Title of Invention

SYSTEM FOR ENHANCED DELIVERY OF BENEFIT AGENTS, PROCESS THEREOF AND COSMETIC COMPOSITIONS THEREFROM

Abstract The invention relates to a pro-vesicles for enhanced delivery of skin benefit agents through formation of vesicular phases in the presence of water in topically applied cosmetic products, said pro-vesicles comprising: (i) the benefit agent to be delivered; (ii) a phospholipid; (iii) a mono-di-or tri-ester of glycerol; (iv) a straight or branched chain propyl or butyl ester of C14 to C18 fatty acid; and (v) a cosmetically acceptable base.
Full Text FORM -2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
(See Section 10)



SYSTEM FOR ENHANCED DELIVERY OF BENEFIT AGENTS, PROCESS THEREOF AND COSMETIC COMPOSITIONS THEREFROM
HINDUSTAN LEVER LIMITED, a company incorporated under the Indian Companies Act, 1913 and having its registered office at Hindustan Lever House, 165/166, Backbay Reclamation, Mumbai -400 020, Maharashtra, India
The following specification describes the invention




Technical field
The invention relates to a system for enhanced delivery of skin benefit agents, more particularly, a pro-vesicle for enhanced delivery of skin lightening or UV blocking agents to the skin. The invention also relates to a cosmetic composition comprising the delivery system of the invention.
Background and Prior Art
Liposomes have been known since the 1960s and are reported to be used in various applications. Liposomes are small microencapsulates formed from certain surface active molecules, most commonly phospholipids, which in aqueous media arrange themselves into a bi- layered membrane defining a microscopic closed vesicle. Liposomes are known to have good penetration capability through the skin and therefore are employed to deliver actives transdermally. It has been exploited to a large extent in the field of transdermal and targeted delivery of drugs and therapeutic agents in the field of medicine. Liposomes, in the recent past, have also been used in cosmetic formulations such as skin creams.
WO95/35095 (Yissum, 1995) describes a cosmetic or medical composition for topical application to the skin comprising a phospholipid, a lower aliphatic alcohol of two to four carbon atoms and optionally a glycol and at least 20% water. This publication teaches delivery of active ingredients which may have medicinal properties or cosmetic benefits like anti-aging, tanning among others.
US2002/0012647 (Cannell) describes a composition comprising at least one organic phospholipid capable of forming bilayers in aqueous solution, at least one amphoteric surfactant present in amount greater than the phospholipid and at least one non-ionic surfactant present in amount greater than the phospholipid, wherein the combined amounts of the essential ingredients is such as to allow at
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least one water-insoluble ingredient selected from waxes, unneutralised and partially neutralised water-insoluble polymers, resins and latexes to be incorporated into an aqueous solution.
US6497888 (L'Oreal 2002) describes a process, composition and kit for limiting the penetration into the skin and/or other keratinous fibers of at least one cosmetically and/or pharmaceutically active agent. The composition comprises along with the base composition of an effective amount of a disperson of vesicles in a medium, the vesicles comprising at least one ceramide of formula (I)


