CN114053251A - Sulfated polysaccharide inhalation preparation and application thereof in preventing and treating new coronavirus related diseases - Google Patents
Sulfated polysaccharide inhalation preparation and application thereof in preventing and treating new coronavirus related diseases Download PDFInfo
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- CN114053251A CN114053251A CN202010744043.6A CN202010744043A CN114053251A CN 114053251 A CN114053251 A CN 114053251A CN 202010744043 A CN202010744043 A CN 202010744043A CN 114053251 A CN114053251 A CN 114053251A
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- sulfated polysaccharide
- inhalation
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- sulfate
- sulfated
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Abstract
The invention discloses a sulfated polysaccharide inhalation preparation and application thereof in preventing and treating new coronavirus related diseases, wherein the preparation comprises sulfated polysaccharide and pharmaceutically acceptable auxiliary materials, and the sulfated polysaccharide comprises one or more of non-anticoagulant heparin, pentosan sulfate, PI-88, chondroitin sulfate, dermatan sulfate, holothurian glycosaminoglycan and holothurian fucosan. The sulfated polysaccharide inhalation preparation of the invention has good stability, can be stored for a long time, and does not deteriorate or change color. Meanwhile, the administration mode of the sulfated polysaccharide inhalation preparation is adopted, so that the sulfated polysaccharide medicine can be directly delivered to the lung of a new coronary patient, is accurately positioned and takes effect quickly. According to the advantages of inhalation preparation administration, the invention introduces sulfated polysaccharide drug to prevent and treat diseases such as virus resistance, inflammation resistance, anticoagulation embolism and the like of a new coronavirus patient.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a sulfated polysaccharide inhalation preparation, application thereof in preventing and treating respiratory tract infection, inflammation and blood coagulation embolism related to new coronavirus, and a preparation method of the sulfated polysaccharide inhalation preparation.
Background
The new coronavirus (new coronavirus, SARS-CoV-2) is a significant threat to human health and economic development worldwide. By the end of 6 months in 2020, new coronavirus has caused the infection of more than one million people and the death of more than one million people worldwide. The severe incidence of new coronavirus infection is above 10%, dyspnea and/or hypoxemia occur in patients after one week of onset, and severe patients rapidly progress to acute respiratory distress syndrome, septic shock, refractory metabolic acidosis and blood coagulation dysfunction and multiple organ failure. The main lesion site of severe patients with new coronary pneumonia (Corona Virus Disease 2019, COVID-19) is the lung, which needs respiratory support. To date, there is no effective prophylactic or therapeutic approach to combat new coronary pneumonia caused by new coronary viruses.
The novel coronaviruses belong to a member of the coronavirus family and are single-stranded (+) RNA viruses. The virions of the coronavirus family are surrounded by a fat membrane, the surface of which has three glycoproteins: spinous process glycoproteins (S, Spike Protein, which are receptor binding sites, cytolytic and major antigenic sites); small Envelope glycoproteins (E, Envelope proteins, smaller, Envelope-bound proteins) and Membrane glycoproteins (M, Membrane proteins, responsible for transmembrane transport of nutrients, budding release of nascent viruses, and formation of viral Envelope).
When coronavirus infects cells, host cell receptors are firstly identified by virtue of spinous glycoprotein (S protein), fusion of virus membrane and cell membrane is induced, after the two are combined, the cell membrane adsorbs and internalizes the virus, and the virus enters cytoplasm and then is unshelled to release virus genetic materials (RNA). The new coronavirus can recognize angiotensin converting enzyme II (ACE2) and can enter cells expressing ACE2, so that ACE2 plays a crucial role in new coronavirus infection. When new coronavirus enters host cell, the RNA of virus will combine with ribosome of host cell to synthesize RNA replicase, which is used to form new virus RNA. The new viral RNA binds to the proteins produced by the hydrolases, assembles into large quantities of new virus, releases the original host cells, and continues to infect new targets. The infection of new coronavirus is mainly lung cells, and after the infection of lung, the integrity of pulmonary alveolar capillary membrane can be seriously damaged, inflammatory hyperemia appears, meanwhile, fibroblasts in lung can carry out compensatory proliferation and differentiation in order to compensate the damaged part, and a large amount of fibrous tissues without gas exchange function can replace alveoli, thus gradually causing pulmonary fibrosis. Once pulmonary fibrosis is formed, the ventilation function of the body is reduced, the amount of oxygen entering blood is insufficient, patients suffer from hypoxia and dyspnea, and patients with severe symptoms suffer from acute respiratory distress syndrome and multiple organ dysfunction syndrome and further die.
Sulfated polysaccharides (Sulfated polysaccharides) are acidic polysaccharides with sulfate group modification, including various natural Sulfated polysaccharides extracted from animals and plants, heparin, chondroitin sulfate, and artificially sulfonated synthetic or modified polysulfate polysaccharides, etc. The sulfated polysaccharide has antiviral effect, and the main mechanism is that the negative charge of the sulfate group of the sulfated polysaccharide is combined with the positive charge of the virus protein through electrostatic effect to block the binding site of enveloped virus and cell receptor, so as to prevent the adsorption of the virus and host cells and inhibit the infection process. The sulfated polysaccharide also has anti-inflammatory, anticoagulant and antithrombotic effects, and can be used for preventing and treating inflammatory reaction and thrombo-embolic diseases caused by viral infection.
During the course of the disease progression in the new coronary disease mentioned above, sulfated polysaccharides may play a role in several links:
(1) according to the literature (So Young Kim et al, PLOS Pathogens, year 2020, 4, draft of electronic manuscript paper (network publication)), at the beginning of infection with new coronavirus, negative charges of its sulfate group are used to bind with positive charges of viral proteins (such as spinous process glycoprotein (S protein), which has continuous basic amino acid (R (arginine) + K (lysine)) region) (fig. 1) through electrostatic interaction, So as to block the binding site of enveloped virus and cell receptor (ACE2), thereby preventing the adsorption of virus to host cells and inhibiting the infection process.
(2) Another potential route of infection of the new coronaviruses, probably through binding of the S protein to heparan sulfate in recipient cells (some viruses (e.g. herpes simplex) have been shown in the literature to bind to host glycosaminoglycans (known as heparan sulfate). Sulfated polysaccharides are heparan sulfate analogues that competitively prevent binding of the virus to heparan sulfate on the surface of recipient cells, thereby preventing adsorption of the virus to host cells and inhibiting infection.
