster, post herpes zoster nerve damage pain, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, joint pain, osteoarthritis pain, back pain, pain caused by gout, pain caused by soft tissue injury, post-operative incision pain, burn pain or pain during burn decrustation.

The present invention also provides a method of treatment using the aforementioned pharmaceutical formulation (referring to the aforementioned various pharmaceutical formulations, such as hydrogel pharmaceutical formulations, non-lipid pharmaceutical formulations, or lidocaine-containing formulations) for the treatment of pain: pain during herpes zoster, pain of nerve damage after herpes zoster, pain of neuroma, pain of phantom limbs, neuralgia around diabetes, joint pain, pain of osteoarthritis, back pain, pain caused by gout, pain caused by soft tissue injury, pain after incision after operation, pain caused by burn or pain when decrustation is burned; the treatment method comprises the following steps: and completely enclosing a preparation layer formed by the drug preparation in an enclosed space formed by the medical covering film and the surface of human body tissues.

In the above treatment method, the treatment method may comprise the steps of: and coating the medicinal preparation on the medical covering film, and fixing a preparation layer formed by the medicinal preparation in a closed space formed by the medical covering film and the surface of the human body tissue.

In the above treatment method, the treatment method may comprise the steps of: applying the pharmaceutical preparation on the surface of the human body tissue to form a preparation layer, covering the preparation layer with the medical covering film, and fixing the preparation layer in the closed space formed by the medical covering film and the surface of the human body tissue.

In the above treatment method, the medical covering film may be a medical covering film conventionally used in the art, and is preferably a medical covering film as defined in the above system.

In the above treatment method, the length of the outer edge of the medical covering film from the outer edge of the preparation layer formed by the pharmaceutical preparation is 5mm or more, preferably 2 to 4 cm.

In the above treatment method, when the pharmaceutical preparation is applied to intact skin or near intact skin (such as skin of postherpetic neuralgia or skin of arthralgia), it is preferable that the pharmaceutical preparation is kept on the surface of the human body tissue for 6 hours or more, 8 hours or more, 12 hours or more, 18 hours or more, 24 hours or more, or 30 hours or more. The time for holding the pharmaceutical preparation on the surface of the human body tissue can be relatively short, preferably 5min to 50min, when the pharmaceutical preparation is applied to burn pain or burn pain during decrustation. When the pharmaceutical preparation is applied to a post-operative incision, it is preferable to maintain the pharmaceutical preparation on the surface of the human body tissue for a period of time ranging from 2 hours to 48 hours, more preferably from 6 hours to 24 hours.

In the above treatment method, preferably, the thickness of the pharmaceutical preparation on the surface of the human body tissue is maintained to be 0.5 mm or more, 1 mm or more, or 2 mm or more.

When the pain to be treated is herpes zoster phase pain, postherpetic neuralgia or diabetic peripheral neuralgia, the treatment method preferably comprises the steps of: applying the drug formulation to the central area of the mesh-like glue layer of the medical drape as defined in the aforementioned system such that the edge areas of the mesh-like glue layer are not being applied by the drug formulation, obtaining a medical drape with a formulation layer; covering the medical covering film with the preparation layer on the surface of the human body tissue, and enabling the preparation layer to be in contact with the surface of the human body tissue, wherein the edge area is adhered to the skin outside the surface of the human body tissue, so that the preparation layer is fixed on the skin outside the surface of the human body tissue and is completely enclosed in the enclosed space formed by the medical covering film and the surface of the human body tissue; wherein the length of the outer edge of the medical covering film away from the outer edge of the preparation layer is more than 5 mm; the thickness of the preparation layer is more than 0.5 mm; holding the formulation layer and the medical drape film on the human body tissue surface for a period of 6 hours or more. In the above treatment method, the preparation layer is completely enclosed in the enclosed space. When the barrier film used for the barrier film layer is a material impermeable to water vapor, the moisture in the formulation layer does not evaporate, so that the moisture in the formulation layer can be well maintained. When the barrier film used by the barrier film layer has a certain water vapor permeability, the water in the preparation layer can be evaporated, at the moment, the water vapor permeability of the barrier film can be reasonably selected according to the water content in the preparation layer and the required service time, and the barrier film selected according to the principle can ensure that the transdermal absorption speed of the effective components in the preparation layer is not influenced within the required service time.

When the pain to be treated is neuroma pain, phantom limb pain, joint pain, osteoarthritis pain, back pain, pain caused by gout or pain caused by soft tissue injury, the method of treatment preferably comprises the steps of: covering the human body tissue surface coated with a preparation layer formed from the pharmaceutical preparation with a mesh adhesive layer as defined in the aforementioned system with a central region of the mesh adhesive layer in contact with the preparation layer and with an edge region of the mesh adhesive layer adhering to the skin outside the human body tissue surface to fix the preparation layer on the skin outside the human body tissue surface and to completely enclose the preparation layer within the enclosed space formed by the medical cover film and the human body tissue surface; wherein the length of the outer edge of the medical covering film away from the outer edge of the preparation layer is more than 5 mm; the thickness of the preparation layer is more than 0.5 mm; holding the formulation layer and the medical drape film on the human body tissue surface for a period of 6 hours or more.

When the pain treated is post-operative incision pain, the treatment method preferably comprises the steps of: the medicine preparation is smeared on the operation incision which is sewed up, so that the operation incision is covered by a preparation layer formed by the medicine preparation with the thickness of more than 1 mm, and the time for keeping the medicine preparation on the operation incision is more than 3 hours. More preferably, the layer of the pharmaceutical preparation is completely enclosed within the enclosed space formed by the medical cover film and the surface of the human body tissue as defined in the aforementioned system.

When the pain treated is post-operative incision pain, the treatment method preferably comprises the steps of: placing a hydrogel drug formulation into the incised tissue prior to surgical incision closure; wherein the hydrogel pharmaceutical preparation contains 0.2-4 wt% sodium alginate, pH buffer pair, local anesthetic and water; the pH buffer is to water dissolved in the pharmaceutical formulation; the local anesthetic in the pharmaceutical formulation comprises a dissolved local anesthetic and an undissolved local anesthetic; the pH buffer pair is a buffer consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate; the local anesthetic is lidocaine or bupivacaine; the pH value of the hydrogel pharmaceutical preparation is 7.8-8.8; the concentration of the dissolved local anesthetic in the hydrogel drug formulation is 5 mg/ml or less, and the concentration of the local anesthetic in the hydrogel drug formulation is 20 mg/ml or more; the amount of the hydrogel drug formulation placed into the incised tissue ranges from 0.1 grams per centimeter of incision length to 1 gram per centimeter of incision length.

Wherein, more preferably, the concentration of the local anesthetic in the hydrogel pharmaceutical preparation is more than 40 mg/ml.

Wherein, more preferably, the treatment method further comprises the following steps: the aforementioned medicinal preparation is applied to a surgical incision that has been sutured, the surgical incision is covered with a preparation layer formed of the medicinal preparation having a thickness of 1 mm or more, and the medicinal preparation is held on the surgical incision for 3 hours or more. Even more preferably, the layer of the pharmaceutical preparation is completely enclosed within the enclosed space formed by the medical cover film as defined in the aforementioned system and the surface of the human body tissue.