Wherein R1 is chosen from saturated and unsaturated, linear and branched C1 -C32 alkyl groups and R2 is chosen from saturated and unsaturated, linear and branched C1 to C50 alkyl groups.
While many methods and compositions have been described for penetration of skin benefit and skin care actives through liposomes, there exists a need to develop better and more effective methods and compositions to achieve these ends. It is thus an object of the invention to provide for a composition that provides for enhanced delivery of skin benefit agents to the skin. It is another object of the invention to provide for a composition that while providing enhanced delivery of skin benefit agents to the skin, are stable by virtue of being encapsulated in the delivery system of the cosmetic composition.
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Summary of the invention
Thus according to one aspect of the invention there is provided pro-vesicles for enhanced delivery of skin benefit agents through formation of vesicular phases in the presence of water in topically applied cosmetic products, said pro-vesicles comprising
(i) the benefit agent to be delivered
(ii) a phospholipid
(iii) a mono, di or tri ester of glycerol and
(iv) a straight or branched chain propyl or butyl ester of C14 to C^ fatty acid and
(v) a cosmetically acceptable base.
According to another aspect of the invention there is provided a cosmetic composition for enhanced delivery of skin benefit agents comprising the pro-vesicle of the invention and water such that the weight ratio of pro-vesicle and water is at least 1:1.
According to yet another aspect of the invention there is provided a process process for the preparation of the pro-vesicle of the invention comprising the steps of
(i) preparing a slurry of said benefit agent, said lecithin, said mono, di or tri
ester of glycerol and said straight or branched chain propyl or butyl ester
of C14 to C-18 fatty acid in a non-aqueous solvent and
(ii) mixing said slurry with the cosmetically acceptable base to form a mixture
and
(iii) separating the non-aqueous solvent from said mixture to form granular
pro-vesicle.
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Detailed description of the invention
The first aspect of the invention provides for a pro-vesicle for enhanced delivery of skin benefit agents through formation of vesicular phases in the presence of water in topically applied cosmetic products. The pro-vesicle comprises the benefit agent to be delivered, a phospholipid, a mono, di or tri ester of glycerol and a straight or branched chain propyl or butyl ester of C14 to C18 fatty acid and a cosmetically acceptable base. The benefit agent to be delivered may be a hydrophobic or hydrophilic benefit agent, preferably a skin lightening agent, a sun screen or a UV blocking agent. Suitable example of skin lightening agent which is delivered by the pro-vesicle of the invention is niacinamide and suitable sun screen or UV blocking agent is 2-ethylhexyl-p-methoxycinnamate or butylmethoxydibenzoylmethane. These skin benefit agents are present in an amount in the range of 0.1 to 40% by weight of the pro-vesicle
The phospholipid
The phospholipid of the invention is derived from a lecithin, which could be from any source, preferably from soy lecithin. It is preferred that the lecithin comprises at least 32% phospholipid. The phospholipid is preferably present in an amount in the range of 0.5 to 50% by weight of the pro-vesicle.
Mono, di or tri ester of glycerol
Another essential component of the pro-vesicle of the invention is a mono, di or tri-ester of glycerol preferably a mono ester of glycerol. The glycerol is preferably esterified with a fatty acid having 14 to 20 carbon atoms, more preferably 16 to 18 carbon atoms which may be saturated or unsaturated. Thus the preferred glycerol esters are glycerol mono stearate, glycerol mono oleate or glycerol mono palmitate of which glycerol mono stearate is the most preferred. The mono, di or tri ester of glycerol is present in an amount in the range of 2 to 25% by weight of the pro-vesicle.
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Propyl or butyl ester of C-14 to C18 fatty acid
The pro-vesicle of the invention comprises a straight or branched chain propyl or butyl ester of C14 to C18 fatty acid, preferably an isopropyl ester of C14 to C18 fatty acid. The compounds that are more preferred include isopropyl myristate, iso-propyl ester of hydrogenated 12-hydroxystearic acid or iso-propyl palmitate, of which iso-propyl ester of hydrogenated 12-hydroxystearic acid is the most highly preferred compound. The propyl or butyl ester of C14 to C18 fatty acid is preferably present in an amount in the range of 0.5 to 15% by weight of the pro-vesicle.
Cosmetically acceptable base
The pro-vesicle of the invention comprises a cosmetically acceptable base. Suitable examples which are preferred include glucose, sorbitol, talc or stearic acid. The cosmetically acceptable base is present in an amount in the range of 30 to 96% by weight of the pro-vesicle.
Sterol
The pro-vesicle of the invention optionally comprises a sterol. It has been observed that the inclusion of the sterol in the pro-vesicle of the invention enhances the stability of the pro-vesicle. The sterol may be a phytosterol or a cholesterol, preferably a cholesterol. When present, the sterol is preferably present in an amount in the range of 0.1 to 8% by weight of the pro-vesicle.
Process for the preparation of the pro-vesicle
The process for the preparation of the pro-vesicle of the invention comprises the steps of
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(i) preparing a slurry of the benefit agent, the phospholipid, the mono, di or tri ester of glycerol and said straight or branched chain propyl or butyl ester of C14 to C18 fatty acid in a non-aqueous solvent and
(ii) mixing said slurry with the cosmetically acceptable base to form a mixture and (iii)separating the non-aqueous solvent from said mixture to form granular pro-vesicle.
The slurry is preferably prepared at a temperature higher than 40 °C. The nonaqueous solvent is preferably a straight or branched chain alcohol with carbon chain length of 1 to 4, of which ethanol is the most preferred solvent. The nonaqueous solvent is preferably present in an amount in the range of 5 to 40%, more preferably 10 to 30% by weight of the slurry. The non-aqueous solvent is separated from the mixture by drying preferably under vacuum.
Cosmetic composition
A cosmetic composition as per the invention comprises the pro-vesicle of the invention and water such that the weight ratio of pro-vesicle and water is at least 1:1, preferably at least 1:4. The cosmetic composition may optionally comprise other cosmetic benefit agents e.g. one or more of emollients, humectants, or thickeners. The cosmetic composition of the invention is prepared by mixing the pro-vesicle of the invention with the water and the other optional ingredients, if present. The pro-vesicle is preferably added to the composition at the end of the mixing preferably at low shear. The temperature at which this process is carried out is preferably in the range of 50 to 70 °C.
