DUAL COMPOSITION COSMETIC PRODUCT WITH A CONCENTRATION SENSITIVE AND AN INCOMPATIBLE ACTIVE RESPECTIVELY PLACED WITHIN FIRST AND SECOND COMPOSITIONS

Abstract: A cosmetic product is provided packaged in a dispenser with separate first and second storage areas. The first of the areas contains a first cosmetic composition containing a first dermal active agent, preferably selected from keratolytic skin agents. Particularly preferred are alpha- and beta-hydroxy carboxylic acids as first dermal active placed in a composition having a pH from about 1 to about 5.5. The second area contains a second cosmetic composition with a second dermal agent incompatible with the first composition. Particularly preferred second dermal agents are retinoids, vitamins, enzymes and anti-oxidants. Most preferred is retinol. The dispenser allows transfer of the first and second compositions through an exit nozzle in a respective dispensing weight ratio of from about 30:1 to about 2:1.

Description: DUAL COMPOSITION COSMETIC PRODUCT WITH A CONCENTRATION SENSITIVE AND AN INCOMPATIBLE ACTIVE RESPECTIVELY PLACED WITHIN FIRST AND SECOND COMPOSITIONS The invention concerns a cosmetic product with dual compositions, preferably stored in separate compartments, each composition containing a skin active with at least one of the actives being incompatible in a composition containing the other. A soft, supple and flexible skin has a marked cosmetic appeal. As human skin ages with advancing years, the epidermis can become folded, ridged or furrowed to form wrinkles. These signal loss of youthful appearance and herald the transition to old age. Exposure to excessive doses of sunlight accelerates the transition process. Moreover, the outer layer of the epidermis known as the stratum corneum can become dry and flaky following exposure to cold weather or excessive contact with detergents or solvents . Science has discovered a few active substances which can counter the ageing process. Among these are the retinoids and the alpha-hydroxy carboxylic acids. Unfortunately these active substances can be incompatible under certain conditions. Retinol rapidly degrades m a acidic environment that may be most conducive to the alpha- hydroxys . Combinations of these actives have been reported in U.S. Patent 5,935,589 (Mu herjee et al.) which places the actives in separate emulsions within a single composition. Retinol is stabilised at a neutral pH in an oil-in-water emulsion. An alpha-hydroxy carboxylic acid such as glycolic acid is dispersed within a water-m-oil emulsion. Both of these emulsions are then carefully combined to form a single cosmetic composition. A problem for such compositions is that over time there will be leakage between the separate emulsions resulting m retinol degradation. A more direct solution is placement of the different actives into compositions held in separate compartments of a dispenser. Illustrative is U.S. Patent 5,914,116 (Suares et al.) disclosing releasably lockable stackable ars and dual compartment pumps. These packages are designed to deliver the separate actives at different times rather than through simultaneous dosing. In U.S. Patent 5,137,178 (Stokes et al.) a dual compartmented squeezable cosmetic dispenser is disclosed which allows for simultaneous extrusion of separate composition streams. Whilst each of the aforementioned systems have their particular advantage, they introduce certain disadvantages. Actives placed in dual stream dispensing compartments must be doubly concentrated. Only half of each stream contributes to the final dispensed combined stream concentration. For instance, delivery of 8% alpha-hydroxy carboxylic acid requires a 16% concentrated stream from an equally dispensing dual stream package. High concentration presents problems. Significant skin irritation and erythema may result from localised, non-fully mixed deposition of the stream onto the skin. Internal stability at high concentration may also be compromised. There is need for a better solution. WO 98/50012 (Noordam et al.) discusses the problem of stabilising a low pH emulsion of Vitamin C to prevent oxidation of the active. Stabilisation is achieved by placing a relatively concentrated aqueous Vitamin C composition in one compartment of a multi-compartment dispensing system. A second compartment contains a cosmetic carrier composition. When ready for use, a small volume of the Vitamin C concentrate is dispensed alongside a larger volume of the carrier base, each being expressed from a separate compartment. A similar approach has been disclosed by Airspray® in product brochure literature for their Symbio dual-chamber dispenser. Two non-compatible ingredients are separated each from the other until the moment of