Claims:CLAIMS
We Claim:
1. A topical gel dispersion comprising:
(i) 0.04- 0.1 wt% Tretinoin,
(ii) 1-1.2 wt% Clindamycin Phosphate,
(iii) one or more viscosity enhancers,
(iv) one or more surfactants,
(v) one or more emollients, and
(vi) one or more pharmaceutically acceptable excipients.

2. The topical gel dispersion as claimed in claim 1 comprising:
(i) 0.04- 0.1 wt% Tretinoin,
(ii) 1-1.2 wt% Clindamycin Phosphate,
(iii) 0-1.5 wt% of one or more viscosity enhancers,
(iv) 0-3% wt% of one or more surfactants,
(v) 0-2 wt% of one more emollients, and
(vi) one or more pharmaceutically acceptable excipients.

3. The topical gel dispersion as claimed in claim 1, wherein the Tretinoin is in the form of microparticles or microspheres or both.

4. The topical gel dispersion composition as claimed in claim 1, wherein the emollients are selected from one or more of cyclomethicone-dimethicone copolyol silicone fluid, cyclomethicone-dimethiconol, dimethicone and silicon gum or any mixture thereof.

5. The topical gel dispersion as claimed in claim 1, wherein the viscosity enhancers are selected from one or more of acrylate polymers, carboxyvinyl polymers, pectin, carrageenan, alginic acid and its salts, or mixtures thereof.

6. The topical gel dispersion as claimed in claim 5, wherein the viscosity enhancer comprises of an acrylate polymer.

7. The topical gel dispersion as claimed in claim 1, wherein the surfactant is selected from one or more of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glyceryl and steroidal esters, organosilicone co-polymers, such as silicone glycol co-polymers, silicone-silicone co-polymers, polyorganosiloxanes and polyorganosilanols, or any mixture thereof.

8. A process for preparing the topical gel dispersion of claim 1, the process comprising the steps of:
i) preparing a first dispersion comprising the viscosity enhancer,
ii) preparing a solution comprising the surfactants and the emollients,
iii) preparing a solution comprising Clindamycin Phosphate,
iv) combining the solutions obtained in (ii) and (iii) with (i) to form a second dispersion,
v) preparing a third dispersion comprising Tretinoin microparticles,
vi) combining the second and third dispersions and to form the uniform gel dispersion.
, Description:The following specification describes the invention and the manner in which it is performed:

TOPICAL GEL DISPERSIONS COMPRISING TRETINOIN AND CLINDAMYCIN
FIELD OF THE INVENTION
The present invention relates to topical gel dispersions comprising Tretinoin and Clindamycin. The invention also provides the process for preparation of such compositions.

BACKGROUND OF THE INVENTION
Acne vulgaris is a follicular disease characterized by pilosebaceous inflammations such as comedones, papules, pustules, cysts and nodules. Chiefly a disease of adolescence (and often a cause of emotional distress), acne originates endogenously and stems from multifactorial influences. Major progressive factors in the development of acne include hyperkeratosis of the follicular epithelium, increased sebum production, and proliferation of Propionibacterium acnes. These factors are primarily responsible for hyperkeratosis of the follicle lining, including retention of keratin and sebum, as well as the free fatty acid by-products of P. acnes metabolization which can lead to inflamed acne papules and pustules.
Till date, there is a clear gap in the understanding of the pathogenesis of acne. Use of systemic and topical medications, including tetracycline, has been used to manage and control acne. However, none have been a cure for all. This has led to a common use of “polypharmacy”, whereby physicians employ simultaneous treatment with a variety of modalities. The search for improved acne treatments has been widespread and continuous during the past several decades. Enhanced cosmetic properties to encourage user compliance, the use of topical therapies in place of systemic drugs to reduce toxicity and side effects, and the introduction of new drugs and formulations represent the forefront of acne treatment advances.

Topical retinoids are both comedolytic and anti-comedogenic and have been shown to reduce formation of microcomedones and comedones. They also have direct and indirect anti-inflammatory actions and normalize desquamation which facilitates penetration of other topical agents. They are inherently irritating and historically associated with poor tolerability, resulting in limited patient adherence.

Numerous efforts have been made to reduce irritation of retinoids by reducing the concentration of active drug or incorporating ingredients into the vehicle that are intended to hydrate and offset the irritating effects of the drugs. Tretinoin has been incorporated in porous drug loaded microbead-in-gel delivery system or in substantially non-porous polymeric microparticles. These are described in U.S. Pat. Nos. 4,690,825, 5,145,675, 5,955,109, 5,135,740, 5,316,774, 8053000 & 8603539 among others. Despite an improved efficacy in the treatment of acne, irriration potential still remained a concern.

Tretinoin topical compositions containing an additional active such as Clindamycin, which have a mechanism of action that is complementary to topical retinoids, have been explored. US Pat No. 6387383 describes an aqueous gel composition consisting of crystalline suspension of 1.2 wt% of Clindamycin in combination with 0.025 wt% Tretinoin. The composition is commercially marketed under the trademark of ZIANA gel. The trials with ZIANA gel suggested that it did not provoke degree of irritation associated with standard solubilized formulations of Tretinoin.

Interestingly, a clinical study comparing tolerability of ZIANA gel composition with a 0.1 wt% Tretinoin encapsulated in the form of microsphere gel formulation found that the cutaneous irritation in terms of erythema, scaling, itching, burning or stinging was lesser for the combination indicating that combination was more tolerable as compared to 0.1 wt% Tretinoin contained in microspheres. The authors speculated that anti-inflammatory properties of Clindamycin, higher concentration of Tretinoin in microspheres along with slower release of Tretinoin (partly solubilized and partly suspended) provided better tolerability. Further, the authors suggested that additional research may be needed to understand the actual contribution of each of the factors on tolerability. Despite of ZIANA gel being superior in terms of tolerability in comparison to microsphere formulation, the approved ZIANA gel label reported the occurrence of Erythema in 35% of subjects at baseline and 26 % as well as at the end of the safety studies.

Several other studies have investigated formulations containing 0.025 wt% Tretinoin and 1 wt% Clindamycin and compared it with formulation containing 0.025 wt% Tretinoin alone in the treatment of moderate to severe Acne. Inspite of superior efficacy, cutaneous tolerability still remained a concern with combination product.

A clinical study comparing adjuvant therapy of fixed combination gel containing Benzyl peroxide 5 wt% and Clindamycin 1 wt% plus 0.04 wt% Tretinoin microsphere gel with adjuvant therapy of fixed combination gel containing Clindamycin Phosphate 1.2 wt% and Tretinoin 0.025 wt% gel plus 5 wt% Benzyl Peroxide wash found that both treatments were safe, efficacious and well tolerated.

The studies till date suggest that though the irritation of Tretinoin is concentration dependent, it is influenced by the characteristics of the delivery system and formulation as well as the patient’s skin type and there still remains a need to evaluate the efficacy and tolerability of Tretinoin-Clindamycin especially in relation to one of the factors i.e. Tretinoin concentration to achieve a better product for the treatment of Acne Vulgaris.

The present invention relates to a topical composition containing Tretinoin and Clindamycin wherein the release of Tretinoin is sustained using polymers and plasticizers. It is envisaged that the modulation of release of Tretinoin from the topical composition allows the use of greater than 0.025 wt% concentration of Tretinoin currently available in the combination with Clindamycin as ZIANA gel. Further, a concentration range of 0.04 wt % to 0.1 wt% of Tretinoin in combination with Clindamycin in the concentration range of 1 to 1.2 wt% may aid in achieving a better product in terms of safety, tolerability and efficacy.

SUMMARY OF THE INVENTION
The present specification relates to a topical gel dispersion comprising Tretinoin and Clindamycin.
In one aspect, the present specification related to a topical gel dispersion comprising:
(i) 0.04- 0.1 wt% Tretinoin,
(ii) 1-1.2 wt% Clindamycin Phosphate,
(iii) one or more viscosity enhancers,
(iv) one or more surfactants,
(v) one or more emollients, and
(vi) one or more pharmaceutically acceptable excipients.
In another aspect, the present invention provides a process for the preparation of the topical gel dispersion comprising 0.04 wt % to 0.1 wt% Tretinoin and 1-1.2 wt% Clindamycin.
In yet another aspect, the present invention provides a method for treating acne in a human subject, which method comprises administering a drug combination comprising Tretinoin and Clindamycin in a composition described above to an affected area of the subject's skin having such disorder in an amount and for a period of time sufficient to improve the skin disorder.
DESCRIPTION OF THE INVENTION
The present specification relates to a topical gel dispersion comprising Tretinoin and Clindamycin.
In one aspect, the present specification relates to a topical gel dispersion comprising:
(i) 0.04- 0.1 wt% Tretinoin,
(ii) 1-1.2 wt% Clindamycin Phosphate,
(iii) one or more viscosity enhancers,
(iv) one or more surfactants,
(v) one or more emollients, and
(vi) one or more pharmaceutically acceptable excipients.

