WO2017017625A1 - A stable topical pharmaceutical composition comprising nanonized silver sulfadiazine - Google Patents

A stable topical pharmaceutical composition comprising nanonized silver sulfadiazine Download PDF

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WO2017017625A1
WO2017017625A1 PCT/IB2016/054490 IB2016054490W WO2017017625A1 WO 2017017625 A1 WO2017017625 A1 WO 2017017625A1 IB 2016054490 W IB2016054490 W IB 2016054490W WO 2017017625 A1 WO2017017625 A1 WO 2017017625A1
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Prior art keywords
pharmaceutical composition
topical pharmaceutical
stable topical
composition according
silver sulfadiazine
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PCT/IB2016/054490
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French (fr)
Inventor
Neeta Gupta
Anil MAKWANA
Simrata Bedi
Ravi Kochhar
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Sun Pharmaceutical Industries Limited
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Publication of WO2017017625A1 publication Critical patent/WO2017017625A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the present invention relates to a stable topical pharmaceutical composition
  • a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of preservatives or antioxidants.
  • Silver sulfadiazine was first described in 1943 by Wruble and was found to be mildly antiseptic.
  • U.S. Patent No. 3,761,590 describes a process for preparing a thick cream ointment containing silver sulfadiazine, which rejuvenated the compound for the topical treatment of burns.
  • Silver sulfadiazine (1% w/w) in the form of a cream, has been in clinical use in the USA since 1973.
  • silver sulfadiazine and chlorhexidine compounds have been clinically established. It is well known that silver sulfadiazine is effective against a wide variety of gram-positive and gram-negative organisms, including Pseudomonas and Candida.
  • antioxidants for example hydrogen peroxide
  • preservatives in the topical composition may cause irritation to the inflamed and/or burned skin.
  • compositions comprising nanonized silver sulfadiazine, wherein the composition is substantially free of preservatives or antioxidants.
  • the pharmaceutical composition of the present invention is advantageous over the currently available marketed products by having improved stability without using preservatives or antioxidants.
  • the nanonized composition does not show signs of blackening. This surprising result occurs without the use of antioxidants, which is unexpected.
  • a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of preservatives or antioxidants.
  • a first aspect of the present invention provides a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of preservatives or antioxidants.
  • the nanonized silver sulfadiazine is present in an amount of from 0.1% w/w to 1.0% w/w of the total weight of composition.
  • the nanonized silver sulfadiazine is present in an amount of from 0.25% w/w to 0.75% w/w of the total weight of composition.
  • the stable composition further comprises chlorhexidine gluconate in an amount of from 0.1% w/w to 0.5% w/w of the total weight of composition.
  • the stable composition is used to treat burn wounds.
  • the stable composition is used to prevent and treat wound sepsis.
  • the stable composition exhibits reduced skin irritancy in comparison to silver sulfadiazine compositions comprising antioxidants or preservatives.
  • nanonanonized refers to a particle size distribution of silver sulfadiazine wherein the dso value is from about 20 nm to 200 nm and the dgo value is about from 200 nm to 600 nm as determined by a Malvern ® Mastersizer ® , based on the principle of laser diffraction, or refers to a Z-average particle size of less than or equal to 600 nm, e.g., Z- average particle size between 150 nm and 500 nm.
  • the Z-average particle size is the mean diameter based on the intensity of light scattered, as determined using a Nanosizer ® or Zetasizer ® , based on the principle of dynamic light scattering.
  • '3 ⁇ 4 ⁇ value means at least 90% of silver sulfadiazine particles have a volume diameter in the specified range when measured by a light scattering method such as a Malvern ® Mastersizer ® .
  • do value means at least 50% of silver sulfadiazine particles have a volume diameter in the specified range when measured by a light scattering method such as a Malvern ® Mastersizer ® .
  • the nanonized silver sulfadiazine has a surface area of more than 40 m 2 /g, when determined by a Malvern ® Mastersizer ® .
  • a second aspect of the present invention provides a process of preparation of a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the nanonization is carried out in a vessel made up of or coated with non-reactive materials, and wherein the composition is substantially free of preservatives or antioxidants.
  • the non-reactive materials are selected from the group consisting of ceramics, zirconium oxide, silicon carbide, and mixtures thereof.
  • the vessel may be made up of non-reactive materials or coated with non-reactive materials.
  • stable refers to a pharmaceutical composition of a nanonized silver sulfadiazine which does not change color when subjected to the stability conditions of 40°C and 75% RH relative humidity for a period of 12 months.
  • the composition may also be stable for up to 18 months when subjected to the stability conditions of 40°C and 75% RH relative humidity.
  • substantially free refers to a pharmaceutical composition of silver sulfadiazine, wherein preservatives or antioxidants are not present in an amount generally used alone or in combination in a pharmaceutical composition to prevent oxidation or microbial growth.
  • the amounts of preservatives or antioxidants alone or in combination are less than 0.25% w/w of the total weight of the pharmaceutical composition.
  • antioxidants are selected from the group comprising sodium metabisulfite, butylated hydroxytoluene, hydrogen peroxide, butylated hydroxyanisole, propyl gallate, ethyl gallate, methyl gallate, ascorbic acid, tocopherol, and mixtures thereof.
  • preservatives are selected from the group comprising methylparaben, propylparaben, benzyl alcohol, benzoic acid, sodium benzoate, chlorocresol, sorbic acid and its salt, phenylethyl alcohol, and mixtures thereof.
  • the pharmaceutical composition for topical application may be in the form of a cream, lotion, ointment, or gel.
  • Silver sulfadiazine is dispersed, and chlorhexidine gluconate is solubilized in a cream or a lotion base.
  • Topical compositions of silver sulfadiazine may be formulated using standard techniques known in the industry.
  • such compositions may be produced as oil-in-water or water-in-oil emulsions using suitable proportions of a hydrophobic phase with the addition of a thickening agent and a hydrophilic phase.
  • Such compositions further include pharmaceutically acceptable excipients selected from the group comprising emulsifying agents, chelating agent, thickening agents, pH modifiers, and mixtures thereof.
  • the hydrophobic phase may include mineral oils such as liquid paraffin, a vegetable oil such as peanut oil or castor oil, or mixtures thereof.
  • Suitable chelating agents are selected from the group comprising dimercaprol, ethylenediaminetetraacetic acid (EDTA), disodium edetate, ethylene glycol tetraacetic acid, lipoic acid, and, mixture thereof.
  • the chelating agent may be present in an amount of from 0.001% w/w to 1.0% w/w of the total weight of composition.
  • Thickening agents may be used according to the characteristics of the base, and are selected from the group comprising soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, povidone, wool-fat, hydrogenated lanolin, beeswax, and mixtures thereof.
  • Suitable emulsifying agents are selected from the group comprising cetomacrogol, non-ethoxylated glyceryl monostearate, carbopols, cetearyl alcohol, sodium stearoyl lactylate, lecithin, and mixtures thereof.
  • Suitable pH modifiers are selected from the group comprising citric acid, sodium citrate, acetic acid, sodium acetate, phosphoric acid, sodium phosphate, borax, sodium hydroxide, and mixtures thereof.
  • Conventional size reduction techniques for preparing nanonized particles include grinding or milling in an air-jet mill or impact mill, a ball mill, a media mill such as a sand mill, a Dyno ® mill, or a bead mill.
  • the grinding media in these mills can comprise spherical particles such as glass beads or zirconium oxide beads.
  • the grinding vessel may be coated with or made up of non-reactive materials, for example, ceramics, zirconium oxide, or silicon carbide.
  • Disodium edetate was dissolved in purified water.
  • step 2 Povidone was dissolved into the solution of step 1 under stirring to obtain a solution.
  • step 3 Silver sulfadiazine was dispersed into the solution of step 2 to form a slurry.
  • the hydrophobic phase was prepared by mixing together cetostearyl alcohol,
  • cetomacrogol cetomacrogol, and light liquid paraffin, and then heating the mixture to 65°C to 70°C to form an oily phase.
  • step 6 The oily phase of step 5 was added slowly under homogenization to water heated to 70°C to 75°C to form an emulsion, which was then cooled under stirring.
  • step 7 The silver sulfadiazine slurry of step 4 and the rinsing of step 4 were added into the bulk of step 6, and mixed.
  • step 8 The pH of the emulsion of step 8 was adjusted to pH 6 using phosphoric acid and sodium phosphate.
  • Example 1-9 were subjected to stability studies at temperature 40°C and humidity 75% RH for a period of 12 months to observe the color change. No visual color change was observed in any of the compositions under the stress conditions.

