Title of Invention

A PROCESS FOR THE MANUFACTURE OF ANTI-DANDRUFF HAIR OIL COMPOSITIONS

Abstract This invention describes safe anti-dandruff hair oil compositions for effective mitigation of the proliferation of the dandruff causing yeast viz., M.furfun Synergistic combination of certain vegetable oils selected from sesame oil, soyabean oil and/or castor oil, preferably sesame oil, and their mixtures with other oils, with triacetin in which triacetin is 5 - 50% weight.
Full Text

Field of invention
This invention relates to safe anti-dandruff hair oil compositions. Background and prior art
Dandruff is a scaly condition of the scalp and proliferation of Pityrosporum ovale (P.ovale) / Malassezia furfur (M.furfur) has been considered as quite an important causative factor (McGinley K.J, Leyden J.J, Marples R.R, Kligman A.M : J. Invest Derm. 64 : 401 - 405, 1975). Midgley G et al.. have reported that the genus Pityrosporum / Malassezia is a lipid dependent yeast, growing very well in media containing lipids. Oleic acid is found to be the most suitable fatty acid for its lipid requirement (Midgley G, Gueho E, Guillet J : in Topley & Wilson's 'Microbiology & Microbial infections - Medical Mycology', Vol.4, 9th Ed., 1998). Different modes of intervention such as inhibitors of epidermal proliferation, keratolytic agents, anti-mycotic agents described as efficacious approaches for mitigating dandruff have been reviewed by Pierre G.A, in chapter 19 of The Science of Hair Care' Ed. Charles Zviak, Marcel Dekker, New York, pp 501 - 511, 1986. A number of compounds are now known to be useful in mitigating dandruff via., inhibiting M.furfur proliferation. These are for example compounds such as Zinc pyrithione (ZPT) (Imokama G, Shimizu H, Okamota K : J. Soc. Cosmet Chem., 33 : 27 - 37, 1982); Amphotericin B (Marcon M.J, Durrel D.E, Powell D.A, Buesching W.J : Antimicrob. Agents Chemo, 33 (6) : 951 - 953, 1987); Nystatin (Graybi J.R, Revankan S.G., Patterson T.F : in Topley & Wilson's 'Microbiology & Microbial Infection - Medical Mycology', Vol. 4, 9th Ed., 1998); Ketoconazole (Hammer K.A, Carson C.F, Riley T.V : Antimicrob. Agents Chemo, 44 (2) : 467 - 469, 2000; Butterfield W, Roberts M.M, Dave V.R : 6. Jour Derm, 116 : 233 - 235, 1987); Climbazole (Schmidt A, Ruehl - Hoerster B: Arzneim. Forsch., 46 (4) : 442 - 444, 1996) etc., There are different types of compositions in which such materials are incorporated at very low levels. But all these are compounds whose safety limits are restrictive and hence generally brought in contact with the scalp for a short period of time and washed away. They are therefore not optimal solutions for alleviating dandruff. There is hence a need for compositions with materials effective in mitigating dandruff in a more friendly
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way. It is a common practice in India and some neigbouring countries to apply a spoon full of vegetable hair oil on the head either before or after the bath. Dandruff condition is not uncommon in this part of the worid. A potentially leave-on product such as a hair oil containing a safe anti-dandruff agent will be an advantageous proposition for alleviating dandruff condition.
Triacetin, (1,2,3-propanetriol triacetate), is a colouriess, oily liquid with a fatty odour and a bitter taste, Triacetin is a triglyceride prepared out of acetic acid and glycerol. It is widely used as a plasticiser and a solvent for diverse applications. Among the many specific reported attributes of triacetin, it is reported as a topical antifungal (The Merck Index, 13th Edn., Merck & Co., Inc., (2001); page 1711, item 9664), it is known to be antipruritically effective (USP 6117904, WOP 0117526), is fungistatic and fungicidal (USP 4556560, USP 6162420 and GBP 845029), can help in reducing sebum secretion (USP 4172149) and is useful in treating lypolitic dermatitis (EP 0922457).
USP 4,556,560 (1985) for example, employs among other compounds zinc salts of 6 to 12 carbon fatty acids as lipase inhibiting agents for the treatment and prevention of diaper rash etc.. The compositions disclosed are not relevant to the present invention.
EP 0922457 (1999) This invention describes compositions comprising cationic compounds and triacetin (and like compounds) in cosmetic compositions in the form of lotions, creams, powders, oils, foams and the like and be applied to the skin to prevent or reduce or to treat skin rash or diaper rash resulting from lypolytic dermatitis. This patent is therefore, not relevant to the present invention.
GBP 845029 (1960) A pharmaceutical composition comprising 5 - 95% of triacetin in an inert pharmaceutical carrier containing sufficient acidic material to provide a pH of 3.5 to 6.5 when on the skin, said composition being free from acids and alkalis which maintain the pH outside the prescribed range and free from buffers which interfere with maintaining the pH within the prescribed range. The carrier may be carbowax, an isopropanol-water mixture, polyethylene glycol, calcium silicate or talc. Propellants may