In another aspect, the present specification relates to a topical gel dispersion comprising:
(i) 0.04- 0.1 wt% Tretinoin,
(ii) 1-1.2 wt% Clindamycin Phosphate,
(iii) 0-1.5wt% of one or more viscosity enhancers,
(iv) 0-3 wt% of one or more surfactants,
(v) 0-2 wt% of one or more emollients, and
(vi) one or more pharmaceutically acceptable excipients.

The present invention relates to a novel topical gel dispersion composition for localized delivery of active agents for the treatment of skin diseases, in particular acne vulgaris. One important aspect of the present invention is to prepare a dispersion wherein the release of one of the active agents is sustained by incorporating it in the form of microparticles or microspheres and the second active agent is dissolved in the delivery vehicle. Processes for the preparation of the dispersion are described.
One of the active agents is a retinoid, while the second active agent is an antibiotic.
The terms “active agent,” and “active” are used herein to include any agent that is included in a composition for its effect.
An antibiotic is generally viewed as a drug that inhibits the growth of an unwanted microorganism. Representative examples of topical antibiotics include lincomycins, (e.g. clindamycin), erythromycin, minocycline, and tetracycline, and the pharmaceutically-acceptable salts, esters, or prodrugs thereof. e.g. the antibiotic is Clindamycin Phosphate.
A “retinoid” is a keratolytic drug related to retinoic acid and generally includes chemical entities such as retinol and its esters and closely related naturally-occurring derivatives and structurally-related synthetic analogs. This includes, for example, retinol, retinal, tretinoin (all-trans retinoic acid), isotretinoin, adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid), and the like. e.g. the retinoid is Tretinoin.
The terms “microparticulates,” “microparticles” or “microparticulate phase” are used interchangeably and are intended to mean the polymeric microparticles of the invention as described herein.
The term “substantially non-porous” is intended to mean microparticles that can have surface pores, internal pores, or both, but generally lack an interconnected network of pores open to the surface. Such a substantially non-porous product as defined by the porosity and pore volume is obtained by altering the ratio of polymer to plasticizer and controlling the processing parameters during the manufacture of the microparticle phase. Thus, increasing the concentration of the plasticizer in the microparticle composition will generally provide a product with a lower porosity. Further, lower porosity can also be imparted to the microparticle phase through slower drying at ambient temperatures. An elevated temperature for example can enhance the rate of solvent evaporation, but result in a product with a higher porosity.
Preparation of the Microparticles and of the Dispersion Composition
The microparticles may be formed by different techniques including solvent evaporation, coacervation phase separation, spray drying, spray congealing, supercritical fluid extraction, fluidized bed coating, pan coating and other techniques known in the art. In one aspect, solvent evaporation is used to prepare the microparticles of this invention due to its wide spread use and ease of processing. The disclosure for the process for the preparation of the tretinoin microparticles (Example 1) are described in US Pat. Nos. 8053000 & US 8603539 which is incorporated herein by reference. Additionally, determination of parameters such as morphology, particle size distribution, surface area, pore diameter, total pore volume of the microparticles were carried out as described in US Pat. Nos. 8053000 & 8603539.
The microparticles can be of any shape including spherical, oblong, irregular, ellipsoidal and the like. The size of the microparticles generally ranges from about 0.01 µm to 1 mm, or about 0.1 µm to 500 µm, or about 1 µm to 250 µm. The surface area of the microparticles may range from about 0.01 to about 500 m2/g, or about 0.05 to about 50 m2/g. The total pore volume of the microparticles can range from about 0.00001 cm3/g to about 0.1 cm3/g, or about 0.0001 cm3/g to about 0.05 cm3/g and the average pore diameter can range from about 0.1 nm to about 300 nm, or about 1 nm to about 100 nm.

The formed drug-loaded microparticles are readily dispersed and can be incorporated into fluid delivery vehicles containing another active. The composition has excellent spreadability with a minimum, and frequently an absence, of grittiness. Such a dispersion upon application to a body forms a film with microparticles dispersed within, wherein each microparticle functions as a distinct site for the controlled release of one active agent, with synergistic release of another active present in the delivery vehicle. The release of the active agent from the microparticles can be readily modulated through a combination of the hydrophobic polymer (or combination of polymers) and the plasticizer as disclosed in US Pat. Nos. 8053000 & 8603539. While the onset of release of the other active from the delivery vehicle is quicker as drug is in the dispersed state in the delivery vehicle. The amount of active agent incorporated into the composition depends upon the characteristics of the active agent, the desired release profile and the duration of action intended at the local site of action. A concentration range of 0.04 wt % to 0.1 wt% of Tretinoin in combination with Clindamycin in the concentration range of 1 to 1.2 wt% is preferred.

The absence of large concentrations of volatile organic solvents such as ethanol and the like in the final product also leads to a composition, which is stable for a prolonged period of time upon storage.

Such a dispersion comprising more than one actives aid in reducing the number of applications of the product and also a consequent reduction in the irritation potential of active agents incorporated into the composition.

These and other aspects and embodiments of the present invention are described in greater detail below.

The polymeric materials such as water insoluble or swellable polymers as well as plasticizers used in the preparation of microparticles of the present invention are disclosed in US Pat. Nos. 8053000 & 8603539 and both the references are incorporated herein.

Delivery Vehicle
The delivery vehicle should be biocompatible with no undue irritation to the application site. It should be stable enough to not result into phase separation post incorporation of microparticles at the temperature of storage. Further, the delivery vehicle should be immiscible with the dispersed microparticles and have excellent spreadability on application to a surface to rapidly form a film and thus the delivery system of the composition.

Useful hydrophilic fluids for the delivery vehicle include water, glycerol, propylene glycol, sorbitol and other higher alcohols and their mixtures in different proportions. A small percentage of a volatile solvent such as ethanol, acetone, or ethyl acetate and the like can be incorporated to aid processing and is within the scope of the invention.

Viscosity Enhancers
The viscosity of a fluid delivery vehicle can be enhanced through the addition of viscosity enhancers or gelling agents such as acrylate polymers such as carbopols (including those sold as ULTREZ™), carboxyvinyl polymers, pectin, carrageenan, alginic acid and its salts, gelatin, gums such as xanthan, tragacanth, guar, and chitosan, colloidal silicon dioxide, povidones, polyvinyl alcohols, cetostearyl alcohol, polyethylene oxides, polyoxyethylene-propylene glycol copolymers such as poloxamers, high molecular weight polyethylene glycols, cellulose polymers like hydroxypropyl cellulose, hydroxypropyl methylcelluloses, methylcelluloses, sodium carboxymethyl celluloses, starches, bentonite (VEEGUM™), propylene carbonate, and other materials. Combinations of these viscosity enhancers can also be used as desired and can be employed in amounts ranging from about 0.01% to about 1.5% by weight are within the scope of this invention.

Additives
Appropriate agents can be added to the composition of the invention to provide the desired properties such as pH, salt concentration, colors and fragrances. Where required, preservatives, antioxidants, opacifiers, emulsifiers, surfactants, emollients, and permeation enhancers can be added to improve the performance of the delivery composition. The use of such materials for formulation of an aesthetically appealing and stable composition for local application is well known to the person who is skilled in the art of preparation of pharmaceutical products. Different classes of compounds from all these categories are included within the scope of the invention without limitation.

The formulation may also contain one or more surfactants. Surfactants in a gel formulation are generally nonionic, anionic, cationic, amphoteric surfactants as emollient surfactants. Suitable surfactants include, but are not limited to, nonionic surface active agents, e.g., polysorbate (TWEEN®, EMULROR®, TRITON® and SIMULSOL® M-53), sorbitan monostearate, polyglyceryl-4 oleate, polyoxyethylene(4)lauryl ether or trivalent cationic and the like, and sodium lauryl sulphate and mixtures thereof. The preferred surfactants include polysorbate 80 or emollient surfactants like polypropylene glycol (PPG) stearyl ethers like PPG ethers of stearyl alcohol like PPG-20 methyl glucose ether distearate, PPG-15 Stearyl Ether and PPG-11 Stearyl Ether. More preferably PPG-20 methyl glucose ether distearate or mixtures thereof. Surfactants can be employed in amounts ranging from about 0.01% to about 3% by weight of the composition.
The formulation may additionally contain the silicone emollients comprising a combination of cyclomethicone, dimethicone copolyol, dimethiconol or silicone gum. In particular, it is desirable to use a combination of DC 3225C, DC 1401 and optionally DC 1418. Dow Corning 3225C is a mixture of cyclomethicone-dimethicone copolyol silicone fluid having a viscosity at 25°C of 100-1,000 cst and a specific gravity at 25°C of 0.963. Amounts of this particular silicone will be present from 1 to 10% of the total composition. Dow Corning 1401 is a blend of Cyclomethicone and Dimethiconol having a viscosity at 25°C of 5,000-7,000 cst and a specific gravity at 25°C of 0.960. Amounts of DC 1401 may range from 0.5 to 10%, preferably from 2 to 6% by weight of the total composition. Dow Corning 1418 is a blend of dimethicone and a silicone gum having a viscosity at 25°C of 350,000-750,000 cst and a specific gravity at 25°C of 0.970. Amounts of the DC 1418 will range from 0.1 to 10%, preferably from 0.5 to 5% by weight of the total composition.
Preservatives can desirably be incorporated into the controlled release system for stabilizing actives to protect against the growth of potentially harmful microorganisms. Suitable preservatives for compositions of the present invention include alkyl esters of para-hydroxybenzoic acid like methylparaben and propylparaben, benzoates, hydantoin derivatives, propionate salts, sorbic acid, benzyl alcohol, imidazolidinyl urea, sodium dehydroacetate and a variety of quaternary ammonium compounds. Appropriate preservatives can be selected to satisfy the preservative challenge test and to provide product stability. The preservative can be chosen based on the consideration of possible incompatibilities between the preservative and other ingredients in the release system. Preservatives can be employed in amounts ranging from about 0.01% to about 2 wt % by weight of the composition.

The formulation may further consist of a chelating agent. Examples of suitable chelating agents include, but are not limited to, citric acid, nitrilotriacetic acid (“NTA”), any form of ethylene diamine tetraacetic acid (“EDTA”), hydroxyethyl ethylene diamine triacetic acid (“HEDTA”), diethylene triamine pentaacetic acid (“DTPA”), propylene diamine tetraacetic acid (“PDTA”), ethylene diamine-N,N?-di(hydroxyphenylacetic) acid (“EDDHA”), ethylene diamine-N,N?-di-(hydroxy-methylphenyl acetic acid (“EDDHMA”), ethanol diglycine (“EDG”), trans-1,2-cyclohexylene dinitrilotetraacetic acid (“CDTA”), glucoheptonic acid, gluconic acid, sodium citrate, phosphonic acid, salts thereof, and the like. Chelating agents may be employed in amounts ranging from about 0.01% to about 2% by weight of the composition.

Aqueous phases can be modified by the addition of agents serving as humectants. Examples are glycerin, sorbitol, mannitol, xylitol, maltitol, corn syrup, sugars, alcohol sugars, mineral salts, and combinations thereof.

Delivery System
The microparticles of the invention when incorporated into a delivery vehicle form the delivery system of the composition. When an active agent is included in both the microparticulate phase and the delivery vehicle, a delivery system is formed which permits modulated delivery of the different active agents with different desired profiles to the local application site.
Once prepared, the microparticulates can be incorporated into the delivery vehicle either as a dry powder to be dispersed into the delivery vehicle or as a wet cake after recovery in the microencapsulation process without drying. Typically, up to about 50%, or up to about 10%, by weight of the microparticulate phase will be incorporated into a delivery vehicle. The amounts incorporated will vary from active agent to active agent, and from composition to composition, and are all within the scope of this invention. Any known techniques for preparation of the final composition are acceptable such as simple mixing, blending, use of a planetary mixer and the like.

The compositions of this invention can be part of a kit or device and can be filled into tubes, jars, bottles, aerosol containers, and any other form of packaging that will allow ease of application locally such as to the skin. The composition is meant to be applied locally, either manually or by using a convenient applicator, for patient compliance and ease of applicability. The dose, number and frequency of applications can be decided by a person skilled in the art of treating local conditions such as a physician, a podiatrist and the like.

The following examples further explain certain specific aspects and embodiments of the invention in more detail and are not to be construed as limiting the scope of the invention.

EXAMPLES
Example 1
Preparation of microparticles containing Tretinoin

Ingredients
Concentration
(% w/w)
Dispersed Phase
Tretinoin 1.75
Ethyl Cellulose 87.7
Butylated Hydroxy Toluene 1.77
Isopropyl Myristate 8.78
Methylene Chloride 105
Continuous Phase
Polyvinyl Alcohol 0.5
Purified water 100

Process
1. In the first vessel, Ethyl Cellulose, Isopropyl Myristate, Tretinoin and BHT were dissolved in methylene chloride to form a clear solution.
2. In the separate vessel, Polyvinyl Alcohol was dissolved in water to prepare the continuous phase.
3. This solution in Step 1 was added to Polyvinyl Alcohol solution under homogenization at 4,000 rpm.
4. Stirring was continued using mechanical stirrer till Methylene Chloride evaporated and microparticles were formed.
5. The microparticles were allowed to settle in the system, supernatant was decanted, and then remaining material was filtered and washed with 500 ml of purified water 2-3 times at room temperature and dried under vacuum in a vacuum desiccator containing dried self-indicating silica gel.
Example 2-4

Preparation of microparticulate dispersion containing 0.04 wt% Tretinoin and 1 wt% Clindamycin

Ingredients
Concentration (% w/w)
Example 2 Example 3 Example 4
Microparticles of Example 1 2.40 2.40 2.40
Clindamycin Phosphate 1.05 1.05 1.05
Acrylate Polymer 1.50 1.50 1.50
Disodium Edetate 0.05 0.05 0.05
Methyl Paraben 0.2 0.20 0.20
Propylene glycol 5.50 5.50 5.50
Glycerin 5.0 5.0 5.0
Trolamine 0.8 0.8 0.8
Cyclomethicone & Dimethicone copolyol (Dow Corning 3225C) 2.0 2.0 2.0
PPG-20 Methyl Glucose Ether Distearate 2.0 2.0 2.0
Polysorbate 80 0.03 0.03 0.03
Purified water qs qs qs

Example 5-6

Preparation of microparticulate dispersion containing 0.1 wt% Tretinoin and 1 wt% Clindamycin

Ingredients
Concentration (% w/w)
Example 5 Example 6
Microparticles of Example 1 6.0 6.0
Clindamycin Phosphate 1.05 1.05
Acrylate Polymer 1.50 1.50
Disodium Edetate 0.05 0.05
Methyl Paraben 0.20 0.20
Propylene glycol 5.50 5.50
Glycerin 5.0 5.0
Trolamine 0.8 0.8
Cyclomethicone & Dimethicone copolyol (Dow Corning 3225C) 2.0 2.0
PPG-20 Methyl Glucose Ether Distearate 2.0 2.0
Polysorbate 80 0.03 0.03
Purified water qs qs

Process for preparation of microparticulate dispersion of Examples 2-6:
1. In the first vessel, required quantity of Purified Water (about 45% w/w) was added and heated up to 80°C. Disodium Edetate followed by Methyl Paraben were added to water and dissolved to form a clear solution. Acrylate Polymer was added to form a uniform dispersion (ensuring dispersion being free of lumps). Half the quantity of Glycerin was added to Acrylate Polymer dispersion under homogenization and stirred followed by cooling of the bulk to 60°C.
2. In the separate vessel, a clear solution containing PPG-20 Methyl Glucose Ether Distearate, polysorbate 80 and Dow Corning 3225C was prepared with continuous stirring. The solution was slowly transferred to Acrylate Polymer dispersion in Step 1 and stirred under homogenization.
3. In the separate vessel, Clindamycin Phosphate in Water was dissolved under stirring. The solution was transferred to Acrylate Polymer dispersion in Step 2 and stirred under homogenization.
4. In the separate vessel, remaining half quantity of Glycerin, Propylene Glycol, Polysorbate 80 and Water were added. Tretinoin containing microparticles was added to form a uniform dispersion. The dispersion was added to Acrylate Polymer dispersion in Step 3 and stirred.
5. In the separate vessel, Trolamine was dissolved in about 1% w/w of Purified Water and added to Acrylate Polymer dispersion in Step 4 and stirred and gel dispersion with required pH was achieved.

Example 7
Clinical Evaluation

This clinical data shows the advantages of a composition of the invention as compared to Tretinoin 0.025% Gel and Clindamycin 1% Gel in the treatment of Acne Vulgaris. A randomized multi-centre double-blind clinical trial was conducted comparing a composition of this invention (Example 2), with commercially available Tretinoin 0.025% Gel and Clindamycin 1 wt% gel preparation once daily for the treatment of Acne Vulgaris. Seven hundred and fifty patients, were randomized in 2:2:1 ratio [Example 2: Tretinoin 0.025 wt% gel: Clindamycin 1 wt% gel] were treated for up to 12 weeks.

Evaluations included efficacy and safety assessments. Efficacy was evaluated by assessing the reduction in acne lesion count, severity of lesions, ISGA score and physician's global assessment. Safety evaluation included local cutaneous tolerability assessment. The data on lesion counts are summarized.

Comparison of Baseline and end of study lesion counts, mean percent change for all formulations
Characteristics 0.025 wt% Tretinoin Gel
1 wt% Clindamycin Gel

Example 2 composition
All

Acne lesion count- Inflammatory Lesions
Baseline (mean count) 29.93 29.83 29.42 29.70
End of study (mean count) 8.87 10.28 6.88 8.35
Mean % change 70.87 66.14 77.11 72.42
p value (Example 2 composition Vs Tretinoin gel, Example 2 composition Vs Clindamycin gel) 0.007* 0.000* NA NA
Acne lesion count- Non-Inflammatory Lesions
Baseline (Mean count) 39.01 38.38 38.28 38.59
End of study (mean count) 12.64 16.97 11.62 13.10
Mean % change 67.14 59.24 71.27 67.21
p value (Example 2 composition Vs Tretinoin gel, Example 2 composition Vs Clindamycin gel) 0.022* 0.000* NA NA
Total Acne Lesion Count
Baseline(Mean count) 68.94 68.21 67.70 68.30
End of study (Mean count) 21.50 27.25 18.50 21.45
Mean % change 68.73 61.46 73.29 69.10
p value (Example 2 composition Vs Tretinoin gel, Example 2 composition Vs Clindamycin gel) 0.009* 0.000* NA NA
* Statistically significant

Overall there was 72.42% reduction in the inflammatory, 67.21% in non-inflammatory and 69.10% reduction in the total acne lesions count from baseline, which was statistically significant (p=0.000). Among the groups, a statistically significant difference in mean % reduction in inflammatory (p=0.007), non-inflammatory (p=0.022) and total lesion count (p=0.009) was observed in subjects who received Example 2 composition compared to 0.025% tretinoin gel group. This difference was statistically significant (p=0.000) while comparing Example 2 composition with 1% Clindamycin gel too. Previous clinical trials have documented the mean % change in inflammatory (48-61%, and 52.6-70%), non-inflammatory (36-50% and 43.8-57.6%) and total lesions counts (41-54% and 46.3-62%) with clindamycin-tretinoin combination. In our study a mean percentage change of 77.11% in the inflammatory acne lesions, 71.27% in non-inflammatory lesions and 73.29% in the total acne lesions counts was found with Example 2 gel group which was statistically significant. The higher response rate seen in our study for the Example 2 composition group is possibly related to using microsphere delivery system for Tretinoin which might have allowed better penetration and higher retention of Tretinoin at the site of lesion.

At the end of the study, 41% subjects in Example 2 group achieved ISGA grading of 0 or 1 (clear or almost clear) compared to 31.67 % in 0.025 wt% Tretinoin gel group and 27.33 % (41) in 1 wt % Clindamycin gel group which was found to be statistically significant. The two grade improvement in ISGA score from baseline to week 12 was seen in 45.67 % subjects in Example 2 composition group compared to 36% in 0.025 wt% Tretinoin gel group and 28.67 % in 1 wt% Clindamycin gel group which was statistically significant.

Local tolerability assessment had shown all the three formulation groups were well tolerated by the subjects. Itching and erythema were the commonest events reported. These events showed a progressive decline over the course of treatment with respect to incidence as well as severity. At week 12, erythema and burning were reported in 15.81 % and 13.60 % subjects respectively in 0.025% Tretinoin gel group and 10.11% and 8.30 % in Example 2 group respectively which was found to be statistically significant.

Tolerability assessment (%) among the different study groups
Visit Symptom
0.025 wt% Tretinoin Gel
1 wt% Clindamycin Gel
Example 2 composition
Total
Week 2
(Visit 2) Erythema 34.84% 24.31% 34.13% 32.46%
Scaling 34.84% 19.44% 30.03% 29.83%
Itching 37.28% 27.78% 36.52% 35.08%
Burning 32.40% 20.14% 28.67% 28.45%
Stinging 14.29% 10 (6.94%) 9.22% 10.77%
Week 4
(Visit 3) Erythema 30.85% 17.02% 29.37% 27.50%
Scaling 25.89% 13.48% 22.73% 22.14%
Itching 29.79% 21.99% 31.82% 29.06%
Burning 23.76% 10.64% 23.43% 21.02%
Stinging 12.06% 4.26% 10.14% 9.73%

Week 8
(Visit 4) Erythema 25.09% 10.29% 22.11% 20.98%
Scaling 17.82% 11.76% 20.00% 17.53%
Itching 17.09% 16.18% 20.70% 18.39%
Burning 17.82% 10.29% 19.30% 16.95%
Stinging 8.73% 3.68% 11.23% 8.76%

Week 12
(Visit 5)
Erythema 15.81% 8.27% 10.11% 12.02%
Scaling 11.76% 6.77% 14.08% 11.73%
Itching 12.50% 7.52% 11.19% 11.00%
Burning 13.60% 5.26% 8.30% 9.82%
Stinging 6.25% 5.26% 8.66% 7.04%

Comparison of Tolerability assessment (%) between the 0.025 wt% Tretinoin gel group
and Example 2 composition group
Visit Symptom 0.025 wt% Tretinoin Gel Example 2 composition
(N=300) p value
Week 2
(Visit 2) Erythema 34.84% 34.13% 0.857
Scaling 34.84% 30.03% 0.216
Itching 37.28% 36.52% 0.849
Burning 32.40% 28.67% 0.329
Stinging 14.29% 9.22% 0.058
Week 4
(Visit 3) Erythema 30.85% 29.37% 0.701
Scaling 25.89% 22.73% 0.380
Itching 29.79% 31.82% 0.600
Burning 23.76% 23.43% 0.926
Stinging 12.06% 10.14% 0.046

Week 8
(Visit 4) Erythema 25.09% 22.11% 0.405
Scaling 17.82% 20.00% 0.510
Itching 17.09% 20.70% 0.276
Burning 17.82% 19.30% 0.653
Stinging 8.73% 11.23% 0.324

Week 12
(Visit 5)
Erythema 15.81% 10.11% 0.047
Scaling 11.76% 14.08% 0.419
Itching 12.50% 11.19% 0.635
Burning 13.60% 8.30% 0.047
Stinging 6.25% 8.66% 0.282

Despite use of higher strength of Tretinoin, we have seen a significantly better tolerability with Example 2 group compared to Tretinoin 0.025 wt% gel group with respect to symptoms of erythema and burning of tretinoin. At the end of study (12 weeks or last evaluation) it was concluded that the synergistic effect of the microsphere formulation of 0.04 wt% Tretinoin with 1 wt% Clindamycin displayed superior efficacy, faster onset of action and better tolerability compared to commercially available 0.025 wt% Tretinoin microsphere gel and 1 wt% Clindamycin gel preparations.