WO2019059867A1 - Hemostatic compositions of chitosan and alginate - Google Patents

Hemostatic compositions of chitosan and alginate Download PDF

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Publication number
WO2019059867A1
WO2019059867A1 PCT/TR2018/050506 TR2018050506W WO2019059867A1 WO 2019059867 A1 WO2019059867 A1 WO 2019059867A1 TR 2018050506 W TR2018050506 W TR 2018050506W WO 2019059867 A1 WO2019059867 A1 WO 2019059867A1
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Prior art keywords
alginate
μηι
composition according
chitosan
granule composition
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PCT/TR2018/050506
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French (fr)
Inventor
Dicle Güner
Özlem KENAR
Arzu Palantöken
Ali TÜRKYILMAZ
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Montero Gida Sanayi Ve Ticaret Anonim Sirketi
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Publication of WO2019059867A1 publication Critical patent/WO2019059867A1/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0052—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/04—Alginic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the present invention relates to pharmaceutical hemostatic compositions in the form of granule comprising chitosan or pharmaceutically acceptable salts thereof and alginate.
  • Bleeding also known as hemorrhaging or haemorrhaging, is blood escaping from the circulatory system. Bleeding can occur internally, where blood leaks from blood vessels inside the body, or externally, either through a natural opening such as the mouth, nose, ear, urethra, vagina or anus, or through a break in the skin. Excessive blood loss is one of the leading causes of death following severe injury in the battlefield or civilian world. The stopping or controlling of bleeding is called hemostasis and is an important part of both first aid and surgery.
  • Chitosan is a derivative of chitin and it is modified natural, biodegradable, biocompatible, non toxic, as well as linear nitrogenous polysaccharides, a basic polysaccharide homo- polymer. It is a cationic polysaccharide derived from the partial deacetylation of chitin from the exoskeleton of crustaceans, including shrimp, lobster, and crabs. Its chemical structure is shown in the formula 1 .
  • Alginate is the term usually used for the salts of alginic acid, but it can also refer to all the derivatives of alginic acid and alginic acid itself. Alginate is present in the cell walls of brown algae as the calcium, sodium, potassium and magnesium salts of alginic acid. Alginate is a naturally occurring anionic polymer typically obtained from brown seaweed, and has been extensively investigated and used for many biomedical applications, due to its biocompatibility, low toxicity, relatively low cost, and mild gelation by addition of divalent cations. Structure of alginic acid is shown in the Formula 2.
  • EP1976537 discloses a powder composition comprising a chitosan salt and a medical surfactant for use in controlling bleeding.
  • Patent application WO2007009050 discloses a hemostatic agent comprising a hemostatic material such as chitosan in a granule or particle form.
  • EP2683345 patent application relates to a haemostatic material which comprising hemostat agent such as chitosan and a bioadhesive agent for use in controlling bleeding.
  • WO2016120620 describes a solid composition comprising chitosan and at least one triprotic acid.
  • the main object of the present invention is to provide hemostatic granule compositions comprising chitosan or pharmaceutically acceptable salts thereof and alginate.
  • a further object of the present invention is to provide stable granule compositions which doesn't degrade in difficult storage conditions such as hot, cold or humid enviroments.
  • Another object of the present invention is to provide sterile granule compositions which reduces the risk of infection by its antimicrobial, antibacterial and antifungal properties.
  • Another object of the present invention is to provide a hemostatic granule composition with optimum porosity.
  • a further object of the present invention is to provide a biodegradable hemostatic composition.
  • the present invention relates to hemostatic granule compositions comprising chitosan or pharmaceutically acceptable salts thereof and alginate.
  • the granule composition comprises chitosan or pharmaceutically acceptable salts thereof and alginate, wherein the weight ratio of chitosan or pharmaceutically acceptable salts thereof to alginate is between 0.25 and
  • the term "granule” refers to aggregations of fine particles of powders.
  • the amount of chitosan or pharmaceutically acceptable salts thereof is 10.00% to 40.00% by weight of the total composition.
  • the amount of alginate or pharmaceutically acceptable salts thereof is 10.00% to 40.00% by weight of the total composition.
  • the weight ratio of chitosan or pharmaceutically acceptable salts thereof to alginate is between 0.25 and 4.00.
  • 'particle size distribution means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis).
  • Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles, as illustrated below.
  • the angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering.
  • the particle size is reported as a volume equivalent sphere diameter.
  • D10 means, the size at which 10% by volume of the particles are finer
  • D50 means the size at which 50% by volume of the particles are finer
  • D90 means the size at which 90% by volume of the particles are finer.
  • the D10 particle size value of alginate is ranging between 1 ⁇ to 100 ⁇ . Preferably this value is ranging between 5 ⁇ to 45 ⁇ . In the preferred embodiment of the invention, the D50 particle size value of alginate is ranging between 10 ⁇ to 200 ⁇ . Preferably this value is ranging between 25 ⁇ to 150 ⁇ .
  • the D90 particle size value of alginate is ranging between 50 ⁇ to 300 ⁇ . Preferably this value is ranging between 75 ⁇ to 270 ⁇ .
  • the D10 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 1 ⁇ to 100 ⁇ . Preferably this value is ranging between 20 ⁇ to 80 ⁇ .
  • the D50 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 50 ⁇ to 200 ⁇ . Preferably this value is ranging between 100 ⁇ to 180 ⁇ . In one preferred embodiment, the D90 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 100 ⁇ to 400 ⁇ . Preferably this value is ranging between 250 ⁇ to 350 ⁇ .
  • the ratio of the D90 particle size value of alginate to the D90 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 0.1 and 1.0.
  • alginate is selected from sodium alginate, calcium alginate, potassium alginate and magnesium alginate.
  • the alginate is sodium alginate.
  • the D90 particle size value of sodium alginate is ranging between 250 ⁇ to 280 ⁇ .
  • the alginate is calcium alginate.
  • the D90 particle size value of calcium alginate is ranging between 60 ⁇ to 80 ⁇ . Owing to these ratios, optimum porosity which is essential for optimized blood absorption capability is obtained.
  • the composition further comprises stabilizing agents, acidifying agents, solvents, diluents or mixtures thereof.
  • Suitable stabilizing agents are selected from polyvinyl alcohol, acacia, agar, alginic acid, aluminum monostearate, ammonium alginate, bentonite, calcium stearate, carbomer, carboxymethylcellulose sodium, carrageenan, cellulose, microcrystalline and carboxymethylcellulose sodium, cyclodextrin, ethylene glycol stearates, glyceryl monostearate, hydroxypropyl cellulose, hypromellose, lecithin, magnesium aluminum silicate, monoethanolamine, pectin, poloxamer, propylene glycol, propylene glycol alginate, raffinose, trehalose, xanthan gum, zinc acetate or mixtures thereof.
  • the stabilizing agent is polyvinyl alcohol.
  • the stabilizing agent is present in an amount of between 10.0% and 25.0% by weight of the total composition.
  • the stabilizing agent When the stabilizing agent is used in these specific ratios, the problem of stability of chitosan which is due to hygroscopic properties of chitosan and alginate, is solved and the stability of the granule composition is ensured. Thus, the long shelf-life, even in difficult conditions, is provided.
  • Suitable acidifying agents are selected from acetic acid, citric acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, formic acid, monobasic potassium phosphate, phosphoric acid, sodium dihydrogen phosphate dihydrate, tartaric acid, aluminum potassium sulfate, anhydrous citric acid, anhydrous sodium dihydrogen phosphate or mixtures thereof.
  • the acidifying agent is acetic acid.
  • the acidifying agent is present in an amount of between 10.0% and 30.0% by weight of the total composition.