When the pain treated is post-operative incision pain, the treatment method preferably comprises the steps of: placing the pharmaceutical preparation into the incised tissue prior to surgical incision suturing; the amount of the pharmaceutical formulation placed into the incised tissue is 0.1-2 grams per centimeter of incision length.

When the pain to be treated is burn pain or burn decrustation pain, the treatment method preferably comprises the steps of: applying said pharmaceutical formulation to a burn or burn surface requiring eschar removal and maintaining said pharmaceutical formulation on said burn surface for a period of time greater than 5 minutes. More preferably, the pharmaceutical formulation is completely enclosed in the formed formulation layer within the enclosed space formed by the medical cover film and the surface of the human body tissue as defined in the aforementioned system.

In the present invention, the central region refers to a region of the mesh-like adhesive layer that is not in contact with the outer edge of the mesh-like adhesive layer, and the edge region refers to another region of the mesh-like adhesive layer that is not in the central region.

In the present invention, intact skin means skin in which the main barrier (stratum corneum) to foreign substances is intact.

In the present invention, the human body tissue surface may be a complete or incomplete skin surface, a complete or incomplete mucosal surface or an open human body surface.

In the invention, the components in the pharmaceutical preparation are uniformly mixed.

In the present invention, "long-term" in the expression "long-term analgesic" and the like means a period longer than 6 hours, 12 hours, and even 24 hours or more.

The expression "capable of anaesthetizing intact skin within 120 minutes" in the present invention means that the skin of most people will be anaesthetised within said time after application of said pharmaceutical preparation at normal room temperature, it being understood from a medical point of view that the description of such is not necessarily that the skin of each person will be anaesthetised within said time.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The positive progress effects of the invention are as follows:

the pharmaceutical preparation and the system containing the same are mainly applied to the surface of a human body (complete skin or open human body surface) needing analgesia, and can achieve continuous analgesia effect for 6, 12, 18, 24, 36, 48 or even longer hours.

Drawings

Fig. 1 is a schematic structural view of each layer of the medical covering film used in the examples;

FIG. 2 is a schematic view showing the structure of a medical cover film used in the examples;

fig. 3 is a top view of a medical cover film coated with a formulation layer formed of the drug formulation;

fig. 4 is a sectional view of the medical cover film and the pharmaceutical preparation in a use state.

Description of reference numerals:

barrier film layer 10

Adsorption layer 20

Mesh adhesive layer 30

Glue free area 31

Glue areas 32

Formulation layer 40

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The pharmaceutical preparations used in the following effect examples were all those of the examples left for 14 days or longer.

When lidocaine and xanthan gum were contained in the pharmaceutical preparation in the following examples, no macroscopic lidocaine crystal was observed after leaving for fourteen days; when the pharmaceutical preparation contains lidocaine but not xanthan gum, the lidocaine crystal can be seen by observation after being placed for fourteen days.

Example 1

A pharmaceutical formulation comprising the ingredients shown in the following table:

composition (I)	Mass percent or molar concentration
		Lidocaine	5％
Disodium hydrogen phosphate	0.094mol/L
		Sodium dihydrogen phosphate	0.006mol/L
Xanthan gum	4％
		Sodium hydroxide	0.08％
Water (W)	Make up to 100%

The preparation method of the pharmaceutical preparation comprises the following steps:

sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate and xanthan gum are added to water and stirred until a homogeneous viscous liquid is obtained. Then adding lidocaine, heating to 80 ℃, rapidly stirring, and cooling to room temperature to obtain the final product.

In the pharmaceutical preparation, the pH buffer pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate; xanthan gum is a thickening agent and also a suspending agent.

Effect data: recording the obtained medicinal preparation as a medicinal preparation A, wherein the obtained medicinal preparation is a viscous solution containing dissolved lidocaine and undissolved lidocaine, and the undissolved lidocaine exists in the viscous solution in the form of suspension crystals; pharmaceutical formulation a had a pH of about 8; a total of 50 mg of lidocaine per gram of pharmaceutical formulation a, wherein: about 3 mg is dissolved lidocaine and about 47 mg is undissolved suspended lidocaine crystals.

Example 2

sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, Pemulen TR-2 and hydroxyethyl cellulose were added to water and stirred until a homogeneous viscous liquid was obtained. Then adding lidocaine and glycerol, heating to 80 deg.C, rapidly stirring, and cooling to room temperature.

In the pharmaceutical preparation, the pH buffer pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate; the sodium hydroxide is used for adjusting the pH value and participates in a pH buffering pair; pemulen TR2 is a suspending agent; hydroxyethyl cellulose is a thickener and suspending agent.

Effect data: recording the obtained medicinal preparation as a medicinal preparation B, wherein the obtained medicinal preparation is a viscous solution containing dissolved lidocaine and undissolved lidocaine, and the undissolved lidocaine exists in the viscous solution in the form of suspension crystals; the pH of the resulting pharmaceutical formulation is about 8; each gram of drug formulation B had less than 5 mg of lidocaine dissolved, the remainder being present as undissolved suspended crystals.

Example 3

Effect data: recording the obtained medicinal preparation as a medicinal preparation C, wherein the obtained medicinal preparation is a viscous solution containing dissolved lidocaine and undissolved lidocaine, and the undissolved lidocaine exists in the viscous solution in the form of suspension crystals; the pH of the resulting pharmaceutical formulation is about 8; each gram of pharmaceutical formulation C had less than 5 mg of lidocaine dissolved, the remainder being present as undissolved suspended crystals.

Example 4

A pharmaceutical preparation comprises the following components

Composition (I)	Mass percent or molar concentration
		Lidocaine
	10％
		Sodium tetraborate	0.03mol/L
Sodium hydroxide	0.06％
		Hydroxyethyl cellulose	3％
Glycerol	5％
		Water (W)	Make up to 100%

sodium hydroxide, sodium tetraborate and hydroxyethyl cellulose are added to water and stirred until a homogeneous viscous liquid is obtained. Then adding lidocaine and glycerol, heating to 80 deg.C, rapidly stirring, and cooling to room temperature.

In the pharmaceutical formulation, the pH buffer pair consists of sodium tetraborate and sodium hydroxide; hydroxyethyl cellulose is a suspending agent and a thickening agent.

Effect data: recording the resulting pharmaceutical preparation as pharmaceutical preparation D, which is a viscous solution containing dissolved lidocaine and undissolved lidocaine, wherein the undissolved lidocaine is present in the viscous solution in the form of suspended crystals; the pH of the resulting pharmaceutical formulation is above 8; total 100 mg of lidocaine per gram of pharmaceutical formulation D, wherein: the dissolved lidocaine was below 5 mg and the undissolved suspended lidocaine crystals were above 95 mg.

Example 5

composition (I)	Mass percent or molar concentration
		Bupivacaine	8％
Disodium hydrogen phosphate	0.094mol/L
		Sodium dihydrogen phosphate	0.006mol/L
Sodium hydroxide	0.08％
		Hydroxyethyl cellulose	3％
Glycerol	15％
		Water (W)	Make up to 100%

sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, glycerol and hydroxyethyl cellulose are added to water and stirred until a homogeneous viscous liquid is obtained. Then adding bupivacaine and glycerol, heating to 80 ℃, rapidly stirring, and cooling to room temperature to obtain the compound bupivacaine.