(3) During the course of the patient's disease, the capillaries in the patient's lungs are severely damaged, and inflammatory congestion occurs, causing a thromboembolism or a pulmonary obstruction. The sulfated polysaccharide has anti-inflammatory and antithrombotic anticoagulant activity, and can effectively prevent and treat local inflammation and blood coagulation embolism (especially pulmonary embolism), prevent, slow and repair inflammatory reaction, and protect the functions of organs such as lung. Among the sulfated polysaccharides, heparin and low-molecular heparin have been widely used for the symptomatic treatment of new coronary patients against thrombosis.
In addition, since sulfated polysaccharides are polyanionic compounds having a large amount of negative charges, they are difficult to administer by gastrointestinal absorption, and usually administration by injection is selected. However, the injection is highly irritating, and the drug tends to accumulate in organs such as the liver and kidney. Therefore, it is very important to develop a sulfated polysaccharide preparation which is convenient to administer, good in compliance, good in targeting property or accurate in administration.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the technical problems, the invention provides a sulfated polysaccharide inhalation preparation which has good stability, convenient administration, good compliance, good targeting property or accurate administration and can treat and prevent new crown diseases.
Means for solving the problems
In order to solve the above technical problems, the present invention provides a sulfated polysaccharide inhalation preparation, which is characterized by comprising a sulfated polysaccharide and a pharmaceutically acceptable excipient.
Preferably, the sulfated polysaccharide comprises one or more of non-anticoagulant heparin, pentosan sulfate, PI-88, chondroitin sulfate, dermatan sulfate, holothurian glycosaminoglycans and holothurian fucoidans.
Preferably, the pharmaceutically acceptable auxiliary materials comprise an isotonic regulator and/or a pH regulator and a solvent.
More preferably, the isotonic adjusting agent is a combination of one or more of sodium chloride, potassium chloride, glucose and mannitol for adjusting the sulfated polysaccharide inhalation formulation to an isotonic solution.
More preferably, the pH regulator is a combination of one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, for regulating the pH of the sulfated polysaccharide inhalation formulation to between 4 and 7.
More preferably, the solvent is water.
Preferably, the preparation comprises the following components in parts by weight:
the sulfated polysaccharide comprises one or more of non-anticoagulant heparin, pentosan sulfate, PI-88, chondroitin sulfate, dermatan sulfate, sea cucumber glycosaminoglycan and sea cucumber fucosan, the isotonic regulator is one or more of sodium chloride, potassium chloride, glucose and mannitol, the pH regulator is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide and potassium hydroxide, and the solvent is water.
More preferably, the formulation comprises, in parts by weight:
preferably, the sulfated polysaccharide inhalation formulation is an aerosolized inhalation formulation for oral inhalation.
Preferably, the sulfated polysaccharide inhalation formulation is obtained by placing a liquid medicine in an atomizing device.
Preferably, the formulation is a sterile solution.
The invention also provides a preparation method of the sulfated polysaccharide inhalation preparation, which comprises the following steps:
taking sulfated polysaccharide, isotonic regulator and water for injection according to the formula amount, stirring and dissolving at room temperature, regulating pH value with pH regulator, filtering the solution, and bottling to obtain sulfated polysaccharide inhalation preparation.
Preferably, the method further comprises the step of sterilizing by filtration or/and steam terminal sterilization before potting.
More preferably, the method comprises:
(1) the formula is as follows: sulfated polysaccharide 50.0g and sodium chloride 4.0g, appropriate amount of hydrochloric acid, and injectable water to 1000 ml;
(2) adding sulfated polysaccharide, sodium chloride and water for injection in the formula amount in the step (1), dissolving, adjusting pH to 5.0 with hydrochloric acid, sterilizing, filtering, and aseptically packaging in 5ml ampoule bottle.
The invention also provides application of the sulfated polysaccharide inhalation preparation in preparing a medicament for preventing and treating diseases related to the new coronavirus.
Preferably, the new coronavirus related diseases comprise respiratory tract infection, inflammation and thrombo-embolism caused by the new coronavirus.
The invention also provides application of the sulfated polysaccharide inhalation preparation in preparing medicaments for preventing and treating respiratory infection, inflammation and blood coagulation embolism caused by influenza virus, adenovirus, respiratory syncytial virus, parainfluenza virus, rhinovirus, cytomegalovirus, EB virus and coronavirus.
ADVANTAGEOUS EFFECTS OF INVENTION
The sulfated polysaccharide inhalation preparation of the invention has good stability, can be stored for a long time, and does not deteriorate or change color. Meanwhile, the administration mode of the sulfated polysaccharide inhalation preparation is adopted, so that the sulfated polysaccharide medicine can be directly delivered to the lung of a new coronary patient, is accurately positioned and takes effect quickly. According to the advantages of inhalation preparation administration, the invention introduces sulfated polysaccharide drug to prevent and treat diseases such as virus resistance, inflammation resistance, anticoagulation embolism and the like of a new coronavirus patient.
The sulfated polysaccharide inhalation preparation provided by the invention takes sulfated polysaccharide as a medicinal active ingredient, has wide pharmacological activity, is convenient and quick in an atomizing oral inhalation mode, and has better clinical medication compliance.
Drawings
FIG. 1 is a schematic representation of glycosaminoglycan binding motifs in the spinous process Glycoprotein (SGPS protein) of SARS-CoV-2 (New coronaviruses), SARS-CoV (SARS virus) and MERS-CoV (middle east respiratory syndrome coronavirus).
Detailed Description
Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[ definition of terms ]
Unless otherwise indicated, the following terms have the following meanings.
Inhalation formulation refers to liquid or solid formulations of a raw drug dissolved or dispersed in a suitable medium for delivery as a vapor or aerosol to the lungs for local or systemic effect. The inhalation preparation is the first choice medicine form for treating respiratory system diseases such as bronchial asthma, obstructive pulmonary disease (one of the main symptoms of new coronary pneumonia) and the like. Inhalation formulations include mainly inhalation aerosols, powder inhalers and liquid formulations for nebulizers 3. Inhalation formulations, especially for aerosol therapy, have the following advantages: 1) compared with systemic administration, the preparation has the advantages of small dosage and quick action. 2) According to different medicines, the traditional Chinese medicine composition has the effects of thinning sputum, eliminating inflammation, relieving bronchospasm, relieving laryngeal edema, resisting infection and the like, and becomes an effective means for improving the smooth airway; the indications for inhalation formulations, especially for aerosol therapy, are mainly: 1) the sputum is thick; 2) inflammatory diseases of the airways; 3) obstructive diseases of the airways; 4) laryngeal disease; 5) others require administration via airway respiration.
The sulfated polysaccharide is white amorphous powder, has no odor, is easily soluble in water, and is insoluble in organic solvent such as ethanol and diethyl ether. The sulfated polysaccharide medicament can be directly delivered to the lung of a new coronary patient by adopting an administration mode of an inhalation preparation, is accurately positioned and quickly takes effect. According to the advantages of inhalation preparation administration, the sulfated polysaccharide drug is introduced to prevent and treat diseases such as virus resistance, inflammation resistance, anticoagulation embolism and the like of a new coronavirus patient.