also be included. Any inorganic or organic acid which is non-toxic and non-irritating to the skin in the amounts required may be used, particularly acetic or propionic acid or mixtures of propionic acid with other acids or acidic materials. The compositions have antifungal properties. This invention does not indicate any hair oil composition.
USP 6162420 (2000) This teaches nail varnish composition for treating onychomycoses with glyceryl triacetate (triacetin) (1-25% preferably 0.1 - 1.0% by weight.) In a simple example formulation shown is glyceryl triacetate 6.0 wt. %, isopropyl alcohol 47.0 wt.%, ethyl acetate 32.0 wt. %, copolymer of methyl vinyl ether and maleic acid monobutyl ester 15.0 wl. %.
USP 6117904, (2000) finds triacetin to be of value in the relief & treatment of pruritus due to leukoclastic vasculitis, macular lesion from drug allergies, skin conditions associated with renal diseases, dry skin, dandruff, anal itch, poison ivy, poison oak, poison sumac, insect bites, vaginitis, bladder infection, diaper rash, cradle cap and eczema. Typical oinment compositions for topical application described therein contain 20gm of triacetin in 80gm of Aquaphor. RTM. (which is a composition of petrolatum, mineral oil, mineral wax and wool wax alcohol). Creams containing 20% by weight triacetin, 20% self emulsifying bees wax, 40% mineral oil and -20% water have also been described. Dermatological lotions with 20% by weight triacetin in propylene glycol has been described. But these are not useful as hair oils, nor do they contain any vegetable oil.
WOP 0117526 (2001) This patent is almost same as above, however, it extends the activity of the compounds like triacetin to mono, di or tri - glyceride esters of fatty acids C2 - C22, cyclic, saturated or unsaturated like oleic, linoleic, linolenic. arachidonic acids. Glyceride of hydroxy fatty acids like recinoleic acid in these glycerides has neither been mentioned nor indicated. Positional and geometric isomers of unsaturated fatty acids are considered within the scope of the formula of the (active) compound. Its presence in composition is from 5 -100% by weight with a pharmaceutically acceptable carrier. The typical compositions are same as in USP 6117904, additionally

compositions or mono and an-acean replacing magnet habe alsobeen reported. It
should be noted that in this patent, any composition of triacetin along with another triglyceride ester has not been shown, nor suggested.
USP 4172149 (1979) This invention relates to a method for treating living skin in which there is an excessive secretion of sebum. The triglycerides that may be used in accordance with this invention are described by a general formula wherein R\ R^ and R^ are straight chain, branched chain, saturated or unsaturated aliphatic hydrocarbon radicals containing 1 to 20 carbon atoms. Triacetin, tributyrin, tricaprylin, tricaproin as also their distribution in a pharmaceutically acceptable vehicle in the form of simple solutions, lotions, creams, ointments etc., are described. It may be noted however that the triglycerides described herein are not as naturally existing mixed triglycerides ir vegetable oils along with their lipid associates and that the compositions disclosed do not have any vegetable oil. There is no indication that a combination of triacetin and certain vegetable oils will give synergy in inhibiting M.furfur, nor any vegetable oil compositions of triacetin are described.
Object
The principal object of the present invention is to develop a safe hair oil composition, which will effectively mitigate proliferation of the dandruff causing yeast viz. M. Furfur.
Summary of the invention
Accordingly, the present invention provides a process for the manufacture of synergistic anti-dandruff hair oil compositions for effective mitigation of the proliferation of the dandruff causing yeast viz. M. Furfur, comprising taking sesame oil at least 40% by wt, or soybean oil at least 40% by wt., or castor oil at least 40 % by wt.; triacetin 5 - 50 % by wt., and blending them additionally with one or more of other vegetable oils selected from sesame oil, soybean oil, castor oil, coconut oil and groundnut oil, and / or conventional hair oil additives for making up the remaining percentage by wt.

Description of the invention
The present invention discloses safe anti-dandruff hair oil compositions for effective mitigation of the proliferation of the dandruff causing yeast M. furfur, comprising a synergistic composition of vegetable oils such as sesame oil, soyabean oil, castor oil with triacetin in which triacetin is 5 - 50% by weight. The anti-dandruff hair oil formulations have triacetin preferably at 5 - 50% by weight, sesame oil at least 40% by weight and one or more of other vegetable oils. These hair oils may have one or more additives such as colour, perfume, sunscreen agent and functional oil soluble herbal extracts in appropriate quantities.
The invention is best illustrated by the examples of the hair oil compositions of the invention, in which triacetin and vegetable oil showing synergistic action are present. In addition, the composition may have certain additives such as colour, perfume and other functional additives like herbal extracts for cooling or soothing nerves like amia extract, hair growth like brahmi extract.
We shall describe in examples the study of minimum inhibitory concentrations (MIC) of triacetin & some oils and some oil mixtures and some compostions with different percentages of triacetin added to them against Malassezia furfur (Pityrosporum ovale). This study clearly demonstrates that only certain compositions show synergistic features.
The anti-fungal mode of action of triacetin has been discussed in the prior art. It is reported that glyceride per se is substantially inactive and that the activity is due to the splitting (hydrolysis) of the glyceride to free acetic acid and glycerine, as a result of the action of the esterase enzymes found abundantly in skin, serum and fungi. The organism itself liberates esterase (fat splitting enzyme) which results in the liberation of acetic acid and glycerine in situ at the site of infection in the amounts required. While acetic acid is known to be anti-fungal in character, it is possible that glycerine also plays a role and contributes to the over all activity. Investigations further indicate that the fats splitting enzymes are inactivated at the lower pHs and the acid liberated at the higher pHs is inactivated due to salt formation.

As far as we are aware, there is no study, however, on action of triacetin and any vegetable oil or their combinations on M.furfur reported so far. We have examined by the standard method for examining minimum inhibitory concentration, triacetin and number of vegetable oils and their mixtures. We find that certain oils like sesame oil, soya bean oil, castor oil show synergistic effect in mitigating M.furfur when combined with triacetin. Not all vegetable oils do that, but the presence of these oils does not affect the synergy of the synergistic mixture. It may be noted that each vegetable oil has a peculiar (i) fatty acid composition, (ii) glyceride composition and (iii) lipid associates including unsaponifiables.
The observed synergistic improvement of effectiveness against M.furfur could well be a consequence of the fatty acid distribution of such total compositions and/or facilitation by the lipid associates present in such vegetable oils.
Examples
The invention will now be illustrated by way of examples. The examples are by way of illustration only and in no way restrict the scope of the invention.
The materials used in this invention are Vegetable oils:
Coconut oil
Source: Geographically available in Chennai was used. Refined oil: FFA 0.93 %
Groundnut oil
Source: Geographically available in Chennai was used. Refined oil: FFA 0.07 %
Sesame oil/Gingelly oil
Source: Geographically available in Chennai was used. Refined oil: FFA 1.59 % The brands tested were Idayam, Sugam, V.V.S.Anandam & Thangam gingelly oil.

lustard oil
source: Geographically available in Chennai was used. Refined oil: FFA 1.12 %.
oyabean oil
ource: Geographically available in Chennai was used. Refined oil: FFA 0.064%
aster oil
ource: Geographically available in Chennai was used. Refined oil: FFA 0.685%
riacetin
source; Analytical grade, supplied by Sigma Aldrich Co., St. Louis, MO, USA.
stimation of Minimum Inhibitory Concentration (MiC) values
he Minimum Inhibitory Concentration (MIC) value of triacetin (neat) and vegetable oils leat) were determined against the yeast Malassezia furfur {Pityrosporum ovale). MIC ; the minimum / least amount of an antimicrobial that will inhibit visible growth of the rganism after a suitable period of incubation. MIC was determined by macro broth ouble dilution method as per the NCCLS guidelines published by the National ommittee for Clinical Laboratory Standards (Reference method for broth dilution for nti-fungal susceptibility testing of yeasts. Approved Standard M27A, 1997; National ommittee for Clinical Laboratory Standards, Wayne, PA, USA).
reparation of stock solution
tock solution of the test samples were prepared by dissolving the neat samples in solvent containing ethyl myristate, carbon-di-sulfide, and xylene [25 ml of solvent was prepared by adding 23 ml of ethyl myristate, 1.5 ml carbon-di-sulfide, and 0.5 ml xylene, mixed thoroughly. The mixture was sterilized by filtering through a sterile 0.22 m filter] (Smith M.D., Navilliat : J. Microbiol. Methods, 28 : 21 - 24, 1997). The neat sample so dissolved in the solvent was further diluted with appropriate volume of Sabouraud Dextrose Broth (SDB) in order to give a final concentration of 20,000 \xg I ml (reference