The cosmetic composition may also comprise other components to act as a diluant, dispersant or carrier for other materials present in the composition, so as to facilitate their distribution when the composition is applied to the skin.
These additional materials, other than water, can include liquid or solid emollients, solvents, humectants, thickeners and powders. Examples of each of
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these types of additional materials, which can be used singly or as mixtures, are as follows:
Emollients, such as stearyl alcohol, glyceryl monoricinoleate, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate,. hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, eicosanyl alcohol, behenyl alcohol, cetyl palmitate, silicone oils such as dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, cocoa butter, corn oil, cotton seed oil, olive oil, palm kernel oil, rape seed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower seed oil, avocado oil, sesame seed oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum jelly, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate;;
Propellants, such as propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide;
Solvents, such as ethyl alcohol, isopropanol, acetone, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether;
Powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silica sodium polyacrylate, tetra alkyl and/or trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate.
These additional materials are preferably present from 10 to 99.9%, preferably from 50 to 99% by weight of the cosmetic composition, and can, in the absence of other cosmetic adjuncts, form the balance of the composition.
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Optional skin benefit agents:
Skin lightening ingredients can be advantageously included in the composition to provide skin lightening effects, other than as provided through the pro-vesicle of the invention. These may include vitamin B6, vitamin C, vitamin A or their precursors and mixtures. Especially preferred additional vitamin is vitamin B6. Other skin lightening actives known in the art can also be employed in the invention. Non limiting examples of skin lightening actives useful herein include aloe extract, ammonium lactate, azelaic acid, kojic acid, lactic acid, linoleic acid, magnesium ascorbyl phosphate, 5-octanoyl salicylic acid, 2,4 resorcinol derivatives, 3,5 resorcinol derivatives, salicylic acid, 3,4,5 trihydroxybenzyl derivatives, and mixtures thereof. The composition preferably comprises from about 0.1% to about 10%, more preferably from about 0.1% to about 5%, of a skin lightening ingredient.
The composition of the invention may include an effective amount of a sunscreen or sun-block agent, other than that provided through the pro-vesicle of the invention. Organic and inorganic sunscreens/sun-blocks may be suitably employed in the composition. Suitable organic sunscreen agents include 2-ethylhexyl-p-methoxycinnamate, butylmethoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid and mixtures thereof. A safe and effective amount of sunscreen may be used in the compositions useful in the subject invention. The composition preferably comprises from about 0.1% to about 10%, more preferably from about 0.1% to about 5%, of a sunscreen agent.
Inorganic sun-blocks are also preferably used in the present invention. These include, for example, zinc oxide iron oxide, silica, such as fumed silica, and titanium dioxide. Ultrafine titanium dioxide in either of its two forms, namely water-dispersible titanium dioxide and oil- dispersible titanium dioxide is especially suitable for the invention. Water-dispersible titanium dioxide is ultra-fine titanium dioxide, the particles of which are non-coated or which are coated with a material to impart a hydrophilic surface property to the particles. Examples
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of such materials include aluminium oxide and aluminium silicate. Oil-dispersible titanium dioxide is ultrafine titanium dioxide, the particles of which exhibit a hydrophobic surface property, and which, for this purpose, can be coated with metal soaps such as aluminium stearate, aluminium laurate or zinc stearate, or with organosilicone compounds.
By "ultrafine titanium dioxide" is meant particles of titanium dioxide having an average particle size of less than 100 nm, preferably 70 nm or less, more preferably from 10 to 40 nm and most preferably from 15 to 25 nm.
Ultrafine titanium dioxide is the preferred inorganic sun-block agent. The total amount of sun block that is preferably incorporated in the composition according to the invention is from 0.1 to 5% by weight of the composition.
Optional cosmetic ingredients
The compositions of the present invention can comprise a wide range of other optional components. The CTFA Cosmetic Ingredient Handbook, Second Edition, 1992, which is incorporated by reference herein in its entirety, describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples include: antioxidants, binders, biological additives, buffering agents, colorants, thickeners, polymers, astringents, fragrance, humectants, opacifying agents, conditioners, exfoliating agents, pH adjusters, preservatives, natural extracts, essential oils, skin sensates, skin soothing agents, and skin healing agents.
The invention will now be illustrated with the following non-limiting examples.
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Examples
The vesicles as listed in table -1 were prepared, as per the procedure detailed
below.
The materials (lecithin, the benefit agent niacinamide (1 gram), the esters and
sterol) listed under each example were taken in a beaker and mixed with the
ethanol to a homogeneous mixture. The mixture was then sprayed on to stearic
acid after which it was vacuum dried for 5 hours to prepare the pro-vesicles. The
encapsulation efficiency of the niacinamide was determined as follows.
Encapsulation efficiency of Niacinamide
The pro-vesicle samples prepared was dissolved in the phosphate buffer saline
(PBS buffer of 7.4 pH) by stirring for 15 minutes at room temperature. The
niacinamide content of the solution (A) was measured by HPLC method. Part of
the dispersion was centrifuged several times till the all solid pellet was separated.
The supernatant was injected into an HPLC column to measure the
unencapsulated niacinamide content (B). The encapsulation efficiency was
determined by
EE%= (A-B)/A*100
Table-1