The sulfated polysaccharides are acidic polysaccharides with sulfate modifications, including naturally extracted, chemically modified, and artificially synthesized sources. Factors influencing the biological activities of sulfated polysaccharides such as antiviral activity, anti-inflammatory activity and anticoagulant embolism mainly lie in the sulfation substitution degree, the sugar chain molecular structure composition, the molecular weight and the like, and the higher the sulfation degree is, the stronger the activities of the antiviral activity, the anti-inflammatory activity and the anticoagulant embolism activity is; the sulfate radical content of the naturally extracted sulfated polysaccharide is 20-40%, while the sulfate radical content of the artificially (sulfonated) synthesized sulfated polysaccharide can reach 50-60%.
Wherein, Heparin, the name of English is Heparin, the main sugar unit is iduronic acid-glucosamine, the schematic (main) structural formula is:
Low Molecular Heparin, called Low Molecular Weight Heparin in England, is a small Molecular Heparin prepared by depolymerizing unfractionated Heparin, the main sugar unit is also iduronic acid-glucosamine, the Weight average Molecular Weight is less than 8000Da, and the sulfate group content is about 38%. The low molecular heparin is divided into a plurality of types according to different depolymerization preparation modes, including enoxaparin sodium, dalteparin sodium, nadroparin calcium, tinzaparin sodium and the like, and is mainly clinically used as an antithrombotic drug for treating and preventing diseases such as deep venous thrombosis and the like.
Non-anticoagulant Heparin, known by the name of Non-anticoagulant Heparin, is chemically modified to remove anticoagulant activity, and still retains the main sugar unit structure of Heparin, but has only very low anticoagulant activity. The general molecular weight of the non-anticoagulant heparin is less than 10000Da, the content of sulfate radical is about 38 percent, and the non-anticoagulant heparin is usually prepared by oxidizing and destroying pentasaccharide sequence with anticoagulant activity of the heparin by sodium periodate and is mainly applied to anti-inflammation and anti-tumor.
Pentosan sulfate, known in english as pentasan Polysulfate, has xylose and 4-methyl-oxy-glucuronic acid as main sugar units, and has a schematic (main) structural formula:
the sulfate group content is about 50% and the weight average molecular weight is about 5000 Da. The source is that the plant xylan is synthesized by artificial sulfonation, and the plant xylan is mainly applied to anti-inflammatory and antithrombotic treatment.
PI-88, major sugar UnitIs mannose, with a schematic (main) structural formula:
the sulfate group content is about 60%, and the weight average molecular weight is about 2400Da, and the sulfate group is artificially synthesized and used for resisting tumors in clinical tests.
Chondroitin sulphate, having the english name Chondroitin Sulfate, the main sugar unit glucuronic acid-galactosamine, and the schematic (main) structural formula:
the content of sulfate radical is about 25%, the weight average molecular weight is more than 50000Da, and the animal cartilage is extracted and clinically applied to blood fat reduction and anti-inflammation.
The Chondroitin Sulfate is modified by artificial sulfonation and increasing sulfation, and the main sugar unit of the Chondroitin Sulfate is the same as that of the Chondroitin Sulfate, but the content of Sulfate groups reaches 50 percent.
Dermatan Sulfate, having the english name Dermatan Sulfate, has a major sugar unit iduronic acid-galactosamine, and a schematic (major) structural formula:
the sulfate group content is about 30 percent, the weight-average molecular weight is more than 25000Da, the sulfate group is originated from intestinal mucosa of domestic mammals and is one of main components of clinical hypolipidemic and vascular disease drugs (antithrombotic) (drug name: sulodexide).
Holothurian glycosaminoglycans, known in english as Holothurian glycoaminoglycans, with a major sugar unit of glucuronic acid (fucose) -galactosamine, with a schematic (main) structural formula:
a sulfate group content of about 35% and a weight average molecular weight>40000Da is natural macromolecular polysaccharide extracted from Stichopus japonicus, and has anticoagulant, antitumor and antiinflammatory activities.
Sea cucumber fucosan, having the english name of holothuian Fucoidan, has a fucose as a main sugar unit, and has a schematic (main) structural formula:
the sulfate group content was about 30%, and the weight average molecular weight was about>100000Da, which is another polysulfated polysaccharide extracted from Stichopus japonicus and mainly used for anti-inflammatory and anti-tumor.
The sulfated polysaccharide disclosed by the invention has the advantages that the active pharmaceutical ingredients (original drugs) are white to light yellow amorphous powder, are tasteless, are easily soluble in water, and are insoluble in organic solvents such as ethanol, diethyl ether and the like.
The invention provides a sulfated polysaccharide inhalation preparation, which comprises sulfated polysaccharide and pharmaceutically acceptable auxiliary materials.
In a preferred embodiment, the sulfated polysaccharide comprises one or more of non-anticoagulant heparin, pentosan sulfate, PI-88, chondroitin sulfate, dermatan sulfate, holothurian glycosaminoglycans and holothurian fucoidans, for example, a combination of non-anticoagulant heparin, pentosan sulfate and holothurian glycosaminoglycans.
Heparin and low molecular heparin are sulfated polysaccharides, have strong anticoagulation and antithrombotic activity, are widely used as anticoagulation and antithrombotic medicaments clinically, and are also applied to symptomatic treatment and prevention of thrombus of new coronary patients in an injection administration mode, and the dosage is usually below 1 mg/kg/day. Because heparin drugs have strong anticoagulant and antithrombotic activities, and are likely to cause complications such as bleeding when applied in large doses, the sulfated polysaccharide inhalation preparation of the present invention does not use heparin and low molecular weight heparin in view of safety of application. On the other hand, the non-anticoagulant heparin in the sulfated polysaccharide is chemically modified heparin with low anticoagulant activity, and usually the anticoagulant activity is below 10U/mg, but the anti-inflammatory activity, the antiviral activity and the like of the non-anticoagulant heparin are kept, so that the non-anticoagulant heparin is a more preferable choice for treating the diseases related to the new coronavirus or the heparin derivative. The preparation method of non-anticoagulant heparin generally comprises the steps of carrying out sodium periodate oxidation destruction on heparin pentasaccharide sequences serving as anticoagulant active sites and the like.
In a preferred embodiment, the pharmaceutically acceptable excipients comprise an isotonicity adjusting agent and/or a pH adjusting agent and a solvent. The isotonic regulator is one or more of sodium chloride, potassium chloride, glucose and mannitol. The pH regulator is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide and potassium hydroxide. The solvent is water.
