EP4626404A1 - Dermal thermosensitive gel formulations for the treatment of inflammation-related edema and various pains - Google Patents

Dermal thermosensitive gel formulations for the treatment of inflammation-related edema and various pains

Info

Publication number
EP4626404A1
EP4626404A1 EP23898458.7A EP23898458A EP4626404A1 EP 4626404 A1 EP4626404 A1 EP 4626404A1 EP 23898458 A EP23898458 A EP 23898458A EP 4626404 A1 EP4626404 A1 EP 4626404A1
Authority
EP
European Patent Office
Prior art keywords
chitosan
gel formulation
formulation according
polymer
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23898458.7A
Other languages
German (de)
French (fr)
Inventor
Muhammet Davut Arpa
Ebrar Elif KESMEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Istanbul Medipol Universitesi
Original Assignee
Istanbul Medipol Universitesi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Istanbul Medipol Universitesi filed Critical Istanbul Medipol Universitesi
Publication of EP4626404A1 publication Critical patent/EP4626404A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the invention relates to sprayable dermal thermosensitive gel formulations developed for the treatment of inflammation-related edema and various pains.
  • Benzydamine is a non-steroidal anti-inflammatory with analgesic, antiseptic and antimicrobial effects, which is often used locally in the treatment of oral diseases such as oral mucositis and mouth ulcers.
  • Benzydamine offers significant advantages in the prevention and treatment of mucositis topically as it inhibits the production of TNF-a. Benzydamine not only stops the progression of mucositis severity but also reduces the intensity of pain.
  • Benzydamine is generally used alone or in combination with various active ingredients as a spray or mouthwash at very low concentrations such as 0.15% in the treatment of oral infections.
  • benzydamine hydrochloride is also used topically on the skin to eliminate various painful conditions such as edema, inflammation and sprain, bruising, and lumbago due to soft tissue injuries caused by various reasons such as surgery and trauma.
  • These products which are generally used commercially in the form of semi-solid gel and cream containing benzydamine at concentrations of 3-5%, are applied 2-3 times a day depending on the condition of the disease.
  • Gels are the formulations that provide higher patient. -compliance than semi-solid oil-based formulations such as creams and ointments.
  • semi-solid formulations also have problems in terms of patient compliance, such as not spreading comfortably to the application area, the amount applied depending on eyeball estimate (apply in the size of a chickpea grain, etc.).
  • in situ gel formulations have started to be developed to overcome such problems. These systems, which gel in situ, are liquid at room temperature or at the temperature where they are stored, and they gel depending on the temperature, pH, or ionic activation in the area where they are applied. Therefore, these systems are more easily applicable formulations because they are in liquid form during application. The fact that they can be sprayed makes them frequently preferred in the pharmaceutical industry in recent years.
  • thermosensitive gels Temperature-sensitive in situ gels are called thermosensitive gels. These systems are dosage forms that gel when they come into contact with the body. Sprayable thermosensitive gel formulations should generally be gellable between 28-34°C, at the same time their viscosity at storage temperature is generally expected to be less than 350 mPa.s. Poloxamers are the most commonly used polymers in the preparation of thermosensitive gels. Poloxamers are polyethylene oxide - polypropylene oxide - polyethylene oxide (PEO-PPO-PEO) triblock copolymers that can dissolve in an aqueous medium to form clear gels. Their high water content has a positive effect on drug absorption, and they are also biocompatible and have low toxicity.
  • PEO-PPO-PEO polyethylene oxide - polypropylene oxide - polyethylene oxide
  • Poloxamer 407 is one of the poloxamers with high solubility capacity consisting of 70% POE and 30% PPO
  • Poloxamer 188 is one of the emulsifiers, dispersing agents, and wetting agents consisting of 80% POE and 20% PPO and is used to increase the bioavailability of low solubility active ingredients.
  • These synthetic polymers with non-ionic properties can interact with hydrophobic surfaces and biological membranes due to their amphiphilic properties.
  • Semi-solid dosage forms such as gels, creams, ointments, and oral formulations containing the same active ingredients, which contain nonsteroidal anti-inflammatory agents and are used topically on application, are frequently used to relieve inflammation-related edema and various pains.
  • Active ingredients such as naproxen sodium, metamizole, and benzydamine hydrochloride are compounds used for this purpose.
  • Benzydamine hydrochloride has 3-5% products commercially available in gel, and cream form prepared using various polymers.
  • disadvantages such as transferring the gel, and cream formulations from the tube, not distributing them widely or evenly over the application surface in a desired manner, or the dose of the application depending on the patient's rule of thumb or eyeball estimate.
  • cream formulations are oil-based, they generally have disadvantages such as lower skin permeability and lower patient compliance than gels.
  • EP2689774B1 relates to a thermo-reversible hydrogel composition
  • a thermo-reversible hydrogel composition comprising a water-soluble block copolymer and gelling agent.
  • the document in question contains a formulation containing 3% benzydamine- but does not mention a sprayable, bioadhesive, and thermosensitive formulation for dermal application.
  • the present invention is in the form of temperature-sensitive (thermosensitive) and sprayable gel formulations containing benzydamine hydrochloride to be used for the relief of problems and pain such as various sprains, dents, inflammatory edema, etc.
  • Sprayable in situ gel formulations allow a standard dose to be applied to the spray head in one press/application. Therefore, the administered dose does not differ from person to person or between per application.
  • the gel formulation can be sprayed at room temperature (20-25°C) as it has a low viscosity (100-350 mPa.s). This is not the case for traditional gels and creams.
  • thermosensitive sprayable formulations When thermosensitive sprayable formulations are sprayed, they spread more easily to a large area and are gelled by the effect of body temperature (37°C) when it comes into contact with the body. While their easy flow provides ease of application, their water-based nature enables superiority over ointments and creams in terms of passing through the skin such as a gel.
  • temperature-sensitive (thermosensitive) sprayable gel formulations containing benzydamine hydrochloride were obtained to be used for the elimination of problems and pain such as sprain, bruise, inflammation-related edema, etc. in order to eliminate the existing disadvantages of semi-solid formulations in terms of application.
  • hydroxypropyl methyl-cellulose which is a cellulose derivative, is also used.
  • Cellulose-derived polymers are used in many different drug delivery systems such as gel and film due to their bioadhesive effects.
  • Bioadhesive polymers adhere to the area where they are applied and ensure that the drug formulation stays in that area for a longer time. Thus, they can improve the bioavailability of the active ingredient by increasing the duration of action of the drug.
  • its permeability-enhancing properties provide an advantage in terms of bioavailability.
  • Non-ionic hydroxypropyl methyl -cellulose provides both bio-adhesive properties and contributes to the structural integrity of the thermosensitive gel.
  • this semi -synthetic polymer is biocompatible and biodegradable. Hydroxypropyl methyl-cellulose is also preferred in the preparation of systems due to its sol-gel effect.
  • the invention offers significant advantages in terms of ease of application and use compared to gel formulations containing benzydamine hydrochloride in the art:
  • -It is in sprayable form, and it is an important advantage that it is in sprayable form, in addition, not all in situ gels/thermosensitive gels are sprayable, for this, the viscosity of the formulation must be at certain intervals.
  • Sprayable thermosensitive gel formulation containing benzydamine hydrochloride characterized in that it comprises the following:
  • Benzydamine hydrochloride in the amount of 2-10% by weight as active ingredient, Non-ionic or cationic polymer in the rate of 0.05-20% by weight as bioadhesive polymer,
  • Poloxamer 407 a water-soluble triblock copolymer comprising 70% of unit a and 30% of unit b, represented by the general formula HO-(EO) a (PO)b(EO) a -H at a ratio of 10- 28% by weight as a thermosensitive polymer,
  • Poloxamer 188 water-soluble triblock copolymer, represented by the general formula HO-(EO) a (PO)b(EO) a -H at a rate of 1-20% by weight as a thermosensitive polymer, wherein the unit a comprises 80% and the unit b comprises 20%, Optionally, moisturizing agent in the ratio of 1-10% by weight, Optionally, desired amount of fragrance agent,
  • Benzydamine may exhibit toxic effects if used in doses of more than 10%, as well as disrupting the structure of the formulation.
  • Poloxamers and HPMC provide a sol-gel, that is, a thermosensitive effect, and HPMC also has a bioadhesive feature.
  • Jasmine essence, peppermint essence, lavender essence, and the like can be preferred as scenting agents.
  • the moisturizing agent may be selected from the group comprising glycerin, sorbitol, propylene glycol, polyethylene glycol, and butylene glycol.
  • a non-ionic polymer is a cellulose-derived polymer.
  • the cellulose-derived polymer is hydroxypropyl methyl cellulose or hydroxyethyl cellulose.
  • Cationic polymer is chitosan or its derivatives.
  • Chitosan is preferably dissolved in an organic acid selected from the group of acetic acid, hydrochloric acid, glutamic acid, citric acid, aspartic acid, and lactic acid.
  • Water-soluble thiolate chitosan, chitosan salt or chitosan alkyl ammonium can be used as chitosan derivatives.
  • Chitosan glutamate, chitosan chloride, chitosan lactate, chitosan citrate, chitosan acetate or chitosan aspartate can be used as chitosan salt.
  • Method of preparing the gel formulation of the invention comprising the following process steps: a) Completely dissolving Pol oxamer 407 and Pol oxamer 188, which are polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) copolymers, in a calculated amount of distilled water, b) Keeping the prepared solution in the refrigerator at 2-8°C for 24-48 hours, c) On the other hand, dissolving hydroxypropyl methylcellulose (HPMC) in the remaining part of the distilled water by stirring at 20-25°C for 4-12 hours, d) Combining the HPMC solution and the solution containing the poloxamers by stirring at 20-25°C on a stirrer, e) Adding the active ingredient benzydamine hydrochloride to the solution container and mixing at 200-500 rpm for 1-3 hours.
  • Pol oxamer 407 and Pol oxamer 188 which are polyethylene oxide-polypropylene oxide-
  • glycerin is optionally added as a moisturizing agent and mixed at 200-500 rpm for 30 minutes-2 hours at room temperature and optionally homogenized by adding a fragrance agent.
  • the dissolution in step a continues until the polymers dissolve by stirring at low speed (300 rpm) in the cold-water bath for about 2 hours.
  • Viscosity analyses are of great importance in terms of the applicability and sprayability of in situ gels.
  • viscosity analyses of the formulations developed in Brookfield DV2T RV viscometer were performed. Analyses were carried out at 25°C.
  • Gelation temperature analyzes were performed on a magnetic heating stirrer. In situ gels stored at +4°C were taken from the refrigerator and started to be stirred at 300 rpm on a magnetic heating stirrer in a beaker. The temperature of the device was increased by 2°C per minute to determine the temperature at which the sol formulation began to gel. The temperature value at the time when the magnetic stirrer rod in the beaker stopped was recorded as the gelling temperature of the formulation. Table 1 shows the findings of viscosity and gelling temperature. pH analyses were carried out at 25°C. The pH values of the formulations were determined by immersing the probe of the pH meter in the in-situ gel. The pH values of the developed formulations are generally expected to be between 4 and 6 in order to be compatible with the body. The pH values of the formulations were found to be between 5.5 and 5.9.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pain & Pain Management (AREA)
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Abstract

The invention is sprayable dermal thermosensitive gel formulation developed for the treatment of inflammation-related edema and various pains and comprises 2-10% benzydamine hydrochloride by weight, 0.05-20% bio.adhesive polymer by weight, 10-28% Poloxamer 407 or 1-20% Poloxamer 188 as thermosensitive polymer and distilled water by weight to complete the total weight to 100%.

Description

DERMAL THERMOSENSITIVE GEL FORMULATIONS FOR THE TREATMENT OF INFLAMMATION-RELATED EDEMA AND VARIOUS PAINS
Technical Field
The invention relates to sprayable dermal thermosensitive gel formulations developed for the treatment of inflammation-related edema and various pains.
State of the Art (Background)
Benzydamine is a non-steroidal anti-inflammatory with analgesic, antiseptic and antimicrobial effects, which is often used locally in the treatment of oral diseases such as oral mucositis and mouth ulcers. Benzydamine offers significant advantages in the prevention and treatment of mucositis topically as it inhibits the production of TNF-a. Benzydamine not only stops the progression of mucositis severity but also reduces the intensity of pain.
Benzydamine is generally used alone or in combination with various active ingredients as a spray or mouthwash at very low concentrations such as 0.15% in the treatment of oral infections. However, benzydamine hydrochloride is also used topically on the skin to eliminate various painful conditions such as edema, inflammation and sprain, bruising, and lumbago due to soft tissue injuries caused by various reasons such as surgery and trauma. These products, which are generally used commercially in the form of semi-solid gel and cream containing benzydamine at concentrations of 3-5%, are applied 2-3 times a day depending on the condition of the disease.
Gels are the formulations that provide higher patient. -compliance than semi-solid oil-based formulations such as creams and ointments. However, semi-solid formulations also have problems in terms of patient compliance, such as not spreading comfortably to the application area, the amount applied depending on eyeball estimate (apply in the size of a chickpea grain, etc.). In recent years, in situ gel formulations have started to be developed to overcome such problems. These systems, which gel in situ, are liquid at room temperature or at the temperature where they are stored, and they gel depending on the temperature, pH, or ionic activation in the area where they are applied. Therefore, these systems are more easily applicable formulations because they are in liquid form during application. The fact that they can be sprayed makes them frequently preferred in the pharmaceutical industry in recent years.
Temperature-sensitive in situ gels are called thermosensitive gels. These systems are dosage forms that gel when they come into contact with the body. Sprayable thermosensitive gel formulations should generally be gellable between 28-34°C, at the same time their viscosity at storage temperature is generally expected to be less than 350 mPa.s. Poloxamers are the most commonly used polymers in the preparation of thermosensitive gels. Poloxamers are polyethylene oxide - polypropylene oxide - polyethylene oxide (PEO-PPO-PEO) triblock copolymers that can dissolve in an aqueous medium to form clear gels. Their high water content has a positive effect on drug absorption, and they are also biocompatible and have low toxicity. Poloxamer 407 is one of the poloxamers with high solubility capacity consisting of 70% POE and 30% PPO, Poloxamer 188 is one of the emulsifiers, dispersing agents, and wetting agents consisting of 80% POE and 20% PPO and is used to increase the bioavailability of low solubility active ingredients. These synthetic polymers with non-ionic properties can interact with hydrophobic surfaces and biological membranes due to their amphiphilic properties.
Semi-solid dosage forms such as gels, creams, ointments, and oral formulations containing the same active ingredients, which contain nonsteroidal anti-inflammatory agents and are used topically on application, are frequently used to relieve inflammation-related edema and various pains. Active ingredients such as naproxen sodium, metamizole, and benzydamine hydrochloride are compounds used for this purpose. Benzydamine hydrochloride has 3-5% products commercially available in gel, and cream form prepared using various polymers. However, there are several disadvantages such as transferring the gel, and cream formulations from the tube, not distributing them widely or evenly over the application surface in a desired manner, or the dose of the application depending on the patient's rule of thumb or eyeball estimate. Again, since cream formulations are oil-based, they generally have disadvantages such as lower skin permeability and lower patient compliance than gels.
EP2689774B1 relates to a thermo-reversible hydrogel composition comprising a water-soluble block copolymer and gelling agent. The document in question contains a formulation containing 3% benzydamine- but does not mention a sprayable, bioadhesive, and thermosensitive formulation for dermal application. Brief Description and Objects of the Invention
The present invention is in the form of temperature-sensitive (thermosensitive) and sprayable gel formulations containing benzydamine hydrochloride to be used for the relief of problems and pain such as various sprains, dents, inflammatory edema, etc.
Sprayable in situ gel formulations allow a standard dose to be applied to the spray head in one press/application. Therefore, the administered dose does not differ from person to person or between per application. At the same time, the gel formulation can be sprayed at room temperature (20-25°C) as it has a low viscosity (100-350 mPa.s). This is not the case for traditional gels and creams. When thermosensitive sprayable formulations are sprayed, they spread more easily to a large area and are gelled by the effect of body temperature (37°C) when it comes into contact with the body. While their easy flow provides ease of application, their water-based nature enables superiority over ointments and creams in terms of passing through the skin such as a gel.
With the invention, temperature-sensitive (thermosensitive) sprayable gel formulations containing benzydamine hydrochloride were obtained to be used for the elimination of problems and pain such as sprain, bruise, inflammation-related edema, etc. in order to eliminate the existing disadvantages of semi-solid formulations in terms of application. For this purpose, while preparing temperature-sensitive gels using poloxamers, hydroxypropyl methyl-cellulose, which is a cellulose derivative, is also used.
Cellulose-derived polymers are used in many different drug delivery systems such as gel and film due to their bioadhesive effects. Bioadhesive polymers adhere to the area where they are applied and ensure that the drug formulation stays in that area for a longer time. Thus, they can improve the bioavailability of the active ingredient by increasing the duration of action of the drug. At the same time, its permeability-enhancing properties provide an advantage in terms of bioavailability. Non-ionic hydroxypropyl methyl -cellulose provides both bio-adhesive properties and contributes to the structural integrity of the thermosensitive gel. However, this semi -synthetic polymer is biocompatible and biodegradable. Hydroxypropyl methyl-cellulose is also preferred in the preparation of systems due to its sol-gel effect. The invention offers significant advantages in terms of ease of application and use compared to gel formulations containing benzydamine hydrochloride in the art:
-It is in sprayable form, and it is an important advantage that it is in sprayable form, in addition, not all in situ gels/thermosensitive gels are sprayable, for this, the viscosity of the formulation must be at certain intervals.
- Upon contact with the body, it will immediately become gelled, allowing it to spread evenly over a wider area.
-The administration dose has been standardized against gel formulations.
-There are poloxamers that provide thermosensitive properties and polymers with bioadhesive properties in the gel formulation of the invention.
Detailed Description of the Invention
Sprayable thermosensitive gel formulation containing benzydamine hydrochloride (w/w), characterized in that it comprises the following:
Benzydamine hydrochloride in the amount of 2-10% by weight as active ingredient, Non-ionic or cationic polymer in the rate of 0.05-20% by weight as bioadhesive polymer,
Poloxamer 407, a water-soluble triblock copolymer comprising 70% of unit a and 30% of unit b, represented by the general formula HO-(EO)a(PO)b(EO)a-H at a ratio of 10- 28% by weight as a thermosensitive polymer,
Poloxamer 188, water-soluble triblock copolymer, represented by the general formula HO-(EO)a(PO)b(EO)a-H at a rate of 1-20% by weight as a thermosensitive polymer, wherein the unit a comprises 80% and the unit b comprises 20%, Optionally, moisturizing agent in the ratio of 1-10% by weight, Optionally, desired amount of fragrance agent,
Distilled water by weight to complete the total weight to 100%, and that it has a viscosity of 100-350 mPa.s at room temperature (20-25°C) and that it can gel in the temperature range of 28-34°C.
All components in the formulation affect the viscosity and temperature of the gel. Benzydamine may exhibit toxic effects if used in doses of more than 10%, as well as disrupting the structure of the formulation. Poloxamers and HPMC provide a sol-gel, that is, a thermosensitive effect, and HPMC also has a bioadhesive feature.
Jasmine essence, peppermint essence, lavender essence, and the like can be preferred as scenting agents.
The moisturizing agent may be selected from the group comprising glycerin, sorbitol, propylene glycol, polyethylene glycol, and butylene glycol.
A non-ionic polymer is a cellulose-derived polymer. The cellulose-derived polymer is hydroxypropyl methyl cellulose or hydroxyethyl cellulose.
Cationic polymer is chitosan or its derivatives. Chitosan is preferably dissolved in an organic acid selected from the group of acetic acid, hydrochloric acid, glutamic acid, citric acid, aspartic acid, and lactic acid.
Water-soluble thiolate chitosan, chitosan salt or chitosan alkyl ammonium can be used as chitosan derivatives. Chitosan glutamate, chitosan chloride, chitosan lactate, chitosan citrate, chitosan acetate or chitosan aspartate can be used as chitosan salt.
Method of preparing the gel formulation of the invention, comprising the following process steps: a) Completely dissolving Pol oxamer 407 and Pol oxamer 188, which are polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) copolymers, in a calculated amount of distilled water, b) Keeping the prepared solution in the refrigerator at 2-8°C for 24-48 hours, c) On the other hand, dissolving hydroxypropyl methylcellulose (HPMC) in the remaining part of the distilled water by stirring at 20-25°C for 4-12 hours, d) Combining the HPMC solution and the solution containing the poloxamers by stirring at 20-25°C on a stirrer, e) Adding the active ingredient benzydamine hydrochloride to the solution container and mixing at 200-500 rpm for 1-3 hours. In the method, glycerin is optionally added as a moisturizing agent and mixed at 200-500 rpm for 30 minutes-2 hours at room temperature and optionally homogenized by adding a fragrance agent. Preferably, the dissolution in step a continues until the polymers dissolve by stirring at low speed (300 rpm) in the cold-water bath for about 2 hours.
Viscosity, pH, and gelling temperature analyses
Viscosity analyses are of great importance in terms of the applicability and sprayability of in situ gels. In this context, viscosity analyses of the formulations developed in Brookfield DV2T RV viscometer were performed. Analyses were carried out at 25°C.
Gelation temperature analyzes were performed on a magnetic heating stirrer. In situ gels stored at +4°C were taken from the refrigerator and started to be stirred at 300 rpm on a magnetic heating stirrer in a beaker. The temperature of the device was increased by 2°C per minute to determine the temperature at which the sol formulation began to gel. The temperature value at the time when the magnetic stirrer rod in the beaker stopped was recorded as the gelling temperature of the formulation. Table 1 shows the findings of viscosity and gelling temperature. pH analyses were carried out at 25°C. The pH values of the formulations were determined by immersing the probe of the pH meter in the in-situ gel. The pH values of the developed formulations are generally expected to be between 4 and 6 in order to be compatible with the body. The pH values of the formulations were found to be between 5.5 and 5.9.