method for broth dilution for anti-fungal susceptibility testing of yeasts. Approved Standard M27A, 1997; National Committee for Clinical Laboratory Standards, Wayne, PA, USA). All test solutions were prepared afresh prior to determination of MIC.
Preparation of inoculum : Inocula were prepared by growing M. furfur on Sabouraud Dextrose Agar (SDA) with 1% Tween - 80 for 72 hrs. Colonies were suspended in SDB and counts were determined photometrically (Hammer K.A et a! : Antimicrob. Agents Chemc, 44(2): 467 - 469. 2000).
Serial dilutions : Serial dilutions for the assay - a series of 50% dilutions of each test sample solution was made in test tubes with SDB + 1% Tween - 80 as diluent (Table 1) (In Bailey & Scott's Diagnostic Microbiology. 9th Ed., 1996). Each tube was inoculated with M. furfur {0,5rr\\) of about 2x10^ CPU / ml viable counts.


Tubes were incubated at 32 + 1 Deg. C for 48 hrs. & then 10 ^1 aliquot from each tube were spot inoculated onto SDA with 1% Tween-80. The resultant subcultures were incubated for 3 - 4 days, when the colonies became visible. The lowest concentration of the test sample inhibiting growth of M.furfuron the subculture plate was taken as MIC of the test material. Assays were repeated thrice to confirm reproducibility of results.
Example I: MIC (iig/ml) is the minimum inhibitory concentration expressed as |ag/ml, when assayed via the double dilution protocol described earlier probing only two fold dilutions. The MIC values obtained for the vegetable oils studied and triacetin (as described by the double dilution method) used in the experimental compositions are shown in Table 2.
Table 2 : MIC of neat test substances

Example II : Estimation of MIC values of combinations of triacetin with vegetable oils against M. furfur
a. Different compositions of triacetin and gingelly oil were prepared in which triacetin was 0.5%, 1%, 5%, 10%, 20%. 30%, 40%, 50% & 90% (w/w). These compositions were examined for their respective MIC values following the procedure described earlier, in example I. The MIC values obtained for the combinations of triacetin and gingelly oil at different proportions are given in Table 3. These are graphically shown in Figure I, in the accompanying drawing. Table 3 and the Figure I clearly show the synergistic effect of the compositions containing triacetin and gingelly oil in different proportions.

b. Triacetin & other vegetable oil compositions ; As described above, compositions of triacetin with other vegetable oils (at 5% and 10% w/w concentration) was prepared and MIC values estimated. The MIC values obtained for the combinations of triacetin and vegetable oils at different proportions are given in Table 4.

It will be seen from Tables 2, 3 & 4 that binary composition of triacetin with gingelly (sesame) oil, castor oil and soyabean oil show pronounced lowering of MIC values, as compared to the individual components. This synergistic enhancement of M.furfur inhibition leading to lower MIC values is best with triacetin - gingelly oil system. No lowering of MIC values were observed in the other binary compositions involving triacetin and vegetable oils such as coconut oil, groundnut oil and mustard oil.

Binary compositions of vegetable oils amongst themselves, in the absence of tracetin, did not show any synergistic activity, proving that triacetin is essential for the observed lowering of MIC against M.furfur. Binary compositions of 5 - 50% triacetin in gingelly oil uniquely exhibited synergistic anti-dandruff properties as shown in the graph; compositions of triacetin and castor oil as well as triacetin and soyabean oil also result in synergistic lowering of MICs against M.furfur and this synergism is not universally exhibited when triacetin is mixed with the other vegetable oils.
Example ill: The sesame oil from various sources were tried out to see if there is any variation in MIC values when combined with triacetin. The MIC values observed are in Table 5.

As seen from the results, no variation in synergism is observed, even when sesame oil procured from various sources were used in combination with triacetin.
Example IV : Ternary system using triacetin - gingelly oil
Gingelly oil was mixed with other vegetable oils in a 1 : 1 ratio and made as binary mixtures. Compositions of 5% and 10% triacetin in these binary mixtures were made

and MIC values were determined by the procedure as described earlier. The MIC values observed are in Table 6.
Admixing triacetin - gingelly oil composition with other vegetable oils did not enhance synergy as shown in Table 6 - the least MIC being 312.5 g/ml as seen for the binary compositions of triacetin - gingelly oil.