application. The Symbio package has two separate chambers, each connected to its own pump, with one of the chambers being smaller and arranged to deliver a concentrate of an unstable cosmetic substance. Amongst the unstable substances mentioned are Vitamin A (retinol), Vitamin C (ascorbic acid) and Vitamin E (alpha-tocopherol ) . However, there is no suggestion that the larger container include any skin actives other than some enzymes and pigmentation control agents. The technology does not present a solution for delivering actives from a dual compartment in a manner that provides nearly identical stored and skin delivered concentrations. Focus is rather upon an active that is stored highly concentrated but delivered dilute. Accordingly, it is an advantage of the present invention to be able to provide a cosmetic product that can deliver to the skin a first dermal active agent in a concentration not substantially different from its stored concentration and simultaneously from a separate stream deliver a second dermal active incompatible with the first. A further advantage of the present invention is to be able to provide a cosmetic product that delivers an acidic first dermal active to skin at a concentration not substantially different from its stored concentration simultaneously with a second dermal active pH incompatible with the first dermal active . Still a further advantage of the present invention is to be able to provide a cosmetic product that delivers a combination of first and second dermal actives from separate compositions in a manner assuring a synergistic skin benefit effect of the combination. Yet a further advantage of the present invention is to be able to provide a cosmetic product that delivers a combination of first and second dermal actives from separate compositions in a manner which is relatively non-irπtatmg to the skin. These and other advantages of the present invention will become more readily apparent from consideration of the following summary and detailed description. Thus, according to a first aspect, there is provided a cosmetic product which includes: (1) a first cosmetic composition including from about 0.1 to about 20% by weight of said first composition of a first dermal active in a pharmaceutically acceptable carrier, the first dermal active being capable of irritating the skin; (ιι)a second cosmetic composition including from about 0.01 to about 20% by weight of said second composition of a second dermal active incompatible with the first cosmetic composition and delivered in a pharmaceutically acceptable carrier; and (m) a dispenser with first and second areas to separately store the respective first and second cosmetic compositions, and wherein the first and second compositions are dispensed to an exit nozzle in a respective dispensing weight ratio of from about 30:1 to about 2:1. Now it has been found that a first dermal active can be delivered to skin at concentrations not much different than its storage concentration and simultaneously be combined with a separately stored second dermal active incompatible with the first. Unequal volumes of the two compositions at the point of use are transferred from a dispenser. The weight ratio of first to second cosmetic composition may range from about 30:1 to about 2:1, preferably from about 15:1 to about 8:1, optimally about 11:1. By this arrangement, the first dermal active is delivered in a concentration not much than about 10 or 20% less than its stored concentration. Delivery of the compositions of the present invention may be through a dual compartment dispenser. A particularly useful device is sold by Airspray International Inc. under the package trademark of Symbio®. The package has two separate chambers, each connected to its own pump. Both pumps are activated by the same actuator. By depressing the actuator, compositions held in each of the chambers are simultaneously pumped out and mixed in a controlled ratio. One of the chambers is a traditional container connected to its own pump by means of a dip tube. Within that chamber is a smaller one in the form of a cartridge equipped with a plug in the bottom, which moves up during use thus keeping both the cartridge and its contents air-free. Each pump stroke delivers approximately 0.4 grams of product. Per stroke, the product delivery ratio between the first outer container and the cartridge is about 11:1. Pump systems are not the only type of dispensers useful for the present invention. Delivery may be through a squeezable plastic tube containing two discrete compositions stored in separate areas one above the other in a manner similar to systems for striping toothpaste. Illustrative of this technology is U.S. Patent 4,211,341 (Weyn), herein