Table 1. Viscosity and gelling temperature values of some in situ gel samples
Example formulations of the invention:
Example 1 :
Example 2:
Example 3 :
Example 4: Example 5:
Example 6:

Claims

CLAIMS A sprayable thermosensitive gel formulation, characterized in that it comprises the following:
• Benzydamine hydrochloride in the amount of 2-10% by weight as active ingredient,
• Non-ionic or cationic polymer in the rate of 0.05-20% by weight as bioadhesive polymer,
• Poloxamer 407 polymer, a water-soluble triblock copolymer, represented by the general formula HO-(EO)a(PO)b(EO) a-H at a rate of 10-28% by weight as a thermosensitive polymer, wherein the unit a comprises 70% and the unit b comprises 30%,
• Poloxamer 188 polymer, a water-soluble triblock copolymer, represented by the general formula HO-(EO)a(PO)b(EO)a-H at a rate of 1-20% by weight as a thermosensitive polymer, wherein the unit a comprises 80% and the unit b comprises 20%,
• Distilled water by weight to complete the total weight to 100%. The gel formulation according to Claim 1, characterized in that it has a viscosity in the range of 100-350 mPa.s at room temperature in the range of 20-25°C. The gel formulation according to the Claim 1, characterized in that it can gel in the temperature range of 28-34°C. The gel formulation according to Claim 1, characterized in that it comprises 1-10% by weight of moisturizing agent. The gel formulation according to Claim 4, characterized in that the moisturizing agent is selected from the group containing glycerin, propylene glycol, polyethylene glycol, sorbitol, butylene glycol or binary combinations thereof. The gel formulation according to Claim 1, characterized in that it comprises an effective amount of odorant.
7. The gel formulation according to Claim 1, characterized in that the non-ionic bioadhesive polymer is a cellulose-derived polymer.
8. The gel formulation according to Claim 7, characterized in that the cellulose-derived polymer is hydroxypropyl methyl-cellulose or hydroxyethyl cellulose.
9. The gel formulation according to Claim 1, characterized in that it is a chitosan or derivatives of the cationic polymer with bioadhesive properties.
10. The gel formulation according to Claim 9, characterized in that it is a solution of chitosan in a suitable organic acid.
11. The gel formulation according to Claim 10, characterized in that said organic acid is acetic acid, hydrochloric acid, glutamic acid, citric acid, aspartic acid, or lactic acid.
12. The gel formulation according to Claim 9, characterized in that the chitosan derivative is water-soluble thiolate chitosan, chitosan salt, or chitosan alkyl ammonium.
13. The gel formulation according to Claim 12, characterized in that the chitosan salt is chitosan glutamate, chitosan chloride, chitosan lactate, chitosan citrate, chitosan acetate or chitosan aspartate.
14. A method of preparing the gel formulation according to any one of the preceding claims, characterized in that it comprises the following steps: a) Completely dissolving Pol oxamer 407 and Pol oxamer 188, which are polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) copolymers, in distilled water, b) Keeping the prepared solution in the refrigerator at 2-8°C for 24-48 hours, c) Dissolving the non-ionic or cationic polymer in distilled water by stirring at 20-25°C for 4-12 hours, d) Combining the solution containing non-ionic or cationic polymer solution and poloxamers by stirring at 20-25°C on a stirrer, e) Adding the active ingredient benzydamine hydrochloride to the prepared solution and mixing at 200-500 rpm for 1-3 hours.
15. The method according to Claim 12, characterized in that it comprises the process step of mixing at 200-500 rpm at room temperature for 30 minutes to 2 hours by adding moisturizing agent.
16. The method according to Claim 12, characterized in that it comprises the process step of homogenizing by adding fragrance agent.
17. The method according to Claim 14, characterized in that step c is carried out by dissolving hydroxypropyl methyl- cellulose as a non-ionic polymer in water.
EP23898458.7A 2022-12-01 2023-10-18 Dermal thermosensitive gel formulations for the treatment of inflammation-related edema and various pains Pending EP4626404A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022/018327A TR2022018327A1 (en) 2022-12-01 2022-12-01 DERMAL THERMOSENSITIVE GEL FORMULATIONS FOR THE TREATMENT OF INFLAMMATION-RELATED EDEMA AND VARIOUS PAINS
PCT/TR2023/051159 WO2024118019A1 (en) 2022-12-01 2023-10-18 Dermal thermosensitive gel formulations for the treatment of inflammation-related edema and various pains

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