AU771707B2

AU771707B2 - A topical anti-itch formulation and a process for the preparation thereof

Info

Publication number: AU771707B2
Application number: AU97047/01A
Authority: AU
Inventors: Khaiat Alain; Thomas Mini; Gadgil Sandeep; Manke Ajit Sitaram
Original assignee: Johnson and Johnson Pvt Ltd
Current assignee: Johnson and Johnson Pvt Ltd
Priority date: 2001-12-05
Filing date: 2001-12-05
Publication date: 2004-04-01
Anticipated expiration: 2021-12-05
Also published as: CN1263474C; AU9704701A; EP1461057A1; CN1516593A; WO2003047609A1; JP2005515204A

Description

53268 GEH:PFB P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant: JOHNSON JOHNSON LIMITED, INDIA Actual Inventors: THOMAS MINI GADGIL SANDEEP MANKE AJIT SITARAM KHAIAT ALAIN Address for Service: COLLISON CO., 117 King William Street, Adelaide, S.A. 5000 Invention Title: A TOPICAL ANTI-ITCH FORMULATION AND A PROCESS FOR THE PREPARATION THEREOF The following statement is a full description of this invention, including the best method of performing it known to us: *ooooo* method of performing it known to us: FIELD OF INVENTION This invention relates to a topical anti-ith formulation and a process for the prprton thereof.

PRIOR ART For treating dermatological conditions like pruntis, topical -formulations of corticosteroids such as hydrocortisone, dexamethasone or betamethasone are generally used. The side effects/adverse effects of long term use of corticosteroids such as skin thinning or atrophy are clinically well known and reported (Medicine in practice, Issue 1, pg 14).

The herb centella asiatica. is well known to have medicinal properties. Centella whole extract isolated from the herb is purified for therapeutic use. Purified centelia, extract enriched with its triterpene actives viz asiaticocide, asiatic acid and madecassic acid in 1% is reported to be used.

in healing of various types of wounds or ulcers or in disinfection thereof or in. cicatrisation dhereof by regeneration or in stimulation of skin and also as a scar miisgagent, ("Clinical study of a new antikeloid agent", Annals of Plastic Surgery, Vol 3, No1, pp 13 to 21, by Bosse JP etal French Patent No 2594690A, European Patent No 22046A, Belgium Patent No 699410A).

Preparation of purified centella, extract by techniques like nanofifiviion, liquid-liquid extraction or column chromatorahy is laborious, time consuming and expensive. thus. rendering purified centella extract very expensive.

Tea tree oil in 0.2% and above is reported to exhibit antibacterial properties and is used in cosmetics and toiletries ("Optimising the activity of tea tree oil in cosmetics and toiletries" a Paper presented at the 4th Joint Conference of Australian and New Zealand Societies of Cosmetic Chemists, Surfer's Paradise, Australia, 1994).

OBJECTS OF INVENTION An object of the invention is to provide a topical anti-itch 10 formulation, which provides fast and effective relief from itching.

Another object of the invention is to provide a topical anti-itch formulation, which also provides cooling and moisturising effects.

Another object of the invention is to provide a topical anti-itch formulation, which is safe for use over a long period of time.

Another object of the invention is to provide a topical anti-itch formulation, which is economical.

Another object of the invention is to provide a topical anti-itch formulation which is easy and convenient to use.

Another object of the invention is to provide a process for preparing a topical anti-itch formulation which provides fast and effective relief from itching.

Another object of the invention is to provide a process for preparing a topical anti-itch formulation which also provides cooling and moisturising effects.

10 Another object of the invention is to provide a process for preparing a topical anti-itch formulation which is safe for use over a long period of time.

Another object of the invention is to provide a process for 15 preparing a topical anti-itch formulation which is economical.

Another object of the invention is to provide a process for preparing a topical anti-itch formulation which is easy and convenient to use.

DETAILED DESCRIPTION OF INVENTION According to the invention there is provided a topical anti-itch formulation comprising centella asiatica whole extract in 0.1- 2% by weight and tea tree oil in 0.1 2% by weight in combination with formulating agents.

According to the invention there is also provided a process for preparing a topical anti-itch formnulation comprising mixing centella, asistica, whole extract in 0. 1 by weight and tea tree oil in 0.l1 2o/o by s weigh with formulating agents at 25-800C.

The formulation may comprise a cooling cum moisturising agent in 0.3 by weight and the process may comprise mixiing a cooling cum moisturising agent in 0.3 by weight with the centella asiatica whole tio extract and tea tree oil and formulating agents.

1Te cooling cum moisturising agent may be menthone glycerine acetal or a mixture of 5-methyl-2-(1-methylethyl)-cyclohexmnol, menthol propylene glycol carbonate, menthol ethylene glycol carbonate and peppermint oil, herein after referred -to as menthol-mint. compound.