incorporated by reference. First dermal actives may be selected from a wide range of substances, especially keratolytic agents such as alpha- and beta- hydroxycarboxylic acids. The invention is particularly useful for hydroxycarboxylic acids because of their high level of irritancy and requirements for separation from many other actives susceptible to decomposition by low pH conditions. Thus, advantageously the first composition will maintain a low pH environment ranging from about 1 to about 5.5, preferably from about 2 to about 4.5. It has been noted that a low pH alpha-hydroxy carboxylic acid containing composition has serious skin stinging consequences if used at too high a concentration. Where a level of 10% alpha-hydroxy carboxylic acid is desired to be placed onto the skin, a dual compartment container that delivers equal volumes from each compartment must store a 20% concentration alpha-hydroxy carboxylic acid. The double strength active at that level is extremely stinging. The present invention avoids the problem by permitting delivery of the alpha-hyαroxy carboxylic acid at a level much less than at double strength. In a preferred embodiment, the first of the compositions according to the present invention contains at least one alpha-hydroxy carboxylic acid as the first dermal active agent. The alpha-hydroxy carboxylic acids are represented by formula I having the structure: Rl I R—C —COOH (I) OH wherein R and R 1 are H, F, Cl, Br, alkyl, aralkyl or aryl groups of saturated or unsaturated, lsomeric or non- lsomeric, straight or branched chain, having 1 to 25 carbon atoms, or cyclic form having 5 or 6 ring members, and in addition, R and R may carry OH, CHO, COOH and alkoxy groups having 1 to 9 carbon atoms, the alpha-hydroxy acid existing as a free acid, and as stereoisomers, and D, L, and DL forms when R and R are not identical. Illustrative of this group of materials are 2- hydroxyethanoic acid (glycolic acid) ; 2-hydroxypropanoιc acid (lactic acid) ; 2-methyl 2- hydroxypropanoic acid (methyllactic acid) ; 2-hydroxybutanoιc acid; 2-hydroxypentanoιc acid; 2-hydroxyhexanoιc acid; 2-hydroxyheptanoιc acid; 2-hydroxyoctanoιc acid; 2- hydroxynonanoic acid; 2-hydroxydecanoιc acid; 2-hydroxyundecanoιc acid; 2- hydroxydodecanoic acid (alpha-hydroxylauπc acid) ; 2-hydroxytetradecanoιc acid (alpha-hydroxymyπstic acid) ; 2-hydroxyhexadecanoιc acid (alpha-hydroxypalmitic acid) ; 2- hydroxyoctadecanoic acid (alpha-hydroxysteaπc acid) ; 2-hydroxyeιcosanoιc acid (alpha-hydroxyarachidomc acid) ; 2-phenyl 2-hydroxyethanoιc acid (mandelic acid); 2,2- diphenyl 2-hydroxyethanoιc acid (benzilic acid) ; 3-phenyl 2- hydroxypropanoic acid (phenyl lactic acid) ; 2-phenyl 2-methyl 2-hydroxyethanoιc acid (atrolactic acid); 2-(4'- hydroxyphenyl ) 2-hydroxyethanoic acid; 2- (4 ' -chlorophenyl 2-hydroxyethanoic acid; 2- ( 3' -hydroxy- ' -methoxyphenyl ) 2-hydroxyethanoic acid; 2- (4 ' -hydroxy-3' -methoxyphenyl) 2-hydroxyethanoic acid; 3' - (2-hydroxyphenyl) 2- hydroxypropanoic acid; 3- ( 4 ' -hydroxyphenyl) 2-hydroxypropanoιc acid; and 2-(3',4'- dihydroxyphenyl) , and 2-hydroxyethanoic acid. Most preferred of this group of materials are glycolic acid, lactic acid and 2-hydroxyoctanoιc acid (also known as hydroxycaprylic acid) . Levels of alpha-hydroxy carboxylic acids may range from about 0.1 to about 20%, preferably between about 1 and 12%, more preferably between about 4 and about 10% by weight of the first composition. When the first dermal active is a beta-hydroxy carboxylic acid, the most preferred is salicylic acid. Also suitable are Cχ-Cιo alkyl salicylic acids such as 5-n- octanoylsalicylic acid. Cosmetic compositions containing the hydroxy carboxylic acids preferably have a pH ranging from about 1 to about 5.5, preferably from about 2.5 to about 4.5, optimally between about 3 and about 4. The first compositions are ordinarily aqueous emulsions of the oil-in-water or water-in-oil type. Most preferably, the first compositions are oil-in-water type emulsions. Amounts of water may range from about 20 to about 90%, preferably from about 40 to about 70%, optimally from about 50 to about 65% by weight. By the term "pharmaceutically acceptable carrier" is meant either water, oil or a combination of water and oil phases. A variety of water soluble and water insoluble substances may constitute the respective phases. Emollient substances are particularly useful. These may include silicone oils, synthetic esters, fatty acids, fatty alcohols, humectants (especially polyhydric alcohols) and thickeners/viscosifiers. Silicone oils may be divided into the volatile and non- volatile variety. The term "volatile" as used herein refers to those materials which have a measurable vapour pressure at ambient temperature. Volatile silicone oils are preferably chosen from cyclic or linear polydimethylsiloxanes containing from about 3 to about 9, preferably from about 4 to about 5, silicon atoms. Linear volatile silicone materials generally have viscosities less than about 5 centistokes at 25°C whilst cyclic materials typically have viscosities of less than about 10 centistokes. Non-volatile silicone oils useful as an emollient material include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers (e.g. dimethicone copolyol) . The essentially non-volatile polyalkyl siloxanes useful herein include, for example, polydimethyl siloxanes with viscosities of from about 5 to about 100,000 centistokes at 25°C. Among the preferred non-volatile emollients useful in the present compositions are the polydimethyl siloxanes having viscosities from about 10 to about 400 centistokes at 25°C. Among the suitable ester emollients are: (1) Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examples thereof include methyl myπstate, methyl stearate, oleyl myπstate, oleyl stearate, and butyl oleate . (2) Ether-esters such as fatty acid esters of ethoxylated fatty alcohols. (3) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and all-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 mono-oleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters . (4) Wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate. (5) Sterols esters, of which cholesterol fatty acid esters are examples thereof. Also useful as emollients are C 8 -C 22 fatty acids. These include lauric acid, myristic acid, palmitic acid, oleic acid, linoleic acid, stearic acid, behenic acid, erucic acid and mixtures thereof. Amounts of fatty acid may range from about 0.1 to about 20%, preferably from about 1 to about 15%, optimally from about 2 to about 10% by weight of either first or second compositions. Most preferred is stearic acid. Fatty alcohols having from 8 to 22 carbon atoms may also be employed. Typical fatty alcohols include lauryl alcohol, myristyl alcohol, palmityl alcohol, oleyl alcohol, stearyl alcohol, linoleyl alcohol, behenyl alcohol and mixtures thereof. Most preferred is palmityl alcohol. Amounts of the fatty alcohol may range from about 0.05 to about 20%, preferably from about 0.1 to about 10%, optimally from about 0.2 to about 1% by weight of either first or second compositions . Humectants of the polyhydric alcohol-type may also be included in the compositions of this invention. The humectant aids in increasing the effectiveness of the emollient, reduces scaling, stimulates removal of built-up scale and improves skin feel. Typical polyhydric alcohols include glycerol, polyalkylene glycols and more preferably alkylene polyols and their derivatives, including propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol, isoprene glycol, hexylene glycol, 1,3-butylene glycol, 1, 2, 6-hexanetrιol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. The amount of humectant may range anywhere from about 0.5 to about 30%, preferably between 1 and 15% by weight of either first or second compositions. Thickeners/viscosiflers in amounts up to about 5% by weight of the first or second composition may also be included. As known to those skilled n the art, the precise amount of thickeners can vary depending upon the consistency and thickness of the composition which is desired. Exemplary thickeners are xanthan gum, sodium carboxymethyl cellulose, hydroxyalkyl and alkyl celluloses (particularly hydroxypropyl cellulose) which is polyacrylamide such as found in Sepigel 305® and Sclerotium gums, magnesium aluminum silicates sold as Veegum® and aluminum octenyl starches such as Dry Flo®. Preservatives can desirably be incorporated into the cosmetic compositions of this invention to protect against the growth of potentially harmful microorganisms. Suitable traditional preservatives for compositions of this invention are alkyl esters of para-hydroxybenzoic acid. Other preservatives which have more recently come into use include hydantoin derivatives, propionate salts, and a variety of quaternary ammonium compounds Cosmetic chemists are familiar with appropriate preservatives and routinely choose them to satisfy the preservative challenge test and to provide product stability. Particularly preferred preservatives are disodium EDTA, butylated hydroxy toluene, phenoxyethanol, methyl paraben, butyl paraben, propyl paraben, lmidazolidmyl urea (commercially available as Germall 1157), sodium dehydroacetate and benzyl alcohol. The preservatives should be selected having regard for the use of the composition and possible incompatibilities between the preservatives and other ingredients in the emulsion. Preservatives are preferably employed in amounts ranging from about 0.01% to about 2% by weight of the first or second compositions. Colorants and fragrances may also be included in compositions of the present invention. Each of these substances may range from about 0.05 to about 5%, preferably between about 0.1 and about 3% by weight for the first or second compositions. Sunscreens may be included in compositions of the present invention. These may be of the organic or inorganic variety. The inorganic sunscreens include titanium dioxide, zinc oxide and mixtures thereof. Typical organic sunscreens may be classified into such groups as: para-ammo benzoates, salicylates, cinnamates, benzophenones and combinations thereof. Particularly preferred are octyl methoxy cinnamate (available as Parsol MCX®) , 2-hydroxy-4-methoxy benzophenone (known as Benzophenone-3 ) and Avobenzene (available as Parsol 1789®) . Amounts of the sunscreen may range from about 0.1 to about 10%, preferably from about 5 to about 12% by weight of first or second compositions. Surfactants may also be employed in compositions of the present invention. They may be of the cationic, anionic, nonionic or amphoteπc variety. Nonionic surfactants include alkoxylated, fatty alcohols, alkoxylated fatty acids and alkoxylated sorbitan esters. They also may include alkyl polyglycosides and gluconamides . Anionic surfactants may include alkyl sulphates, alkyl ether sulphates, acyl lsethionates, lactylates, sarcosmates, taurates and combinations thereof. Suitable amphoteric surfactants include cocoamido-propyl betaine and dimethyl alkyl amme oxides. Amounts of the surfactant may range anywhere from about 0.1 to about 10%, preferably from about 1 to about 5% by weight of first or second compositions. The second composition of this invention will contain a second dermal active incompatible with the first composition. By the term "incompatible" is meant that any skin benefit normally imparted by contact with the second dermal active is at least partially impaired or inactivated. Illustrative but non-limiting examples of such actives include retinoids, vitamins, enzymes and anti-oxidants as well as combinations thereof. The term "retinoids" is meant to include, retinol in all its isomeric forms including cis and trans isomers, C 2 -C 22 retinyl esters such as ret yl acetate, retinyl propionate, retinyl lmoleate, retinyl ascorbate, retinyl phosphate, retinal and its isomers, and retmoic acid as well as any combinations thereof. Vitamins suitable for the present invention are Vitamin C (including derivatives such as magnesium ascorbyl phosphate) , Vitamin D, niacinamide, Vitamin E and combinations thereof. Enzymes suitable for the present invention include proteases (such as tripos , alpha-chymotrypsm, papain, bromelain and pepsin), lipases, oxidases (such as glutathme peroxidase and coenzyme Q10), elastases, superoxide dismutase and combinations thereof. Anti-oxidants suitable for the present invention include green tea, hawthorn, gmkgo biloba, catech , beta-carotene, lipoic acid, glutathione, methionme, silymarin, grapeskm/seed extracts, melanin, rosemary extracts, tocopherol sorbate and combinations thereof . Amounts of the second dermal active may range from about 0.01 to about 20%, preferably from about 0.1 to about 10%, more preferably from about 0.8 to about 4%, optimally from about 2 to about 2.6% by weight of the second composition. The second composition may be anhydrous or aqueous. When aqueous it may have a pH ranging from about 6.5 to about 8.5, preferably from about 7 to about 8. The second composition may contain many of the same pharmaceutically acceptable carriers as those described above. Preferably, this composition will be of the oil-in- water type. However, ordinarily the composition will have different physical and chemical components than that of the first composition. Except m the operating and comparative examples, or where otherwise explicitly indicated, all numbers this description indicating amounts of material are to be understood as modified by the word "about". The following examples will more fully illustrate the embodiments of this invention. All parts, percentages and proportions referred to herein and in the appended claims are by weight unless otherwise illustrated. EXAMPLES 1-8 A set of first and second compositions according to the present invention are outlined in Table I below. Each of these combinations are delivered from a dual compartment package, particularly a Symbio® dual dispensing pump container. TABLE I EXAMPLE 9 A clinical study was conducted to evaluate the sting reduction benefits associated with dispensing dermal actives in unequal concentration from a dual dispensing package. Formulations Product A 8.7% glycolic acid formula was placed in the outer chamber of the inventive example dispensing pump (Airspray) . The inner chamber contained a base formula without any glycolic acid. The dispensing ratio of this package is such that when dispensed, 11 parts of the outer formula was dispensed with 1 part of the inner formula. Thus the final concentration of glycolic acid exposed to the skin in the co-dispensed product was 8%. Product B (Comparative) 16% glycolic acid was formulated in the same base formula as in Product A and placed in one compartment of a commercially available 1:1 dispensing ratio dual chambered pump. The other chamber contained the same formula as that in the inner chamber of Product A. Thus the final concentration of glycolic acid exposed to the skin was also 8% when co- dispensed. Test design: Six subjects were pre-selected on the basis of their ability to sense a stinging or burning sensation from alpha hydroxy acid products and in addition on their ability to discriminate between formulations containing 16% glycolic acid and 8% glycolic acid. The areas of skin near each nostril and above the lip were first tape stripped with a D- squame strip to remove dirt and oil. About 3 mg of each of product A and B were dispensed on the left and right index fmger of each subject. The subjects, who were blinded with respect to any knowledge about the products, were asked to apply each product on either tape stripped area at the same time. They were asked to evaluate within a minute of application as to whether they sensed a greater burning or stinging on one siαe compared to the other. Results Five out of the six subjects immediately sensed greater stinging from the product B. The results thus demonstrate that the delivery of glycolic acid in unequal dispensing ratio as set forth in this invention offers a benefit in reducing the immediate negative sensations of stinging caused by the sudden exposure of the skin to a high concentration of glycolic acid as would be encountered in the 1:1 dispensing packages. The foregoing description and examples illustrate selected embodiments of the present invention. In light thereof variations and modifications will be suggested to one skilled the art, all of which are within the spirit and purview of this invention.

Claims: CLAIMS : 1. A cosmetic product comprising: (l) a first cosmetic composition including from 0.1 to 20% by weight of the first composition of a first dermal active in a pharmaceutically acceptable carrier, the first dermal active being capable of irritating the skin; (ιι)a second cosmetic composition including from 0.01 to 20% by weight of the second composition of a second dermal active incompatible with the first cosmetic composition and delivered a pharmaceutically acceptable carrier; and (in) a dispenser with first and second areas to separately store the respective first and second cosmetic compositions, and wherein the first and second compositions are dispensed to an exit nozzle in a respective dispensing weight ratio of from about 30:1 to about 2:1. 2. The product according to claim 1 wherein the dispensing weight ratio of first to second composition is from about 15:1 to about 8:1. 3. The product according to claim 1 or claim 2 wherein the first dermal active is an alpha- or beta- hydroxycarboxylic 4. The product according to any of the preceding claims wherein the second dermal active is selected from retinoids, vitamins, enzymes, anti-oxidants and combinations thereof. 5. The product according to claim 4 wherein the second dermal agent is retinol. 6. The product according to claim 5 wherein the retinol is present m an amount from 0.8 to 4% by weight of the second composition. 7. The product according to any of the preceding claims wherein the dispenser has first and second compartments and is fitted with a pump mechanism, the pump mechanism comprising a separate pump for each of the first and second compartments . 8. The product according to any of the preceding claims wherein the first cosmetic composition has a pH ranging from 1 to 5.5. 9. The product according to any of the preceding claims wherein the second composition is anhydrous. 10. The product according to any of the preceding claims wherein the dispenser is a flexible walled tube wherein dispensing occurs by external hand pressure against walls of the tube.

Inventors: CHANDAR PREM, HAGUE JONATHAN DAVIDE, HARYO SURYO DWIWAHYU, SCOTT IAN RICHARD, SULISTYOWATI ENDAH, WEINKAUF RONNI LYNN, CHANDAR, PREM, HAGUE, JONATHAN, DAVIDE, HARYO SURYO, DWIWAHYU, SCOTT, IAN, RICHARD, SULISTYOWATI, ENDAH, WEINKAUF, RONNI, LYNN
Applicants: LEVER HINDUSTAN LTD, UNILEVER NV, UNILEVER PLC, HINDUSTAN LEVER LIMITED
Application year: 2001
Main classification: A61K7
IPC codes: A61K8, A61Q19, B65D81