In a preferred embodiment, the formulation comprises, in parts by weight:
0.1-20% of sulfated polysaccharide;
0-10% of an isotonic regulator, preferably the amount adjusted to be isotonic with the solution;
a proper amount of pH regulator, preferably an amount for regulating the pH of the preparation to 4-7;
70-99% of solvent;
the sulfated polysaccharide comprises one or more of non-anticoagulant heparin, pentosan sulfate, PI-88, chondroitin sulfate, dermatan sulfate, sea cucumber glycosaminoglycan and sea cucumber fucosan, the isotonic regulator is one or more of sodium chloride, potassium chloride, glucose and mannitol, the pH regulator is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide and potassium hydroxide, and the solvent is water.
In a more preferred embodiment, the formulation comprises, in parts by weight:
sulfated polysaccharides 0.5-10%, such as 0.5%, 1%, 2%, 5%, 10%, etc.;
the isotonicity adjusting agent is 0.2-5%, e.g., 0.2%, 0.4%, 0.6%, 0.9%, 1%, 2%, 3%, 4%, 5%, etc., preferably adjusted to an amount that is isotonic to the solution;
the amount of the pH regulator is the amount corresponding to the pH of the preparation being regulated to 4-7, preferably the amount corresponding to the pH being regulated to 5-7, and more preferably the amount corresponding to the pH being regulated to 5;
the solvent is 85 to 95%, for example, 85%, 88%, 90%, 92%, 95%, etc.
In a preferred embodiment, the sulfated polysaccharide inhalation formulation is an aerosolized inhalation formulation for oral inhalation.
In a preferred embodiment, the sulfated polysaccharide inhalation formulation is obtained by placing a liquid drug in an atomizing device. The medicine (solution) is dispersed into tiny fog drops or particles by an atomizing device, the tiny fog drops or particles are suspended in gas and are deposited in respiratory tract and/or lung by inhalation, thereby achieving the effects of resisting virus infection, eliminating inflammation and preventing and treating thrombo-embolism.
In a preferred embodiment, the formulation is a sterile solution.
The sulfated polysaccharide inhalation formulations of the present invention may be prepared according to methods generally known in the art for aerosolizing inhalation formulations. Preferably, the present invention also provides a method for preparing the above sulfated polysaccharide inhalation formulation, comprising the steps of:
taking sulfated polysaccharide, isotonic regulator and water for injection according to the formula amount, stirring and dissolving at room temperature, regulating pH value with pH regulator, filtering the solution, and bottling to obtain sulfated polysaccharide inhalation preparation.
In a preferred embodiment, the method further comprises the step of sterilizing by filtration or/and steam terminal sterilization before potting.
In a preferred embodiment, the sulfated polysaccharide inhalation formulation is packaged in 1 to 10ml medium boron silicon drop vials (ampoules) and stored at 2 to 25 ℃ without freezing.
In a preferred embodiment, the method comprises:
(1) the formula is as follows: sulfated polysaccharide 50.0g and sodium chloride 4.0g, appropriate amount of hydrochloric acid, and injectable water to 1000 ml;
(2) adding sulfated polysaccharide, sodium chloride and water for injection in the formula amount in the step (1), dissolving, adjusting pH to 5.0 with hydrochloric acid, sterilizing, filtering, and aseptically packaging in 5ml ampoule bottle.
The invention also provides application of the sulfated polysaccharide inhalation preparation in preparing a medicament for preventing and treating diseases related to the new coronavirus. Because available animal models of pneumonia caused by new coronavirus (infection, inflammation and thrombo-embolism) are difficult to obtain, similar animal models of pneumonia caused by influenza virus are selected, and the treatment or prevention effect of the group of sulfated polysaccharide inhalation preparations (including but not limited to sea cucumber glycosaminoglycan and pentosan sulfate) on infection, inflammation, thrombo-embolism and the like caused by virus is examined in a simulation mode. The results show that: the sulfated polysaccharide inhalation preparation can obviously reduce the pulmonary index of a virus-infected rat, slow down the severity of inflammation and is in a dose-effect relationship, so that the sulfated polysaccharide inhalation preparation can be potentially applied to the prevention and treatment of diseases related to new coronavirus infection.
Preferably, the new coronavirus related diseases comprise respiratory tract infection, inflammation and thrombo-embolism caused by the new coronavirus.
The invention also provides application of the sulfated polysaccharide inhalation preparation in preparing medicaments for preventing and treating respiratory infection, inflammation and blood coagulation embolism caused by influenza virus, adenovirus, respiratory syncytial virus, parainfluenza virus, rhinovirus, cytomegalovirus, EB virus and coronavirus.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments, but the present invention is not limited to the scope of the present invention.
Example 1
An inhaled sulfated polysaccharide preparation with non-anticoagulant heparin as the active pharmaceutical ingredient was prepared according to the formulation composition in table 1 and the following preparation steps:
table 1 example 1 formulation
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) At room temperature, taking the injection water, non-anticoagulant heparin (sodium) and sodium chloride in the formula amount, stirring and dissolving, and adjusting the pH to 5.0 by using hydrochloric acid;
2) the resulting solution was filtered through a second grade sterilization (0.22 μm);
3) aseptically filling into a 5ml ampoule bottle to obtain a sulfated polysaccharide inhalant preparation (specification: 250mg, 50mg/ml, 5.0 ml/bottle; active pharmaceutical ingredients: non-anticoagulant heparin).
Example 2
An inhaled sulfated polysaccharide preparation having an active pharmaceutical ingredient of pentosan sulfate was prepared according to the formulation composition in Table 2 and the following preparation steps:
table 2 example 2 formulation
| Components | Name (R) | In proportion of | Amount of prescription |
| Active pharmaceutical ingredient | Pentosan sulfate (sodium) | 10.0％ | 100.0g |
| pH regulator | Sulfuric acid | Proper amount of | Amount (adjusting pH to 4.0) |
| Solvent(s) | Water for injection | To 100.0％ | To 1000ml |
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) At room temperature, taking the injection water and sodium pentosan sulfate in the formula amount, stirring and dissolving, and adjusting the pH to 4.0 by using sulfuric acid;
2) sterilizing and filtering the obtained solution by a 0.22 mu m filter membrane, and filling and sealing the solution in a 1ml ampoule bottle;
3) and (4) performing terminal moist heat steam sterilization (121 ℃, 15min) to obtain a sulfated polysaccharide inhalation preparation (specification: 100mg, 100mg/ml, 1.0 ml/bottle; active pharmaceutical ingredients: pentosan sulfate).
