Technical Field of the Invention;

The present invention relates to a stable topical gel formulation comprising therapeutically effective amount of (a) Adapalene, (b) Clindamycin and (c) Niacinamide along with pharmaceutical acceptable excipients, useful in the treatment of acne vulgaris.

Background of the Invention:

Acne vulgaris (or cystic acne) is a common human skin disease, characterized by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), pustules (pimples), Nodules (large papules) and possibly scarring. Acne affects mostly skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back. Severe acne is inflammatory, but acne can also manifest in non-inflammatory forms. The lesions are caused by changes in pilosebaceous units, skin structures consisting of a hair follicle and its associated sebaceous gland, changes that require androgen stimulation. Acne vulgaris is an inflammatory disease of the sebaceous glands characterized by an eruption of the skin, often pustular in nature but not suppurative.

The following are the 4 primary factors that are believed to lead to the formation of acne vulgaris:

• Increased sebum output resulting in oily, greasy skin

• Increased bacterial activity normally due to an overabundance of Propionibacterium acnes

• Plugging of the follicle or pilosebaceous duct

• Inflammation caused by substances leaking into the dermis

Acne lesions change over time from blackheads and whiteheads to inflammatory lesions that upon healing may leave pigmentary changes, cysts or scars. Acne occurs most commonly during adolescence, and often continues into adulthood. In adolescence, acne is usually caused by an increase in testosterone, which people of both genders accrue during puberty. For most people, acne diminishes over time and tends to disappear - or at the very least decrease - by age 25. There is, however, no way to predict how long it will take to disappear entirely, and some individuals will carry this condition well into their thirties, forties, and beyond. Apart from scarring, the main effects of acne are psychological, such as reduced self-esteem and in very extreme cases, depression or suicide. Acne usually appears during adolescence, when people already tend to be most socially insecure. Early and aggressive treatment is therefore advocated by some to lessen the overall long-term impact to individuals.

Hence, there exists a need to provide a solution to the above-described shortcomings of the presently known treatments. Adapalene, chemically (6-[3-(l-adamantyl)-4-methoxyphenyl]-2-naphthoic acid), is an anti¬acne agent indicated for the topical treatment of acne vulgaris. It is a white to off-white powder, which is soluble in Tetrahydrofuran, very slightly soluble in ethanol and practically insoluble in water. Clindamycin, an antibiotic of the lincosamide class, is often used in topical preparations for acne treatment. Clindamycin phosphate is a water soluble ester of the semi synthetic antibiotic produced by a 7 (S)-Chloro substitution of the 7 ® - Hydroxyl group of the parent antibiotic lincomycin. Nicotinamide is a water-soluble vitamin and is part of the vitamin B group. Niacinamide is able to reduce the amount of oil or sebum that the glands secrete. The reduction in the amount of oil that the glands pump out reduces blackheads and whiteheads from forming because of clogged pores.

There are certain Patented literature for the treatment of acne which describes as follows:- WO2003000243 discloses an antimicrobial oil-in-water nanocmulsion composition for an acne treatment, comprising a solvent and a surfactant, wherein said antimicrobial oil-in-water nanoemulsion kills or disables microorganisms when in contact with said microorganisms. WO2012053014 discloses a composition for use in the treatment of acne comprises a combination of clindamycin and adapalene or salts thereof, in the form of nano size droplets. WO2008017914 discloses a topical preparation for treating mild to severe acne in the form of a pharmaceutical gel and cream comprising: Retinoid (Tazarotene or Adapalene), Antibiotic (Clindamycin Phosphate) and/or Keratolytic (Benzoyl Peroxide in microsponges) as active ingredients and a carrier formulated with all or some of the following components: Propylene glycol, Polyoxyl 35 Castor Oil, Mineral Oil, Emulsifying nonionic wax (Polawax), Polysorbates, Glycerine, Carbomers, Disodium EDTA, Triethanolamine, Ethanol, Antioxidants and preservatives.

WO2006048747 discloses a topical pharmaceutical composition suitable for the treatment of skin disorder comprising (a) a therapeutically effective amount of at least one antiacne agent selected from adapalene, isotretinoin, tretinoin and at least one antibiotic agent selected from azithromycin, clarithromycin, lincomycin, clindamycin, erythromycin, clindamycin as active pharmaceutical ingredients; and (b) a hydrophilic matrix such as carbopol, capable of providing a constant and uniform release of the active pharmaceutical ingredients. The topical cream or gels for acne treatment known in the art and available in the market shows certain drawbacks such as irritation after application. To overcome this problem of irritation, the inventors of the present invention have come up with a liquid crystalline gel formulation comprising therapeutically effective amount of (a) Adapalene, (b) Clindamycin and (c) Niacinamide along with pharmaceutical acceptable excipients, which has the advantage of minimal or nil irritation and with additional cooling sensation after application when compared to simple cream or gel or emulgel preparations containing Adapalene or its combinations.

The Clindamycin used in the present formulation is a semi-synthetic antibiotic which reduces acne and lessens inflammation. It also decreases the bacterial resistance that often occurs when antibiotics are used. Adapalene of the present formulation unclogs pores and helps in reducing the infection/inflammation. Further, use of niacinamide helps to improve the skin's natural immunities to the harmful bacteria causing blemishes. Hence, the liquid crystalline gel formulation of the present invention comprising (a) Adapalene, (b) Clindamycin and (c) Niacinamide shows synergistic effect as compare to the methods known in the art.

Summary of the Invention:

In accordance with above, the present invention provides a stable topical liquid crystalline gel formulation comprising therapeutically effective amount of (a) Adapalene, (b) Clindamycin and (c) Niacinamide along with pharmaceutical acceptable excipients, useful in the treatment of acne vulgaris.

Detailed Description of the Invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. The present invention provides a stable topical liquid crystalline gel formulation comprising therapeutically effective amount of (a) Adapalene, (b) Clindamycin and (c) Niacinamide along with pharmaceutical acceptable excipients, useful in the treatment of acne vulgaris. The Clindamycin used in the present invention, may be incorporated in its topically bioavailable form preferably Clindamycin Phosphate. The pharmaceutical acceptable excipients may selected from gelling agent, humectants, cold emulsifiers, emulsifying wax, oil base, preservatives, antioxidants, buffering agent, chelating agent, penetration enhancer, co-solvent, Carbopol, pH adjuster along with vehicle, surfactant, solubilizer, emulsifier and combinations thereof.

The topical formulation of the present invention includes humectants selected from Glycerin, Propylene Glycol and the like; Cold emulsifiers selected from Polasperse QBE [PEG-7 GlycerylCocoate (and) SorbitanOleate (and) Caprylic/Capric Triglyceride (and) Aqua (and) Carbomer (and) Tri (PPG-3 Myristyl Ether) Citrate (and) SorbitanLaurate]; a gelling agent such as Carbomer; emulsifying wax such as Polawax GP 200; pH adjuster such as Sodium hydroxide (10% Solution); other excipients such as Methyl Paraben, Disodium edetate, Cremophor RH 40, Phenoxy Ethanol and purified water. In a preferred embodiment, the present invention provides a stable topical liquid crystalline gel formulation comprises 0.1% w/w of Adapalene, 1.0% w/w of Clindamycin, 4.0% w/w of Niacinamide and 2.0 % to 5.0% w/w of Polawax GP 200 along with pharmaceutical acceptable excipients. In another preferred embodiment, the present invention provides a stable topical liquid crystalline gel formulation comprises;

a) Adapalene in an amount of 0.1 % w/w;

b) Clindamycin in an amount of 1.0% w/w;

c) Niacinamide in an amount of 4.0% w/w;

d) Polawax GP 200 in an amount of 2.0 % to 5.0% w/w;

e) Carbomer in an amount of 0.5% to 1.5% w/w;

f) Optionally Aloe vera in an amount of about 10% w/w;

g) Glycerin in an amount of 6.0% w/w;

h) Polasperse QBE in an amount of 2.0 % to 4.0% % w/w and other excipients. (Based on 100% total weight of the formulation)

In another embodiment, the addition of Aloe vera renders a soothing texture to the formulation. In another embodiment, the addition of humectants reduces the irritation produced due to Adapalene. In yet another embodiment, the addition of cold emulsifier imparts a cooling sensation on application to the skin. In another preferred embodiment, the present invention provides "Liquid Crystal Technology" to prepare the formulation; wherein the addition of emulsifying wax, preferably Polawax GP 200 facilitates the formation of liquid crystals within the emulsion. These liquid crystals provides for timed-release hydration and functions as a slow release delivery mechanism for actives. Hence by exploring a unique technology of liquid crystalline gel formulation nearly eliminate or reduces the reported irritation due to Adapalene to the minimum.

Accordingly, a stable topical liquid crystalline gel formulation of the present invention comprises;

a) 0.1 % w/w of Adapalene,

b) 1.0% w/w of Clindamycin,

c) 4.0% w/w of Niacinamide and

d) 2.0 % to 5.0% w/w of Polawax GP 200 along with pharmaceutical acceptable excipients; wherein, Polawax GP 200 facilitates the formation of liquid crystals within the emulsion to provide sustained release of actives.

In yet another embodiment, the present invention utilizes Emulgel technology to formulate a stable topical dosage form comprising the above said formulation. The prepared stable topical formulation of the present invention is kept at a value between 4.0 and 6.0; preferably between 4.0 and 5.0; more preferably around 4.5 - 5.0. The stability of the formulation at different pH values between 5.0 and 6.0 was studied and the interpretation of results is depicted in below Table 1.

Table 1

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

We Claim,

1. A stable topical liquid crystalline gel formulation, useful in the treatment of acne vulgaris comprises;
a) 0.1% w/w of Adapalene,
b) 1.0% w/w of Clindamycin,
c) 4.0% w/w of Niacinamide and
d) 2.0 % to 5.0% w/w of Polawax GP 200 along with pharmaceutical acceptable excipients; wherein, Polawax GP 200 facilitates the formation of liquid crystals within the emulsion to provide sustained release of actives.

2. The stable topical liquid crystalline gel formulation according to claim 1, wherein said pharmaceutical acceptable excipients are selected form gelling agent, humectants, cold emulsifiers, emulsifying wax, oil base, preservatives, antioxidants, buffering agent, chelating agent, penetration enhancer, co-solvent, Carbopol, pH adjuster along with vehicle, surfactant, solubilizer, emulsifier and combinations thereof.

3. The stable topical liquid crystalline gel formulation according to claim 1, wherein said formulation optionally comprises 10% w/w of Aloe vera.

4. The stable topical liquid crystalline gel formulation according to claim 1, wherein said formulation comprises;

a) Adapalene in an amount of 0.1 % w/w;

b) Clindamycin in an amount of 1.0% w/w;

c) Niacinamide in an amount of 4.0% w/w;

d) Polawax GP 200 in an amount of 2.0 % to 5.0% w/w;

e) Carbomer in an amount of 0.5% to 1.5% w/w;

f) Optionally Aloe vera in an amount of about 10% w/w;

g) Glycerin in an amount of 6.0% w/w;

h) Polasperse QBE in an amount of 2.0 % to 4.0% % w/w and other excipients.

5. The stable topical liquid crystalline gel formulation according to claim 1, wherein said formulation is prepared using Liquid Crystal Technology.

6. The stable topical liquid crystalline gel formulation according to claim 1, wherein said formulation is optionally prepared using Emulgel Technology.