Field of the Invention
The present invention relates to a stable topical pharmaceutical composition
5 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
10 cream ointment containing silver sulfadiazine, which rejuvenated the compound for the
topical treatment of bums. 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
15 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
20 common characteristic of all silver salts. The color change occurs in spite of the product
containing methylparaben, a preservative.
Therefore, it known in the art that silver sulfadiazine is prone to oxidation, thereby
causing the product to tum 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
25 marketed micronized product, which necessitates the inclusion of antioxidant(s) in the
pharmaceutical composition.
30
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
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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
5 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.
10
Summary ofthe 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
15 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 offrom 0.1% w/w to 1.0% w/w of the total weight of
20 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 offrom 0.1% w/w to 0.5% w/w of the total weight
25 of composition.
According to another embodiment, the stable composition is used to treat bum
wounds.
According to another embodiment, the stable composition is used to prevent and
treat wound sepsis.
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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
5 wherein the d50 value is from about 20 nm to 200 nm and the d90 value is about from 200
nm to 600 nm as determined by a Malvern® Mastersizer®, based on the principle oflaser
diffraction, or refers to a Z-average particle size ofless than or equal to 600 nm, e.g., Zaverage
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®
10 or Zetasizer®, based on the principle of dynamic light scattering.
The term "d90 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
15 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
20 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
25 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
30 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
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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
5 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
10 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
15 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
20 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
25 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
30 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.
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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.
5 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
10 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
15 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
20 without departing from the spirit and scope of the invention.
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EXAMPLES
Nanonized Silver Sulfadiazine Cream
Examples 1-4
Ingredients Quantity (%w/w)
Ex.l Ex.2 Ex.3 Ex.4
*Silver sulfadiazine 0.500 0.500 0.500 0.500
Chlorhexidine gluconate
solution IP equivalent to 0.200 0.200 0.200 0.200
chlorhexidine gluconate
Disodium edetate 0.010 0.005 0.005 0.005
Povidone 0.100 0.100 0.100 0.100
Cetostearyl alcohol 9.600 7.200 12.000 12.000
Cetomacrogol 2.500 3.750 1.250 3.750
Light liquid paraffin 8.000 4.000 12.000 4.000
Sodium phosphate q.s. q.s. q.s. q.s.
Phosphoric acid q.s. q.s. q.s. q.s.
Purified water q.s. to 100.000 g 100.000 g 100.000 g 100.000 g
5 Examples 5-9
Ingredients Quantity (%w/w)
Ex.5 Ex.6 Ex. 7 Ex.8 Ex.9
*Silver sulfadiazine 0.500 0.500 0.500 0.500 0.500
Chlorhexidine gluconate
solution IP
0.200 0.200 0.200 0.200 0.200
equivalent to
chlorhexidine gluconate
Disodium edetate 0.015 0.015 0.015 0.005 0.015
Povidone 9.600 0.100 0.100 0.100 0.100
Cetostearyl alcohol 7.200 12.000 12.000 7.200 7.200
Cetomacrogol 3.750 3.750 1.250 1.250 1.250
Light liquid paraffin 12.000 12.000 4.000 12.000 4.000
Sodium phosphate q.s. q.s. q.s. q.s. q.s.
Phosphoric acid q.s. q.s. q.s. q.s. q.s.
Purified water q.s. to 100.000 g 100.000 g 100.000 g 100.000 g 100.000 g
* 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 m2/g,
respectively.
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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.
5 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.
10 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.
15 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
20 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.

We claim:
1 1. A stable topical pharmaceutical composition comprising nanonized silver
2 sulfadiazine and one or more pharmaceutically acceptable excipients, wherein the
3 composition is substantially free of preservatives or antioxidants.
1 2. The stable topical pharmaceutical composition according to claim 1, wherein the
2 silver sulfadiazine is present in an amount of from 0.1% w/w to 1.0% w/w of the total
3 weight of the composition.
1 3. The stable topical pharmaceutical composition according to claim 1, wherein the
2 silver sulfadiazine is present in an amount of0.05% w/w of the total weight of the
3 composition.
1 4. The stable topical pharmaceutical composition according to claim 1, wherein the
2 nanonized silver sulfadiazine has a d50 value of from about 20 nm to 200 nm.
1 5. The stable topical pharmaceutical composition according to claim 1, wherein the
2 nanonized silver sulfadiazine has a d9o value of from about 200 nm to 600 nm.
1 6. The stable topical pharmaceutical composition according to claim 1, wherein the
2 nanonized silver sulfadiazine has a surface area of more than 40 m2 /g.
1 7. The stable topical pharmaceutical composition according to claim 1, wherein the
2 pharmaceutically acceptable excipients are selected from the group consisting of
3 emulsifying agents, chelating agents, thickening agents, pH modifiers, and mixtures
4 thereof.
1 8. The stable topical pharmaceutical composition according to claim 7, wherein the
2 chelating agents are selected from the group comprising dimercaprol,
3 ethylenediaminetetraacetic acid (EDTA), disodium edetate, ethylene glycol tetraacetic
4 acid, lipoic acid, and mixtures thereof.
1 9. The stable topical pharmaceutical composition according to claim 1, wherein the
2 composition further comprises chlorhexidine gluconate in an amount of from 0.1% w/w to
3 0.5% w/w ofthe total weight of the composition.
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1 10. The stable topical pharmaceutical composition according to claim 1, wherein the
2 composition shows no visual color change when stored at temperature 40°C and humidity
3 75% RH for a period of 12 months.
1 11. The stable topical pharmaceutical composition according to claim 1, wherein the
2 nanonization is carried out in a vessel made up of or coated with non-reactive materials.
1 12. The stable topical pharmaceutical composition according to claim 11, wherein the
2 non-reactive material is selected from the group consisting of ceramics, zirconium oxide,
3 silicon carbide, and mixtures thereof.
1 13. The stable topical pharmaceutical composition according to claim 1, wherein the
2 preservatives or antioxidants, alone or in combination, are present in the composition in an
3 amount ofless than 0.25% w/w of the total weight of the pharmaceutical composition.
1 14. The stable topical pharmaceutical composition according to claim 1, wherein the
2 preservatives are selected from the group comprising methylparaben, propylparaben,
3 benzyl alcohol, benzoic acid, sodium benzoate, chlorocresol, sorbic acid and its salt,
4 phenylethyl alcohol, and mixtures thereof.
1 15. The stable topical pharmaceutical composition according to claim 1, wherein the
2 antioxidants are selected from the group comprising sodium metabisulfite, butylated
3 hydroxytoluene, hydrogen peroxide, butylated hydroxyanisole, propyl gallate, ethyl
4 gallate, methyl gallate, ascorbic acid, tocopherol, and mixtures thereof.