  • Suitable solvents are selected from water, alcohol, methlylen chloride, acetone, ethanol, diclorometan, n-hexane, dioxane, chloroform, dimethylformamide, dimethyl sulfoxide, propanol ,1 -butanol, 2-butanol, ethyl acetate, ethyl ether, heptane, pentane, 1 -pentanol, 1 - propanol, 2-propanol or mixtures thereof.
  • the solvent is alcohol or water.
  • Suitable diluents are selected from calcium carbonate, calcium phosphate, lactose monohydrate, lactose, dibasic calcium phosphate, microcrystalline cellulose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, or mixtures thereof.
  • the composition comprises;
  • the granule compositions mentioned above are prepared by following these steps: a. dispersing sodium alginate in the water/alcohol mixture by mixing them for one day at room temperature (first solution)
  • compositions mentioned above are prepared by following these steps: a. dispersing calcium alginate in the water/alcohol mixture by mixing them for one day at room temperature (first solution)

Abstract

The present invention relates to pharmaceutical hemostatic compositions in the form of granule comprising chitosan or pharmaceutically acceptable salts thereof and alginate.

Description

HEMOSTATIC COMPOSITIONS OF CHITOSAN AND ALGINATE
Technical Field
The present invention relates to pharmaceutical hemostatic compositions in the form of granule comprising chitosan or pharmaceutically acceptable salts thereof and alginate.
Background of the Invention
Bleeding, also known as hemorrhaging or haemorrhaging, is blood escaping from the circulatory system. Bleeding can occur internally, where blood leaks from blood vessels inside the body, or externally, either through a natural opening such as the mouth, nose, ear, urethra, vagina or anus, or through a break in the skin. Excessive blood loss is one of the leading causes of death following severe injury in the battlefield or civilian world. The stopping or controlling of bleeding is called hemostasis and is an important part of both first aid and surgery.
Chitosan is a derivative of chitin and it is modified natural, biodegradable, biocompatible, non toxic, as well as linear nitrogenous polysaccharides, a basic polysaccharide homo- polymer. It is a cationic polysaccharide derived from the partial deacetylation of chitin from the exoskeleton of crustaceans, including shrimp, lobster, and crabs. Its chemical structure is shown in the formula 1 .
Figure imgf000002_0001
= H or COCH3
Formula 1 "Alginate" is the term usually used for the salts of alginic acid, but it can also refer to all the derivatives of alginic acid and alginic acid itself. Alginate is present in the cell walls of brown algae as the calcium, sodium, potassium and magnesium salts of alginic acid. Alginate is a naturally occurring anionic polymer typically obtained from brown seaweed, and has been extensively investigated and used for many biomedical applications, due to its biocompatibility, low toxicity, relatively low cost, and mild gelation by addition of divalent cations. Structure of alginic acid is shown in the Formula 2.
Figure imgf000003_0001
In prior art, there are patents relating to hemostatic compositions. EP1976537 discloses a powder composition comprising a chitosan salt and a medical surfactant for use in controlling bleeding. Patent application WO2007009050 discloses a hemostatic agent comprising a hemostatic material such as chitosan in a granule or particle form. EP2683345 patent application relates to a haemostatic material which comprising hemostat agent such as chitosan and a bioadhesive agent for use in controlling bleeding. WO2016120620 describes a solid composition comprising chitosan and at least one triprotic acid.
There is a need in the art for a hemostatic composition which having sufficient hemostatic effect and long shelf-life. Chitosan and alginate have different mechanisms of hemostasis. Using these polymers in one dosage form ensures the desired hemostatic effect. However, it's known that the problem of poor stability of chitosan-based products which as a result of hygroscopic properties of chitosan, restricts its practical applicability. Thus, it has become a great challenge to establish sufficient shelf-life for chitosan formulations. Since the present invention comprises alginate which is essential to provide desired hemostatic effect, due to its hygroscopic properties, this problem is more significant. US5836970 describes a wound dressing comprising chitosan and alginate. This patent disclosed the bacteriostatic and hemostatic properties of chitosan and the absorbency of alginate. US2016346239 relates to hemostatic compositions comprising calcium alginate; a chitosan; epsilon-aminocaproic acid; an acid selected from aminomethylbenzoic acid and tranexamic acid; and tannin.
There is still a need in the art to develop a safe, efficient, biodegradable, non-toxic and stable pharmaceutical composition having hemostatic effect and bacteriostatic activity. By this need, the stable formulation having bacteriostatic activity and high hemostatic effect which is provided with good blood absorption capability and optimum porosity has been developed for use in controlling bleeding.
Detailed description of the invention The main object of the present invention is to provide hemostatic granule compositions comprising chitosan or pharmaceutically acceptable salts thereof and alginate.
A further object of the present invention is to provide stable granule compositions which doesn't degrade in difficult storage conditions such as hot, cold or humid enviroments.
Another object of the present invention is to provide sterile granule compositions which reduces the risk of infection by its antimicrobial, antibacterial and antifungal properties.
Another object of the present invention is to provide a hemostatic granule composition with optimum porosity.
A further object of the present invention is to provide a biodegradable hemostatic composition. The present invention relates to hemostatic granule compositions comprising chitosan or pharmaceutically acceptable salts thereof and alginate.
According to this invention, the granule composition comprises chitosan or pharmaceutically acceptable salts thereof and alginate, wherein the weight ratio of chitosan or pharmaceutically acceptable salts thereof to alginate is between 0.25 and As used herein, the term "granule" refers to aggregations of fine particles of powders.
In one embodiment, the amount of chitosan or pharmaceutically acceptable salts thereof is 10.00% to 40.00% by weight of the total composition.
In one embodiment, the amount of alginate or pharmaceutically acceptable salts thereof is 10.00% to 40.00% by weight of the total composition. During the development study of this invention, it has been observed that, hemostatic effect of the composition is provided by using chitosan and alginate in a specific amount.
According to these embodiments, the weight ratio of chitosan or pharmaceutically acceptable salts thereof to alginate is between 0.25 and 4.00.
Surprisingly, it has been found that, when chitosan and alginate are used in one dosage form, the particle size distributions of alginate and chitosan or pharmaceutically acceptable salts thereof play a significant role for hemostatic effect of the granule composition. These specific values ensure optimum porosity for the composition. Porosity determines the blood absorption capability which is essential for providing the hemostatic effect of the composition. When the particle size of chitosan or pharmaceutically acceptable salts thereof and alginate is chosen in specific ranges, optimized blood absorption capability which is very important for use in controlling bleeding is obtained.
As used herein, 'particle size distribution' means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis). Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles, as illustrated below. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter. According to this measuring method, the term D10 means, the size at which 10% by volume of the particles are finer and D50 means the size at which 50% by volume of the particles are finer and D90 means the size at which 90% by volume of the particles are finer.
In the preferred embodiment, the D10 particle size value of alginate is ranging between 1 μηι to 100 μηι. Preferably this value is ranging between 5 μηι to 45 μηι. In the preferred embodiment of the invention, the D50 particle size value of alginate is ranging between 10 μηι to 200 μηι. Preferably this value is ranging between 25 μηι to 150 μηι.
In the preferred embodiment, the D90 particle size value of alginate is ranging between 50 μηι to 300 μηι. Preferably this value is ranging between 75 μηι to 270 μηι.
In one preferred embodiment, the D10 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 1 μηι to 100 μηι. Preferably this value is ranging between 20 μηι to 80 μηι.
In the preferred embodiment of the invention, the D50 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 50 μηι to 200 μηι. Preferably this value is ranging between 100 μηι to 180 μηι. In one preferred embodiment, the D90 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 100 μηι to 400 μηι. Preferably this value is ranging between 250 μηι to 350 μηι.
In one embodiment, the ratio of the D90 particle size value of alginate to the D90 particle size value of chitosan or pharmaceutically acceptable salts thereof is ranging between 0.1 and 1.0.
In one embodiment, alginate is selected from sodium alginate, calcium alginate, potassium alginate and magnesium alginate.
In a preferred embodiment, the alginate is sodium alginate. According to this preferred embodiment, the D90 particle size value of sodium alginate is ranging between 250 μηι to 280 μηι. In a preferred embodiment, the alginate is calcium alginate.
According to this preferred embodiment, the D90 particle size value of calcium alginate is ranging between 60 μηι to 80 μηι. Owing to these ratios, optimum porosity which is essential for optimized blood absorption capability is obtained.
According to one embodiment, the composition further comprises stabilizing agents, acidifying agents, solvents, diluents or mixtures thereof.
Suitable stabilizing agents are selected from polyvinyl alcohol, acacia, agar, alginic acid, aluminum monostearate, ammonium alginate, bentonite, calcium stearate, carbomer, carboxymethylcellulose sodium, carrageenan, cellulose, microcrystalline and carboxymethylcellulose sodium, cyclodextrin, ethylene glycol stearates, glyceryl monostearate, hydroxypropyl cellulose, hypromellose, lecithin, magnesium aluminum silicate, monoethanolamine, pectin, poloxamer, propylene glycol, propylene glycol alginate, raffinose, trehalose, xanthan gum, zinc acetate or mixtures thereof.
In a preferred embodiment, the stabilizing agent is polyvinyl alcohol.
In one embodiment, the stabilizing agent is present in an amount of between 10.0% and 25.0% by weight of the total composition.
When the stabilizing agent is used in these specific ratios, the problem of stability of chitosan which is due to hygroscopic properties of chitosan and alginate, is solved and the stability of the granule composition is ensured. Thus, the long shelf-life, even in difficult conditions, is provided.
Suitable acidifying agents are selected from acetic acid, citric acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, formic acid, monobasic potassium phosphate, phosphoric acid, sodium dihydrogen phosphate dihydrate, tartaric acid, aluminum potassium sulfate, anhydrous citric acid, anhydrous sodium dihydrogen phosphate or mixtures thereof.
In a preferred embodiment, the acidifying agent is acetic acid.
In one embodiment, the acidifying agent is present in an amount of between 10.0% and 30.0% by weight of the total composition.
Suitable solvents are selected from water, alcohol, methlylen chloride, acetone, ethanol, diclorometan, n-hexane, dioxane, chloroform, dimethylformamide, dimethyl sulfoxide, propanol ,1 -butanol, 2-butanol, ethyl acetate, ethyl ether, heptane, pentane, 1 -pentanol, 1 - propanol, 2-propanol or mixtures thereof.
In a preferred embodiment, the solvent is alcohol or water.
Suitable diluents are selected from calcium carbonate, calcium phosphate, lactose monohydrate, lactose, dibasic calcium phosphate, microcrystalline cellulose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, or mixtures thereof.
In one embodiment, the composition comprises;
a. 10.0% to 40.0% chitosan or pharmaceutically acceptable salts thereof b. 10.0% to 40.0% alginate
c. 10.0% to 25.0% polyvinyl acohol
d. 10.0% to 30.0% acetic acid
e. 10.0% to 30.0% alcohol The granule compositions mentioned above are prepared by following these steps:
a. dispersing alginate in the water/alcohol mixture by mixing them for one day at room temperature (first solution)
b. on the other hand, adding chitosan, polyviny alcohol and glacial acetic acid to the other half of the water under stirrer (second solution)
c. mixing the second solution for 24 hours
d. mixing the first solution and the second solution for 2 hours e. placing the solution in the freeze-drying flasks and freezing for 24 hours f. lyophilizing for 96 hours or drying until dry granules are obtained
Example 1 :
Figure imgf000009_0001
Water and alcohol have been removed during the drying process.
The granule compositions mentioned above are prepared by following these steps: a. dispersing sodium alginate in the water/alcohol mixture by mixing them for one day at room temperature (first solution)
b. on the other hand, adding chitosan, polyviny alcohol and glacial acetic acid to the other half of the water under stirrer (second solution)
c. mixing the second solution for 24 hours at 50 °C
d. mixing the first solution and the second solution for 2 hours
e. placing the solution in the freeze-drying flasks and freezing at -80 °C for 24 hours f. lyophilizing at -85 °C for 96 hours or drying at 50°C until dry granules are obtained
Example 2:
Figure imgf000009_0002
Water and alcohol have been removed during the drying process The granule compositions mentioned above are prepared by following these steps: a. dispersing calcium alginate in the water/alcohol mixture by mixing them for one day at room temperature (first solution)
b. on the other hand, adding chitosan, polyviny alcohol and glacial acetic acid to the other half of the water under stirrer (second solution)
c. mixing the second solution for 24 hours at 50 °C
d. mixing the first solution and the second solution for 2 hours
e. placing the solution in the freeze-drying flasks and freezing at -80 °C for 24 hours f. lyophilizing at -85 °C for 96 hours or drying at 50°C until dry granules are obtained

Claims

1 . A granule composition comprising chitosan or pharmaceutically acceptable salts thereof and alginate, wherein the weight ratio of chitosan or pharmaceutically acceptable salts thereof to alginate is between 0.25 and 4.00.
2. The granule composition according to claim 1 , wherein the D10 particle size value of alginate is ranging between 1 μηι to 100 μηι.
3. The granule composition according to claim 1 , wherein the D50 particle size value of alginate is ranging between 10 μηι to 200 μηι
4. The granule composition according to claim 1 , wherein the D90 particle size value of alginate is ranging between 50 μηι to 300 μηι.
5. The granule composition according to claim 1 , wherein the D10 particle size value of chitosan is ranging between 1 μηι to 100 μηι.
6. The granule composition according to claim 1 , wherein the D50 particle size value of chitosan is ranging between 50 μηι to 200 μηι.
7. The granule composition according to claim 1 , wherein the D90 particle size value of chitosan is ranging between 100 μηι to 400 μηι.
8. The granule composition according to any of the preceeding claims, wherein the ratio of the D90 particle size value of chitosan or pharmaceutically acceptable salts thereof to D90 particle size value of alginate is between 0.1 and 1 .0.
9. The granule composition according to any of the preceeding claims, wherein said alginate is sodium alginate.
10. The granule composition according to claim 9, wherein the D90 particle size value of sodium alginate is ranging between 250 μηι to 280 μηι.
1 1 . The granule composition according to any of the preceeding claims, wherein said alginate is calcium alginate.
12. The granule composition according to claim 1 1 , wherein the D90 particle size value of calcium alginate is ranging between 60 μηι to 80 μηι.
13. The granule composition according to claim 1 , wherein the amount of chitosan or pharmaceutically acceptable salts thereof is 10.00% to 40.00% by weight of the total composition.
14. The granule composition according to claim 1 , wherein the amount of alginate or pharmaceutically acceptable salts thereof is 10.00% to 40.00% by weight of the total composition.
15. The granule composition according to any of the preceding claims, wherein the composition further comprising stabilizing agents, acidifying agents, solvents, diluents or mixtures thereof.
16. The granule composition according to claim 15, wherein the stabilizing agent is selected from a group comprising polyvinyl alcohol, acacia, agar, alginic acid, aluminum monostearate, ammonium alginate, bentonite, calcium stearate, carbomer, carboxymethylcellulose sodium, carrageenan, cellulose, microcrystalline and carboxymethylcellulose sodium, cyclodextrin, ethylene glycol stearates, glyceryl monostearate, hydroxypropyl cellulose, hypromellose, lecithin, magnesium aluminum silicate, monoethanolamine, pectin, poloxamer, propylene glycol, propylene glycol alginate, raffinose, trehalose, xanthan gum, zinc acetate or mixtures thereof, preferably the stabilizing agent is polyviny alcohol.
17. The granule composition according to claim 16, wherein the stabilizing agent is present in an amount of between 10.0% and 25.0% by weight of the composition.
18. The granule composition according to claim 15, wherein the acidifying agent is selected from a group comprising acetic acid, citric acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, formic acid, monobasic potassium phosphate, phosphoric acid, sodium dihydrogen phosphate dihydrate, tartaric acid, aluminum potassium sulfate, anhydrous citric acid, anhydrous sodium dihydrogen phosphate or mixtures thereof, preferably the acidifying agent is acetic acid.
19. The granule composition according to claim 18, the acidifying agent is present in an amount of between 10.0% and 30.0% by weight of the total composition.
20. The pharmaceutical composition according to any of the preceding claims, comprising:
a. 10.0% to 40.0% chitosan or pharmaceutically acceptable salts thereof b. 10.0% to 40.0% alginate
c. 10.0% to 25.0% polyvinyl acohol
d. 10.0% to 30.0% acetic acid
e. 10.0% to 30.0% alcohol 21 . The process for preparation of the composition according to claim 20, wherein the process comprising the following steps:
a. dispersing alginate in the water/alcohol mixture by mixing them for one day at room temperature (first solution)
b. on the other hand, adding chitosan, polyviny alcohol and glacial acetic acid to the other half of the water under stirrer (second solution) c. mixing the second solution for 24 hours
d. mixing the first solution and the second solution for 2 hours
e. placing the solution in the freeze-drying flasks and freezing for 24 hours f. lyophilizing for 96 hours or drying until dry granules are obtained
PCT/TR2018/050506 2017-09-20 2018-09-19 Hemostatic compositions of chitosan and alginate WO2019059867A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
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CN113521379A (en) * 2021-07-12 2021-10-22 重庆大清海德生物技术有限公司 Preparation method of large-wound chitosan hemostatic particles
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CN115531596A (en) * 2021-06-30 2022-12-30 苏州美创医疗科技有限公司 Hemostatic gel composition and method of making same
CN115779136A (en) * 2022-12-15 2023-03-14 湖南中腾湘岳生物科技有限公司 Medical hemostatic material and preparation method thereof
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CN111729126A (en) * 2020-07-10 2020-10-02 北京红立方医疗设备有限公司 Hemostatic material based on combination of chitosan and tissue factor and preparation method thereof
CN111729126B (en) * 2020-07-10 2022-04-05 北京红立方医疗设备有限公司 Hemostatic material based on combination of chitosan and tissue factor and preparation method thereof
WO2022038637A1 (en) * 2020-08-18 2022-02-24 Amrita Vishwa Vidyapeetham Hemostatic agent and method of production thereof
CN115531596A (en) * 2021-06-30 2022-12-30 苏州美创医疗科技有限公司 Hemostatic gel composition and method of making same
CN113521379A (en) * 2021-07-12 2021-10-22 重庆大清海德生物技术有限公司 Preparation method of large-wound chitosan hemostatic particles
CN114984304A (en) * 2022-07-13 2022-09-02 温州市安多多医疗器械有限公司 Antibacterial hemagglutination-stopping rubber powder and preparation method thereof
CN114984304B (en) * 2022-07-13 2023-07-18 温州市安多多医疗器械有限公司 Antibacterial hemostatic gel powder and preparation method thereof
CN115779136A (en) * 2022-12-15 2023-03-14 湖南中腾湘岳生物科技有限公司 Medical hemostatic material and preparation method thereof
CN115779136B (en) * 2022-12-15 2024-04-12 湖南中腾湘岳生物科技有限公司 Medical hemostatic material and preparation method thereof

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