DESC:FIELD OF INVENTION:
The present invention relates to a topical composition for treatment acne vulgaris more particularly to topical gel comprising Minocycline or pharmaceutically acceptable salts thereof. The topical gel of the present invention is oil and fat free, alcohol free.
BACKGROUND:
Acne vulgaris is a chronic inflammatory dermatosis and the most common skin condition globally. A study by Global Burden of Disease reported acne as the eighth most prevalent disease worldwide. [Brown SK, Shalita AR. Acne vulgaris. Lancet. 1998;351:1871-1876]. Pathogenesis of acne generally involved four factors -i) excess of sebum (sticky oily, substance produced by sebaceous glands) production, ii) abnormal keratinization, iii) bacterial colonization by Propionibacterium acnes and iv) inflammation. [Suh DH, Kwon HH., Br J Dermatol 2015; 13–19].
Oral use of Antibiotics are commonly prescribed medicines by dermatologists and only class of antibiotics with the United States Food and Drug Administration (FDA) indications for acne treatment. As tetracycline is frequently prescribed it has been routinely modified and various synthetic forms has been isolated these include lymecycline, methacycline, minocycline, rolitetracycline, and doxycycline. Among all these synthetic tetracyclines Minocycline is mostly prescribed for treatment of acne. Minocycline is available in oral and topical form, it is a broad-spectrum antibiotic approved for acne in those 12 years of age and older. Oral Minocycline is mostly prescribed and also available commercially. However, prolonged use of oral minocycline causes side effects and developed bacterial resistance to clindamycin and other antibiotics commonly used to treat acne.
Therefore, topical treatment of acne is being preferred. Only Topical minocycline foam 4% commercially available as Amzeeq™ in USA for the treatment of inflammatory lesions of non-nodular, moderate to severe acne vulgaris (acne) in patients aged more than 9 years. Various efforts have been made in formulating topical preparation.
US5122519A discloses stable, cosmetically acceptable gel formulations of the tetracycline antibiotics for the topical treatment of acne in humans. The patent discloses a stable topical gel comprising minocycline hydrochloride, gelling agent, Isopropyl palmitate and cyclomethicone.
GB Patent No. 1592053 discloses a pharmaceutical composition wherein oxytetracycline is stabilized by incorporating it with an alkaline earth metal ion, polyvinylpyrrolidone and an aliphatic amide and adjusting pH to 5.0 to 7.5.
US11324691B2 discloses a gel or foam composition having a tetracycline for treating rosacea and/or acne. It further discloses a hydrophobic gel or foam composition comprising a minocycline antibiotic and hydrophobic composition comprises a gelled oil.
US9539266B2 discloses a topical minocycline composition with reduced fluorescence are provided. The topical minocycline composition comprising a porous, ceramic calcium phosphate particles having a pore size ranging from 2 nm to 100 nm and loaded with a minocycline active agent, wherein the amount of minocycline active agent associated with the particles ranges from 0.1 to 100 mg/g and the composition is a formulation configured to be applied to a keratinized skin surface location of a mammal.
D. Lac, M. Hermsmeier, X. Chen, N. Yam, A. Yamamoto, S. Huang, T. Sawant, K.F. Chan, U. Nagavarapu, Topical Minocycline Formulations: Evaluation and Comparison of Dermal Uptake Efficacy, International Journal of Pharmaceutics: X (2019) discloses stable and potent topical hydrophilic minocycline gel formulations that have the ability to penetrate the skin and directly target the epidermis and the pilosebaceous unit, thereby delivering a local, targeted treatment of acne vulgaris.
In the dry state, minocycline hydrochloride is stable at room temperature. However, it rapidly undergoes 4-epimerization and oxidative degradation and is more susceptible to degradation as compared to other tetracyclines. As Minocycline is found to be unstable in aqueous form when stored at room temperature for longer period of time and is also sensitive to light. Due to this reason Minocycline has been formulated with lipophilic excipients. However, the presence of oil and fat causes stickiness and greasiness on the skin which is already acne and oil prone thus limit treatment efficacy, patient satisfaction and adherence. The use of oil and fat as a base also limit its penetration, bioavailability and buildup on skin.
However, use of Alcohol or hydrophilic bases have tendency to pick up moisture (hygroscopic) and thus can cause instability issues which is limiting as compared to hydrophobic bases. Also alcohol gel based formulation causes stinging sensation when applied to inflamed or broken skin. Therefore, there still an unmet medical need to improve the treatment of acne vulgaris by providing alternative composition of minocycline hydrochloride.
SUMMARY OF THE INVENTION:
The present inventors have developed a gel-based composition which aims at utilizing hydrophobic, non-aqueous silicones and silicone elastomers to form a topical gel of minocycline hydrochloride. The gel is designed to contain lipophilic antioxidants to prevent oxidative degradation of the active ingredient. In order to ensure improved stability, the gel is designed to contain least possible excipients or carriers of the active ingredients.
Lipophilic excipients or carriers such as hydrophobic silicone fluids can be used to suspend the micronized active ingredients. Cyclomethicones which are cyclic dimethyl polysiloxane compounds are used in the present invention. Semisolid, soft, transparent gel like silicone polymer called elastomer can be used to provide body the topical gel of minocycline. The preferred antioxidants that are added to the composition include butylated hydroxyl anisole, butylated hydroxytoluene, propyl gallate, monothioglycerol and the likes. Hydrophobic oils, fats and waxes including free fatty and their esters are avoided as they have tendency to occlude the pores of the skin.
In another aspect the present invention provides a stable topical gel formulation comprising effective amount of Minocycline hydrochloride and a suitable base which is oil free, fat free, alcohol free and non-greasy and have improved feel when applied topically, besides ensuring that the stability of drug is not compromised.
The present invention is also directed to a process for preparing topical gel comprising Minocycline which is free from alcohol, oil and fats.
Detailed Description of the invention:
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutically or cosmetically/dermatologically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical or Cosmeceuticals composition. These ingredients are suitable for use in contact with tissues (e.g., the skin or hair) without undue toxicity, incompatibility, instability, irritation, allergic response, and the like.
The term “topical” refers to the drug delivery which is applied topically over skin to provide topical therapeutics effects.
The term “oil or wax free” refers to topical gel which doesn’t comprises Hydrophobic oils, fats and waxes including free fatty and their esters and do not clog the skin and is non-greasy and have improved feel when applied topically.
The term “non-comedogenic” refers to ingredients or excipients which won’t clog or block the pores skin.
The present invention provides an improved topical formulation comprising an effective amount of Minocycline or pharmaceutically acceptable salts thereof.
In an another embodiment the topical formulation can be formulated in form of Cream, lotion, gel, emulsion or solution more preferably gel.
The present invention provides an improved topical gel formulation which is a clear, oil-free, fat and alcohol free composition and therefore non-greasy to the skin and touch. The oil free topical gel provides a method of treatment of acne without leaving a greasy or oily residue on acne prone skin.
The present invention relates to a topical gel used for uniform application of effective amount of Minocycline or pharmaceutically acceptable salts thereof in a vehicle which is non-­irritating, non-drying and non-comedogenic. The Minocycline is accurately delivered to the surface of the skin and is readily absorbed.
The formulation is oil- and fat-free, and therefore less comedogenic than marketed oil based gel during prolonged use. The formulation of the present invention thus allows for greater amounts of Minocycline to be applied to the skin over time, since the side-effects of the Minocycline and vehicle are minimized.
The formulation can also be alcohol-free, so as to be less drying and irritating to the skin, with use. The present invention avoids the harsh use of organic solvents which may irritate the skin.
The main benefits of present invention are that they do not clog the pores which can lead to breakouts and pimples. The topical gel is a clear, light weight and non-greasy feel on the skin.
In an embodiment the present invention provides a hydrophobic base which is essentially free from oil.
In an another embodiment the hydrophobic base comprises synergistic combination of gelling agents, anti-oxidants solubilized in a suitable solvent or vehicle.
The hydrophobic base does not include Hydrophobic oils, fats and waxes including free fatty and their esters which have tendency to occlude the pores of the skin which can cause acne and oil and increase the risk of clogged pores. In an another embodiment the topical gel is also free from any alcohol.
The topical gel of the invention comprises a gelling agent in a suitable concentration. A preferred thickener suitable for use herein is anhydrous silicone elastomer. The silicone elastomer can be acylic, linear or organo-functional polydimethylsiloxanes. The elastomer provides stabilizing and rheology modifying properties imparting soft feel and high spreadability to the present formulation.
In an another embodiment the present invention comprises one or more antioxidants but are not limited to, water soluble antioxidants, lipid-soluble antioxidants, vitamin C, vitamin C palmitate, propyl gallate, vitamin E (tocopherol), Monothioglycerol, tert-butyl ether-hydroxybenzoate fennel, 2,6 di-tert-butyl-p-cresol, Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or combinations thereof.
In an another embodiment antioxidant is present in amount of about 0.005 to 5% w/w more preferably 0.005 to 0.5% w/w.
In an embodiment preferred antioxidant is Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or combinations thereof.
In an another embodiment preferred antioxidant is Butylated Hydroxyanisole (BHA) present in an amount ranging from 0.005 to 0.05 % w/w more preferably 0.010% w/w.
In an another embodiment the topical gel further comprises one more antioxidant which is Butylated Hydroxytoluene (BHT) present in an amount ranging from 0.05 to 1% w/w more preferably 0.200 % w/w.
In an another embodiment the preferred antioxidant is Monothioglycerol present in an amount ranging from 0.05 to 1% w/w more preferably 0.200 % w/w.
In an another embodiment the present invention comprises silicone oils. Non-limiting examples include silicone oils (e.g., volatile and non-volatile oils), gels, and solids. In a preferred embodiment, the silicon containing compounds includes a silicone oils such as a polyorganosiloxane. Non-limiting examples of polyorganosiloxanes include dimethicone, cyclomethicone, phenyl trimethicone, trimethylsilylamodimethicone, stearoxytrimethylsilane, or mixtures of these and other organosiloxane materials in any given ratio in order.
In a preferred embodiment the solvent/vehicle is Cyclomethicones. Cyclomethicones are cyclic dimethyl polysiloxane compounds which can be used to suspend the micronized active ingredients in the formulation.
In an embodiment cyclomethicone is present an amount ranging from 10-40% w/w more preferably 20-30 wt. % w/w.
In an another embodiment preferred solvent/vehicle is Isopropyl myristate present in an amount ranging from 1 to 20% more preferably 1 to 10% w/w.
The present invention provides a topical gel comprising an effective amount of Minocycline or pharmaceutically acceptable salts thereof; one or more antioxidants selected from Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), Monothioglycerol; a gelling agent and a suitable solvent/vehicle.
In an another embodiment the present invention provides a topical gel comprising:
i. 4.00% w/w Minocycline Hydrochloride as active agent and
ii. 28.50% w/w Cylcomethicone as Solvent/Vehicle and;
iii. 0.010% w/w Butylated Hydroxyanisole (BHA) as antioxidant and;
iv. 0.200% w/w Butylated Hydroxytoluene (BHT) as antioxidant and;
v. Elastomer as Gelling agent in a required amount
In an another embodiment the present invention provides a topical gel comprising:
i. 4.00% w/w Minocycline hydrochloride as active agent and
ii. 23% w/w Cylcomethicone as solvent/vehicle and;
iii. 0.200% w/w Monothioglycerol as antioxidant and;
iv. Elastomer as gelling agent in a required amount
In an another embodiment the topical gel comprises:
i. 4.00% w/w Minocycline hydrochloride equivalent to Minocycline and;
ii. 23.01% w/w Cyclomethicone and;
iii. 5.01% w/w of Isopropyl myristate and;
iv. 0.010% w/w of Butylated Hydroxyanisole and;
v. 0.200% w/w of Butylated Hydroxytoluene
In an embodiment the present invention provides process of preparation of topical gel wherein the process comprises dissolving antioxidant(s) in a suitable solvent, to this solution dispersed the Minocycline with stirring. To this solution mix gelling agent to obtain a stable gel having desired consistency.
In an another embodiment the topical gel of present invention provides a method of treating moderate to severe acne when applied topically to the skin. The topical gel is safe to use in patients above 9 years of age.
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 liming the present invention in any way, as many other variations thereof are possible within the scope of the invention.
EXAMPLES
Example-1 Preparation of Minocycline gel
S. No. Ingredients % (w/w) Role
1. Minocycline Hydrochloride equiv. to Minocycline anhydrous 4.000 Active ingredient
2. Cylcomethicone NF5 28.50 Vehicle
3. Butylated Hydroxyanisole (BHA) 0.010 Antioxidant
4. Butylated Hydroxytoluene (BHT) 0.200 Antioxidant
5. Elastomer-10 (Csilcare CPDCL) q.s. to 100 Gelling agent

Dissolve BHA and BHT in cyclomethicone, disperse micronized minocycline in it with stirring and finally admix with stirring, elastomer to obtain gel having desired consistency.
Example 2 Preparation of Minocycline gel
S. No. Ingredients % (w/w) Role
1. Minocycline Hydrochloride equiv. to Minocycline anhydrous 4.000 Active ingredient
2. Cylcomethicone NF5 23.0 Vehicle
3. Monothioglycerol 0.200 Antioxidant
4. Elastomer-10 (Csilcare CPDCL) q.s. to 100 Gelling agent

Dissolve monothioglycerol in cyclomethicone, disperse micronized minocycline in it with stirring and finally admix with stirring, elastomer to obtain gel having desired consistency.
Example-3 Preparation of Minocycline gel
Stability Study:
The Minocycline gel obtained from example 1 & 2 were subjected to stability study. In this study degradation product of Minocycline epiminocycline, was measured over 7 days at high temperature (50°C).
Epiminocycline content Example 1 Example 2
Initial 0.72 0.75
After 7 days at 50°C 0.70 0.78

Example 4 Preparation of Minocycline gel
S. No. Ingredients % (w/w) Role of Ingredients
1. Minocycline Hydrochloride USP equiv. to Minocycline 4.000 Active ingredient
2. Cylcomethicone N5 23.01 Vehicle
3. Isopropyl myristate 5.011 Vehicle
4. Butylated Hydroxyanisole IP 0.010 Antioxidant
5. Butylated Hydroxytoluene IP 0.200 Antioxidant
6. Elastomer-10 100.00 Gelling agent

In the main manufacturing vessel take elastomer 10. In another container take 10% cyclomethicone. Add BHA and BHT and heat up to 40° C & transfer the solution to vessel containing elastomer and mix well.
In another container take isopropyl myristate and add dispensed quantity of minocycline, mix well and transfer the dispersion to mixture of elastomer and cyclomethicone. Mix well to obtain a homogeneous gel.
Example 5: Long Term Stability Data
The Minocycline gel obtained from example 3 were subjected to stability study. In this study degradation product of Minocycline epiminocycline, was measured over 5 months at temperature 40°C and at RH 75%
Epiminocycline content Example 4
Initial 0.71
3 months 40/75 0.75
6 months 40/75 0.79

It was found that the Minocycline gel obtained from example 4 was found to be stable when stored at temperature 40°C and at RH 75% for 6 months.
,CLAIMS:1. A topical composition comprising therapeutically effective amount of Minocycline or pharmaceutically acceptable salts thereof wherein the composition is free from oil and alcohol-based components.
2. A topical composition as claimed in claim 1 is a topical gel.
3. A topical gel as claimed in claim 1 wherein Minocycline hydrochloride present in a range from about 0.1 to 10% w/w.
4. A topical gel as claimed in claim 2 further comprises one or more antioxidants in a range from 0.005 to 0.5% w/w.
5. A topical gel as claimed in claim 4 wherein one or more antioxidants are selected from vitamin C, vitamin C palmitate, propyl gallate, vitamin E (tocopherol), Monothioglycerol, tert-butyl ether-hydroxybenzoate fennel, 2,6 di-tert-butyl-p-cresol, Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or combinations thereof.
6. A topical gel as claimed in claim 5 wherein antioxidant is Monothioglycerol.
7. A topical gel as claimed in claim 5 wherein antioxidant is Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or combination thereof.
8. A topical gel as claimed in claim 2 further comprises one or more solvent/vehicle in a range of 2 to 30% w/w.
9. A topical gel as claimed in claim 2 further comprises one or more solvent/vehicle selected from cyclomethicone, Isopropyl mysristate or combinations thereof.
10. A topical gel as claimed in claim 2-9 comprises:
i. 4.00% w/w of Minocycline hydrochloride equivalent to Minocycline and;
ii. 23.01% w/w of Cyclomethicone and;
iii. 5.01% w/w of Isopropyl myristate and;
iv. 0.010% w/w of Butylated Hydroxyanisole and;
v. 0.200% w/w of Butylated Hydroxytoluene
Wherein the topical gel is free from oil and alcohol components.