In the pharmaceutical preparation, the pH buffer pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate; hydroxyethyl cellulose is a suspending agent and a thickening agent.

Effect data: recording the obtained medicinal preparation as a medicinal preparation E, wherein the obtained medicinal preparation is a viscous solution containing dissolved bupivacaine and undissolved bupivacaine, and the undissolved bupivacaine exists in the viscous solution in the form of suspension crystals; the pH of the resulting pharmaceutical formulation is about 8; most bupivacaine exists as undissolved suspended crystals.

Example 6

composition (I)	Mass percent or molar concentration
		Lidocaine	8％
Disodium hydrogen phosphate	0.28mol/L
		Sodium dihydrogen phosphate	0.02mol/L
Xanthan gum	2.0％
		Water (W)	Make up to 100%

disodium hydrogen phosphate, sodium dihydrogen phosphate, xanthan gum and water are stirred until a uniform viscous liquid is obtained. Then adding lidocaine, heating to 80 ℃, rapidly stirring, and cooling to room temperature to obtain the final product.

In the pharmaceutical preparation, the pH buffer pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate; xanthan gum is a thickener and suspending agent.

Effect data: recording the resulting pharmaceutical formulation as pharmaceutical formulation F, the resulting pharmaceutical formulation being a viscous solution containing dissolved lidocaine and undissolved lidocaine, wherein the undissolved lidocaine is present in the viscous solution in the form of suspended crystals; the pH of the resulting pharmaceutical formulation is about 8; each gram of drug formulation F had less than 5 mg of lidocaine dissolved, with the remainder being present as undissolved suspended crystals.

Example 7

composition (I)	Mass percent or molar concentration
		Lidocaine	8％
Disodium hydrogen phosphate	0.28mol/L
		Sodium dihydrogen phosphate	0.02mol/L
Sodium salt of sodium acid	2.0％
		Water (W)	Make up to 100%

disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium alginate and water are stirred until a uniform viscous liquid is obtained. Then adding lidocaine, heating to 80 ℃, rapidly stirring, and cooling to room temperature to obtain the final product.

In the pharmaceutical preparation, the pH buffer pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate; sodium alginate is a thickener and suspending agent.

Effect data: the resulting pharmaceutical preparation was designated as pharmaceutical preparation G, which was a hydrogel-form pharmaceutical preparation containing dissolved lidocaine and undissolved lidocaine. Wherein undissolved lidocaine is present in the hydrogel in the form of suspended crystals; the pH of the resulting pharmaceutical formulation is about 8; each gram of pharmaceutical formulation G had less than 5 mg of lidocaine dissolved, the remainder being present as undissolved suspended crystals.

Example 8

disodium hydrogen phosphate, sodium dihydrogen phosphate, xanthan gum, sodium hyaluronate and water are stirred until a uniform viscous liquid is obtained. Then adding lidocaine, heating to 80 ℃, rapidly stirring, and cooling to room temperature to obtain the final product.

In the pharmaceutical preparation, the pH buffer pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate; sodium alginate and xanthan gum are thickening and suspending agents.

Effect data: the resulting pharmaceutical preparation was designated as pharmaceutical preparation H, which was a hydrogel-form pharmaceutical preparation containing dissolved lidocaine and undissolved lidocaine. Wherein undissolved lidocaine is present in the hydrogel in the form of suspended crystals; the pH of the resulting pharmaceutical formulation is about 8; each gram of pharmaceutical formulation H had less than 5 mg of lidocaine dissolved, with the remainder being present as undissolved suspended crystals.

Example 9

composition (I)	Mass percent or molar concentration
		Lidocaine
	20％
		Disodium hydrogen phosphate	0.28mol/L
Sodium dihydrogen phosphate	0.02mol/L
		Sodium salt of sodium acid	2.0％
Xanthan gum	0.2％
		Water (W)	Make up to 100%

Effect data: the resulting pharmaceutical preparation was designated as pharmaceutical preparation J, which was a hydrogel-form pharmaceutical preparation containing dissolved lidocaine and undissolved lidocaine. Wherein undissolved lidocaine is present in the hydrogel in the form of suspended crystals; the pH of the resulting pharmaceutical formulation is about 8; less than 5 mg of lidocaine dissolved per gram of pharmaceutical formulation J, the remainder being present as undissolved suspended crystals.

Example 10

A pharmaceutical preparation for controlling pain at an incision in a surgical operation. The components are as follows:

composition (I)	Mass percent or molar concentration
		Sodium salt of sodium acid	2.5％
Sodium dihydrogen phosphate	0.01mol/L
		Disodium hydrogen phosphate	0.19mol/L
Lidocaine	5％
		Water (W)	Make up to 100%

putting sodium dihydrogen phosphate and disodium hydrogen phosphate into water, dissolving completely, adding sodium phosphate, and stirring until completely dissolving; adding lidocaine, heating to 70 deg.C, stirring for 10 min, and cooling to room temperature.

In the pharmaceutical preparation, the pH buffer pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate, and the sodium hyaluronate is a gelling agent which is safely absorbed by body tissues.

Effect data: the resulting pharmaceutical preparation was designated as pharmaceutical preparation K, which was a hydrogel-form pharmaceutical preparation containing dissolved lidocaine and undissolved lidocaine. Wherein undissolved lidocaine is present in the hydrogel in the form of suspended crystals; the pH of the resulting pharmaceutical formulation is about 8; less than 5 mg of lidocaine dissolved per gram of pharmaceutical formulation K, the remainder being present in the form of undissolved suspended crystals.

Example 11

composition (I)	Mass percent or molar concentration
		Carboxylated chitosan	4％
Sodium dihydrogen phosphate	0.01mol/L
		Disodium hydrogen phosphate	0.19mol/L
Bupivacaine	4％
		Water (W)	Make up to 100%

adding sodium dihydrogen phosphate and disodium hydrogen phosphate into water, dissolving completely, adding carboxylated chitosan, and stirring until completely dissolving; bupivacaine was added, heated to 70 ℃ and stirred for 10 minutes, cooled to room temperature. And (5) obtaining the product.

In the pharmaceutical preparation, the pH buffering pair consists of disodium hydrogen phosphate and sodium dihydrogen phosphate, and the carboxylated chitosan is a gelling agent which is safely absorbed by body tissues.

Effect data: the resulting pharmaceutical preparation was designated as pharmaceutical preparation L, which was a hydrogel-form pharmaceutical preparation containing dissolved bupivacaine and undissolved bupivacaine. Wherein undissolved bupivacaine is present in the hydrogel in the form of suspended crystals; the pH of the resulting pharmaceutical formulation is about 8; each gram of drug formulation L had less than 5 mg of bupivacaine dissolved therein, and the remainder of the bupivacaine was present as undissolved suspended crystals.

Examples 12 to 23

Examples 12-23 were prepared by replacing the local anesthetic of example 1 with tetracaine, articaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, mepivacaine, prilocaine, ropivacaine, trimecaine, benzocaine, or procaine, respectively.

Examples 24 to 29

As shown in fig. 1 and 2, the medical covering film comprises a barrier film layer 10, an adsorption layer 20 and a mesh adhesive layer 30, wherein the adsorption layer 20 is compounded on the barrier film layer 10, and the mesh adhesive layer 30 is compounded on the adsorption layer 20.

Wherein, the reticular rubber layer 30 is composed of a group of parallel warps and a group of parallel wefts, the warps and the wefts are vertically arranged, and the distance between two adjacent warps is equal to the distance between two adjacent wefts. The warp and weft threads of the mesh-like rubber layer 30 constitute the rubber-covered regions 32, and the other regions of the mesh-like rubber layer 30 except the warp and weft threads constitute the rubber-free regions 31.

Wherein, the absorption layer 20 is adhered on the barrier film layer 10 by glue, and the reticular rubber layer 30 is adhered on the absorption layer 20 by spraying.

Wherein, the material of the barrier film layer 10 and the material of the absorption layer 20, the kind of glue of the mesh-shaped glue layer 30, the thickness of the mesh-shaped glue layer 30, the ratio of the area of the glue-free region 31 of the mesh-shaped glue layer 30 to the total area of the mesh-shaped glue layer 30, and the length stretch ratio of the medical covering film in all directions are shown in table 1.

TABLE 1 Material and structural parameters of medical coverlay films of examples 24-29

In table 1, the side length a refers to the side length of each square constituting the glue-free area 31; the ratio b is the ratio of the area of the adhesive-free region 31 to the total area of the mesh-like adhesive layer 30.

Example 30

7 formulations containing dissolved and undissolved lidocaine were prepared with the ingredients listed in the table below.

In the 7 preparations, the combination of xanthan gum, hydroxypropyl cellulose, hydroxyethyl cellulose, starch, Pemulen TR-2 and sodium hydroxide is a suspending agent and has the function of a thickening agent; the combination of sodium dihydrogen phosphate and disodium hydrogen phosphate is a pH buffering pair. In the 7 formulations, the mass percent of dissolved lidocaine was about 0.5% or less, with the remainder being present as undissolved particles.

In making each of the above formulations, all the ingredients of the formulation were put together and stirred until the suspending agent was completely dissolved, and then the formulation was heated to 80 ℃ and rapidly stirred, cooled and stored at room temperature. After 14 days, it was observed that there were macroscopic lidocaine crystals in each of the xanthan gum-free formulations 3, 4, 5, and 6, and none of the xanthan gum-containing formulations 1, 2, and 7.

This unexpected finding shows that xanthan gum has the effect of inhibiting the growth of lidocaine crystals, which in turn makes lidocaine more uniformly distributed in the formulation containing xanthan gum and also makes better contact with the skin during use.

Effect example 1

As shown in fig. 3, a layer of 2 mm thick drug formulation a was applied to a 10 cm x 10 cm piece of the mesh adhesive layer 30 of the medical drape of example 28, covering a 6 cm x 6 cm area of the central area of the mesh adhesive layer 30. The medical drape with the drug formulation A was applied to the back skin of a human subject, with the drug formulation A in direct contact with the skin along a 2 cm wide peripheral region around the mesh adhesive layer 30, the peripheral region of the mesh adhesive layer 30 forming a flat, square enclosure with the skin, and the middle 6X 6 cm layer of the drug formulation A (i.e., the formulation layer 40 shown in FIG. 4) enclosed within this enclosure, resulting in the condition shown in FIG. 4. Part of the pharmaceutical preparation a in the enclosed space is adsorbed by the non-woven fabric layer in the middle through the non-glue area 31 of the mesh glue layer 30, thereby being fixed in place.

The skin covered with drug preparation a was anesthetized after about 90 minutes, and drug preparation a was removed from the skin 24 hours after the start of administration; the skin covered with drug formulation a was still under anaesthesia both when drug formulation a was removed and one hour after removal.

The system comprising the medical cover film and the pharmaceutical preparation A can fix the pharmaceutical preparation A on the skin well during the use period, can keep the moisture in the pharmaceutical preparation A well, and can maintain the pH value of the pharmaceutical preparation A at about 8 all the time during the use period.

Effect example 2

One patient had postherpetic neuralgia on the back skin for over 8 years. The affected skin is approximately a 15 cm x 30 cm rectangle. A20 cm by 35 cm piece of medical drape was cut from a roll of 20 cm wide and 200 cm long medical drape (as in example 28). The pharmaceutical formulation B was applied to the middle 16 cm x 31 cm area of the network gel layer to form a 1 mm thick layer. The affected skin was covered with the medical cover film with the pharmaceutical preparation B so that the affected skin was completely covered with the pharmaceutical preparation B layer. The 2 cm wide peripheral region of the adhesive mesh layer directly contacts the skin and forms a flat, square enclosure with the skin, and the central 16 cm x 31 cm layer of the drug formulation B (i.e., formulation layer 40 shown in fig. 4) is enclosed within this enclosure, resulting in the condition shown in fig. 4. Part of the medicinal preparation B in the closed space is adsorbed by the non-woven fabric layer through the adhesive-free area of the reticular adhesive layer, so that the medicinal preparation B is fixed in place.

After about 90 minutes, the patient began to experience a significant reduction in pain. The patient maintained the pharmaceutical preparation B and the medical drape on the skin for 18 hours, and her daily activities and sleep did not leave the pharmaceutical preparation B from the original application site because most of the pharmaceutical preparation B was adsorbed by the nonwoven fabric layer. Over the next several months, she repeatedly used the pharmaceutical preparations B-L in the same manner and all achieved similar satisfactory results.

The system comprising the medical cover film and the pharmaceutical preparation B can fix the pharmaceutical preparation B on the skin of the affected part well during the use period, can keep the water content in the pharmaceutical preparation B well, and can maintain the pH value of the pharmaceutical preparation B at about 8 all the time during the use period.

Effect example 3

In order to relieve the pain of the operation incision of a patient in caesarean section, the medical staff covered the operation incision after suturing with a 3 mm thick 1.5 cm wide strip of the pharmaceutical preparation C (the length of the layer of the pharmaceutical preparation C was slightly longer than the length of the operation incision) and covered the pharmaceutical preparation C with the medical covering film of example 29, and the pharmaceutical preparation C was enclosed in the enclosed space formed by the medical covering film and the skin, to form the state shown in fig. 4. The lidocaine molecules in drug formulation C immediately began to infiltrate the incision and surrounding tissue. Since the concentration of dissolved lidocaine in the pharmaceutical preparation C is 0.5% or less, lidocaine in the pharmaceutical preparation C permeates into the incision tissue in a sustained release form.

The pH buffering pair in pharmaceutical formulation C helps to maintain the pH of pharmaceutical formulation C at around 8, thereby enhancing the sustained release function of pharmaceutical formulation C (see the related discussion in the summary of the invention section). The pain of the surgical incision of the patient is obviously relieved within 15 minutes, and the satisfactory analgesic effect lasts for more than 12 hours. When the patient feels pain again, the medical staff removes the pharmaceutical preparation C and the medical covering film and then uses a new pharmaceutical preparation C and medical covering film by the same operation method. Later, every time the patient needs analgesia, the medical staff uses the pharmaceutical preparation C and the medical covering film by the same operation method, and the same technical effects can be achieved.

The system comprising the medical cover film and the pharmaceutical preparation C can fix the pharmaceutical preparation C to the skin of the affected part well during the use period, can keep the water content in the pharmaceutical preparation C well, and can maintain the pH value of the pharmaceutical preparation C at about 8 during the use period.

Effect example 4

The entire right leg and a portion of the pelvis of a patient are resected due to bone cancer. After the resection, she felt severe pain in the skin of the incision side (the incision side was covered by the patient's own skin left during the surgery). The pain is believed by physicians to be caused by nerve damage resulting from surgery. In addition, she also felt that the right calf, which had not been present, had severe phantom limb pain (phantom limb pain is a pain often felt by amputees on a limb that had not been present). To alleviate both of these pains, the medical staff applied the pharmaceutical preparation D of about 1 mm thickness to the skin of the affected part and covered the pharmaceutical preparation D with the medical covering film of example 29, and enclosed the pharmaceutical preparation D in the enclosed space formed by the medical covering film and the skin, to form the state shown in FIG. 4.

After one hour, her skin pain and phantom limb pain had substantially disappeared. She kept pharmaceutical formulation D on the skin for 24 hours. The effective analgesic effect was maintained for about 24 hours after the pharmaceutical preparation D was removed. This patient repeats the above-described administration every two days for many subsequent weeks. The analgesic effect was so satisfactory that she did not need oral analgesics most of the time.

The system comprising the medical cover film and the pharmaceutical preparation D can fix the pharmaceutical preparation D to the skin of the affected part well during the use period, can keep the moisture in the pharmaceutical preparation D well, and can maintain the pH value of the pharmaceutical preparation D at about 8 all the time during the use period.

Effect example 5

One patient had severe postherpetic neuralgia for about 8 years with skin 30 cm x 30 cm on the back and 15 cm x 15 cm on the chest. None of the available treatments was effective. The drug preparation C having a thickness of about 2 mm and the medical cover film of example 29 were covered on the skin of the affected part, and the drug preparation C was enclosed in the enclosed space formed by the medical cover film and the skin, to thereby obtain the state shown in FIG. 4.

After one hour, the patient began to experience a significant reduction in pain. The pharmaceutical preparation C and the medical drape were removed after being kept on the skin for 36 hours. The analgesic effect was very satisfactory within these 36 hours, except for the first hour.

Effect example 6

In order to relieve the pain of the operation incision of a patient with cholecystectomy, the medical staff covered the surgical incision after suturing with a layer of 3 mm thick pharmaceutical preparation E and covered the pharmaceutical preparation E by the method as in effect example 3, and enclosed the pharmaceutical preparation E in the enclosed space formed by the medical covering film and the skin, to form the state shown in fig. 4. The bupivacaine molecules in pharmaceutical formulation E immediately began to infiltrate the incision and surrounding tissue.

Since the concentration of bupivacaine dissolved in the pharmaceutical preparation E is 0.5% or less, the bupivacaine in the pharmaceutical preparation E permeates into the incision tissue in a sustained release form. While the pH buffering pair in pharmaceutical formulation E helps to maintain the pH of pharmaceutical formulation E at around 8, thereby enhancing the sustained release function of pharmaceutical formulation E (see the related discussion in the summary of the invention section). The patient's surgical incision pain began to be significantly reduced within 15 minutes. Satisfactory analgesic effect lasts more than 12 hours. Thereafter, each time the patient has a need for analgesia, the medical staff uses the combination of the pharmaceutical preparation E and the medical drape in the same manner.

The system comprising the medical cover film and the pharmaceutical preparation E can fix the pharmaceutical preparation E on the skin of the affected part well during the use period, can keep the moisture in the pharmaceutical preparation E well, and can maintain the pH value of the pharmaceutical preparation E at about 8 all the time during the use period.

Effect example 7

Both shoulders of a patient suffer from pain caused by scapulohumeral periarthritis. A layer of the pharmaceutical preparation F having a thickness of 1 to 2 mm was applied to the skin of the shoulders of the patient and covered with the medical drape as described in example 28, and the pharmaceutical preparation F was enclosed in the enclosed space formed by the medical drape and the skin, to form the state shown in FIG. 4.

After three hours, the pain in the shoulders of the patient substantially disappeared. This satisfactory analgesic effect lasts 8 hours in one shoulder joint and more than 18 hours in the other.

The system comprising the medical cover film and the pharmaceutical preparation F can fix the pharmaceutical preparation F on the skin of the affected part well during the use period, can keep the moisture in the pharmaceutical preparation F well, and can maintain the pH value of the pharmaceutical preparation F at about 8 all the time during the use period.

Effect example 8

The medicinal preparation G is coated on a layer of the medicinal preparation G which is already covered on a burn wound, and the medicinal preparation G is sealed in a sealed space formed by the medical covering film and the skin to form a state shown in figure 4.

The pharmaceutical preparation G immediately starts to deliver lidocaine to the wound tissue, and the pain of the wound is greatly reduced. Because of the slow-release function of the pharmaceutical preparation G, lidocaine penetrates the wound surface in a slow-release manner, so that the analgesic effect lasts for many hours and the concentration of lidocaine in the blood circulation is much lower than would be the case with cardiac side effects. Thereafter, when analgesia is required, the above procedure is repeated.

The same method is used for controlling the pain caused in the decrustation process of the burn wound and achieves the same technical effect.

The system comprising the medical cover film and the pharmaceutical preparation G can fix the pharmaceutical preparation G on the skin of the affected part well during the use period, can keep the water content in the pharmaceutical preparation G well, and can maintain the pH value of the pharmaceutical preparation G at about 8 all the time during the use period.

Effect example 9

One patient had pain in the knee joint caused by osteoarthritis. A layer of the pharmaceutical preparation H having a thickness of about 1 mm was applied to the skin of the entire knee joint, and the pharmaceutical preparation H was covered with the medical covering film of example 29 to enclose the pharmaceutical preparation H in the enclosed space formed by the medical covering film and the skin, to form the state shown in fig. 4.

The patient removed this pharmaceutical preparation H after keeping it on the knee joint for 18 hours and repeated the same procedure every day. The pain of this patient is thus greatly reduced.

The system comprising the medical cover film and the pharmaceutical preparation H can fix the pharmaceutical preparation H on the skin of the affected part well during the use period, can keep the water content in the pharmaceutical preparation H well, and can maintain the pH value of the pharmaceutical preparation H at about 8 all the time during the use period.

Effect example 10

A patient with pain caused by gout at the ankle joint was administered the pharmaceutical preparation C in the same manner as in effect example 9, and the pharmaceutical preparation C was enclosed in the enclosed space formed by the medical drape and the skin, to form the state shown in fig. 4.

The pain of this patient is thus greatly reduced. The system comprising the medical cover film and the pharmaceutical preparation C can fix the pharmaceutical preparation C to the skin of the affected part well during the use period, can keep the water content in the pharmaceutical preparation C well, and can maintain the pH value of the pharmaceutical preparation C at about 8 during the use period.

Effect example 11

One patient suffered from back pain. The pharmaceutical preparation C was administered in the same manner as in effect example 9, and was enclosed in the enclosed space formed by the medical cover film and the skin, resulting in the state shown in fig. 4.

Effect example 12

In order to relieve the pain of the operation incision of a patient in caesarean section, the medical staff covered and fixed the pharmaceutical preparation B on the operation incision after suturing with the medical covering film of example 29, and enclosed the pharmaceutical preparation B in the enclosed space formed by the medical covering film and the skin, to form the state shown in fig. 4.

The lidocaine molecules in drug formulation B immediately began to infiltrate the incision and surrounding tissue and entered the tissue in a sustained release manner for 12 hours. The pain of the surgical incision of the patient is obviously relieved within 15 minutes, and the satisfactory analgesic effect lasts for more than 12 hours. Thereafter, the medical staff used the pharmaceutical preparation B and the medical drape in the same manner whenever the patient had a pain relieving need.

The system consisting of the medical covering film and the medicinal preparation B can well fix the medicinal preparation B on the skin of an affected part during the period of use, well keep the water in the medicinal preparation B, and keep the pH value of the medicinal preparation B at about 8 during the period of use.

Effect example 13

The pharmaceutical preparations of examples 1 to 23 and the medical coverlay of examples 24 to 29 were used for treating pain during herpes zoster, postherpetic neuralgia, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, arthralgia including osteoarthritis pain, soft tissue injury, gout, surgical incision pain, burn and scald pain, or pain during burn and scab removal by using the methods of effect example 1 and effect example 3, and all of the pharmaceutical preparations exhibited continuous analgesic effects for 12 to 30 hours.

The system comprising the medical cover film and the pharmaceutical preparation can fix the pharmaceutical preparation on the skin of an affected part well during the use period, can keep the moisture in the pharmaceutical preparation well, and can maintain the pH value of the pharmaceutical preparation at about 8 all the time during the use period.

Effect example 14

To alleviate the pain of the surgical incision in an abdominal surgery patient, the medical staff placed pharmaceutical preparation H in the surgical incision before the final suture. The amount of drug formulation H placed was 0.2 grams of drug formulation H per centimeter of incision length. After the drug formulation H was placed, the incision was normally sutured.

After placement in the incision, the dissolved lidocaine molecules in drug formulation H begin to diffuse out of the hydrogel form of the drug formulation and into the incision and surrounding tissue. Since only a small portion of the lidocaine in the drug preparation H is in a dissolved state, and only dissolved lidocaine molecules can diffuse out of the hydrogel-form drug preparation and enter tissues in contact with the hydrogel-form drug preparation, the majority of the lidocaine in the drug preparation H exists in the drug preparation H in the form of particles and cannot enter human tissues. As the dissolved lidocaine leaves the hydrogel-form drug formulation through a diffusion process, the undissolved lidocaine particles will gradually dissolve to maintain the concentration of lidocaine at the saturation concentration in the hydrogel-form drug formulation.

The lidocaine in the pharmaceutical preparation H enters the incision tissue of the operation in a sustained-release manner for more than 24 hours, and provides satisfactory analgesia for more than 24 hours for patients.

Effect example 15

To alleviate the pain of a surgical incision in a cesarean delivery patient, the health care professional placed pharmaceutical formulation J into the surgical incision prior to final suturing.

The amount of drug formulation J placed was 0.2 grams of drug formulation J per centimeter of incision length. After placement of pharmaceutical formulation J, the incision was closed normally. After placement in the incision, the dissolved lidocaine molecules in drug formulation J begin to diffuse out of the hydrogel form of the drug formulation and into the incision and surrounding tissue. Since only a small portion of the lidocaine in drug preparation J is in a dissolved state, and only dissolved lidocaine molecules can diffuse out of the hydrogel-form drug preparation and enter tissues in contact with the hydrogel-form drug preparation, the majority of the lidocaine in drug preparation J exists in drug preparation J in the form of particles and cannot enter human tissues. As the dissolved lidocaine leaves the hydrogel-form drug formulation through a diffusion process, the undissolved lidocaine particles will gradually dissolve to maintain the concentration of lidocaine at the saturation concentration in the hydrogel-form drug formulation.

The lidocaine in the pharmaceutical preparation J enters the operation incision tissue in a sustained-release manner for more than 48 hours, and provides satisfactory analgesia for more than 48 hours for a patient.

Effect example 16

To alleviate the pain of the surgical incision in one of the abdominal surgery patients, the medical staff placed pharmaceutical formulation J into the surgical incision prior to the final suture. The amount of drug formulation J placed was 0.2 grams of drug formulation J per centimeter of incision length. After placement of pharmaceutical formulation J, the incision was closed normally. In addition, the medical staff also applied the pharmaceutical preparation J to the already sutured incision (method and cover film same as effect example 13).

After placement in the incision, the dissolved lidocaine molecules in drug formulation J begin to diffuse out of the hydrogel form of the drug formulation and into the incision and surrounding tissue. Since only a small portion of the lidocaine in drug preparation J is in a dissolved state, and only dissolved lidocaine molecules can diffuse out of the hydrogel-form drug preparation and enter tissues in contact with the hydrogel-form drug preparation, the majority of the lidocaine in drug preparation J exists in drug preparation J in the form of particles and cannot enter human tissues. As the dissolved lidocaine leaves the hydrogel-form drug formulation through a diffusion process, the undissolved lidocaine particles will gradually dissolve to maintain the concentration of lidocaine at the saturation concentration in the hydrogel-form drug formulation.

The lidocaine in the pharmaceutical preparation J enters the operation incision tissue in a sustained-release manner for more than 48 hours, and provides satisfactory analgesia for more than 48 hours for a patient. In addition, the lidocaine molecules in the layer J of the drug formulation applied to the already sutured incision will diffuse into the incised tissue in a slow release manner, providing additional long-term analgesia to the patient.

Effect example 17

Before suturing an incision for a caesarean section of a patient, the doctor extrudes the pharmaceutical preparation K stored in a syringe into a cylindrical strip having a diameter of about 5mm, and places the strip into the incision (about 0.2 g of the pharmaceutical preparation K per cm of the length of the incision tissue), and then suturing the incision by a conventional method.

Sodium alginate, because of its certain internal cohesion, does not flow into the body tissue as quickly, but is absorbed slowly, thus remaining in the incised tissue for a relatively long time. During this dwell time, only a small portion of the lidocaine in pharmaceutical formulation K sutured in the incised tissue was present in dissolved form, and the concentration of dissolved lidocaine in pharmaceutical formulation K was below 5 mg/ml, with the remainder being present as undissolved particles. Since only the dissolved lidocaine can enter the surrounding tissues through the diffusion process to play a role in analgesia, the undissolved lidocaine particles in the pharmaceutical preparation K do not directly participate in the diffusion process, but are slowly dissolved along with the absorption of the dissolved lidocaine by the tissues of the human body, so as to keep the concentration of the dissolved lidocaine always at the saturation concentration until all the particles are dissolved. Since the process of slowly dissolving the undissolved lidocaine is a very slow process, the process of leaving the pharmaceutical preparation K to enter the human tissue is a slow release process.

The pharmaceutical formulation K of example 10 had a relatively long analgesic effect time (longer than 12 hours). The phosphate pH buffering pair in the pharmaceutical preparation K can help reduce the change of pH, thereby reducing the change of saturated concentration of lidocaine, and achieving the effect of supporting the sustained-release function.

Effect example 18

Before suturing an incision for a caesarean section of a patient, a doctor puts a drug preparation L stored in a syringe in the form of a cylindrical stick having a diameter of about 4 mm into the incision (about 0.13 g of the drug preparation L per cm of the length of the incision tissue), and then suturing the incision by a conventional method.

Sodium alginate, because of its certain internal cohesion, does not flow into the body tissue as quickly, but is absorbed slowly, thus remaining in the incised tissue for a relatively long time. During this dwell time, only a small portion of the bupivacaine in the drug formulation L sutured into the incised tissue was present in dissolved form, and the concentration of the dissolved bupivacaine in the drug formulation L was below 5 mg/ml, with the remainder being present as undissolved particles. Because only the dissolved bupivacaine can enter the surrounding tissues through the diffusion process to play a role in relieving pain, undissolved bupivacaine particles in the pharmaceutical preparation L do not directly participate in the diffusion process, but are slowly dissolved along with the absorption of the dissolved bupivacaine by human tissues so as to keep the concentration of the dissolved bupivacaine at the saturated concentration all the time until all the particles are dissolved. Since the process of slowly dissolving the undissolved bupivacaine is a very slow process, the process of leaving the pharmaceutical preparation L and entering the human tissue of the bupivacaine is a slow release process.

The pharmaceutical formulation L of example 11 had a relatively long analgesic effect time (longer than 12 hours). The phosphate pH buffering pair in the pharmaceutical preparation L can help reduce the change of pH, thereby reducing the change of the saturated concentration of bupivacaine and achieving the effect of supporting the slow release function.

While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.

Claims

1. A pharmaceutical formulation comprising water, a pH buffering pair, and a local anesthetic; the pH buffered pair is dissolved in water in the pharmaceutical formulation and forms a pH buffered solution; the local anesthetic in the pharmaceutical formulation comprises a dissolved local anesthetic and an undissolved local anesthetic; the mass percentage of the total of the dissolved local anesthetic and the undissolved local anesthetic in the pharmaceutical preparation is more than 2% and is not 100%; the pH buffer solution enables the mass percentage of the dissolved local anesthetic in the pharmaceutical preparation to be less than 1% and not 0; the local anesthetic in the pharmaceutical preparation is lidocaine, tetracaine, bupivacaine, articaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, mepivacaine, prilocaine, ropivacaine, tricaine, benzocaine or procaine; the sum of the mass percentages of the components in the pharmaceutical preparation is 100%.

2. The pharmaceutical formulation of claim 1, wherein the pH buffer pair is a pH buffer pair effective to resist pH change of the pharmaceutical formulation in a pH range of 7 to 13, preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate, a pH buffer pair consisting of dipotassium hydrogen phosphate and potassium dihydrogen phosphate, a pH buffer pair consisting of sodium tetraborate and sodium hydroxide, or a pH buffer pair consisting of trimethylolaminomethane and HCl, more preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate, or a pH buffer pair consisting of sodium tetraborate and sodium hydroxide, further more preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate;

when the pH buffer pair is a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate, the molar concentration of the pH buffer pair in the pharmaceutical formulation is preferably 0.02 to 0.4mol/L, more preferably 0.05 to 0.3mol/L or 0.1 to 0.3mol/L, further more preferably 0.08 to 0.22 mol/L; wherein the ratio of the molar concentration of sodium dihydrogen phosphate to the molar concentration of disodium hydrogen phosphate in the pharmaceutical formulation is preferably 14:1 to 19: 1.

3. The pharmaceutical formulation of claim 1 or 2, wherein the pharmaceutical formulation has a pH of 7-13, 7-11, or 7.5-9.5; preferably, the pH buffer pair is selected to control the pH of the pharmaceutical formulation within the aforementioned range during preparation of the pharmaceutical formulation; preferably, during the preparation of the pharmaceutical preparation, before the addition of the pH buffer pair, an alkaline substance is used to adjust the pH value of the system to the aforementioned range, and then the pH buffer pair capable of forming a pH buffer solution corresponding to the pH value is added; the alkaline substance is preferably one or more of sodium tripolyphosphate, sodium bicarbonate, sodium hydroxide and potassium hydroxide, more preferably sodium hydroxide and/or potassium hydroxide, and still more preferably sodium hydroxide.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the local anesthetic in the pharmaceutical preparation is present in the pharmaceutical preparation in a mass percentage of 3% or more, 4% or more, 5% or more, 8% or more, or 10% or more, preferably 3% to 15%, 4% to 10% or 5% to 8%;

and/or the mass percentage of the dissolved local anesthetic in the pharmaceutical preparation is less than 0.7%, 0.5% -0.7% or less than 0.5%;

and/or the local anesthetic in the pharmaceutical preparation is lidocaine, tetracaine or bupivacaine, preferably lidocaine or tetracaine, more preferably lidocaine.

5. A pharmaceutical formulation according to any one of claims 1 to 4, wherein the pharmaceutical formulation comprises a suspending agent, preferably carbomer, preferably Pemulen TR-2 or Carbopol 971; the mass percentage of the suspending agent in the pharmaceutical preparation is preferably 0.10-0.50%;

and/or, the pharmaceutical formulation comprises a thickening agent, preferably one or more of xanthan gum, starch, carbomer and cellulose, more preferably one or more of xanthan gum, starch, hydroxyethyl cellulose and hydroxypropyl cellulose; the mass percentage of the thickening agent in the pharmaceutical preparation is preferably 0.2-8%, more preferably 1-6%, and even more preferably 2-5%;

and/or, the pharmaceutical formulation comprises glycerol and/or propylene glycol; the mass percentage of the glycerol and/or the propylene glycol in the pharmaceutical preparation is preferably 2-25%.

6. The pharmaceutical formulation of any one of claims 1-5, wherein the pharmaceutical formulation has a non-flow property, wherein the non-flow property is such that the surface of the pharmaceutical formulation in a container does not flow to a horizontal plane during the 12 hours of standing after being stirred.

7. The pharmaceutical formulation according to any one of claims 1 to 6, wherein the local anesthetic is tetracaine, the mass percentage of tetracaine in the pharmaceutical formulation is 0.5% or more, and the mass percentage of tetracaine dissolved in the pharmaceutical formulation is 0.1% or less;

or the local anesthetic is lidocaine, the mass percentage of the lidocaine in the pharmaceutical preparation is more than 2% or more than 3%, and the mass percentage of the lidocaine dissolved in the pharmaceutical preparation is less than 1%.

8. The pharmaceutical formulation of claim 1, further comprising a gelling agent, wherein the gelling agent is present in the pharmaceutical formulation in an amount of 0.2% to 5% by weight; the mass percentage of the gelling agent in the pharmaceutical preparation is preferably 0.5-4%, more preferably 1.0-3.0%;

wherein, the gelling agent is preferably one or more of xanthan gum, hyaluronic acid and a salt of a hyaluronic acid, more preferably xanthan gum, hyaluronic acid or a salt of an hyaluronic acid, and further more preferably a mixture of xanthan gum and hyaluronic acid or a mixture of xanthan gum and sodium alginate;

wherein, in the hyaluronic acid, preferably more than 95 wt% of the hyaluronic acid is non-crosslinked hyaluronic acid, and more preferably 98 wt% -100 wt% of the hyaluronic acid is non-crosslinked hyaluronic acid;

wherein, in the sodium hyaluronate, more preferably 95 wt% or more of the sodium hyaluronate is non-crosslinked sodium hyaluronate, and more preferably 98 wt% -100 wt% of the sodium hyaluronate is non-crosslinked sodium hyaluronate.

9. The pharmaceutical formulation of claim 8, wherein the gelling agent is sodium hyaluronate, and the gelling agent is present in the pharmaceutical formulation in an amount of 0.2% to 4% by weight, the pH buffer pair is a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate, the local anesthetic is lidocaine or bupivacaine, and the pharmaceutical formulation has a pH of 7.8 to 8.8; the concentration of the local anesthetic in the pharmaceutical preparation is more than 20 mg/ml or more than 40 mg/ml; the concentration of the dissolved local anesthetic in the pharmaceutical formulation is less than 5 mg/ml;

or the gelling agent is hyaluronic acid or a salt of hyaluronic acid, the mass percentage of the gelling agent in the pharmaceutical preparation is 0.2% -5%, the pH value of the pharmaceutical preparation is 7.8-8.8 due to the pH buffer solution formed by the pH buffer pair, the concentration of the dissolved local anesthetic in the pharmaceutical preparation is less than 5 mg/ml, and the concentration of the local anesthetic in the pharmaceutical preparation is more than 20 mg/ml; wherein the mass percentage of the gelling agent in the pharmaceutical preparation is preferably 0.3-3%; the pH buffer pair is preferably a pH buffer pair consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate; the local anesthetic is preferably lidocaine or bupivacaine; the sodium hyaluronate is preferably sodium hyaluronate, and preferably more than 95 wt% of the sodium hyaluronate is non-crosslinked sodium hyaluronate, and more preferably 98-100 wt% of the sodium hyaluronate is non-crosslinked sodium hyaluronate; the pH value of the pharmaceutical preparation is preferably 7.8-8.5; the concentration of the local anesthetic in the pharmaceutical preparation is preferably 40 mg/ml or more.

10. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is free of lipid materials.

11. A pharmaceutical preparation which is a lidocaine-containing preparation, characterized in that the lidocaine-containing preparation contains lidocaine, xanthan gum, and water, and the lidocaine in the lidocaine-containing preparation includes dissolved lidocaine and undissolved lidocaine; the sum of the mass percentages of the components in the preparation containing the lidocaine is 100%;

wherein, the total mass percentage of the dissolved lidocaine and the undissolved lidocaine in the lidocaine-containing preparation is preferably more than 2% and is not 100%; the mass percentage of the dissolved lidocaine in the lidocaine-containing preparation is 1% or less and is not 0; more preferably, the mass percentage of the dissolved lidocaine in the preparation containing lidocaine is 0.1% -1%.

12. The pharmaceutical formulation of claim 11, wherein the lidocaine-containing formulation comprises a pH buffer pair consisting of sodium phosphate dibasic and sodium phosphate monobasic.

13. The pharmaceutical formulation of claim 11 or 12, wherein the lidocaine-containing formulation has a mass percent of lidocaine greater than 1.5%, and not 100%; preferably 2% -8%.

14. A pharmaceutical formulation according to any one of claims 11 to 13, wherein the dissolved lidocaine is present in the lidocaine-containing formulation in a mass percentage of 1% or less or 0.5% or less, and not 0.

15. A pharmaceutical formulation according to any one of claims 11 to 14, wherein the mass percentage of xanthan gum in the lidocaine-containing formulation is greater than 0.1% and not 100%; preferably 0.2% to 10%, more preferably 1% to 6%.

16. A pharmaceutical formulation according to any one of claims 11 to 15, wherein the lidocaine-containing formulation further comprises hydroxypropyl cellulose; the mass percentage of the hydroxypropyl cellulose in the lidocaine-containing preparation is preferably more than 1%, and is not 100%, more preferably 1% -5%.

17. A system for securing a pharmaceutical preparation to the skin, comprising a pharmaceutical preparation according to any one of claims 1-16 and a medical drape for completely enclosing the pharmaceutical preparation within an enclosed space formed by the medical drape and a surface of human body tissue; wherein the human body tissue surface is preferably a surface of intact skin or a surface of incomplete skin, preferably a surface of a burn or a surgical incision.

18. The system for securing a pharmaceutical formulation to the skin of claim 17, wherein said medical cover film comprises a barrier film layer, an absorbent layer and a mesh adhesive layer, one side of said absorbent layer being laminated to said barrier film layer and the other side of said absorbent layer being laminated to said mesh adhesive layer; the area of the non-adhesive area of the reticular adhesive layer accounts for more than 10% of the total area of the reticular adhesive layer and is not 100%; the reticular rubber layer is used for totally enclosing the pharmaceutical preparation in an enclosed space formed by the medical covering film and the surface of the human body tissue;

the material of the barrier film layer is preferably a polyethylene film, an ethylene-vinyl acetate copolymer film or a polyurethane film;

wherein, the adsorption layer is preferably non-woven fabric;

wherein, the reticular rubber layer is preferably a rubber net consisting of curves and/or straight lines; the reticular rubber layer is preferably a rubber net consisting of a group of parallel warps and a group of parallel wefts; more preferably, the warp threads and the weft threads are arranged vertically; still more preferably, the distance between two adjacent warps is equal to the distance between two adjacent wefts;

wherein, the thickness of the reticular rubber layer is preferably 0.25-0.75 mm;

wherein, the adhesive of the reticular adhesive layer is preferably medical pressure-sensitive adhesive which is insoluble in water, more preferably organic silica gel and/or acrylic adhesive;

wherein, preferably, the area of the non-glue area of the reticular glue layer accounts for more than 30% of the total area of the reticular glue layer; more preferably, the area of the non-glue area of the reticular glue layer accounts for more than 50% of the total area of the reticular glue layer; more preferably, the area of the non-adhesive region of the mesh-shaped adhesive layer accounts for more than 70% of the total area of the mesh-shaped adhesive layer, and still more preferably, the area of the non-adhesive region of the mesh-shaped adhesive layer accounts for 70% -90% of the total area of the mesh-shaped adhesive layer;

among them, the length elongation of the medical covering film in all directions is preferably 10% or more, and more preferably 10% to 30%.

19. The system for securing a pharmaceutical preparation to the skin according to claim 17 or 18, wherein the length of the outer edge of the medical cover film from the outer edge of the layer of the pharmaceutical preparation is more than 5mm, preferably 2-4 cm.

20. A process for the preparation of a pharmaceutical formulation according to any one of claims 1 to 16, comprising the steps of: mixing all the components in the pharmaceutical preparation uniformly; the preparation method preferably comprises the steps of: (1) mixing the other components except the local anesthetic in the medicinal preparation to obtain a mixed solution; (2) mixing the mixed solution with the local anesthetic, heating, and cooling to room temperature;

wherein, in the step (2), the heating temperature is preferably 75-85 ℃, and more preferably 80 ℃;

wherein, in step (2), the heating is preferably performed under stirring.

21. Use of a pharmaceutical formulation according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of pain during herpes zoster, post-herpes zoster nerve damage pain, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, joint pain, osteoarthritis pain, back pain, pain caused by gout, pain caused by soft tissue injury, post-operative incision pain, burn pain or pain during burn decrustation.

22. Use of a system for immobilising a pharmaceutical preparation on the skin according to any one of claims 17-19 for the manufacture of a medical device for the treatment of pain during herpes zoster, pain in nerve damage following herpes zoster, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, joint pain, osteoarthritis pain, back pain, pain caused by gout, pain caused by soft tissue injury, post-operative incision pain, burn pain or pain during burn decrustation.