Preferably the mcnthone glycerine acetal or menthol-mint compound is in 0.3-0.5% by weigh.

Formulating agents used to prepare the formulation may be anhydrous lanoline, ethylene glycol monosteate, mineral oil, carbomer, carbopol, propylente glycol, isopropyl myristate, myristyl myristate, sodium dioctyl sulfosuccinate (DOSS), bee wax, borax, absolute alcohol, cetyl.

alcohol stearyl alcohol, a mixture of phenoxyeffimol, methyl paraben, ethyl paraben, propyl paraben mid butyl paraben, ethylene diamine tetracetic acid (EDTA), glyceryl monostearate, benzophenone, benzyl alcohol, propenic acid polymer, polysorbate 20, 2-amino-2-methyl-l-propanoL castor oil, monomer of homopropenic acid, sorbiton monostearate, glycerine or butylated hydroxy toluene (BHT) or mixtures thereof. Dyes like amaranth or brilliant blue or perfumes such as "BBA 1022" of Bush Boake Allen, USA; "BVK 2723" of Takasago, Japan or "Coraillito" of Harmer Reimer, India also may be added to the formulation which may be a gel, cream or lotion.

l0 Preferably the centella asiatica whole extract is in 1 by weight and tea tree oil is in 0.2 2% by weight.

Preferably the mixing of the ingredients of the formulation is carried out at 25-75 0

C.

:The formulation of the invention provides fast and effective relief from itching. Because it is based on centella asiatica whole extract and tea tree oil, both of which are of plant origin, it is safe for use over a long period of time without adverse/side effects. It is economical due to the use of whole extract of centella asiatica which is easily available and cheap. Due to the cooling cum moisturising agent, the affected areas treated with the formulation of the invention experience cooling and soothing effects which provide a sense of immediate relief from itching. Besides these areas also rmman moistuse thereby faiiaigpenetration of the actives into the skin thus accierating healing. It is also convenient to use or apply as a cream, glor lotion.

The following experimental examples are illustrative of the invention but not limitative of the scope thereof.

Exmnple 1 Ingraentes Quantityin gms eve* Centefla asiatica whole extract (Ainsar Pvt Ltd, Indore, India) Tea tree oil (Southern Cross Botanicals, Austalia) Menthone glycerine aceta (1Frescolate" of Harmer and Reiw, Maharashtra, India) Mineral oil (IMarcolw, Esso, France) Anhydrous lanoline Ethylene glycol monostcarate Carbopol Polysorbate 20 Propylene glycol

DOSS

Isopropyl myristate A mixture of phenoxyethnnol, methyl paraben, ethyl paraben, propyl paraben and butyl paraben ("Phenonip",$ NIPA Laboratories, Chennai India) Water 20.0 0.1 q.s to 100 DOSS was dissolved in hot water (150 gins) at 80'C. To propylene glycol at 7011C, phenonip and polysorbate 20 were added and this solution was mixed with the solution of DOSS. Centella asiatica, whole extract followed by carbopol were dispersed in the above solution and the dispersion stirred for 45 minutes. To mineral oil at 70*C, tea tree oil and ethylene glycol monostearate, isopropyl myristate, lanoline anhydrous and "Frescolate" were added and stirred to form an emnulsion. The emulsion was mixed with the above dispersion comprising centella. and cooled to 25 0

C.

NaOH was added to adjust the pH to 6.68 and the formulation was s made upto 100 gins by adding water to obtain a cream.

Exwmple 2 Ingedients Quantity ingms Centella astatica whole extract (Aisa Pvt Ltd, Indore, India) Tea tree oil (Southern Cross Botanicals, Australia) Menthone glycerine acetal ("Frescolate") Bee wax Glyceryl monostearate Mineral oil Marcoll', Esso, France) Polysorbate 20 isopropyl myristate A mixture of phenoxyethanol, methyl.

paraben, ethyl paraben, propyl paraben and butyl paraben ("Phenonip" NIPA Laboratories, Chennai India) Borax

EDTA

Cetyl alcohol Stearyl alcohol Myristyl myristate Sorbiton Monostearate Glycerine

BHT

Perfume ("B3BA 1022"1 of Bush Boake Allen, USA) Water 20.0 0.025 1.50- 1.50 1.00 0.05 0.2 q.s to 100 An aqueous phase was prepared by mixin polysorbate glycerine, centella asiatica whole extrac phenomip, EDTA and -BHT in. water at 70 75'C. An oil phase was prepared by nixing mineral oil, bee wax, glyceryl monostearate, sorbiton monostearate, tea tree oil, myristyl myristat, isopropyl, myristate aid "Frescolate" at 25 0 C. The oil and aqueous phases were mixed together followed by mixing with borax, perfume, cetyl and stearyl alcohol to give a lotion.

Example 3 0 Igredients Quantity in gms 15 20 25 Centella asiatica whole extract (Amsar Pvt Ltd, Indore, India) Tea tree oil (Southern Cross Botanicals, Australia) Carbomer Polysorbate 20 Propylene glycol Glycerine A mixture of phenoxyethanol, methyl paraben, ethyl paraben, propyl paraben and butyl paraben Phenonip",I NIPA Laboratories, Chennai India) 2-amino-2-methyl- 1-propanol.

Absolute alcohol Briiliant blue dye Perfume ("BVK 2723", of Takasago, Japan) 0.2 1.1 12.0 0.3 The above ingredients were mixed together at 25*C to give a transparent gel- Exwmple 4 Ingredients Qumtity in gins Centelia asiatca whole extract (Ainsar Pvt Ltd, Indore, India) Tea tree oil (Southern Cross Botanicals, Australia) 0.2 Menthol-mint compound ("Optanint" of Harmer Reimar, Mahaaslitra, India) 0.3 Propylene glycol Glycerine Polysorbate 20 A mixture of phcnoxyethanol, methyl paraben, ethyl paraben, propyl paraben, and butyl paraben ("Phenoidp NIPA Laboratories, Chennni India) 1.1 202-ammno-2-mediyl-I-propanol castor oil Brifliant blue dye The above ingredients were mixed together at 25 0 C to give a transparent gel.

Example Ingredients Quantityingins Centella, asiatica whole extract (Amsar Pvt Ltd, lndore, India) Tea tree oil (Southern Cross Botanicals, Australia) Benzyl alcohol Ethyl alcohol Benzophenone, Carbomer Propylene glycol water 0.79 2.1 37.0 0.01 0.80 qs to 100 9 9 *9 999...

9.

The above ingredients were mixed- together .at 25 0 C to give a gel.

Example 6 Ingredients Quantityingmis 20 Centella asiatica whole extract (Amsar Pvt Ltd, Indore, India) Tea tree oil (Southern Cross Botanicals, Australia) Menthone glycerine acetal ('Frescolate") Glycerine Propylene glycol A mixture of phenoxyethanoi, methyl paraben, ethyl paraben, propyl paraben and butyl paraben ('Thenonip", NIPA Laboratories, Chennai India) Monomer of homopropenic acid 2,-mo-2-methyl-l1-propanol Polysorbate 20 Absolute alcohol Brilliant blue dye Perfume ("Coraiflito" of Harmer Reimar, Water 20.0 0.3 qs to 100 The above inr~edients were mixed at 30PC to obtain a gel.

Clinical efficacy studies: A blind study was conducted on 15 volunteers in a controlled and randomised manner. Itching was induced in each volunteer by the histamine prick method at three sites in the forearm. The 15 volunteers were divided into 3 groups each of 5 mid were treate after 10 mins of induction of .iflarnmation and itching as indicated in the following Table 1 Table I Group sitel Isitel IIsite II I Placebo Hydrocortisone Gel of gel butyrate crearn(H) Exanple 3 of Locoid, USA (G) II GP

H

III H G

P

The volunteers provided ratings on a scale of 0-4 with respect to the parameters of swelling, redness, pain, itching and erythema wherein "0" implied 100%, "RV implied implied 50%, implied 75% and "4" implied manifestation of the above said paameters. The average ratings of the various parameters by the volunteers in. the three groups using P, G and Hatvarious tfieintervals were asshown in tefolloigTable 2: Table 2

C

C.

C

Parameters Time Sites treated Sites treated Sites treated with G with H with P (mins) Mean SD Mean SD Mean SD 2.5S 0.51 2.33S 0.59 1.33 0.49 3.44S 0.51 3.33S 0.59 2.83 0.61 Swelling 1.5 3.77S 0.42 3.77S 0.54 3.27 0.66 3.94 0.23 4.0 0.0 3.88 0.32 2.72S 0.46 2.83S 0.38 1.77 0.73 3.61S 0.50 3.66S 0.48 3.0 0.59 Redness 1.5 4.OS 0.0 4.OS 0.0 3.33 0.59 4.0 0.0 4.0 0.0 3.88 0.32 0.5 2.55S 0.62 2.44S 0.51 2.11 0.58 1.0 3.5S 0.78 3.613 0.5 3.0 0.59 Pain 1.5 3.94S, 0.23 4.03 0.0 3.55 0.51 3.94 0.23 4.0 0.0 3.94 0.23 2.55 0.62 2.5 0.51 2.33 0.59 3.53 0.78 3.61S .0.5 3.0 0.59 Itching 1.5 3.94S. 0.23 4.03 0.0 3.66 0.48 2.0 3.94 0.23 4.0 0.0 3.94 0.23 2.773 0.43 2.76S 0.44 1.88 0.83 3.663 0.48 3.61S 0.5 3.0 0.48 Erythema 1.5 4.03 0.0 4.OS 0.0 3.33 0.59 4.0 0.0 4.0 0.0 3.88 0.32 SD =Standard deviation S =Sigifficant differences (non-part) The width of the vernier callipers and the areas shown in the following Table 3: vheallscar at the sites was measued, using -alculated at various time 'intervals were as Table 3 Time (minus) Area of sites treated with G Area of sites treated withH Area of sites treated with

P

Mean SD Mean SD Mean SD 9.95S 5.0 9.47S 4.18 12.75 3.07 3.93S 5.60 3.14S 3.67 6.33 3.77 0.693 1.34 0.17S 0. 74 3.18 2.83 0.17 0.74 0.0 0.0 0.56 1.78

SD

S

Standad deviation Significant differences (non-parity) From the above studies it can be inferred tha the anti-itch activity of the formulation of the invention is higher when compared to placebo, and comparable withi hydrocortisone buqtate.' A consumer use test was conducted for mosquito bite on 100 volunteers including women and children under 15 years of age. volunteers (group A) were instructed to use the gel of Example 4 and. the remaining 50 (group B) were instructed to use narcissus esssential balm oil (Mfd by Fugian Qingshan Zhangzhou Perfumery industry, China) which is known to have anti-itch property. The volunteers were asked to rate the various parameters listed in the following Table 4 on a 5-point scale wherein 5 implied excellent, 4 implied very good, 3 implied good, 2 implied fair and 1 implied poor. The average ratings of the volunteers anid the of volunteers who provided the top two ratings of 5 and 4, for the various parameters were as shown i the following Table 4.

Table 4 Avg Top Avg Top Parameters rating A rating A rating B rating

B

VI.. Stops itchiness fast 3.4 50 3.3 49 2) Stops itchiness effectively 3.5 60 3.4 58 3) Long lasting relief 3.2 47 3.0 37 from itchiness 2o4) Does not leave skin sticky/greasy 3.1 40 3.6P 53 Leaves skin feeling cool 3.6 59 3.6 63 6 Suitable for kids/baby 3.4P 40 3.0 32 7) Less eye irritation 1.5P 45 3.1 8) Mildness on skin 3.7P 53 3.4 42 9) Easy to control the *application volume 3.3 41 3.5 46 Easy to spread 3.6 52 3.6 51 11) Absorption easy 3.4 48 3.6 47 P Statistically significant Teresults of the clinical efficacy studies using the formulation.

of dhe invention establish the fast and long lastng anti-itch activity theeof.

Bessbein asyndconveniettoue it wasaso found to be without any sensitisation and safe for use over a long period of time even in the case of children.

Claims

5-methyl-2-(l-methylethyl)-cyclohexanol, menthol propylene glycol carbonate, menthol ethylene glycol carbonate and peppermint oil. A formulation as claimed in claim 4, wherein the menthone glycerine acetal or a mixture of 5-methyl-2-(l-methylethyt)- cyclohexanol, menthol propylene glycol carbonate, menthol ethylene glycol carbonate and peppermint oil is in 0.3 to 0.5% by weight, 6) A formulation as claimed in anyone of claims 1 to which is a gel, creamn or lotion. I j 7) A process for preparing a topical anti-itch formulation comprisn mixig centeila asialica whole extract in 0. 1 2O/o by weight and tea tree oil in 0.1-2%9 by weight with' formulating agents at 25-80*C. 8) A process asclaimed in claim 7, comprising mixing a cooling, cum moistuisn agent in 0.3 -2%o by weight with the centella asiatica, whole extract, tea tree oil and formulating agents. 9) A process as claimed in claim 7 or 8, wherein the centella asiatca whole extract is in 1 to 2%o by weigh and tea tree oil is in0. 2- 2% by weight A process as claimed in claim 8 or 9, wherein the cooling cum moistursn agent is menthone glycerine acetal, or a mixture of methyl-2-(l-methylethyl)-cyclohexanol, menthol propylene glycol carbonate, menthol ethylene glycol carbonate and peppermint oil 11) A process as claimed in claim 10, wherein the menthone glycerine acetal or a mixture of 5-methyl-2-(l-methylethyl)-cyclohexanol, menthol propylene glycol carbonate, menthol ethylene glycol carbonate and peppermint oiisin 0.3 0.5% by weight. 12) A process as claimed in anyone of cluims 7 to 11, for the preparation of a formulation in the form of gel, cream or lotion. 13) A process as climned in any one of claims 7 to 12, wherein the mixing is carrded out at 25 -75 0 C. 14) A process for preparing a topical anti-itch formulation substantially as herein described partcularly with reference to Examnples: I to 6. Dated this 5th day of December 2001 JOHNSON JOHNSON LIMITED, INDIA By their Patent Attorneys COLLISON CO 0