|Title of Invention||
TOPICAL PHARMACEUTICAL COMPOSITIONS CONTAINING ADAPALENE AND CLINDAMYCIN
|Abstract||Pharmaceutical compositions suitable for the treatment of bacterial dermatological infections and processes for their preparation are provided. The pharmaceutical compositions can be a semisolid pharmaceutical composition comprising a therapeutically effective amount of at least one antiacne agent and at least one antibacterial agent as active pharmaceutical ingredients and a hydrophilic matrix having gelling properties and capable of providing a constant and uniform release of the active pharmaceutical ingredients.|
|Full Text||FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
COMPLETE SPECIFICATION (SECTION 10)
"TOPICAL PHARMACEUTICAL COMBINATION COMPRISING AN ANTIBIOTIC AND A RETINOID-LIKE COMPOUND"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION: AND THE MANNER IN, WHICH IT IS TO BE PERFORME
TOPICAL PHARMACEUTICAL COMBINATION COMPRISINGAN ANTIBIOTIC AND A RETINOID-LIKE COMPOUND
BACKGROUND OF THE INVENTION
This application claims priority to United State Provisional Patent Application Number 60/625,872 filed on November 8,2004
The present invention relates generally to pharmaceutical compositions suitable for the treatment of bacterial dermatological infections and processes for their preparation. More specifically, the present invention is directed to topical pharmaceutical combinations comprising an antibiotic and a retinoid-like compound.
Description of the Related Art
Acne vulgaris is an inflammatory disease of the sebaceous glands characterized by an eruption of the skin, often pustular in nature but not suppurative. Acne is a common affliction of the adolescent and affects a small but significant percentage of the adult population. Acne involvement results in unsightly lesions, particularly on the face, and in some cases results in severe scarring.
Many causes have been proposed for acne. However, for a cause to have true validity, the treatment resolving the hypothesized cause must prove to be effective in the vast majority of cases. Causes that have been proposed include, but are not limited to: diet, hormonal disregulation, stress, bacterial overgrowth, heredity and environmental exposure; all of which may cause a deficiency of Coenzyme A.
There are a variety of methods for treating acne vulgaris including administering various agents either orally or topically to the skin. Nevertheless, acne vulgaris is seldom cured and only can be controlled with difficulty. In no case has a treatment designed for any of the
aforementioned causes proven to be uniformly effective. The only treatment that is proven effective in the vast majority of cases is the oral administration of isotretinoin (Accutane®). This medication, however, has numerous side effects; the most disturbing of which being its potential to induce sever birth defects.
In general, topical treatment for an acne related conditions includes a wide variety of topical compositions such as, for example, creams, lotions and solutions. Typically, these products have a single ingredient selected from benzoyl peroxide, aliphatic acids, antibiotics, salicylic acid, vitamin A derivatives, tretinoin, isotretinoin or adapalene. Treatment with such topical compositions is normally the therapy of choice for mild to moderate acne infections. Serious infections may require a longer course of treatment ranging anywhere from a week up to several months.
One ingredient used in topical preparations for acne is Clindamycin. Clindamycin is an antibiotic of the lincosamide class. Clindamycin phosphate is a water soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin.
The chemical name for clindamycin phosphate is methyl 7-chloro-6,7,8-trideoxy-6-(l-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1 -thio-L-threo- -D-galacto-octopyranoside 2-(dihydrogen phosphate).
Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin. Cross resistance has been demonstrated between clindamycin and lincomycin.
Another active ingredient that has important effects in treating acne is adapalene. The chemical name of adapalene is 6-[3-(l-adamantyl)-4-methoxyphenyl]~2-naphthoic acid. Adapalene is a white to off-white powder which is soluble in tetrahydrofuran, sparingly soluble in ethanol, and practically insoluble in water. The molecular formula is C28H28O3 and molecular weight is 412.52. Adapalene is represented by the following structural formula:
Adapalene is a chemically stable, retinoid-like and pharmacological profile studies have demonstrated that adapalene is a modulator of cellular differentiation, keratinization, and inflammatory processes all of which represent important features in the pathology of acne vulgaris.
Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, it is suggested that topical adapalene may normalize the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.
The bacterias associated with acne have a tendency to develop resistance to solo therapy comprising either an antibiotic or a retinoid-like compound during prolonged treatment and may be rendered ineffective when the acne condition is severe. Weiss, J.S., et al., Topical Retinoid and Antibiotic Combination Therapy for Acne Management, J. Drugs Dermatology. Drug Dermatology. Apr.-May 2004: vol. 3, pp. 145-154.
SUMMARY OF THE INVENTION
One aspect of the present invention is to develop a topical dosage form of an antibacterial pharmaceutical composition which provides release of the active pharmaceutical ingredients to the site of absorption or action. A further aspect of the present invention provides a delivery system which releases an antibacterial agent to the site of absorption.
Another aspect of the present invention provides for processes for preparing topical drug delivery systems which release a therapeutically effective amount of one or more active pharmaceutical ingredients to the site of absorption or action.
Accordingly, in one embodiment of the present invention, a semisolid pharmaceutical composition is provided comprising a therapeutically effective amount of at least one antiacne agent and at least one antibacterial agent as active pharmaceutical ingredients and a hydrophilic matrix having gelling properties and capable of providing a constant and uniform release of the active pharmaceutical ingredients.
The present invention provides several advantages including at least:
1. Improved Compliance
3. Enhanced Efficacy
4. Reduction of side effects
The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one
of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician
The term "effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder, condition or causing an action, e.g., inducement of female into labor, is sufficient to effect such treatment or action. The "effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
By "pharmaceutically acceptable" is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarare, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate salts and the like. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, and the like.
The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.
As used herein, the term "viscolising agent" is intended to mean an agent who which helps for increasing the viscosity of the final formulation and helps in building the final consistency to the final formulation. In contact with water it undergoes the polymerization and swells and
forms the semisolid mass. The viscosity built up is dependent upon the degree of polymerization and the ability of the polymer to swell. Such compounds include, by way of example and without limitation, carbomer and the like.
As used herein, the term "alkalizing agent" is intended to mean a compound used to modify pH. In the present invention, sodium hydroxide can be used as an alkalizing agent which imparts the alkalinity to, for example, the carbomer dispersion to form a gel structure.
As used herein, the term "chelating agent" is intended to mean a compound used which forms complex with metal ions and thus prevents the unwanted chemical reactions catalised by these ions. Such compounds include, by way of example and without limitation, disodium edetate and the like.
As used herein propylene glycol in the topical gel formulation of the present invention as a solvent to disperse the active drug, adapalene. Propylene glycol is chemically stable and does not support microbial growth. Topical formulations prepared with propylene glycol do not dry on skin readily after application.
Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides for semi-solid dosage pharmaceutical compositions comprising a therapeutically effective amount of at least one antiacne agent and at least one antibacterial agent as active pharmaceutical ingredients and a hydrophilic matrix having
gelling properties and capable of providing a constant and uniform release of the active pharmaceutical ingredient.
The semisolid pharmaceutical compositions of the present invention are useful in delivering a combination of active pharmaceutical ingredients for the treatment of infections such as, for example, infections due to susceptible strains of streptococci, pneumococci, and staphylococci.
Accordingly, the active pharmaceutical ingredients for use in the present pharmaceutical compositions include, but are not limited to Clindamycin but is related to the all Macrolids e.g. azithromycin, Clindamycin, Erythromycin, Clindamycin etc. pertaining to aerobic bacterial infection in combination with Adapalene as a anti acne agent.
Suitable anti acne and antibiotic agents for use in the pharmaceutical formulation herein include, for example, those disclosed in Remington's Pharmaceutical Sciences, 16th Ed., 1980, Mack Publishing Co., Easton, Pa. and in Goodman and Gilman's The Pharmacological Basis of Therapeutics by Hardman and Limbird, 9th Ed., 1996, McGraw-Hill, N.Y, the contents of which are incorporated by reference herein. Examples of antiacne agents for use herein include, but are not limited to, retinoids such as adapalene, isotretinoin, tretinoin and the like and mixtures thereof. Examples of antibiotic agents for use herein include, but are not limited to, microlids such as azithromycin, clarithromycin, lincomycin, clindamycin, erythromycin, clindamycin and the like and mixtures thereof.
The hydrophilic matrix that gives the semi solid consistency to the active pharmaceutical ingredients advantageously provides a good gelling property which is pH dependant. The hydrophilic matrix generally comprises a water soluble, hydrophilic, high molecular weight, polymers having hydrogen bonding functionality and good biocompatibility. The gelling properties of these polymers are the result of the polymer chains. The chemical nature of these gelling polymers, including chain and side groups and crosslinking agents, generates interactions between the mucosal constituents and the polymer or polymers, such as physical entanglement, Van der Waals interactions, and hydrogen bonding. Thus the long linear chain structure allows them to form a strong interpenetrating network with mucus and help in effective spreading on the mucosal surface uniformally. Accordingly, the hydrophilic matrix
of the present invention includes at least a polyalkylene oxide having a weight average molecular weight of at least about 100,000.
The pharmaceutical composition of the present invention containing the active pharmaceutical ingredients and hydrophilic matrix can further contain one or more pharmaceutically acceptable excipients. Invention can further contain pharmaceutically acceptable excipients. The amount of the additional pharmaceutically acceptable excipients generally varies, e.g., from about 10 % to about 90 % by weight, based on the total weight of the composition.
The pharmaceutically acceptable excipients for use in the pharmaceutical compositions of the present invention include, but are not limited to, chelating agents, solvents (e.g., for drug dispersion), gelling agents, preservatives, surfactants, buffering agents, viscosity builders and the like and mixtures thereof that are typically used in the art for locally applied semisolid dosage forms.
Fillers for use herein may be inert fillers, either water soluble or water insoluble, typically used in the pharmaceutical art for semi solid dosage forms. The amount of fillers varies widely, e.g., from about 1 % to about 90 % by weight, based on the total weight of the composition.
Viscosity builders for use herein can be any viscolising agent typically used in the pharmaceutical art for semi solid dosage forms. Examples includes Carbopol (Carbomer 940). Carbomer has ability to produce high viscosities at low concentration after neutralization, which much greater lot to lot consistency than the neutral gums and does not support microbial growth. Carbomer 940 gels show good plastic flow properties, having a significant yield value (commonly defined as initial resistance to flow under applied stress.) Topical gel prepared with Carbomer 940, shows acceptable thickness and spreads evenly on application to the skin. The amount of viscolising agent varies widely and will ordinarily ranges from about 0.1 % to about 5.0 % by weight, based on the total weight of the composition.
Chelating agents for use herein can be any chelating agent typically used in the pharmaceutical art for semi solid dosage forms. Examples for use herein includes Disodium EDTA and the like and mixtures thereof. The amount of chelating agent can vary widely. For example, the amount of chelating agent will ordinerily range from about 0.1 % to about 5.0 % by weight, based on the total weight of the composition.
The pharmaceutical compositions of the present invention may also contain other ingredients that are also typically used in pharmaceutical compositions such as, for example, preservatives. In one embodiment, Poloxamer 407 is used. The amount of the other ingredients varies widely and can range from about 0.1 % to about 5.0 % by weight, based on the total weight of the composition.
The pharmaceutical compositions of the present invention can further contain a neutralizer e.g. sodium hydroxide, for the adjustment of pH as the degree of polymerization is pH dependant. Useful neutralizers include, but are not limited to, an alkali metal hydroxide such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixtures there of. In one embodiment the neutralizer is sodium hydroxide.
Useful solvents include, but are not limited to, propylene glycol which is chemically stable and does not support the growth of micro-organism. Topical preparation prepared from this solvent does not dry up on the skin.
Formulations for topical use of the pharmaceutical compositions of the present invention can be provided as a topical composition wherein the pharmacologically active ingredients are mixed with the hydrophilic matrix to form the semisolid consistency. In general, the pharmaceutically acceptable aqueous carrier for use in the compositions of the present invention include, but are not limited to, ointments, cream, gels, lotions, pastes and the like.
Ointments, as is well known in the art of pharmaceutical formulation, are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery, and, preferably, will provide for other desired
characteristics as well, e.g., emolliency or the like. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), at pages 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable -bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, see Remington: The Science and Practice of Pharmacy for further information.
Creams, as also well known in the art, are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant.
As will be readily be understood by those skilled in the field of pharmaceutical formulation, gels are semisolid, suspension-type systems. Gel forming agent for use herein can be any gelling agent typically used in the pharmaceutical art for topical semi solid dosage forms. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred "organic macromolecules," i.e., gelling agents, are crosslinked acrylic acid polymers such as the "carbomer" family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol® such as Carbopo 940. Also preferred are hydrophilic polymers such as polyethylene oxides,
polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof. The amount of gelling agents varies widely and will ordinarily ranges from about 0.1 % to about 2.0 % by weight, based on the total weight of the composition. The gel forming agent also work by the principle of copolymerization. Under alkaline pH, carbomer in presence of water undergoes cross linking and forms a gel like structure. The degree of polymerization is dependent upon the pH. At a threshold pH, the viscosities achieved by the polymer grade is the maximum.
Lotions, are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type. Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the like.
Pastes are semisolid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gels. The base in a fatty paste is generally petrolatum or hydrophilic petrolatum or the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base.
In another embodiment of the present invention, semi solid topical dosage forms of the pharmaceutical compositions herein are provided comprising the steps of:
preparation of carbomer phase.
preparation of drug dispersion phase.
preparation of neutralizer solution phase. Preparation of gel.
Preparation and addition of antibacterial agent solution. Formation of semisolid composition.
The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of the claims.
Preparation of a semi solid anti bacterial topical pharmaceutical formulation in the form of a gel.
The ingredients for use in this example are set forth below in Table 1. The final product was made by a cold process and
Incorporated the active ingredients in the product.
STEP No. Ingredients/Components Qty. in %w/w Qty. per batch in Kg. (Batch size: 600 kg)
I Purified Water 66.67 400.00
Disodium Edetate 0.05 0.300
Carbomer 940(Carbopol 940) 0.55 3.300
II Purified Water 0.333 2.00
Sodium Hydroxide 0.078 0.468
III Propylene Glycol 6.667 40.00
Methyl Hydroxybenzoate (Methylparaben) 0.100 0.600
Poloxamer 407(Lutrol F 127/Cresmer PEF 127) 0.100 0.600
Phenoxyethanol 0.250 1.500
IV Propylene Glycol 1.333 8.000
Adapalene (Micronised) 0.105* 0.630
Purified Water (rinsing) 4.167 25.00
V Purified Water 18.00 108.00
Clindamycin Phosphate equivalent to Clindamycin 1.26* 1.0 7.56
Purified Water(rinsing) 0.833 5.000
* inc *includes 5% overages.
PREPARATION OF CARBOMER PHASE
In 750 litre manufacturing vessel equipped with stirrer and filter (200# s.s. sieve) was added purified water disodium edetate Next, Carbomer 940 (Carbopol 940) was added slowly under stirring and allowed to soak for 1 hour.
PREPARATION OF PRESERVATIVES AND DRUG DISPERSION PHASE
Into a 50 liter vessel was added 40 kg propylene glycol. The vessel was heated with the aid of steam up to 60°C to 62°C. Under stirring, methyl hydroxybenzoate (methylparaben) and Poloxamer 407 (Lutrol F 127/ Cresmer F 127), was added until dissolved. The mixture was cooled to45 °C, and 1.5 kg phenoxyethanol was added.
Into a 25 liter vessel was added 8.0 kg propylene glycol, and adapalene (micronised) was dispersed under stirring. The Adapalene dispersion was passed through a 100 # ss sieve to the 50 liter vessel under continued stirring for 10 minutes to form a uniform dispersion.
PREPARATION OF SODIUM HYDROXIDE SOLUTION PHASE
Into a 5 liter ss vessel, was added 2.0 kg purified water. Under stirring sodium hydroxide was then dissolved in the water.
PREPARATION OF GEL
The sodium hydroxide solution of step III was transferred under continuous stirring for 10 minutes to 12 minutes to vessel of step 1 to form opaque semisolid gel.
PREPARATION AND ADDITION OF CLINDAMYCIN PHOSPHATE SOLUTION
Into a 400 liter SS bowl was added 108.0 kg purified water. Under stirring, clindamycin phosphate was added for 10 min. to dissolve completely. The mixture was transfered slowly under stirring to bulk and rinsed with purified water.
The bulk was mixed for 30 minutes at slow speed. The pH was checked at 25°C.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
FEATURES AND ADVANTAGES:
1. A semisolid pharmaceutical composition comprising a therapeutically effective amount of at least one antiacne agent and at least one antibacterial agent as active pharmaceutical ingredients and a hydrophilic matrix having gelling properties and capable of providing a constant and uniform release of the active pharmaceutical ingredients.
2. The semisolid pharmaceutical composition of feature 1, wherein the antiacne agent is a retinoid.
3. The semisolid pharmaceutical composition of feature 2, wherein the retinoid is selected form the group consisting of adapalene, isotretinoin, tretinoin and mixtures thereof.
4. The semisolid pharmaceutical composition of feature 1, wherein the antibacterial agent is a macrolid.
5. The semisolid pharmaceutical composition of feature 4, wherein the macrolid is selected from the group consisting of azithromycin, clarithromycin, lincomycin, clindamycin, erythromycin, clindamycin and mixtures thereof.
6. The semisolid pharmaceutical composition of feature 1, wherein the hydrophilic matrix is a polyalkylene oxide having a weight average molecular weight of at least about 100,000.
7. The semisolid pharmaceutical composition of feature 1, further comprising at least one pharmaceutically acceptable excipient.
8. The semisolid pharmaceutical composition of feature 1, which is a cream, a gel, a lotion, or a paste.
Dated this Twenty seven (27th) day of July 2005.
|Indian Patent Application Number||911/MUM/2005|
|PG Journal Number||52/2010|
|Date of Filing||05-Aug-2005|
|Name of Patentee||Glenmark Pharmaceuticals Limited|
|Applicant Address||B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Raod, Post Box No. 26511 Mumbai- 400 026|
|PCT International Classification Number||A61K31/07|
|PCT International Application Number||N/A|
|PCT International Filing date|