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Abstract

The present invention relates to a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine, wherein the composition is substantially free of preservatives or antioxidants.

Description

A STABLE TOPICAL PHARMACEUTICAL COMPOSITION COMPRISING NANONIZED SILVER SULFADIAZINE
Field of the Invention
The present invention relates to a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of preservatives or antioxidants.
Background of the Invention
Silver sulfadiazine was first described in 1943 by Wruble and was found to be mildly antiseptic. U.S. Patent No. 3,761,590 describes a process for preparing a thick cream ointment containing silver sulfadiazine, which rejuvenated the compound for the topical treatment of burns. Silver sulfadiazine (1% w/w), in the form of a cream, has been in clinical use in the USA since 1973.
The antimicrobial effect of silver sulfadiazine and chlorhexidine compounds has been clinically established. It is well known that silver sulfadiazine is effective against a wide variety of gram-positive and gram-negative organisms, including Pseudomonas and Candida.
It has been reported that the commercially marketed product Silvadene® cream (micronized silver sulfadiazine, 1% w/w) occasionally darkens, either in the jar or after application to the skin. This color change results from a light catalyzed reaction which is a common characteristic of all silver salts. The color change occurs in spite of the product containing methyl paraben, a preservative.
Therefore, it known in the art that silver sulfadiazine is prone to oxidation, thereby causing the product to turn black on exposure to the environment. The nanonized product is more prone to darkening, due to an increased surface area, as compared to the already marketed micronized product, which necessitates the inclusion of antioxidant s) in the pharmaceutical composition.
However, the use of antioxidants, for example hydrogen peroxide, and preservatives in the topical composition may cause irritation to the inflamed and/or burned skin.
There exists a need in the art to provide a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine, wherein the composition is substantially free of preservatives or antioxidants. The pharmaceutical composition of the present invention is advantageous over the currently available marketed products by having improved stability without using preservatives or antioxidants. Surprisingly, in spite of containing nanonized silver sulfadiazine, which increases the surface area of the active ingredient and would be expected to lead to instability, oxidation and therefore darkening of the silver sulfadiazine, the nanonized composition does not show signs of blackening. This surprising result occurs without the use of antioxidants, which is unexpected.
Summary of the Invention
There is provided herein a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of preservatives or antioxidants.
Detailed Description of the Invention
A first aspect of the present invention provides a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of preservatives or antioxidants.
According to one embodiment of the present invention, the nanonized silver sulfadiazine is present in an amount of from 0.1% w/w to 1.0% w/w of the total weight of composition.
According to another embodiment, the nanonized silver sulfadiazine is present in an amount of from 0.25% w/w to 0.75% w/w of the total weight of composition.
According to another embodiment, the stable composition further comprises chlorhexidine gluconate in an amount of from 0.1% w/w to 0.5% w/w of the total weight of composition.
According to another embodiment, the stable composition is used to treat burn wounds.
According to another embodiment, the stable composition is used to prevent and treat wound sepsis. According to another embodiment, the stable composition exhibits reduced skin irritancy in comparison to silver sulfadiazine compositions comprising antioxidants or preservatives.
The term "nanonized" refers to a particle size distribution of silver sulfadiazine wherein the dso value is from about 20 nm to 200 nm and the dgo value is about from 200 nm to 600 nm as determined by a Malvern® Mastersizer®, based on the principle of laser diffraction, or refers to a Z-average particle size of less than or equal to 600 nm, e.g., Z- average particle size between 150 nm and 500 nm. The Z-average particle size is the mean diameter based on the intensity of light scattered, as determined using a Nanosizer® or Zetasizer®, based on the principle of dynamic light scattering.
The term '¾ο value" means at least 90% of silver sulfadiazine particles have a volume diameter in the specified range when measured by a light scattering method such as a Malvern® Mastersizer®.
The term "dso value" means at least 50% of silver sulfadiazine particles have a volume diameter in the specified range when measured by a light scattering method such as a Malvern® Mastersizer®.
According to another embodiment, the nanonized silver sulfadiazine has a surface area of more than 40 m2/g, when determined by a Malvern® Mastersizer®.
A second aspect of the present invention provides a process of preparation of a stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the nanonization is carried out in a vessel made up of or coated with non-reactive materials, and wherein the composition is substantially free of preservatives or antioxidants.
According to one embodiment of this aspect, the non-reactive materials are selected from the group consisting of ceramics, zirconium oxide, silicon carbide, and mixtures thereof.
According to another embodiment, the vessel may be made up of non-reactive materials or coated with non-reactive materials.
The term "stable" as used herein refers to a pharmaceutical composition of a nanonized silver sulfadiazine which does not change color when subjected to the stability conditions of 40°C and 75% RH relative humidity for a period of 12 months. The composition may also be stable for up to 18 months when subjected to the stability conditions of 40°C and 75% RH relative humidity.
"Substantially free" as used herein refers to a pharmaceutical composition of silver sulfadiazine, wherein preservatives or antioxidants are not present in an amount generally used alone or in combination in a pharmaceutical composition to prevent oxidation or microbial growth. In particular, the amounts of preservatives or antioxidants alone or in combination are less than 0.25% w/w of the total weight of the pharmaceutical composition.
Examples of antioxidants are selected from the group comprising sodium metabisulfite, butylated hydroxytoluene, hydrogen peroxide, butylated hydroxyanisole, propyl gallate, ethyl gallate, methyl gallate, ascorbic acid, tocopherol, and mixtures thereof.
Examples of preservatives are selected from the group comprising methylparaben, propylparaben, benzyl alcohol, benzoic acid, sodium benzoate, chlorocresol, sorbic acid and its salt, phenylethyl alcohol, and mixtures thereof.
The pharmaceutical composition for topical application may be in the form of a cream, lotion, ointment, or gel. Silver sulfadiazine is dispersed, and chlorhexidine gluconate is solubilized in a cream or a lotion base.
Topical compositions of silver sulfadiazine may be formulated using standard techniques known in the industry. For example, such compositions may be produced as oil-in-water or water-in-oil emulsions using suitable proportions of a hydrophobic phase with the addition of a thickening agent and a hydrophilic phase. Such compositions further include pharmaceutically acceptable excipients selected from the group comprising emulsifying agents, chelating agent, thickening agents, pH modifiers, and mixtures thereof.
The hydrophobic phase may include mineral oils such as liquid paraffin, a vegetable oil such as peanut oil or castor oil, or mixtures thereof.
Suitable chelating agents are selected from the group comprising dimercaprol, ethylenediaminetetraacetic acid (EDTA), disodium edetate, ethylene glycol tetraacetic acid, lipoic acid, and, mixture thereof. The chelating agent may be present in an amount of from 0.001% w/w to 1.0% w/w of the total weight of composition. Thickening agents may be used according to the characteristics of the base, and are selected from the group comprising soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, povidone, wool-fat, hydrogenated lanolin, beeswax, and mixtures thereof.
Suitable emulsifying agents are selected from the group comprising cetomacrogol, non-ethoxylated glyceryl monostearate, carbopols, cetearyl alcohol, sodium stearoyl lactylate, lecithin, and mixtures thereof.
Suitable pH modifiers are selected from the group comprising citric acid, sodium citrate, acetic acid, sodium acetate, phosphoric acid, sodium phosphate, borax, sodium hydroxide, and mixtures thereof.
Conventional size reduction techniques for preparing nanonized particles include grinding or milling in an air-jet mill or impact mill, a ball mill, a media mill such as a sand mill, a Dyno® mill, or a bead mill. The grinding media in these mills can comprise spherical particles such as glass beads or zirconium oxide beads. The grinding vessel may be coated with or made up of non-reactive materials, for example, ceramics, zirconium oxide, or silicon carbide.
The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limiting of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLES
Nanonized Silver Sulfadiazine Cream
Examples 1-4
Figure imgf000007_0001
Examples 5-9
Figure imgf000007_0002
* Particle size (dso value) and surface area of silver sulfadiazine after milling were determined using a Malvern® Mastersizer® and were found to be 108 nm and 88.99 m g, respectively. Manufacturing process:
1. Disodium edetate was dissolved in purified water.
2. Povidone was dissolved into the solution of step 1 under stirring to obtain a solution.
3. Silver sulfadiazine was dispersed into the solution of step 2 to form a slurry.
4. The slurry was passed through a Dyno® mill until the desired particle size was
obtained, and then the Dyno® mill was rinsed with purified water.
5. The hydrophobic phase was prepared by mixing together cetostearyl alcohol,
cetomacrogol, and light liquid paraffin, and then heating the mixture to 65°C to 70°C to form an oily phase.
6. The oily phase of step 5 was added slowly under homogenization to water heated to 70°C to 75°C to form an emulsion, which was then cooled under stirring.
7. The silver sulfadiazine slurry of step 4 and the rinsing of step 4 were added into the bulk of step 6, and mixed.
8. Chlorhexidine gluconate was added into the bulk of step 7, and mixed.
9. The pH of the emulsion of step 8 was adjusted to pH 6 using phosphoric acid and sodium phosphate.
10. Final weight adjustment was made using purified water, followed by mixing.
Stability studies
The compositions of Example 1-9 were subjected to stability studies at temperature 40°C and humidity 75% RH for a period of 12 months to observe the color change. No visual color change was observed in any of the compositions under the stress conditions.

Claims

We claim: 1. A stable topical pharmaceutical composition comprising nanonized silver sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of preservatives or antioxidants.
2. The stable topical pharmaceutical composition according to claim 1, wherein the silver sulfadiazine is present in an amount of from 0.1% w/w to 1.0% w/w of the total weight of the composition.
3. The stable topical pharmaceutical composition according to claim 1, wherein the silver sulfadiazine is present in an amount of 0.05% w/w of the total weight of the composition.
4. The stable topical pharmaceutical composition according to claim 1, wherein the nanonized silver sulfadiazine has a dso value of from about 20 nm to 200 nm.
5. The stable topical pharmaceutical composition according to claim 1, wherein the nanonized silver sulfadiazine has a ds>o value of from about 200 nm to 600 nm.
6. The stable topical pharmaceutical composition according to claim 1, wherein the nanonized silver sulfadiazine has a surface area of more than 40 m2/g.
7. The stable topical pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from the group consisting of emulsifying agents, chelating agents, thickening agents, pH modifiers, and mixtures thereof.
8. The stable topical pharmaceutical composition according to claim 7, wherein the chelating agents are selected from the group comprising dimercaprol,
ethylenediaminetetraacetic acid (EDTA), disodium edetate, ethylene glycol tetraacetic acid, lipoic acid, and mixtures thereof.
9. The stable topical pharmaceutical composition according to claim 1, wherein the composition further comprises chlorhexidine gluconate in an amount of from 0.1% w/w to 0.5% w/w of the total weight of the composition.
10. The stable topical pharmaceutical composition according to claim 1, wherein the composition shows no visual color change when stored at temperature 40°C and humidity 75% RH for a period of 12 months.
11. The stable topical pharmaceutical composition according to claim 1, wherein the nanonization is carried out in a vessel made up of or coated with non-reactive materials.
12. The stable topical pharmaceutical composition according to claim 11, wherein the non-reactive material is selected from the group consisting of ceramics, zirconium oxide, silicon carbide, and mixtures thereof.
13. The stable topical pharmaceutical composition according to claim 1, wherein the preservatives or antioxidants, alone or in combination, are present in the composition in an amount of less than 0.25% w/w of the total weight of the pharmaceutical composition.
14. The stable topical pharmaceutical composition according to claim 1, wherein the preservatives are selected from the group comprising methylparaben, propylparaben, benzyl alcohol, benzoic acid, sodium benzoate, chlorocresol, sorbic acid and its salt, phenylethyl alcohol, and mixtures thereof.
15. The stable topical pharmaceutical composition according to claim 1, wherein the antioxidants are selected from the group comprising sodium metabisulfite, butylated hydroxytoluene, hydrogen peroxide, butylated hydroxyanisole, propyl gallate, ethyl gallate, methyl gallate, ascorbic acid, tocopherol, and mixtures thereof.
PCT/IB2016/054490 2015-07-27 2016-07-27 A stable topical pharmaceutical composition comprising nanonized silver sulfadiazine WO2017017625A1 (en)

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