Example 3
An inhaled sulfated polysaccharide formulation with PI-88 as the active pharmaceutical ingredient was prepared according to the formulation composition in table 3 and the following preparation steps:
table 3 example 3 formulation
| Components | Name (R) | In proportion of | Amount of prescription |
| Active pharmaceutical ingredient | PI-88 | 2.0％ | 20.0g |
| Isotonic regulator | Sodium chloride | 0.6％ | 6.0g |
| pH regulator | Phosphoric acid | Proper amount of | Amount (adjusting pH to 5.0) |
| Solvent(s) | Water for injection | To 100.0% | To 1000ml |
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) At room temperature, taking the water for injection and pI-88 with the formula amount, stirring and dissolving, and adjusting the pH to 5.0 by using phosphoric acid;
2) sterilizing and filtering the obtained solution by a secondary 0.22 mu m filter membrane, and filling and sealing the solution in a 5ml ampoule bottle;
3) and (4) performing terminal moist heat steam sterilization (121 ℃, 15min) to obtain a sulfated polysaccharide inhalation preparation (specification: 100mg, 20mg/ml, 5.0 ml/bottle; active pharmaceutical ingredients: pI-88).
Example 4
An inhaled sulfated polysaccharide formulation with chondroitin sulfate as the active pharmaceutical ingredient was prepared according to the formulation composition in table 4 and the following preparation steps:
table 4 example 4 formulation
| Components | Name (R) | In proportion of | Amount of prescription |
| Active pharmaceutical ingredient | Chondroitin sulfate | 1.0％ | 10.0g |
| Isotonic regulator | Glucose | 5％ | 50.0g |
| pH regulator | Sodium hydroxide | Proper amount of | Amount (adjusting pH to 7.0) |
| Solvent(s) | Water for injection | To 100.0% | To 1000ml |
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) Dissolving the formula amount of water for injection, chondroitin sulfate and glucose under stirring at room temperature, and adjusting the pH to 7.0 by using sodium hydroxide;
2) the resulting solution was filtered through a second grade sterilization (0.22 μm);
3) aseptically filling into a 10ml ampoule bottle to obtain a sulfated polysaccharide inhalant preparation (specification: 100mg, 100mg/ml, 10.0 ml/bottle; active pharmaceutical ingredients: chondroitin sulfate).
Example 5
An inhaled sulfated polysaccharide formulation with chondroitin sulfate as the active pharmaceutical ingredient was prepared according to the formulation composition in table 5 and the following preparation steps:
table 5 example 5 formulation
| Components | Name (R) | In proportion of | Amount of prescription |
| Active pharmaceutical ingredient | Chondroitin persulfate | 0.1％ | 1.0g |
| Isotonic regulator | Potassium chloride | 0.9％ | 9.0g |
| pH regulator | Potassium hydroxide | Proper amount of | Amount (adjusting pH to 6.0) |
| Solvent(s) | Water for injection | To 100.0% | To 1000ml |
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) At room temperature, taking the water for injection, potassium chloride and chondroitin sulfate according to the formula amount, stirring and dissolving, and adjusting the pH value to 6.0 by using potassium hydroxide;
2) sterilizing and filtering the obtained solution by a secondary 0.22 mu m filter membrane, and filling and sealing the solution in a 5ml ampoule bottle;
3) and (4) performing terminal moist heat steam sterilization (121 ℃, 15min) to obtain a sulfated polysaccharide inhalation preparation (specification: 5.0mg, 1mg/ml, 5.0 ml/bottle; active pharmaceutical ingredients: chondroitin persulfate).
Example 6
An inhaled sulfated polysaccharide formulation with dermatan sulfate as the active pharmaceutical ingredient was prepared according to the formulation composition in table 6 and the following preparation steps:
table 6 example 6 formulation
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) Dissolving the formula amount of water for injection, mannitol and dermatan sulfate at room temperature under stirring, and adjusting pH to 6.0 with hydrochloric acid;
2) sterilizing and filtering the obtained solution by a secondary 0.22 mu m filter membrane, and filling and sealing the solution in a 2ml ampoule bottle;
3) and (4) performing terminal moist heat steam sterilization (121 ℃, 15min) to obtain a sulfated polysaccharide inhalation preparation (specification: 40mg, 20mg/ml, 2.0 ml/bottle; active pharmaceutical ingredients: dermatan sulfate).
Example 7
An inhalation preparation of sulfated polysaccharide having a sea cucumber glycosaminoglycan as an active pharmaceutical ingredient was prepared according to the formulation composition in table 7 and the following preparation steps:
table 7 example 7 formulation
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) Dissolving the formula amount of water for injection, the holothurian glycosaminoglycan and the glucose in a stirring way at room temperature, and adjusting the pH value to 6.0 by using sodium hydroxide;
2) the resulting solution was filtered through a second grade sterilization (0.22 μm);
3) aseptically filling into a 10ml ampoule bottle to obtain a sulfated polysaccharide inhalant preparation (specification: 200mg, 20mg/ml, 10.0 ml/bottle; active pharmaceutical ingredients: sea cucumber glycosaminoglycans).
Example 8
An inhalation preparation of sulfated polysaccharide having a sea cucumber fucosan as an active pharmaceutical ingredient was prepared according to the formulation composition in table 8 and the following preparation steps:
table 8 example 8 formulation
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) Dissolving the formula amount of water for injection, sea cucumber fucosan and glucose under stirring at room temperature, and adjusting the pH to 7.0 by using potassium hydroxide;
2) sterilizing and filtering the obtained solution by a secondary 0.22 mu m filter membrane, and filling and sealing the solution in a 2ml ampoule bottle;
3) and (4) performing terminal moist heat steam sterilization (121 ℃, 15min) to obtain a sulfated polysaccharide inhalation preparation (specification: 100mg, 50mg/ml, 2.0 ml; active pharmaceutical ingredients: sea cucumber fucosan).
Example 9
Sulfated polysaccharide inhalation formulations having active pharmaceutical ingredients of a combination of non-anticoagulant heparin, pentosan sulfate and holothurian glycosaminoglycan were prepared according to the formulation composition in table 9 and the following preparation steps:
table 9 example 9 formulation
Remarking: pH adjusting agent is adjusted according to the actual situation.
1) At room temperature, taking the formula amount of water for injection, non-anticoagulant heparin sodium, sodium pentosan sulfate, holothurian glycosaminoglycan and sodium chloride, stirring and dissolving, and adjusting the pH to 5.0 by hydrochloric acid;
2) the resulting solution was filtered through a second grade sterilization (0.22 μm);
3) aseptically filling into a 5ml ampoule bottle to obtain a sulfated polysaccharide inhalant preparation (specification: 250mg, 50mg/ml, 5.0 ml/bottle; active pharmaceutical ingredients: non-anticoagulant heparin, pentosan sulfate and holothurian glycosaminoglycan. While examples 1 to 9 above are specific embodiments of the preparation of a sulfated polysaccharide inhalation formulation for illustrating the present invention, it should be noted that the formulation and preparation method of the sulfated polysaccharide inhalation formulation are not limited to the specific examples described above, and any formulation based on the present invention and carried out accordingly should be covered within the scope of the present invention.
Example 10
And (3) testing: drug stability test
The formulations and preparation methods shown in Table 1 of example 1 were referred to, but sulfated polysaccharides as pharmaceutically active ingredients were transformed and sterilized by filtration to prepare multi-group sulfated polysaccharide inhalant preparation samples each having a size of 250mg, 50mg/ml and 5.0 ml. Samples were taken and placed under the test conditions of 40 + -2 ℃/RH75 + -5.0%, and the samples were taken at 1 month, 2 months and 3 months respectively, and the change conditions of indexes such as characters, contents, related substances and the like were examined, and the results are shown in Table 10.
Table 10 stability test results of sulfated polysaccharide inhalation formulations
And (4) analyzing results: the sulfated polysaccharide inhalation preparation has good stability. Under the test conditions of accelerating 40 +/-2 ℃/RH75 +/-5.0 percent, the characters have no obvious change, the content and related substances are stable under the high performance liquid detection, the storage lasts for more than 1 month, and the total amount of the related substances does not exceed 0.2 percent.
Example 11
Analysis of inhibitory Effect of sulfated polysaccharide as active ingredient on viruses at cellular level
This example examines the inhibitory effect of the sulfated polysaccharide (pentosan sulfate) and its non-sulfated polysaccharide (pentosan) on the new coronavirus at the cellular level.
Analysis of inhibitory Effect of sulfated polysaccharide as active ingredient on viruses at cellular level
This example examines the inhibitory effect of the sulfated polysaccharide (pentosan sulfate) and its non-sulfated polysaccharide (pentosan) on the new coronavirus at the cellular level.
1. Experimental materials:
test compounds: 1) pentosan sulfate, 2) pentosan (i.e., xylan);
cell: Vero-E6 cells (Vero cells).
2. The experimental method comprises the following steps:
1) taking Vero-E6 cells with good growth state for digestion and passage, diluting and adjusting the cell density to 1 × 105Each 100. mu.L/well was inoculated into a 96-well plate and placed at 37 ℃ in 5% CO2An incubator;
2) culturing for 16h, centrifuging, removing culture medium from the well, washing with 1 × PBS for three times, spin-drying, adding test compound 50 μ L with concentration of 10mg/ml into each well, adding SARS-CoV-2 virus 100 μ L (MOI 0.01), setting normal cell control and virus cell control, standing at 37 deg.C and 5% CO2Continuously culturing in an incubator;
3) after 48h of inoculation, the cell state changes of the tested compound and the virus after combined action are observed under a microscope and the results are recorded.
3. And (3) test results:
through microscope observation, the Vero-E6 cell growth state of the normal cell control group is good, the cell shape is complete, and the cell boundary is clear; the cells of the virus cell control group, namely the virus infected group have a wire drawing phenomenon, have no complete cell morphology and have obvious pathological changes; the tested compound group added with pentosan sulfate has good cell growth state, complete cell shape and no obvious pathological changes; in the control unsulfated polysaccharide (pentosan) group, the proportion of cytopathic variables was less than in the virus-infected group, and some reduction in the pathological changes was observed, but a considerable amount of cytopathic effects, stringiness, and a large number of cellular morphologies were observed.
Example 12
Analysis of Effect of sulfated polysaccharide as active ingredient on swelling of mouse auricle (anti-inflammatory Effect)
Inflammation is the defense response of living tissues with vascular systems to various inflammatory factors, and is the immune response of the body to the isohexide. The basic pathological changes of inflammation include degeneration, exudation and hyperplasia, with clinical manifestations of localized redness, swelling, heat, pain and dysfunction, and systemic reactions such as fever, leukocytosis, and proliferation of the monocyte-macrophage system. Excessive inflammatory response can adversely affect the body, causing secondary pathological injury. Infection of patients with the new coronavirus is mainly caused by lung cells, and after infection, the integrity of an alveolar capillary membrane is seriously damaged, and then inflammatory congestion appears. It is known that sulfated polysaccharides have certain anti-inflammatory effects, for example, heparin can act on acute and chronic inflammation in vitro and in vivo through various ways such as inhibiting selectin, and pentosan sulfate is the only approved drug for clinical interstitial cystitis at present. In this example, the anti-inflammatory effect of sulfated polysaccharides was examined by using an experimental model of inflammation caused by swelling of mouse auricle by xylene.
1. Experimental materials:
test compounds: holothurian glycosaminoglycan, chondroitin sulfate, pentosan sulfate, chondroitin sulfate.
Animals: mice, 18-23g, male and female halves, 6 per group.
2. The experimental method comprises the following steps:
preparing the medicine: preparing a tested compound into 50mg/mL by using deionized water; positive control: dexamethasone and deionized water are prepared into 50 mg/mL; blank control: and (3) water.
The administration mode comprises the following steps: tail vein injection.
The experimental process comprises the following steps: taking 36 healthy mice, randomly dividing 6 groups into 6 males and females, and respectively setting the groups as a sea cucumber glycosaminoglycan drug group, a chondroitin sulfate drug group, a pentosan sulfate drug group, a chondroitin sulfate drug group, a positive control group and a blank control group. The prepared drug solution is injected and administered according to the dose of 0.01ml/1g mouse body weight, the drug is continuously administered for 5 days, 30 mu L of dimethylbenzene is uniformly coated on the two sides of the right ear of the mouse after the last administration for 30min to cause inflammation, the left ear is used as a control, the cervical vertebra is taken off 1h after the inflammation to kill the mouse, the ear piece at the same part of the left ear and the right ear is taken down by a puncher, the weight is analyzed by a balance, and the auricle swelling rate and the auricle swelling inhibition rate are calculated.
3. Results of the experiment
TABLE 11 inhibition of LHG-p-xylene swelling of mouse pinna
| Group of | Rate of swelling | Inhibition rate of swelling |
| Sea cucumber glycosaminoglycan drug group | 108.6％±13.1％* | 20.4％ |
| Chondroitin sulfate drug group | 112.5％±11.2％* | 17.6％ |
| Pentosan sulfate pharmaceutical compositions | 101.6％±11.8％* | 25.5％ |
| Chondroitin persulfate pharmaceutical group | 115.2％±12.9％* | 15.6％ |
| Blank control group | 136.4％±14.7％ | - |
| Positive control group (dexamethasone) | 104.9％±11.3％* | 24.6％ |
Remarking: indicates P <0.05 compared to the blank control group.
The result shows that after the mouse auricle swelling caused by xylene is 1h, the swelling degree of the mouse auricle treated by all sulfated polysaccharide drug groups is reduced, and the difference is obvious (P is less than 0.05) compared with a blank control group, even is equivalent to that of a positive control group (dexamethasone), which indicates that the sulfated polysaccharide can effectively inhibit the mouse auricle swelling inflammatory reaction caused by xylene. Potentially, sulfated polysaccharides can be used to treat inflammation-related diseases such as respiratory inflammation caused by new coronavirus.
Example 13
Anticoagulant activity analysis of sulfated polysaccharides as active ingredients of drugs
This example examines the anticoagulant activity of the sulfated polysaccharide active pharmaceutical ingredient in vitro and the assay is performed according to the potency assay of sodium heparin USP32 (whole sheep plasma assay) with the following results:
TABLE 12 anticoagulant Activity of different sulfated polysaccharide samples (Whole sheep plasma method)
| Name/active pharmaceutical ingredient (/ control) | Anticoagulant activity U/mg |
| Non-anticoagulant heparin | 5.4 |
| Pentosan sulfate | 23.5 |
| PI-88 | 18.6 |
| Chondroitin sulfate | 20.2 |
| Chondroitin persulfate | 49.8 |
| Dermatan sulfate | 23.1 |
| Sea cucumber fucosan | 23.4 |
| Sea cucumber glycosaminoglycans | 24.3 |
| Heparin sodium | 184.7 |
Remarking: mean values from three or more batches of samples.
The results show that: the in vitro anticoagulant activity of most sulfated polysaccharide samples is between 5 and 25U/mg, and has certain anticoagulant activity, but is obviously lower than that of a clinical anticoagulant drug, namely heparin sodium (at 180U/mg or above); the anticoagulant activity of the chondroitin persulfate is stronger and is about 50U/mg. The strength of the anticoagulant activity depends on the sugar unit structure and the composition of the sulfated polysaccharide, and is also related to the degree of sulfation modification. In addition, lower anticoagulant activity suggests a low risk of bleeding.
Example 14
Analysis of antithrombotic Effect of sulfated polysaccharide As pharmaceutical active ingredient
Thrombosis is a pathological cause of venous thrombosis, and pulmonary venous embolism and obstruction are easily caused after new coronavirus infection, so that pulmonary function is reduced or inactivated. Thrombus can aggravate a series of related diseases, and death of patients is easily caused when the diseases are serious, so that the thrombus is one of important causes of death of new coronary patients in the world. Therefore, finding an antithrombotic drug suitable for resisting the new coronavirus has important clinical significance.
1. Experimental materials:
test compounds: non-anticoagulant heparin, pentosan sulfate, pI-88 and holothurian glycosaminoglycan.
Animals: SD rats, male, 3 per group, 230. + -.30 g.
2. The experimental method comprises the following steps:
dosage: 30 mg/Kg; negative control: physiological saline; positive control: warfarin, 1.5 mg/Kg.
The administration mode comprises the following steps: intravenous injection, and administration by intragastric administration of warfarin (after 30 min).
Rats were acclimatized and fasted for one day, and were given a 20% solution of urethane intraperitoneally 2min after dosing and before surgery. The abdominal skin of the anesthetized rat is prepared, sterilized and the abdominal cavity is opened along the leucorrhea line. The small intestine and other organs are pulled out of the abdominal cavity and wrapped with gauze soaked with normal saline. The perivascular connective tissue was isolated blunt, exposing the inferior vena cava and its branches. The abdominal aorta and inferior vena cava were peeled off below the renal veins, and the inferior vena cava was ligated with saline-soaked sutures at the junction of the inferior vena cava and left renal vein. The organ pulled out of the abdominal cavity is placed back into the abdominal cavity according to the anatomical position, and the abdominal cavity is sutured layer by the suture line. After the operation, the rat was placed in an environment of 25 ℃ for 4 hours for blood circulation, the abdominal cavity was opened again, the branches were ligated one by one, 2cm of inferior vena cava was taken out from the ligation site at the junction of the inferior vena cava and left renal vein, and the thrombus was taken out therefrom and weighed.
3. As a result:
TABLE 13 anti-thrombotic Activity of different sulfated polysaccharide samples
| Compounds/doses | Suppository weight (mg) |
| Physiological saline | 17.2±5.1 |
| Warfarin (1.5mg/Kg) | 8.1±2.4** |
| Non-anticoagulant heparin (30mg/Kg) | 10.1±3.9* |
| Pentosan sulfate (30mg/Kg) | 10.3±4.2* |
| pI-88(30mg/Kg) | 9.3±3.3* |
| Sea cucumber glycosaminoglycan (30mg/Kg) | 5.8±4.3** |
Remarking: p <0.05, P <0.01 in comparison to saline group.
As shown in the above table, the suppository weight of rats treated with venous embolism by each sulfated polysaccharide dose group (30mg/Kg) is significantly smaller than that of rats treated with normal saline, wherein the suppository weight of rats treated with holothurian glycosaminoglycan has no significant difference with that of rats treated with 1.5mg/Kg warfarin by intragastric administration. The experimental results show that each sulfated polysaccharide has good anti-venous thrombosis activity. Potentially, can be applied to the prevention and treatment of the diseases related to the thrombo-embolism.
Example 15:
analysis of inhibitory Effect of sulfated polysaccharide inhalation preparation on viral pneumonia in mice
In the course of disease progression of a new coronavirus patient, pulmonary capillaries can be seriously damaged, inflammatory hyperemia appears, and then a thromboembolism or a pulmonary obstruction is caused, meanwhile, fibroblasts in the lung can carry out compensatory proliferation and differentiation in order to make up for damaged parts, a large amount of fibrotic tissues without a gas exchange function can replace alveoli, so that pulmonary fibrosis is gradually caused, once the pulmonary fibrosis is formed, the ventilation function of an organism is reduced, the amount of oxygen entering blood is insufficient, the patient can have hypoxia and dyspnea, and severe patients can have acute respiratory distress syndrome and multiple organ dysfunction syndrome and then die. Therefore, the finding of the medicine suitable for resisting the new coronavirus is of great clinical significance. The sulfated polysaccharide has anti-inflammatory and antithrombotic anticoagulant activity, and can effectively prevent and treat local inflammation and blood coagulation embolism (especially pulmonary embolism), prevent, slow and repair inflammatory reaction, and protect the functions of organs such as lung.