Example No. Soy-Lecithin (grams) Surfacta nt, type Surfactant,(grams) Thatmat, (grams) Ethanol (grams) Stearicacid(grams) Sterol, grams EE%
Ex-1 5 - - - 3 10 0.5 8
Ex-2 10 - - - 5 15 1.0 15
Ex-3 5 Span-60 4 - 3 10 0.5 10
Ex-4 10 Span-60 6 - 5 15 1 17
Ex-5 5 BDHA 0.5 - 3 10 0.5 5
Ex-6 10 BDHA 2 - 5 15 1.0 12
Ex-7 5 DHP+ CTAB 0.5+0.2 - 3 10 0.5 10
Ex-8 10 DHP+ CTAB 2+1 - 5 15 1.0 20
Ex-9 5 GMS 2 - 3 10 0.5 18
Ex-10 5 - - 2 3 10 0.5 15
Ex-11 5 GMS 2 2 3 10 - 40
Ex-12 5 GMS 2 1 3 10 0.5 55
Ex-13 10 GMS 8 3 5 15 1,0 60
Ex-14 5 GMO 2 1 3 10 0.5 45
Ex-15 10 GMO 8 3 5 15 1 50
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Thatmat: Isopropyl ester of hydrogenated 12- hydroxyl stearic acid
BDHA: Benzyl dimethyl hexa decyl ammonium chloride
DHP: Di hexadecyl phosphate
GMS: Glycerol monostearate
GMO Glycerol monooleate
Span-60: Sorbitan monostearate (from SD Fine chemicals)
CTAB: Cetyl trimethyl ammonium bromide
The data in table-1 indicates that examples outside the scope of the invention (Examples 1 to 8) have poor encapsulation efficiencies, in the range of 5 to 20%. However a pro-vesicle prepared as per the invention (Example-11) provides for a very high encapsulation efficiency of 40% which displays synergistic behaviour as compared to the encapsulation efficiencies obtained when pro-vesicles are prepared with each of the ingredients taken individually (examples 9 and 10). The encapsulation efficiency is further improved by the inclusion of the optional ingredient which is sterol (Example - 12). Examples 13 to 15 are other examples within the scope of the invention which display very high encapsulation efficiencies.
Examples 16,17
Cosmetic compositions were prepared without (Example-16) and with the pro-vesicle (Example-17) of the invention and the compositions are summarized in Table-2. The composition of the pro-vesicle as used in Example-17 is given in Table-3.
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Table-2

Ingredients Example-16, wt% Example-17, wt%
Stearic Acid 10.0 2.0 and balance 8% through pro-vesicle
Glycerine 1.0 1.0
Potassium hydroxide 0.6 0.6
Preservatives, methyl and propyl paraben 0.3 0.3
Other minors 1.8 1.8
Niacinamide 1.0 Through pro-vesicle
Parsol MCX 0.75 Through Pro-vesicle
Parsol 1789 0.4 Through Pro-vesicle
Provesicle No included Included
Water To 100 To 100
Table-3

Pro-vesicle ingredients % by weight of the cosmetic composition
Lecithin 1.2
Thatmat 0.2
GMS 1.0
Cholesterol 0.2
Stearic acid 8.0
Niacinmaide 1.0
Parsol MCX 0.75
Parsol 1789 0.40
CTAB 0.2
Tocopherol Acetate 0.001
Total 12.951
A Franz diffusion cell experiment was conducted with creams of Example 16 and 17 using pig ear skin model to determine the percentage of niacinamide present in the skin as opposed to amount present in the donor side and in the receptor side. The Franz diffusion cell experiment is described below.
Franz Diffusion Cell Experiment:
Pig's back skin was used as the model skin for the studies. A freshly available pig's back skin was taken and the epidermis was separated from the dermis
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while keeping the stratum corneum intact. The epidermis was thoroughly washed with phosphate buffer saline ( PBS Buffer; pH 7.4 ). It was placed between a donor and a receptor compartment. Receptor compartment was filled with PBS buffer and temperature of the receptor was maintained at about 32 °C. The cream (about 200 mg) was applied on donor side of skin. After three hours, the receptor solution was collected separately. Donor side was washed five times with 5ml of PBS buffer.
The skin was chopped into small pieces and washed four times with 5ml of PBS and soaked overnight in PBS and methanol. The samples were analysed for Niacinamide by HPLC method.
The analysis indicated that the cream of Example-16 permeated niacinamide content of 5% in the skin while that of Example-17 gave a niacinamide content of about 20%. A transmission electron microscopy (TEM) picture at 80K magnification of the pro-vesicles present in the cream prepared as Example-17 is shown in Figure-1 which clearly indicates the vesicular phase with an average diameter of about 300 nm. The evidence to show that this vesicular phase can also be prepared by addition of the pro-vesicles to water is shown in Figure-2. The invention thus provides for a composition that provides for enhanced delivery of skin benefit agents to the skin.
Dated this 31st day of March 2004

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Documents:

387-MUM-2005-ABSTRACT(8-7-2009).pdf

387-mum-2005-abstract(complete)-(9-3-2006).pdf

387-mum-2005-abstract(granted)-(23-9-2009).pdf

387-MUM-2005-CANCELLED PAGES(8-7-2009).pdf

387-MUM-2005-CLAIMS(8-7-2009).pdf

387-mum-2005-claims(complete)-(9-3-2006).pdf

387-mum-2005-claims(granted)-(23-9-2009).pdf

387-mum-2005-correspondence 1(17-12-2007).pdf

387-mum-2005-correspondence 2(26-5-2008).pdf

387-MUM-2005-CORRESPONDENCE(20-10-2008).pdf

387-MUM-2005-CORRESPONDENCE(8-2-2012).pdf

387-MUM-2005-CORRESPONDENCE(8-7-2009).pdf

387-MUM-2005-CORRESPONDENCE(9-1-2009).pdf

387-mum-2005-correspondence(ipo)-(23-10-2009).pdf

387-mum-2005-correspondence-received-ver-090306.pdf

387-mum-2005-correspondence-received-ver-310305.pdf

387-mum-2005-descripiton (provisional).pdf

387-MUM-2005-DESCRIPTION(COMPLETE)-(8-7-2009).pdf

387-mum-2005-description(complete)-(9-3-2006).pdf

387-mum-2005-description(granted)-(23-9-2009).pdf

387-MUM-2005-DRAWING(8-7-2009).pdf

387-mum-2005-drawing(complete)-(9-3-2006).pdf

387-mum-2005-drawing(granted)-(23-9-2009).pdf

387-mum-2005-drawings.pdf

387-MUM-2005-FORM 1(31-3-2005).pdf

387-mum-2005-form 13(4-10-2007).pdf

387-mum-2005-form 18(17-12-2007).pdf

387-MUM-2005-FORM 18(8-7-2009).pdf

387-mum-2005-form 2(complete)-(9-3-2006).pdf

387-mum-2005-form 2(granted)-(23-9-2009).pdf

387-MUM-2005-FORM 2(TITLE PAGE)-(8-7-2009).pdf

387-mum-2005-form 2(title page)-(complete)-(9-3-2006).pdf

387-mum-2005-form 2(title page)-(granted)-(23-9-2009).pdf

387-MUM-2005-FORM 3(8-7-2009).pdf

387-MUM-2005-FORM 5(8-7-2009).pdf

387-mum-2005-form-1.pdf

387-mum-2005-form-2.doc

387-mum-2005-form-2.pdf

387-mum-2005-form-3-ver-090305.pdf

387-mum-2005-form-3-ver-310305.pdf

387-mum-2005-form-5.pdf

387-MUM-2005-GENERAL POWER OF ATTORNEY(8-7-2009).pdf

387-MUM-2005-OTHER DOCUMENT(8-7-2009).pdf

387-MUM-2005-PCT-IPEA-409(8-7-2009).pdf

387-mum-2005-specification(amended)-(8-7-2009).pdf

abstract1.jpg


Patent Number 236102
Indian Patent Application Number 387/MUM/2005
PG Journal Number 40/2009
Publication Date 02-Oct-2009
Grant Date 23-Sep-2009
Date of Filing 31-Mar-2005
Name of Patentee HINDUSTAN UNILEVER LIMITED
Applicant Address HINDUSTAN LEVER HOUSE, 165/166, BACKBAY RECLAMATION, MUMBAI - 400 020,
Inventors:
# Inventor's Name Inventor's Address
1 BANDYOPADHYAY PRASUN APT # 119, PHASE 1, PRESTIGE LENGLEIGH, ECC ROAD, WHITEFIELD, BANGALORE - 560 066
2 BANDYOPADHYAY PUNAM APT # 119, PHASE 1, PRESTIGE LENGLEIGH, ECC ROAD, WHITEFIELD, BANGALORE - 560 066
PCT International Classification Number A61K31/74
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA