Claims:We Claim:
1. A preservative free, aqueous shampoo composition comprising:
(i) terbinafine hydrochloride,
(ii) zinc pyrithione,
(iii) one or more solubilizers,
(iv) one or more surfactants, and
(v) one or more foaming agents.

2. The shampoo composition as claimed in claim 1, wherein the solubilizers are selected from one or more of hexylene glycol, propylene glycol, polyethylene glycol or mixtures thereof.

3. The shampoo composition as claimed in claim 2, wherein the solubilizer is propylene glycol.

4. The shampoo composition as claimed in claim 1, wherein the surfactants are selected from one or more of sodium lauryl sulfate, triethanolamide lauryl sulfate, sodium laureth sulfate, polysorbate 60, cocamidopropylamine oxide, lauryl amine oxide, lauramido diethanol amide, cocamidopropyl betaine, lauryl dimethyl betaine, cocodimethyl sulfo-propyl betaine, sodium cocoyl sarcosinate, disodium oleamido monoisopropanol amide sulfosuccinate, disodium cocamido mono-isopropanol amide sulfosuccinate, disodium laureth sulfosuccinate, cocoamphocarboxy-glycinate, disodium oleamido monoethanolamide sulfosuccinate, amine glycinates, amine propionates and amine sultaines, or mixtures thereof.

5. The shampoo composition as claimed in claim 1, wherein the foaming agents are selected from one or more of cocamide monoethanolamide, cocamide diethanolamide, oleamide monoethanolamide, oleamide diethanolamide or mixtures thereof.

6. The shampoo composition as claimed in claim 1, wherein the composition further comprises thickening agents selected from one or more of carbomers, acrylates/vinyl neodecanoate crosspolymer, natural gums, cellulose derivatives, PEG 6000, PEG 120, cocomonoethanolamide, PEG-150-Distearate, sodium chloride, ammonium chloride, polyvinyl alcohol or mixtures thereof.

7. The shampoo composition as claimed in claim 1, wherein the composition further comprises a conditioner.

8. The shampoo composition as claimed in claim 1, wherein pH of the composition is in the range of about 5-8.

9. The shampoo composition as claimed in claim 1, comprising:
(i) 0.1% to 5 % (w/w) terbinafine hydrochloride,
(ii) 0.05% to 2 % (w/w) zinc pyrithione,
(iii) 1% to 10% (w/w) one or more solubilizers,
(iv) one or more surfactants, and
(v) one or more foaming agents.
, Description:The following specification particularly describes the invention and the manners in which it is to be performed
PRESERVATIVE FREE SHAMPOO COMPOSITIONS

FIELD OF THE INVENTION

The present invention relates to preservative free, aqueous shampoo compositions of terbinafine hydrochloride and zinc pyrithione. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION

Terbinafine, a synthetic allylamine is commonly used to treat fungal infection. Terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase to result in destruction of the fungal cell wall. Chemically, terbinafine hydrochloride, is (E)- N-(6,6-dimethyl-2-hepten-4-ynyl)- N-methyl-1-naphthalenemethanamine hydrochloride. The empirical formula is C21H26ClN with a molecular weight of 327.90 and the following structural formula:

Terbinafine hydrochloride is a white to off-white fine crystalline powder. It is freely soluble in methanol and methylene chloride, soluble in ethanol and slightly soluble in water.

The prior art discloses oral and topical formulations of terbinafine hydrochloride, such as LAMISIL, which is marketed by Novartis. Oral administration of terbinafine hydrochloride may be used in the treatment of onychomycosis. Available topical formulations of terbinafine base or terbinafine hydrochloride in the form of cream or gel or ointment are for superficial skin infections such as jock itch (tinea cruris), athlete's foot (tinea pedis), and other types of ringworm (tinea corporis).

Polyvalent metal salts of pyrithione (commonly known as 1-hydroxy-2-pyridinethione; 2-pyridinethiol-1-oxide; 2-pyridinethione; 2-mercaptopyridine-N-oxide; pyridinethione; and pyridinethione-N-oxide) are known to be effective antimicrobial agents and are widely used as fungicides and bactericides in products such as antifouling paints and sealants, building products, plastics and goods made therefrom, polyurethane products, textiles, cosmetics, and in anti-dandruff shampoos.

The polyvalent metal salts of pyrithione are only sparingly soluble in water and include magnesium pyrithione, strontium pyrithione, barium pyrithione, copper pyrithione, zinc pyrithione, zirconium pyrithione, cadmium pyrithione, and bismuth pyrithione. The mostly used divalent pyrithione salts are zinc pyrithione and copper pyrithione. Zinc pyrithione has been widely used in anti-dandruff shampoo preparation.

Shampoo is a hair care product, typically in the form of a viscous liquid that is used for cleansing hair. Shampoos are a mixture of various types of surfactants which impart different characteristics to the final product. In general, a shampoo contains a base surfactant(s) for cleansing, a foaming agent, a conditioning agent, small amounts of chelating agents, viscosity and pH adjusters, preservatives, fragrance, miscellaneous "nutritive" ingredients, and water.

Prior art shampoos comprising anti-dandruff agents are designed in such a way that an optimum balance is achieved between efficacy and tolerability; the concentration of the active ingredient in the medicated shampoos is such that as many users as possible are effectively treated and as few as possible suffer adverse effects.

US5456851 discloses an aqueous shampoo composition that contains ketoconazole, a surfactant, a foaming agent, thickener sufficient to give the final formulation a viscosity in the range of about 4,000 to about 9,000 cps at room temperature, preservative, butylated hydroxytoluene or butylated hydroxyanisole, and acid, base or buffer sufficient to give the final composition a pH in the range of from about 4 to about 10.

WO9729733 discloses compositions for body and hair cleansing products, in particular shampoos, comprising one or more fungal ergosterol biosynthesis inhibiting antifungals as a first active ingredient and a pyrithione salt as a second active ingredient. Also disclosed shampoo ingredients comprise one or more of a surfactant, a foaming agent, a thickener, a preservative, an anti-oxidant, and acid or base or buffer sufficient to give the shampoo a pH in the range of from about 4 to about 10.

Due to the nature of the composition, a shampoo is usually a good medium to support microbial growth. Since most surfactants used in the manufacture of shampoos are sold as aqueous solutions or pastes, which are rarely more than 40% (w/w) on the active basis, they will support microbial growth and are frequently preserved with trace levels of formaldehyde by the supplier. In addition, the foaming agent and conditioning agents also provide a good nitrogen source to the microbes in the aqueous environment of the shampoo and present a challenge to selection of an effective preservative system.

Parabens are cost-effective and provide protection against micro-organisms for an extended period of time. While there are multiple types of parabens; methyl, propyl and butylparaben are the most frequently used in shampoo products. In recent years, concern has increased as to their role in producing potentially serious health side effects. For example, accelerate skin ageing process, interfere with male reproductive system and endocrine system, play a role in development of breast cancer etc. There remains, therefore, an unmet need for a preservative free, aqueous shampoo composition.

In an attempt to develop a novel preservative free, aqueous shampoo compositions of terbinafine hydrochloride and zinc pyrithione, the present inventors have surprisingly found that use of one or more solubilizers, one or more surfactants and one or more foaming agents, one or more thickening agents resulted in compositions, which are stable, does not support microbial growth and, therefore is self-preserving without the addition of traditional preservative, and exhibit efficacy comparable to antifungal compositions currently available in the market. The compositions of the present invention are also having smooth conditioning effect. Such preservative free, aqueous shampoo composition of present invention may be used for treating and preventing itching, flaking, and scaling of the scalp caused by dandruff or seborrhea.

SUMMARY OF THE INVENTION

The present specification relates to a preservative free, aqueous shampoo composition of terbinafine hydrochloride and zinc pyrithione and its process for preparation.

In one aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) terbinafine hydrochloride,
(ii) zinc pyrithione,
(iii) one or more solubilizers,
(iv) one or more surfactants, and
(v) one or more foaming agents.

In another aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) terbinafine hydrochloride,
(ii) zinc pyrithione,
(iii) one or more solubilizers,
(iv) one or more surfactants,
(v) one or more foaming agents, and
(vi) one or more thickening agents.

In yet another aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) terbinafine hydrochloride,
(ii) zinc pyrithione,
(iii) proplylene glycol,
(iv) one or more surfactants, and
(v) one or more foaming agents.

In yet another aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) 0.1% to 5 % (w/w) terbinafine hydrochloride,
(ii) 0.05% to 2 % (w/w) zinc pyrithione,
(iii) 1% to 10% (w/w) one or more solubilizers,
(iv) one or more surfactants,
(v) one or more foaming agents, and
(vi) one or more thickening agents.

In yet another aspect, the present specification relates to use of preservative free, aqueous shampoo composition for treating and preventing itching, flaking, and scaling of the scalp caused by dandruff or seborrhea.

DESCRIPTION OF THE INVENTION

The present specification relates to a preservative free, aqueous shampoo composition of terbinafine hydrochloride and zinc pyrithione and its process for preparation.

In one aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) terbinafine hydrochloride,
(ii) zinc pyrithione,
(iii) one or more solubilizers,
(iv) one or more surfactants, and
(v) one or more foaming agents.

In another aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) terbinafine hydrochloride,
(ii) zinc pyrithione,
(iii) one or more solubilizers,
(iv) one or more surfactants,
(v) one or more foaming agents, and
(vi) one or more thickening agents.

In yet another aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) terbinafine hydrochloride,
(ii) zinc pyrithione,
(iii) proplylene glycol,
(iv) one or more surfactants, and
(v) one or more foaming agents.

In yet another aspect, the present specification relates to a preservative free, aqueous shampoo composition comprising:
(i) 0.1% to 5 % (w/w) terbinafine hydrochloride,
(ii) 0.05% to 2 % (w/w) zinc pyrithione,
(iii) 1% to 10% (w/w) one or more solubilizers,
(iv) one or more surfactants,
(v) one or more foaming agents, and
(vi) one or more thickening agents.

As used herein, the term “preservative free” means that the composition is substantially free of preservatives. In the present invention, "the composition being substantially free of preservative" means that: the composition is free of preservative; or, if the composition contains preservative, the level of preservative is very low. In the present invention, the level of preservative, if included by any means, is 0.5 % or less, preferably 0.1 % or less, more preferably 0.05 % or less of the composition. The composition of the present invention is substantially free of suitable preservatives commonly used in conventional shampoo preparation, e.g. methylparaben, propylparaben, butylparaben, ethylparaben, imidazolidinyl urea, phenoxy ethanol, quaternium 15.

As used herein, the term “terbinafine hydrochloride” includes terbinafine or any pharmaceutically acceptable salts or esters or derivatives thereof. The amount of terbinafine hydrochloride employed in the shampoo composition is in the range of 0.01% to 5% (w/w), 0.1% to 2% (w/w) of total composition, e.g. 1% (w/w).

As used herein, the term “pyrithione” includes pyrithione or any pharmaceutically acceptable salts or esters or derivatives thereof, e.g. zinc pyrithione. The amount of zinc pyrithione employed in the shampoo composition is in the range of 0.1% to 5% (w/w), 0.1% to 2% (w/w) of total composition, e.g. 1% (w/w).

As used herein, the term “solubilizers” refers to component that helps in solubilization of terbinafine hydrochloride. Suitable solubilizers include hexylene glycol, propylene glycol, polyethylene glycol or mixtures thereof. Preferred solubilizer includes propylene glycol. The amount of solubilizers employed in the composition is in the range of 1% to 20% (w/w) of total composition, e.g. 3% (w/w), 5% (w/w).

Suitable surfactants for use in the shampoos of the present specification may include sodium C 14-16 olefin sulfonates, sodium lauryl sulfate, TEA lauryl sulfate, sodium laureth sulfate (or sodium lauryl ether sulfate), polysorbate 60, polysorbate 80, cocamidopropylamine oxide, lauryl amine oxide, lauramido DEA, cocamidopropyl betaine, lauryl dimethyl betaine, cocodimethyl sulfo-propyl betaine, sodium cocoyl sarcosinate, disodium oleamido MIPA sulfosuccinate, disodium cocamido MIPA sulfosuccinate, disodium laureth sulfosuccinate, cocoamphocarboxy-glycinate, disodium oleamido MEA sulfosuccinate, amine glycinates, amine propionates and amine sultaines, and mixtures thereof.

Preferably, a mixture of two or more different surfactants , in particular sodium laureth sulfate and sodium cocoyl sarcosinate, or sodium lauryl sulfate, sodium laureth sulfate, TEA lauryl sulfate and cocamidopropyl betaine, may be used in the present shampoos. In the shampoos according to the present invention, the total amount of surfactants may range from about 30% to about 45% (w/w).

In the above definitions, and hereinafter, the term 'MEA' signifies a mono- ethanolamide of formula RCO-NH-CH2CH2-OH, the term 'DEA' signifies di-ethanol amide of formula RCO-N(CH2CH2-OH)2, TEA' signifies triethanolammonium ; the term 'MIPA' signifies a mono-isopropanol amide of formula RCO-NH-CH2-CHOH-CH3 ; wherein each RCO-group is a fatty acid residue, such as a Ci3-i9alkylcarbonyl or Ci3-i9alkenylcarbonyl group.

As used herein, the term “foaming agents” refers to a substance that facilitates formation of foam. Suitable foaming agents (foam boosters and stabilizers) for use in the shampoos of the present specification may be selected from the group of fatty acid mono-and dialkanol-amides comprising cocamide MEA, cocamide DEA, oleamide MEA, oleamide DEA and mixtures thereof. The foaming agent may be present in a range from about 1 to about 20 % (w/w), preferably from about 1 to about 15 % (w/w), in particular about 5 to about 15 % (w/w). These ingredients typically also have a thickening effect on the formulation.

As used herein, the term “thickening agents” refers to a substance that increases the viscosity of the composition. Suitable thickeners include carboxylic acid polymers like carbomers (e.g. Carbopol.RTM. 954), acrylates/vinyl neodecanoate crosspolymer (e.g. Aculyn 38) natural gums (e.g. guar, xanthum), cellulose derivatives (e.g. carboxy methylcellulose, methyl cellulose), PEG 6,000, PEG 120, cocomonoethanolamide, PEG-150-Distearate, sodium chloride, ammonium chloride, polyvinyl alcohol and mixtures thereof.

Since shampoo users expect a shampoo to be slightly viscous, one or more thickeners are often included in the formulation which gives it a viscosity in the range of 5,000 to 55,000 cps at room temperature. Other suitable thickeners are the foaming agents mentioned hereinabove, preferably cocamide MEA. The thickening agent may be present in a range from about 1 to about 10 % (w/w), preferably from about 1 to about 5 % (w/w), in particular about 2 to about 5 % (w/w).

The shampoo compositions of the present specification may further comprise a conditioner such as polyquaternium-7, polyquaternium-10 or a similar cationic quaternary polymer, e.g. a quaternary silicone polymer ; one or more pearlizing agents selected from the group consisting of behenic acid, ethylene glycol monostearate, ethylene glycol distearate, calcium stearate, 1,2-propylene glycol distearate, 1,2-1,3- and 1,4-butylene glycol distearate and mixtures thereof; and/or one or more fragrances and one or more colorants.

The shampoo compositions of the present specification may further comprise an emollient. Suitable emollients include, for example, stearyl alcohol, glyceryl monooleate, glyceryl monoricinoleate, glyceryl monostearate, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoieate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and mixture thereof.

The pH of the shampoo compositions of the present specification are conveniently established using dermatologically acceptable acids, bases and buffers. The pH can range from about 4 to about 10, but preferably is in the range of about 5 to about 8, in particular from about 6.3 to about 7.5.

The shampoo compositions of the present specification may include one or more antioxidants. The antioxidant may be selected from DL-alpha-tocopherol, butylhydroxy toluene (BHT), butylhydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid, propyl gallate, or mixtures thereof. The amount of antioxidant employed in the composition is in the range of 0.01 to about 0.5% (w/w) of total composition, e.g. 0.07% (w/w), or 0.09% (w/w).

The shampoo compositions of the present specification can be prepared by various formulation and mixing techniques or methods known in the art for preparing shampoo compositions. For example; mixture of surfactants, foaming agents, thickeners are heated to 70-75?C to form the surfactant phase. Terbinafine is dissolved in the solvents and added to the surfactant phase. Aqueous phase is prepared by mixing Zinc pyrithione and purified water followed by addition of conditioning agents, preservative and fragrance. The aqueous phase is added to the surfactant phase with continuous stirring.

The shampoo compositions of present specification may be used for treating and preventing itching, flaking, and scaling of the scalp caused by dandruff or seborrhea.

The shampoo compositions of present specification were subjected to accelerated and long term stability studies.

The specification will now be described in greater detail by reference to the following non-limiting examples.

EXAMPLES
Ingredients Example 1
(%w/w) Example 2
(%w/w) Example 3
(%w/w) Example 4
(%w/w)
Terbinafine Hydrochloride 1.00 1.00 1.00 1.00
Zinc pyrithione 1.00 1.00 1.00 1.00
Propylene glycol - 5.00 5.00 7.00
Hexylene glycol 5.00 - - -
Sodium Lauryl Ether Sulfate 35.00 35.00 36.00 35.00
Coco amido propyl Betaine 10.00 10.00 10.00 10.00
Coco Mono Ethanol Amide 1.50 1.50 1.50 1.50
Polysorbate 60 1.00 1.00 1.00 1.00
Cetyl alcohol 2.00 2.00 2.00 2.00
Butylated Hydroxytoluene 0.100 0.100 0.100 0.100
Polyquaternium 10 (Ucare JR 400) 0.200 0.200 0.200 0.200
Acrylates/Vinyl neodecanoate crosspolymer (Aculyn 38) 3.00 3.00 - 3.00
Carboxy methyl cellulose - - 2.00 -
Purified water 40.00 40.00 40.00 38.00
Mid Night Jasmine 0.100 0.100 0.100 0.100
Brilliant blue FCF 0.0003 0.0003 0.0003 0.0003
Sodium Hydroxide 0.1250 0.1250 0.1250 0.1250

Process:

1. Terbinafine hydrochloride was dissolved in a mixture of propylene glycol/hexylene glycol and butylated hydroxytoluene.
2. Multiple aqueous phases were prepared by dispersing zinc pyrithione, polyquaternium 10, brilliant blue FCF, fragrance midnight jasmin in water separately.
3. Surfactant phase was prepared by taking cetyl alcohol, coco mono ethanol amide, polysorbate 60, cocoamido propyl betaine and sodium lauryl ether sulfate/sodium laryl sulfate into a manufacturing vessel. Heat the bulk to 70-75 ° C under stirring with anchor speed at 10 - 15 RPM. Continue stirring until a uniform liquid dispersion is obtained.
4. Terbinafine hydrochloride and different aqueous phases were added sequentially to the surfactant phase prepared in Step 3 with constant stirring.
5. Acrylates/vinyl neodecanoate crosspolymer/carboxy methyl cellulose was added into manufacturing vessel manually under stirring at 15± 5 RPM and mix for 15± 5 Minutes.
6. pH of the bulk dispersion was adjusted within 10% sodium hydroxide solution to get the desired pH (6.3-6.7).

Microbial Enumeration Test:

The self-preservation efficacy of the preservative free shampoo compositions according to the present specification were evaluated through microbiological examination. The test shampoo composition was prepared in accordance with Example 2 and was evaluated in a microbial enumeration test by pour plate method and test for specified microorganisms by direct inoculation method as per protocol set forth by USP. The results are shown in the Table 1. According to the observations, the shampoo composition inhibited the growth of all microorganisms tested.

Table 1: Microbial enumeration test for specified microorganism
Test Parameter Limit Observation
Total Aerobic Microbial Count (TAMC) Not more than 100 CFU / g < 100 CFU/g
Total Combined Yeast and Moulds Count (TYMC) Not more than 10 CFU / g < 10 CFU/g
P. aeruginosa Must be absent in 1 g Absent
S. aureus Must be absent in 1 g Absent

Stability study
The stability of the preservative free shampoo compositions of present specification were evaluated through accelerated stability studies. The composition prepared according to the formula and process of Example 2, was subjected to stability study at various temperature and humidity conditions. The composition was found to be chemically stable under accelerated conditions. Table 2 presents the stability study data.

Table 2: Stability data for Example2 formulation composition
Period Condition Assay %
Related Substances

Target Limit Terbinafine HCl Zinc Pyrithione Target Limit % Total Impurities
Initial
NA NLT 90.0% and NMT 110.0% 101.7 100.1 NMT 2.0% 0.03
1M 25°C /60% RH 102.1 100.7 0.04
40°C /75% RH 101.9 102.0 0.07
2M 25°C /60% RH 102.1 99.5 0.0909
40°C /75% RH 102.2 98.3 0.1154
3M 25°C /60% RH 102.1 99.7 0.0941
40°C /75% RH 102.2 98.3 0.1361
Time Kill kinetics study

Dandruff is a common disease caused by Malassezia species especially Malassezia furfur. Anti-dandruff efficacy of the preservative free shampoo compositions according to the present specification were evaluated through time kill kinetics study and compared with the reference products (Nizoral Shampoo and Scalpe Shampoo). The study was performed using the test and the reference product on Malassezia furfur, the test organism. The culture media, sabouraud dextrose broth was inoculated with the test organism and the test and reference products were also diluted to1:10. The concentration of test organism in the media and the products was maintained same in all the cases. Sampling was done at different time points from the culture flasks and incubated at 35°C±2°C on the sabouraud dextrose agar media via filter paper for 48 h to 72 h. The filter paper was observed for the presence or absence of growth. The number of CFUs on the filter paper was determined only if the count was =100 CFU. >100 CFU was depicted as “Growth” (G) and absence of CFUs on the filter paper was represented as “No growth” (NG). The test shampoo products exhibited time kill kinetics similar to the reference products at 1:10 dilution.

Table 2: Time kill kinetics results
Test/
Reference
Products CFU

Dilution 2 min 5 min 8 min 10 min 30 min 60 min 120 min 180 min 240 min 300 min 24 hr
Test

Terbinafine1% & ZPTO 1% 1:10 NG NG NG NG NG NG NG NG NG NG NG
Sclape Shampoo

(Ketoconazole 2% & ZPTO 1%) 1:10 NG NG NG NG NG NG NG NG NG NG NG
Nizoral Shampoo

(Ketoconazole 1%) 1:10 NG NG NG NG NG NG NG NG NG NG NG