Since animal models of pneumonia caused by new coronavirus (infection, inflammation and thrombo-embolism) are difficult to obtain, similar animal models of pneumonia caused by influenza virus are selected in the present example, and the treatment or prevention effect of the inhalation preparation group of sulfated polysaccharides (including but not limited to holothurian glycosaminoglycan, pentosan sulfate and non-anticoagulant heparin on infection, inflammation and thrombo-embolism caused by virus is simulated and examined.
1. Experimental materials:
the tested drugs are: sea cucumber glycosaminoglycan inhalation preparations, pentosan sulfate inhalation preparations, and non-anticoagulant heparin inhalation preparations.
Virus: influenza A H1N1 mouse lung adapted strain (FM/1/47 strain). Passage of chick embryo, detection in BSL-3 laboratory, split charging, and preservation at-80 deg.C.
Animals: SD rats, 200. + -.20 g, male.
2. The experimental method comprises the following steps:
low dose: 10mg/kg/d, the administration concentration is 20mg/ml, and the administration volume is 0.5 ml/kg;
high dose: 50mg/kg/d, the administration concentration of 100mg/ml and the administration volume of 0.5 ml/kg;
blank model comparison: physiological saline; positive control: duffy, 10 mg/kg/d.
The administration mode comprises the following steps: atomizing for oral inhalation, and administering by intragastric administration.
The male SD rats are randomly divided into 8 groups of 6 rats, namely a blank model control group, a Tamiflu control group, a holothurian glycosaminoglycan inhalation preparation low-dose group, a holothurian glycosaminoglycan inhalation preparation high-dose group, a pentosan sulfate inhalation preparation low-dose group, a pentosan sulfate inhalation preparation high-dose group, a non-anticoagulated heparin inhalation preparation low-dose group and a non-anticoagulated heparin inhalation preparation high-dose group, wherein each group comprises 10 rats. Animals in each experimental group were lightly anesthetized with ether and nasally infected with 15 drops of FM1 influenza virus, LD50, 200 μ L each. The treatment groups started with 24h of infection and were dosed every 12h for 5 consecutive days. The blank control group and the test drug group (low/high dose group) were administered daily by oral inhalation after nebulization with a nebulizer, and by gavage with duffy. Weighing after day 6, then killing, dissecting, taking lung, weighing, and calculating lung index and lung index inhibition rate.
3. As a result:
TABLE 14 Effect of different sulfated polysaccharide inhalation formulations on pulmonary index in rat model of pneumonia
Remarking: p <0.05, P <0.01, compared to the blank model control group.
The pulmonary index reflects the severity of pneumonia, with larger numbers indicating more severe pneumonia. The results in the table show that the low-dose and high-dose sulfated polysaccharide inhalation preparations can obviously reduce the pulmonary index of virus-infected rats and present a certain dose-effect relationship, which indicates that the sulfated polysaccharide inhalation preparations have the effects of preventing and treating viral pneumonia and can be potentially applied to the prevention and treatment of diseases related to new coronavirus infection.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (17)
1. An inhalation formulation of sulfated polysaccharide comprising a sulfated polysaccharide and a pharmaceutically acceptable excipient.
2. The sulfated polysaccharide inhalation formulation of claim 1, wherein the sulfated polysaccharide comprises one or more of non-anticoagulant heparin, pentosan sulfate, PI-88, chondroitin sulfate, dermatan sulfate, sea cucumber glycosaminoglycans, and sea cucumber fucoidans.
3. Inhalation formulation of sulfated polysaccharides according to claim 1, wherein the pharmaceutically acceptable adjuvants comprise isotonic and/or pH adjusting agents and solvents.
4. The sulfated polysaccharide inhalation formulation of claim 3, wherein the isotonicity adjusting agent is a combination of one or more of sodium chloride, potassium chloride, glucose and mannitol.
5. The sulfated polysaccharide inhalation formulation of claim 3, wherein the pH adjusting agent is a combination of one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide.
6. The sulfated polysaccharide inhalation formulation of claim 3, wherein the solvent is water.
7. The sulfated polysaccharide inhalation formulation according to claim 1, comprising in parts by weight:
the sulfated polysaccharide comprises one or more of non-anticoagulant heparin, pentosan sulfate, PI-88, chondroitin sulfate, dermatan sulfate, sea cucumber glycosaminoglycan and sea cucumber fucosan, the isotonic regulator is one or more of sodium chloride, potassium chloride, glucose and mannitol, the pH regulator is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide and potassium hydroxide, and the solvent is water.
8. The sulfated polysaccharide inhalation formulation according to claim 7, comprising in parts by weight:
9. the sulfated polysaccharide inhalation formulation of claim 1, wherein the sulfated polysaccharide inhalation formulation is an aerosolized inhalation formulation for oral inhalation.
10. The sulfated polysaccharide inhalation formulation of claim 1, wherein the sulfated polysaccharide inhalation formulation is obtained by placing a liquid drug in an atomizing device.
11. The sulfated polysaccharide inhalation formulation of claim 1, wherein the formulation is a sterile solution.
12. A process for the preparation of an inhaled formulation of a sulfated polysaccharide according to any one of claims 1 to 11, comprising the steps of:
taking sulfated polysaccharide, isotonic regulator and water for injection according to the formula amount, stirring and dissolving at room temperature, regulating pH value with pH regulator, filtering the solution, and bottling to obtain sulfated polysaccharide inhalation preparation.
13. The method of making an inhaled sulfated polysaccharide formulation according to claim 12, further comprising the step of filtration sterilization or/and steam terminal sterilization prior to encapsulation.
14. A method of preparing an inhaled formulation of a sulfated polysaccharide according to claim 12, wherein the method comprises:
(1) the formula is as follows: sulfated polysaccharide 50.0g and sodium chloride 4.0g, appropriate amount of hydrochloric acid, and injectable water to 1000 ml;
(2) adding sulfated polysaccharide, sodium chloride and water for injection in the formula amount in the step (1), dissolving, adjusting pH to 5.0 with hydrochloric acid, sterilizing, filtering, and aseptically packaging in 5ml ampoule bottle.
15. Use of an inhaled sulfated polysaccharide formulation according to any one of claims 1 to 11 in the manufacture of a medicament for the prevention and treatment of a new coronavirus related disease.
16. The use according to claim 15, wherein said new coronavirus related diseases comprise respiratory infections, inflammation and thrombo-embolism caused by new coronavirus.
17. Use of an inhaled formulation of sulfated polysaccharide according to any one of claims 1 to 11 for the preparation of a medicament for the prevention and treatment of respiratory infections, inflammation and thromboembolism caused by influenza, adenovirus, respiratory syncytial virus, parainfluenza, rhinovirus, cytomegalovirus, epstein barr virus and coronavirus.
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