Different varieties/samples of the compositions A to G of the invention were also prepared by addition of minor quantities of readily available optional ingredients such as colour, perfume, herbal extracts like ex. Ocimum sanctum, Emblica officinalis, Piper nigrum; sunscreen materials like 2-ethylhexyl p-methoxycinnamate; physiological coolants such as menthol; other ingredients like camphor.

Such products were found to be satisfactory for application on scalp and hair as hair oil prior to taking head baths and as leave on hair oil.
Highlights of the invention
It will be clearly seen that the synergistic compositions of the present invention are novel and not anticipated by any of the prior art compositions. Though triacetin is known as an antimicrobial and more specifically also as an antifungal compound in prior art, we have not come across any reference for its anti-dandruff hair oil application. Synergistic compositions of triacetin with vegetable oils for inhibition of Malassezia furfur which is a causative factor for dandruff condition are novel. The synergy is observed between triacetin and only certain vegetable oils; not all oils show this. This observation suggests that lipid associates in those oils help in bringing about this synergy in inhibiting growth of M.furfur
The compositions of the present invention are useful as safe inhibitors of M.furfur, the micro-organism implicated as a causative factor in dandruff situation and provides a friendly option for alleviating dandruff via., application of a hair oil containing essentially triacetin and vegetable oils to deliver the anti-dandruff function. Further, since this functional delivery is via., hair oil it has the advantage of providing anti-dandruff benefit not only as a prior head bath hair oil but also as a leave-on hair oil for hair grooming. The compositions of the present invention being leave-on products have potential for sustained anti-dandruff activity in the scalp for a prolonged period.
Composition of triacetin in gingelly oil will exhibit its activity not only by M.furfur inhibition; but triacetin is known to reduce sebum production (excess sebum production is seen in many dandruff conditions) and it is also known to exhibit anti-pruritic (itching) activity (itching sensation is commonly seen in dandruff scalp). This composition can thus have a multipronged action against dandruff and can thus be a more holistic antidandruff treatment than for example delivery of an anti-dandruff ingredient via., a shampoo vehicle which is a wash off product.



We Claim:
1. A process for the manufacture of synergistic anti-dandruff hair oil compositions for
effective mitigation of the proliferation of the dandruff causing yeast viz. M. furfur,
comprising taking sesame oil at least 40% by wt, or soybean oil at least 40% by wt.,
or castor oil at least 40 % by wt.; triacetin 5 - 50 % by wt., and blending them
additionally with one or more of other vegetable oils selected from sesame oil,
soybean oil, castor oil, coconut oil and groundnut oil, and / or conventional hair oil
additives for making up the remaining percentage by wt.
2. A process for the manufacture of synergistic anti-dandruff hair oil compositions as
claimed in claim 1 wherein, conventional hair oil additives are colour, perfume,
functional ingredients such as sunscreens and other oil soluble herbal extracts in
appropriate quantities known in the art.
3. A process for the manufacture of synergistic anti-dandruff hair oil compositions
substantially as herein described in the text, examples and the drawing.


Documents:

584-che-2003-abstract.pdf

584-che-2003-claims.pdf

584-che-2003-correspondnece-others.pdf

584-che-2003-correspondnece-po.pdf

584-che-2003-description(complete).pdf

584-che-2003-drawings.pdf

584-che-2003-form 1.pdf

584-che-2003-form 19.pdf

584-che-2003-form 26.pdf

584-che-2003-form 3.pdf


Patent Number 197985
Indian Patent Application Number 584/CHE/2003
PG Journal Number 30/2009
Publication Date 24-Jul-2009
Grant Date
Date of Filing 21-Jul-2003
Name of Patentee CAVINKARE PVT. LTD
Applicant Address 237 PETERS ROAD CHENNAI 600 086
Inventors:
# Inventor's Name Inventor's Address
1 NAMBUDIRY MAYARA EASWARAN NARAYANAN R&D CAVINKARE PRIVATE LIMITED RESEARCH AND DEVELOPMENT 148, GANESAN OFFICE COMPLEX PETERS ROAD ROYAPETTAH, CHENNAI 600 014
2 NARAYANAN (MS) MEENAKSHI R&D CAVINKARE PRIVATE LIMITED RESEARCH AND DEVELOPMENT 148, GANESAN OFFICE COMPLEX PETERS ROAD ROYAPETTAH, CHENNAI 600 014
3 KANDASAMY (MS) KAVITHA R&D CAVINKARE PRIVATE LIMITED RESEARCH AND DEVELOPMENT 148, GANESAN OFFICE COMPLEX PETERS ROAD ROYAPETTAH, CHENNAI 600 014
PCT International Classification Number A45D19/16
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA