Novel topical formulations

专利摘要:
The present invention relates to methods of enhancing transmembrane and / or topical penetration of pharmacologically active substances using not only the compositions used in the present invention but also certain vesicle delivery systems as enhancers and optional detergents. Various active agents such as hair growth agents, hair inhibitors, acne treatments, hair loss agents, anti-aging agents and bleaching agents can be effectively delivered to the skin, hair follicles and sebaceous glands using the compositions of the present invention.
公开号:KR20010049428A
申请号:KR1020000028676
申请日:2000-05-26
公开日:2001-06-15
发明作者:니미엑수잔엠；니스트랜드글렌에이；왕조나스씨티；호기엘
申请人:차알스 제이. 메츠；존슨 앤드 존슨 컨수머 캄파니즈, 인코포레이티드；
IPC主号:

专利说明:

Novel topical formulations
The present invention relates to novel vesicle compositions containing useful agents capable of effectively depositing useful agents inside and on the skin and hair, and methods of improving the deposition of such useful agents into and above the skin. The present invention also relates to novel cleaning compositions, in particular shampoos, such as skin and hair cleaning compositions composed of complete and stable vesicles for use in personal cleansing applications.
Therapeutic shampoos composed of various detergents and therapeutic agents are known in the art (see, eg, US Pat. Nos. 5,730,965, 5,723,112 and 5,624,666). These shampoos are usually therapeutic agents (eg chloroxylenol); It consists of anionic surfactants mixed with fungal agents (eg ketoconazole) and / or dandruff treatment agents (eg zinc pyrithione).
In order for the dandruff treatments to be most effective, they must be able to alleviate the falling and itchy symptoms associated with dandruff, as well as be substantial to the skin and hair in order to broaden the efficacy of the dandruff treatment from the next shampoo treatment. Unfortunately, many therapeutic shampoos do not provide sufficient deposition of the formulation over the hair fibers and scalp during the shampooing process. Without this deposition, large amounts of therapeutic agent are washed away, thus providing little therapeutic benefit.
One method known in the art to improve the deposition of a therapeutic agent on hair or skin is to significantly increase the level of the therapeutic agent in a shampoo composition. However, the use of such high levels of therapeutic agents disadvantageously not only increases the cost of the raw materials, but also reduces the soap latherability of the shampoo and adversely affects product stability.
The presence of detergents in dandruff therapeutic shampoos also hinders the ability of the therapeutic agent to deposit on the hair, since they are designed to move or remove oil, oils, dirt and particulates from the hair and scalp during cleaning. In addition, these detergents (such as anionic surfactants) have the adverse effect of making the hair undesirably rough and dry. Thus, the condition of the hair usually requires post-shampoo treatment with the conditioning composition in order to improve the physical properties of the hair.
Because many granules for treating dandruff are insoluble in aqueous media, it is difficult to formulate these preparations into stable aqueous anionic surfactant based dandruff treatment shampoos without the use of inorganic metals or synthetic or natural polymers or rubber suspensions. Unfortunately, mixing dandruff treatments with suspending agents often adversely affects the foaming properties of the shampoo composition. Therefore, there is a need to develop a composition for treating dandruff that can be stabilized in the absence of such suspending agents.
It is known in the art that many useful agents can be carried out via the hair follicle route (see, eg, Scheuplein, J. Invest Dermatol 48: 79-88 (1967); Behl et al., J. Pharm Sci 70: 835 -837 (1981); and lllel et al., J. Pharm Sci 80: 424-427 (1991). Liposomal assisted follicle delivery has been studied as a potential method of direct active agents that affect hair and follicular appendages for their site of action. See, eg, Dowton et al., STP Pharm Sciences 3: 404-407. (1993) (liposomes direct small and large molecules alike into follicles which, once there, can serve as a reservoir for protracted delivery into the dermis) and Niemiec et al. STP Pharm Sciences 4: 145-149 (1994).
One object of the present invention is to provide a variety of active agents comprising: 1) cells from the periphery of the hair follicle or perifollicular cells (eg, hair follicle ducts) and / or 2) cells from either the epidermal and dermal layers proximate the hair axis Or 3) to hair fibers. Another object of the present invention is to contain relatively small amounts of useful agents, but more effectively useful agents (such as dandruff therapies and conditioners) to the skin, hair and hair follicular units, without loss of soap foam or stability of the final product, That is, to produce a formulation that deposits in the pores, sebaceous glands and tubes.
1 is a transmission electron micrograph at 86,000 × magnification of a nonionic liposome composition when promoting aging at 50 ° C. for 4 weeks.
FIG. 2 is a transmission electron photomicrograph at 108,000 × magnification of a nonionic liposome shampoo composition when promoting aging at 50 ° C. for 4 weeks. FIG.
3 is a transmission electron photomicrograph at 80,000 × magnification of a low cation / nonionic liposome shampoo composition when promoting aging at 50 ° C. for 4 weeks.
4 is a transmission electron photomicrograph at 27,000 × magnification of a high cation / nonionic liposome shampoo composition when promoting aging at 50 ° C. for 4 weeks.
FIG. 5 is a scanning electron micrograph of hair fibers in the middle and ends of hair washed 10 times with anionic shampoo at 2000 and 5000 × magnification.
FIG. 6 is a scanning electron photomicrograph of hair fibers in the middle and ends of hair after 10 washes with high cation / nonionic liposome-shampoo (anionic) at magnifications of 2000 and 5000 ×.
7 is a scanning electron photomicrograph of hair fibers in the middle and ends of hair after 10 washes with a commercially available zinc pyrithione-containing dandruff therapeutic shampoo at 2000 and 5000X magnification.
According to the invention, based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) A composition has been found which comprises an effective amount of a useful agent and which consists essentially of and / or promotes topical administration of the useful agent.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer,
B) an effective amount of a useful agent, and
C) A cleaning composition for enhancing topical administration of a useful formulation comprising, consisting essentially of, and / or comprising a detergent.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) to a cleaning composition comprising, consisting essentially of and / or comprising a detergent.
Another aspect of the invention
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) A method of topically administering a composition consisting of an effective amount of a useful agent to a human or animal, consisting essentially of and / or enhancing the topical administration of a useful agent.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) consisting of, consisting essentially of, and / or consisting of, administering an effective amount of a hair loss treatment agent, consisting essentially of, to a desired site for treating hair loss in a human or animal Made, to a method of treating hair loss.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) consisting of, consisting essentially of, and / or consisting of, administering an effective amount of a hair growth inhibitor, consisting essentially of the composition to the desired site for treating hair loss in humans or animals And to a method for inhibiting hair growth.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) treating the effects of aging comprising, and / or consisting essentially of topically administering to the desired site of a human or animal a composition comprising, consisting essentially of, an effective amount of an anti-aging active agent Or a method of minimizing.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) Acne treatment comprising, consisting essentially of and / or consisting of topically administering an effective amount of an acne therapeutic agent, consisting essentially of the composition to the desired site of a human or animal It is about a method.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) A method for depigmentation of the skin, consisting essentially of and / or comprising a topical administration of a composition comprising, consisting essentially of, an effective amount of a bleaching agent to a desired site of a human or animal will be.
Another aspect of the invention is based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer and
B) topically administering a composition consisting of an effective amount of a useful agent selected from the group consisting of dandruff treatment, seborrheic dermatitis treatment, psoriasis treatment and mixtures thereof to a desired site of a human or animal, and / or , To a method of treating dandruff, seborrheic dermatitis and psoriasis and / or symptoms associated therewith.
Combinations of useful agents with nonionic vesicles or cationic / nonionic vesicles can produce formulations that are particularly effective for depositing useful agents within and over skin, hair, and hair follicle units. Similarly, when the formulation is also mixed with a detergent, the resulting cleaning formulation effectively deposits useful formulations within and over the skin, hair and hair follicle units after washing, as well as remaining stable.
The invention will be more fully understood and appreciated by reference to the accompanying drawings and the following detailed description of the invention.
As used herein, the term "vesicle" includes liposomes and other multilamellar structures. For “first” double chain lipids, this means double chain lipids having a cationic or nonionic charge. Similarly, for "first" single-chain lipids, it means single-chain lipids with a cationic or nonionic charge. For “second” double chain lipids, it is either 1) positive charge when the first double chain lipid has a nonionic charge or 2) nonionic or nonionic when the first double chain lipid has a positive charge. It means a single chain lipid with a charge. For a "second" single chain lipid, it is either 1) a positive charge if the first single chain lipid has a nonionic charge or 2) a single having a nonionic charge if the first single chain lipid has a positive charge. Chained lipids. A "vesicle delivery system" as used herein includes both lipid and sterol components including bilayers, as well as encapsulated hydrophilic components therein.
The composition of the present invention comprises a vesicle delivery system for topical delivery of a useful agent to the skin and hair and / or the stomach in the presence of any detergent, wherein the vesicle system comprises: 1) one or more first double-chain lipids; 2) one or more first single chain lipids; 3) sterols; 4) a hydrophilic carrier and 5) optionally one or more second double-chain lipids and / or one or more second single-chain lipids. The vesicles of the present invention consist of an enclosed outer bilayer structure consisting of components 1 to 4 and 5, and contain a hydrophilic carrier therein. The vesicle delivery system may be classified as having a total charge that is nonionic, cationic or cation / nonionic, depending on the choice of lipids to be constructed.
The first component of the vesicle delivery system is the first double-chain lipid, which may consist of one or more nonionic double-chain lipids, one or more cationic double-chain lipids or mixtures thereof. As used herein, the term “double chain lipid” is used herein interchangeably with the term “primary wall material” and the term “basic lipid”. Double-chain lipids consist of a polar head group and two hydrophobic chains. Double-chain lipids constitute the maximum proportion (by weight) of the bilayer forming component of the vesicles, preferably in an amount of at least about 40 and preferably from about 40 to about 95, based on the total weight of the bilayer forming component. exist.
Examples of suitable nonionic double chain lipids include, but are not limited to, glyceryl diesters, alkoxylated amides and mixtures thereof.
Examples of suitable glyceryl diesters include glyceryl diesters which preferably have about 10 to about 30 carbon atoms, more preferably about 12 to about 20 carbon atoms. Preferred glyceryl diesters include, but are not limited to, glyceryl dilaurate ("GDL"), glyceryl dioleate, glyceryl dimyristate, glyceryl distearate ("GDS"), glyceryl sesciole Acrylate, glyceryl stearate lactate and mixtures thereof, with glyceryl dilaurate, glyceryl distearate and glyceryl dimyristate being more preferred.
Examples of suitable alkoxylated amides include compounds according to the structure shown in formula (1).
In Chemical Formula 1,
R is an unbranched alkyl group having from about 8 to about 30 carbon atoms, preferably from about 12 to about 24 carbon atoms,
m is an integer from about 0 to about 100,
b is an integer from about 0 to about 100, provided that the sum of m + b is from about 8 to about 100.
Examples of this group generally represent fatty acids from which RCO is derived from coconut oil, and m and b are both known under the CTFA name "PEG-6 cocoamide" of Formula 1 above, each having an average value of about 6.
Examples of suitable cationic double chain lipids include, but are not limited to, bilayered cationic lipids containing two unsaturated fatty acid chains having from about 10 to about 26 carbon atoms, such as di (soylylethyl) hydroxyethyl Monium methosulfate (DSHM); N- [1- (2,3-Dioleyloxy) propyl] -N, N, N-trimethylammonium bromide (DOTMA); 1,2-dimyristyloxypropyl-N, N-dimethyl-hydroxyethyl ammonium bromide (DMRIE); [N- (N, N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol); Dioctadecyl amidoglysilspermidine (DOGS); Dimethyl dioctadecylammonium bromide (DDAB); Dioleyl phosphatidylethanolamine (DOPE); 2,3-Dioleyloxy-N- [2- (sperminecarbozamide-O-ethyl] -N, N-dimethyl-propanemium trifluoroacetate (DOSPA); 1- [2- (oleoyloxy ) -Ethyl] -2-oleyl-3- (2-hydroxyethyl) imidazolinium chloride (DOTIM); 1,2-dioleoyloxy-3- (trimethylammonio) propane (DOTAP); 1 , 2-diacyl-3-trimethylammonium propane (TAP); 1,2-diacyl-3-dimethylammonium propane (DAP); fatty acid salts of quaternary amines (e.g. dicodimonium chloride (Quaternium 34), 4 Tertiary dimethyldiacyl amines, wherein the acyl group has from about 8 to about 30 carbon atoms, preferably from about 10 to about 24 carbon atoms and derivatives and mixtures thereof (e.g. ammonium derivatives, ie dimethyl dihydrogenation tallow) Ammonium chloride (Quaernium 18), decyl dimethyl octyl ammonium chloride (Quaternium 24, and mixtures thereof), and di (soyloilethyl) hydroxyethylmonium methosulfate (DSHM) Other suitable cationic double-chain lipids are described in the following references cited herein: Fasbener et al., 269 Am J Physiol L45-L5 1 (1995); Solodin et al., 34 Biochemistry 13537-13544 (1995); Felgner et al., 269 J Biol Chem 2550-2561 (1994); Stamatatos et al., 27 Biochemistry 3917-3925 (1986); and Leventis and Silvius, 1023 Biochim Biophys Acta 124-132 (1990).
Some of these cationic double chain lipids (eg, TAP and DAP) are carbon atoms; Various types of chain groups with ratios of saturated bond water (e.g. 14: 0, 16: 0, 18: 0 and 18: 1) and various types of acyl groups (e.g. dimyri) having from about 10 to about 18 carbon atoms Stoil, dipalmitoyl, distearoyl and dioleoyl).
Other double-chain lipids are also nonionic lipid vesicles, cationic lipids with single-chain lipids and sterols in the presence of the only other reagents such as antioxidants, preservatives, buffers, chelating agents, UV stabilizers and mixtures thereof. As long as they form vesicles or nonionic / cationic lipid vesicles, they are considered to be within the scope of the present invention.
The amount of nonionic double chain lipids in the vesicle bilayer is from about 0 to about 95, preferably in the range of about 10 to about 65, based on the total weight of the double chain lipids in the vesicle bilayer. The amount of cationic double chain lipids in the vesicle bilayer is from about 0 to about 95, preferably in the range of about 1 to about 50, based on the total weight of the double chain lipids in the vesicle bilayer. In embodiments in which the vesicle bilayer consists of cationic double chain lipids and nonionic double chain lipids, the amount of cationic double chain lipids and nonionic double chain lipids present is the total weight of cationic double chain lipids and nonionic double chain lipids. On the basis of about 1 to about 50, preferably about 2 to about 30 for cationic double-chain lipids, and about 50 to about 99, preferably about 70 to about non-ionic double-chain lipids. 98.
In the vesicle system the second component is a single chain lipid, which may consist of a nonionic single chain lipid, a cationic single chain lipid or a nonionic / cationic single chain lipid. Single chain lipids are present in the vesicles in an amount of about 1 to about 50, preferably about 2 to about 30, based on the total weight of the vesicle bilayer.
Suitable nonionic single chain lipids consist of a polar head group and one fatty acid chain and are also known as "second wall material" or "second lipid". Examples of suitable nonionic single chain lipids include, but are not limited to, glyceryl monoesters, polyoxyethylene fatty ethers, wherein the polyoxyethylene head group is from about 2 to about 100 groups, and the fatty acid tail group is from about 10 to Alkoxylated alcohols, wherein the alkoxy group has about 1 to about 200 carbon atoms, and the fatty alkyl group has about 8 to about 30, preferably about 10 to about 24 carbons Alkoxylated alkyl phenols wherein the alkoxy group has about 1 to about 200 carbon atoms and the fatty alkyl group has about 8 to about 30, preferably about 10 to about 24 carbon atoms ), Polyoxyethylene derivatives of polyol esters, alkoxylated acids, where the alkoxy groups have from about 1 to about 200 carbon atoms and the fatty alkyl groups are about 8 To about 30, preferably about 10 to about 24 carbon atoms) and mixtures thereof.
Examples of suitable glyceryl monoester nonionic single chain lipids preferably include glyceryl monoesters having from about 10 to about 30 carbon atoms, more preferably from about 12 to about 20 carbon atoms, and mixtures thereof. More preferred glyceryl monoesters include glyceryl caprate, glyceryl caprylate, glyceryl cocoate, glyceryl erucate, glyceryl hydroxystearate, glyceryl isostearate, glyceryl lanoleate, glyceryl laurate , Glyceryl linoleate, glyceryl myristate, glyceryl oleate, glyceryl PABA, glyceryl palmitate, glyceryl ricinoleate, glyceryl stearate, glyceryl tiglycolate and mixtures thereof, glyceryl Most preferred are aryl laurate and glyceryl myristate.
Examples of suitable polyoxyethylene fatty ether nonionic single chain lipids include polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cholesterol ether, polyoxyethylene laurate, polyoxyethylene dilaurate, polyoxyethylene stearate Latex, polyoxyethylene distearate, polyoxyethylene lauryl ether, polyoxyethylene stearyl ether and mixtures thereof. Preferred polyoxyethylene fatty ethers include polyoxyethylene stearyl ether, polyoxyethylene myristyl ether, polyoxyethylene lauryl ether and mixtures thereof, each having about 3 to about 10 oxyethylene units.
Suitable examples of alkoxylated alcohol nonionic single chain lipids include compounds useful as nonionic surfactants and have the structure of Formula 2:
R _5- (OCH ₂ CH ₂ ) _y -OH
In Chemical Formula 2,
R ₅ is an unbranched alkyl group having from about 10 to about 24 carbon atoms,
y is an integer from about 4 to about 100, preferably from about 10 to about 100.
Preferred alkoxylated alcohols are those in which R ₅ is a lauryl group and y has an average value of 23, which is known under the CTFA name "laureth 23" and is commercially available under the trade name "BRlJ 35" (manufactured by Uniqema, Inc .; Wilmington, Delaware.
Suitable examples of alkoxylated alkyl phenol nonionic single chain lipids include compounds generally in accordance with the structure shown in formula (3).
In Chemical Formula 3,
R ₆ is an unbranched alkyl group having from about 10 to about 24 carbon atoms,
z is an integer from about 7 to 120, preferably from about 10 to about 100.
Particularly preferred examples of such groups are those in which R ₆ is a nonyl group and z has an average value of about 14. This material is known under the CTFA name "nonoxynol-14" and is commercially available under the trade name "MAKON 14" from Stepan Company of Northfield Illinois.
Suitable polyoxyethylene derivatives of the polyol ester single-chain nonionic lipids include (1) fatty acids having (a) about 8 to about 22 carbon atoms, preferably about 10 to about 14 carbon atoms, and (b) Sorbitol, sorbitan, glucose, α-methyl glucoside, a polyol selected from the group consisting of polyglucose, glycerin, pentaerythritol and mixtures thereof having an average glucose residue per molecule of about 1 to about 3, (2 A) containing from about 10 to about 120, preferably from 20 to about 80, oxyethylene units, and (3) having from about 1 to about 3 fatty acid residues per mole of polyoxyethylene derivative of the polyol ester There is this.
Examples of preferred polyoxyethylene derivatives of polyol esters include, but are not limited to, PEG-80 sorbitan laurate and polysorbate 20. PEG-80 sorbitan laurate, a sorbitan monoester of lauric acid ethoxylated with an average of about 80 mole of ethylene oxide, is commercially available under the trade name "Atlas G-4280" from ICI Surfactants of Wilmington, Delaware. Polysorbate 20, a laurate monoester of a mixture of sorbitol and sorbitol anhydride condensed with about 20 moles of ethylene oxide, is commercially available under the trade name "Tween 20" from ICI Surfactants of Wilmington, Delaware. Examples of other polyol esters are sorbitan stearate, sold under the trade name “SPAN 60” (Uniqema, Inc.).
Examples of suitable alkoxylated acid single chain nonionic lipids include acids, most often fatty acid and esters of polyalkylene glycols. Representative materials of this group include the CTFA name "PEG-8 laurate" and have the structure shown below:
Most preferred single-chain nonionic lipids include polyoxyethylene fatty ethers, glyceryl monoesters and mixtures thereof, including polyoxyethylene stearyl ethers, polyoxyethylene myristyl ethers, polyoxyethylene lauryl ethers, glyceryl lau More preferred are late, glyceryl myristate, glyceryl stearate and mixtures thereof, each having from about 5 to about 10 oxyethylene units.
Examples of suitable cationic single-chain lipids include, but are not limited to, quaternary trimethylmonoacyl amines, wherein the acyl group has from about 8 to about 30 carbon atoms, preferably about 10 to about 24 carbon atoms, and derivatives and mixtures thereof (eg, Ammonium derivatives, such as stearamidopropyl dimethyl (myristyl acetate) ammonium chloride (Quaternium 70), triethyl hydride tallow ammonium chloride (Quaternium 16), benzalkonium chloride and derivatives thereof).
Other single chain lipids may also be used in combination with non-ionic lipid vesicles, cationic lipid vesicles, or with double-chain lipids in the presence of the only other reagents such as antioxidants, preservatives, buffers, chelating agents, UV stabilizers and mixtures thereof. It is considered to be within the scope of the present invention so long as it forms a nonionic / cationic lipid vesicle.
The amount of nonionic single chain lipids in the vesicle bilayer may range from about 0 to about 70, preferably about 1 to about 30, based on the total weight of the single chain lipids in the vesicle bilayer. The amount of cationic single chain lipids in the vesicle bilayer may range from about 0 to about 70, preferably from about 1 to about 30, based on the total weight of the single chain lipids in the vesicle bilayer. In embodiments wherein the vesicle bilayer consists of cationic single chain lipids and nonionic single chain lipids, the amount of cationic single chain lipids and nonionic single chain lipids is based on the total weight of cationic single chain lipids and nonionic single chain lipids. About 1 to about 50, preferably about 5 to about 20, for cationic single chain lipids, and about 1 to about 50, preferably about 5 to about 20 for nonionic single chain lipids. It can be a range. The selection of any second double-chain lipids and / or any second single-chain lipids for inclusion in the vesicle delivery system is attributable to the respective ability of any lipid to complex with the hair and skin surface and the compatibility of the lipid vesicle itself with Depends on. In general, in the case of using any of these lipids, it is possible to use only lipids which can be complexed to form groups with negative charge when combined with nonionic lipid vesicles, without degrading the nonionic vesicle delivery system. It is preferable.
The third component of the vesicle is a charge generating agent including but not limited to sterols. Examples of suitable sterols include cholesterol and salts and esters thereof, phytocholesterol, hydrocortisone, alpha-tocopherol, beta sitosterol, bisabolol and mixtures thereof, with cholesterol being most preferred.
The fourth component of the vesicle is a hydrophilic component such as water, a polar solvent or a mixture thereof. Examples of polar solvents include, but are not limited to, glycerin, alcohols and glycols, preferably compounds having about 2 to about 6 carbon atoms, propylene glycol, sorbitol, oxyalkylene polymers (eg PEG 4), and mixtures thereof do.
Various combinations and ratios of the first single-chain lipids, the first double-chain lipids, any second single-chain lipids, any double-chain lipids, sterols, hydrophilic components and any other additives make the vesicle delivery system of the present invention. It can be used to The components of the vesicle delivery system and their respective weight ratio contents may be used together with, for example, the desired final properties in the vesicle system, the properties of the different components in the system, the desired use (s) of the vesicle delivery system and / or the vesicle delivery system. Although depending on the form of the non-follicular component, the preferred amount of the components is based on the total vesicle delivery system, so that the first double-stranded lipid is about 40 to about 95, more preferably about 40 to about 60, and optionally The second double-chain lipid is about 0 to about 50, more preferably about 1 to about 20, and the first single-chain lipid is about 1 to about 55, more preferably about 1 to about 35, and any second Single chain lipids are from about 0 to about 50, more preferably from about 1 to about 20, sterols from about 1 to about 50, more preferably from about 1 to about 25, hydrophilic components from about 50 to about 99, more Desirable Preferably from about 60 to about 90.
Particularly preferred nonionic vesicles of the present invention are glyceryl distearate double-chain lipids, based on the total weight of the vesicle bilayer, from about 40 to about 60, preferably from about 40 to about 50; Polyoxyethylene-10-stearyl ether single chain lipids containing about 10 to about 45, preferably about 10 to about 20 and cholesterol about 5 to about 45, preferably about 5 to about 25. Similar nonionic vesicles are described in US Pat. Nos. 4,911,928, 5,032,457, 5,147,723 and 5,260,065, all of which are incorporated herein by reference.
In another particularly preferred embodiment, the nonionic vesicles are based on the total weight of the vesicle bilayer, from about 45 to about 55 glyceryl distearate, from about 1 to about 50 cholesterol, and preferably from about 5 to about 25, and poly Oxyethylene-10-stearyl ether.
Preferred nonionic / cationic vesicles are from about 25 to about 95, preferably from about 30 to about 65, glyceryl distearate double chain lipids, based on the total weight of the vesicle bilayer; Polyoxyethylene-10-stearyl ether single chain lipids from about 1 to about 45, preferably from about 5 to about 35, cholesterol from about 1 to about 40, preferably from about 5 to about 25 and di (isoylethyl) hydr Oxyethylmonium methosulfate (DSHM) cationic double-chain lipids consisting of about 1 to about 45, preferably about 2 to about 25.
In another preferred embodiment, the nonionic / cationic vesicles are from about 25 to about 60, more preferably, based on the total weight of the vesicle bilayer, such as nonionic double-chain lipids (eg, glyceryl dilaurate ("GDL")). Preferably about 23 to about 27; Other nonionic double-chain lipids such as glyceryl distearate ("GDS") about 5 to about 45, more preferably about 23 to about 27; Sterols (eg cholesterol) about 1 to about 40, more preferably about 13 to about 17; Nonionic single chain lipids (eg polyoxyethylene-10-stearyl ether) about 5 to about 40, more preferably about 20 to about 25 and cationic double chain lipids (eg di (soylylethyl) hydroxy Ethylmonium methosulfate) about 1 to about 45, more preferably about 10 to about 15. Without wishing to be bound by theory, if the ratio of GDL: GDS is changed such that the amount of GDL exceeds the amount of GDS, the “penetrant enhancer effect” is enhanced by the excess GDL base formulation. As used herein, the "penetrant enhancer effect" is the transport of the active agent through the stratum corneum to living skin tissue. In other words, where the amount of GDS exceeds the amount of GDL, the "reservoir effect" is dominated by the excess GDS base formulation. As used herein, the "reservoir effect" is the accumulation or retention of active agent in the stratum corneum over time. It is preferable to use surfactants, as well as certain useful agents, such as fungicides, insecticides, humectants and sunscreens in the vesicles having reservoir effect properties. In other words, it is more preferable to use other useful agents such as bleaching agents, acne treatments, dandruff treatments, psoriasis treatments, and hair loss prevention agents in the vesicles having penetrating effect properties.
Nonionic vesicles can preferably be prepared by mixing the appropriate amounts of single-chain lipids, double-chain lipids and sterols under conditions sufficient to produce a homogeneous mixture. The temperature upon mixing may depend, for example, on the melting point of the major lipids, but typically nonionic vesicle systems can be prepared at temperatures between about 65 and about 80 ° C. and under ambient pressure conditions. In order to produce a vesicle system with improved tackiness, single-chain lipids, double-chain lipids and sterols are subjected to high shear under, for example, a device as described in US Pat. No. 5,013,497, incorporated herein by reference. It is more preferable to mix.
Nonionic / cationic vesicles may be prepared by first preparing a nonionic lipid vesicle as described above and then mixing them with a cationic lipid at a room temperature or a phase transition temperature of the nonionic lipid in a mixer (e.g., a Caframo mixer). . In another preferred embodiment, the double chain lipids, single chain lipids, sterols and cationic lipids can be mixed simultaneously using a device as described in US Pat. No. 5,013,497.
For example, additional optional agents, such as other lipids, useful agents, and / or chemical reagents such as buffers, may be added to the vesicles at specific times during their preparation. In general, these optional agents include: 1) internal hydrophilic components of the vesicles; 2) vesicle bilayer or 3) external to the vesicle. When using hydrophobic useful agents (e.g., erubiol, ketoconazole, retinol, benzoyl peroxide and retinoic acid, etc.), it is desirable to mix these useful agents with the vesicle components to ensure that the useful agents are present in the vesicle bilayer. Do. When using hydrophilic useful preparations such as alpha hydroxy acids such as salicylic acid, zinc pyrithione (as fine particles), ascorbic acid, beta hydroxy acid, such useful preparations are mixed with the vesicle component and the useful preparations are hydrophilic components of the vesicles. It is also desirable to ensure that it produces.
For example, in another embodiment in which an agent useful for the exterior of the vesicle present in an external surfactant mixture facing the actual vesicle itself is present, first the useful agent is mixed with the detergent mixture and then the resulting mixture is mixed with other vesicles. Preference is given to mixing with the components. This method may be desirable for useful formulations such as zinc pyrithione. Unexpectedly, vesicle systems in which useful agents are present in the surfactant mixture have been shown to exhibit enhanced delivery of useful agents in follicular gland sebaceous units even when no useful agent is present in the vesicles. Thus, enhanced deposition of useful agents can be achieved regardless of whether the useful agents are incorporated into the vesicles, on the exterior to the vesicles, or in the vesicle bilayers.
Another aspect of the invention relates to a composition comprising the vesicle delivery system described above and a useful agent, wherein the vesicle delivery system can effectively enhance local delivery of a useful agent into and out of the skin and / or follicular branch unit. . "Useful agent" means an active ingredient (eg, a perfume or a medicament) delivered to a desired site inside and / or outside of the skin. "Fragrance" means ingredients suitable for cosmetically treating, providing nutrients, and / or controlling hair and / or skin via topical administration. "Pharmaceutical" means a drug that is hydrophobic or hydrophilic in nature and suitable for topical use. As used herein, "medicament" includes agents that can facilitate recovery from damage and disease.
Examples of suitable useful agents include, but are not limited to, antimicrobial agents, allergic inhibitors, acne treatments, anti-aging agents, preservatives, analgesics, antitussives, antitussives, local anesthetics, hair loss inhibitors, antihistamines, anti-infective agents, inflammation inhibitors, Antiseptics, anticholinergic drugs, vasoconstrictors, vasodilators, wound healing promoters, peptides, polypeptides and proteins, deodorants and antiperspirants, drugs, skin glidants and skin moisturizers, hair conditioners, hair softeners, hair moisturizers, vitamins, tanning Tanning agents, skin lightening agents, antifungal agents (e.g. antifungal agents for foot preparations), hair growth inhibitors, dandruff treatments, seborrheic dermatitis treatments, psoriasis treatments, hair loss promoters, bleaching agents, depilatory agents, shaving preparations, trauma analgesics, fragrances , Stimulant, hemorrhoid remedy, insecticide, toxic ivy product, toxic oak product, combustion product, diaper rash treatment , Sweat preparations, make-up preparations, amino acids and derivatives thereof, herbal extracts, retinoids, flavonoids, sensates, antioxidants, skin conditioners, hair polishes, chelating agents, cell conversion enhancers, colorants, pigments, sunscreens And the like and mixtures thereof.
Examples of suitable vitamins include, but are not limited to, thiamine, nicotinic acid, biotin, pantothenic acid, choline, riboflavin, vitamin B6, vitamin B12, pyridoxine, inositol, carnitine, vitamins A, C, D, E, K and derivatives thereof (e.g. Vitamin B complexes including provitamin) and mixtures thereof.
Examples of suitable fungicides include, but are not limited to, baccitracin, erythromycin, neomycin, tetracycline, chlortetracycline, benzethonium chloride, phenol and mixtures thereof.
Examples of suitable skin glidants and skin moisturizers include, but are not limited to, mineral oils, lanolin, vegetable oils, isostearyl isostearate, glyceryl laurate, methyl glutet 10, methyl glaxet 20 chitosan and mixtures thereof .
Examples of suitable hair conditioners include, but are not limited to, lipophilic compounds such as cetyl alcohol, stearyl alcohol, hydrogenated polydecene and mixtures thereof, as well as behenamidopropyl PG-dimonium chloride, tricetylammonium chloride, dehydrogenation Quaternized compounds such as low amidoethyl hydroxyethylmonium methosulfate and mixtures thereof.
Examples of suitable hair softeners include, but are not limited to, silicone compounds such as nonvolatile or volatile compounds and compounds that are water soluble or water insoluble.
Examples of suitable hair humectants include, but are not limited to, panthenol, panthenyl, ethyl ether, phytantriol and mixtures thereof.
Examples of sunscreen agents include, but are not limited to, butyl methoxydibenzoylmethane, octyl methoxycinnamate, oxybenzone, octocrylene, octyl salicylate, phenylbenzimidazole sulfonic acid, ethyl hydroxypropyl aminobenzoate, menthyl Anthranilates and mixtures thereof.
Examples of suitable tanning agents include, but are not limited to, dihydroxyacetone.
Examples of skin brighteners include, but are not limited to, hydroquinone, catechol and derivatives thereof, ascorbic acid and derivatives thereof and mixtures thereof.
Examples of suitable insecticides (insecticides, scabies and parasitic agents) include, but are not limited to, permethrin, piperonyl butoxide, imidacloprid, N, N-diethyl toluamide (which are primarily metaisomers, namely N, N- Refers to a material containing diethyl-m-toluamide, which is also known as DEET, a compound of formula (5), natural or synthetic pyrethroids, wherein natural pyrethroids are contained in the insecticide; Extracts of ground flowers of Chrysantemum cinerariaefolium or C coccineum and mixtures thereof.
In Chemical Formula 5,
R ₁ is a branched or unbranched alkyl group having about 1 to about 6 carbon atoms,
R ₂ is H, methyl or ethyl,
R ₃ is a branched or unbranched alkyl or alkoxy group having about 1 to about 8 carbon atoms,
X is a -CN or -COOR ₄ group, wherein R ₄ is a branched or unbranched alkyl group having about 1 to about 6 carbon atoms.
In the structure of formula 5, R ₃ is CH ₃ group, R ₁ is n-butyl group, R ₂ is H, X is COOR ₄ , and R ₄ is ethyl ethyl 3- (N-butylacetamido Propionate, which is commercially available under the trade name "Repellent 3535" (Merck KGaA, Darmstadt, Germany).
Examples of antifungal agents for foot preparations include, but are not limited to, tolnaftate.
Examples of suitable hair loss agents include, but are not limited to, calcium thioglycolate, magnesium thioglycolate, potassium thioglycolate, strontium thioglycolate and mixtures thereof.
Examples of suitable external analgesics and local anesthetics include, but are not limited to, benzocaine, dibucaine, benzyl alcohol, camphor, capsaicin, capsicum, capsicum oleoresin, juniper tar, menthol, menthyl nicotinate, methyl salicylate , Phenol, resorcinol, turpentin oil and mixtures thereof.
Examples of suitable antiperspirants and deodorants include, but are not limited to, aluminum chlorohydrate, aluminum zirconium chlorohydrate, and mixtures thereof.
Examples of suitable inducers include, but are not limited to, camphor, menthol, methyl salicylate, peppermint and clove oil, itchtammol and mixtures thereof.
Examples of suitable inflammatory inhibitors include, but are not limited to, hydrocortisone.
Examples of suitable products for treating hemorrhoids include, but are not limited to, anesthetics such as benzocaine, pramoxin hydrochloride and mixtures thereof; Preservatives such as benzethonium chloride; Astringents such as zinc oxide, bismuth subgallate, balsam peru and mixtures thereof; Skin protectants such as cod liver oil, vegetable oils, and mixtures thereof.
Examples of suitable make-up formulations include, but are not limited to, ingredients for lipsticks, rouge, blush, eyeliner, eyeshadow powder, mascara, facial powder and mixtures thereof.
Preferred useful agents include, but are not limited to, elubiol, 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide, finasteride, ketoconazole, salicylic acid, zinc pyrithione, coul tar, benzoyl peroxide , Selenium sulfide, hydrocortisone, sulfur, menthol, pramoxin hydrochloride, tricetylammonium chloride, polyquaternium 10, panthenol, panthenol triacetate, vitamin A and its derivatives, vitamin B and its derivatives, vitamin C and its derivatives, Vitamin D and derivatives thereof, vitamin E and derivatives thereof, vitamin K and derivatives thereof, keratin, lysine, arginine, hydrolyzed wheat protein, hydrolyzed silk protein, octyl methoxycinnamate, oxybenzone, minoxidil, titanium dioxide, Zinc dioxide, retinol, erthromycin, tretinoin and mixtures thereof.
One preferred form of a useful formulation includes therapeutic ingredients effective in the treatment of dandruff, seborrheic dermatitis and psoriasis. Examples of such suitable useful agents include, but are not limited to, zinc pyrithione, selenium sulfide, sulfur; Salicylic acid; Coul tar; Povidone-iodine, imidazole [e.g. ketoconazole, dichlorophenyl imidazolodioxalan (available under the trade name "Elubiol" from Janssen Pharmaceutica, NV), clotrimazole, itraconazole, myconazole , Klimbazole, thioconazole, sulfonazole, butoconazole, fluconazole, myconazolenitrile and possible stereoisomers and derivatives thereof (e.g., anthraline, pyroxtone olamine (octopyroxox)); Selenium sulfide; Cyclopyrox olamine; Psoriasis treatments such as vitamin D homologues such as calcipotriol, calcitriol and tacalateroll; Vitamin A homologues such as esters of vitamin A such as vitamin A palmitate, retinoids, retinol and retinoic acid; Corticosteroids such as hydrocortisone, clobetason, butyrate, clobetasol propionate, and mixtures thereof.
The amount of useful agent to be mixed with the vesicle delivery system may depend, for example, on the desired usefulness produced and the user's susceptibility to the useful agent. Typically, however, useful formulations / vesicle delivery system compositions are based on the total weight of the composition, from about 0.001 to about 20, preferably from about 0.01 to about 5, and from about 0.06 to about 60, preferably from the vesicle delivery system. About 0.6 to about 30.
Unexpectedly, the above-described vesicle delivery system, which may be nonionic or cationic / nonionic in nature, effectively mediates the deposition and penetration of various useful agents (e.g., dandruff therapies) into and onto the skin, followed by topical administration to them. I found it possible.
Another aspect of the invention relates to a composition consisting of a vesicle delivery system, useful agents and detergents. "Detergents" are miscible with vesicle delivery systems, including but not limited to anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants (including betaine surfactants and zwitterionic surfactants) and these By means of known surfactants and / or soaps which may comprise a mixture of
Examples of suitable anionic surfactants include, but are not limited to, alkyl sulfates, sulfate esters of alkylphenoxy polyoxyalkylene ethanol, alpha-olefin sulfonates, betaalkyloxy alkaline sulfonates, alkyl arylsulfonates, alkyl carbonates, alkyls Ether carboxylates, fatty acids, sulfosuccinates, alkyl ether sulfosuccinates, sarcosinates, octoxynol phosphates, nonoxynol phosphates, taurates, fatty taurides, sulfided monoglycerides, fatty acid amido polyoxyethylene Compounds of the group known as sulfates and isethionates and mixtures thereof. Many additional surfactants are described in WO 07/26860 and McCUTCHEON'S DETERGENTS AND EMULSIFIERS (1989), which are incorporated herein by reference. These anionic surfactants are generally present in the composition as neutralized salts in the form of sodium salts, potassium salts, ammonium salts, lithium salts, alkyl ammonium salts or hydroxyalkyl ammonium salts. Preferred anionic surfactants are alkyl sulfates, alkyl ether sulfates, alkyl phosphates, amino acid salts such as N-acyl-L-glutamate, α-olefin sulfonates, alkyl sarcosinates, alkyl benzene sulfonates, acyl isethionates, Alkyl sulfosuccinates, acyl methyl taurates and mixtures thereof, with sodium C14-16 olefin sulfonate, ammonium lauryl sulfate, sodium tridecet sulfate, sodium laureth sulfate, disodium laureth sulfosuccinate desirable.
Examples of suitable nonionic surfactants include, but are not limited to, those set forth in WO 07/26860, polysorbate 20, long chain alkyl glucosides having about 8 to about 22 carbon atoms in alkyl groups, coconut fatty acid monoethanolamide Most preferred are (e.g., cocamide MEA), coconut fatty acid diethanolamide and mixtures thereof. The amount of cationic surfactant or nonionic surfactant used in the detergent base may be included in the vesicle bilayer in addition to the respective amounts of the nonionic surfactant or the cationic surfactant.
Examples of suitable cationic surfactants include, but are not limited to, positively charged at the pH of the shampoo composition, which is generally about pH 10 or less, as well as quaternary ammonium surfactants and quaternary amine surfactants soluble in the shampoo composition, WO 07 Included are compounds shown in / 26860. Preferred cationic surfactants include, but are not limited to, n-acylamidopropyldimethylamine oxide, such as cocamidopropylamine oxide, commercially available under the trade name "Incromine Oxide C" (Croda Inc. Parsippany, New Jersey). .
Examples of suitable amphoteric surfactants include, but are not limited to, the compounds set forth in WO 07/26860, ie ampocarboxylates, alkyl betaines, amidoalkylbetaines, amidoalkylsultaines, ampophosphates, phosphobetaines , Pyrophosphobetaines, carboxyalkyl alkyl polyamines and mixtures thereof. Preferred amphoteric surfactants include amidoalkylbetaines, such as cocamidopropyl betaine, commercially available under the trade name "tegobetaine E" from Goldschmidt Chemical Corporation of Hopewell, Virginia; Alkyl imidazolines having about 8 to about 18 carbon atoms in the alkyl group, such as sodium cocoampopropionate, available under the trade name "Monatheric CA-35" (Mona Industries Inc., Paterson, New Jersey). This includes.
Examples of suitable soaps include fatty acids that react with potassium, sodium, ammonium, lithium, triethanol amine bases to form soaps such as sodium cocoate or triethanolamine cocoate.
In a preferred embodiment, the detergent is based on the total weight of the detergent, based on the total weight of the detergent, from about 0.1 to about 20, preferably from about 5 to about 15, nonionic surfactant from about 0 to about 10, preferably from about 1 to About 7, cationic surfactant, about 0 to about 5, preferably about 0 to about 4 and amphoteric surfactant, about 0.1 to about 15, preferably about 1 to about 10.
In another preferred embodiment, the cleaning composition is based on the total weight of the surfactant, preferably a group consisting of alkyl sulfates, alkyl ether sulfates and mixtures thereof, wherein the alkyl groups have from about 8 to about 18 carbon atoms Anionic surfactants selected from about 50 to about 99, preferably about 80 to about 95 and amphoteric surfactants, preferably cocamidopropyl betaine, about 1 to about 20, preferably about 5 to about 15 do.
In another preferred embodiment, the cleaning composition is based on the total weight of the surfactant, preferably PEG-7 olive oil carboxylate, alkyl sulfates, alkyl ether sulfates and mixtures thereof, wherein the alkyl groups have from about 8 to about carbon atoms From about 50 to about 99, preferably from about 70 to about 90; Preferably from about 1 to about 30, preferably from about 10 to about 25, and optionally cationic surfactants (e.g., cocamoniumcarboyl chloride) selected from the group consisting of cocamidopropyl betaine and mixtures thereof ) About 0 to about 15, preferably about 2 to about 10.
In a preferred embodiment, the surfactant is used in conjunction with a suspending agent for suspending vesicles or particulate actives such as zinc pyrithione. Examples of suitable suspending agents include, but are not limited to: 1) acrylate / aminoacrylate C10-30 alkyl PEG-20 itac, commercially available under the trade name "Structure Plus" from National Starch and Chemical Corporation, Bridgewater, NJ; Acrylate polymers such as nate copolymers and copolymers thereof; 2) fatty acyl derivatives of which the acyl group is of formula (6); 3) esters of long chain fatty acids, such as stearyl stearate, in which the fatty acid is of formula 7; 4) United States Patent No. Re., Incorporated herein by reference. Alkyl dimethylamine oxides having from about 8 to about 18 carbon atoms in the alkyl group as described in 34,584; 5) Methylvinylether / maleic anhydride copolymer (PVM / MA Decadiene Crosspolymer) crosslinked with 1,9-decadiene PolyVM / MA available under the trade name "Stabileze 06 & QM" (International Specialty Products). ; 6) cellulose derivatives such as methylcellulose, hydroxybutyl methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl ethylcellulose, hydroxyethyl cellulose and mixtures thereof; 7) distearyl phthalic acid amide sold under the trademark "Stephan SAB-2" (Stepan Company) and D (hydrogenated) tallow phthalic acid amide sold under the trade name "Stepane TAB-2" (Stepan Company); 8) primary amines having fatty alkyl groups of 16 or more carbon atoms, such as palmitate amines and stearamines; 9) polyacrylic acid (e.g. carbomer) sold under the trade name "Carbopol" (B.F. Goodrich Company); 10) polysaccharide rubbers such as xanthan rubber; 11) colloidal clays such as benzyl dimethyl hydrogenated tallow ammonium montmorillonite (benton 27); 12) colloidal silica and mixtures thereof. Examples of suitable fatty acyl derivatives include ethylene glycol distearate, ethylene glycol monostearate and alkanolamides such as cocamide MEA and mixtures thereof.

In Chemical Formulas 6 and 7,
R ₁₀ is saturated or unsaturated and comprises a carbon chain having from about 7 to about 21 carbon atoms, for example, unsubstituted or substituted by a hydroxyl group,
R ₁₁ is an alkyl group having 8 to about 30 carbon atoms,
R ₁₂ is an alkyl group having 8 to about 30 carbon atoms.
Preferred suspending agents include carbomer, hydroxyethyl cellulose, methylvinylether / maleic anhydride copolymer (PVM / MA copolymer) crosslinked with 1,9-decadiene PolyVM / MA and acrylate / aminoacrylate C10- 30 alkyl PEG-20 itaconate copolymers are included, with acrylate / aminoacrylate C10-30 alkyl PEG-20 itaconate copolymers being most preferred.
Suspensions are preferably used in an amount effective to suspend vesicles or particle active agents. While this amount may depend on the type of useful formulation selected, the viscosity of the desired formulation, and the stability of the formulation, the amount of suspending agent is usually from about 0 to about 1, preferably from about 0.4 to about the total weight of the detergent. In the range of about 0.75.
Suspensions can be mixed simultaneously with detergents, lipids, sterols, useful agents and hydrophilic components. Preferably, the suspending agent may be premixed with the detergent component and the resulting mixture is mixed with the vesicle delivery system component.
Unexpectedly, the vesicle delivery system of the present invention has been found to be effective in delivering useful agents within and over the skin, as well as remaining complete and stable in the presence of various detergents.
The vesicle delivery system, when mixed with useful agents and detergents, is present in an amount effective to ensure that a sufficient amount of useful agent is ensured inside and / or over the skin. The amount of vesicle delivery system used will vary depending on the form and amount of useful formulation desired, the intended use of the final composition, i.e. treatment for maintenance regimens, the amount of detergent present and the sensitivity of the individual user to the composition, but usually The bilayer component: useful agent: detergent weight ratio is about 1 to about 80 parts, preferably about 5 to about 30 parts, and useful agents about 0.001 to about 20 parts, preferably about 0.1 part of the vesicle bilayer component and sterol of the vesicle delivery system. To about 5 parts: detergent may vary from about 1 to about 30 parts, preferably from about 5 to about 20 parts.
Another aspect of the invention relates to a composition consisting of a vesicle delivery system and a detergent. Unexpectedly, the vesicles of the present invention have been found to remain stable and complete in the presence of various detergents, regardless of the presence of useful agents.
When the vesicle delivery system is mixed with a detergent, it is present in an amount effective to remain stable and complete in the presence of the detergent. The amount of vesicle delivery system used will vary depending on the type and amount of detergent desired, the intended use of the final composition, i.e. treatment for maintenance regimens, the amount of detergent present and the individual user's susceptibility to the composition, but usually the vesicle bilayer The amount of ingredients and detergents is based on the total weight of the vesicle bilayer component and detergent, about 0.5 to about 7, preferably about 1 to about 5 and detergents about 5 to about 25, preferably about 8 to about It can be in the range of 20.
The composition of the present invention is not limited thereto, but washing water, baths, lotions, creams, ointments, sprays, aerosols, skin patches, soaps, mousses, tonics, gels, solid preparations designed to remain on the skin and not be washed immediately after administration. Such as sticks), and the like, in various dosage forms for topical administration. In addition, the composition may be applied to the desired site in the form of, for example, lotions, creams, gels, soaps, shampoos, etc., which are designed to be cleaned within the time indicated after application.
Another aspect of the present invention relates to a method for enhancing topical administration of a useful agent comprising topically administering to a human or animal a composition, which may optionally contain a detergent as described above.
The frequency and amount of vesicle delivery system applied depends, for example, on the form and amount of possible useful agents, the intended use of the end product and the sensitivity of the individual user to the composition, but the compositions of the present invention are usually at regular intervals. Should preferably be administered topically to the infected body site about 2 to about 14 times per week. More preferably, the composition is used more often during the initial stages of treatment, for example from about 5 to about 7 times per week, then less frequently if desired to be maintained, for example about 2 per week. To about 5 times.
In a preferred embodiment in which the composition is incorporated into the shampoo, the shampoo is applied to the wet hair and the hair is washed according to known methods. More preferably, the composition remains in the hair for about 0 to about 10 minutes and preferably washes for about 4 to about 7 minutes.
Another preferred embodiment of the present invention comprises the steps of topically administering the above-described composition to the desired site, wherein the useful formulations may each comprise an effective amount of an anti-dandruff agent, a seborrheic dermatitis agent or a psoriasis agent, optionally comprising a detergent. A method of treating symptoms and / or diseases of seborrheic dermatitis and / or psoriasis. As used herein, "dandruff treatment", "seborrheic dermatitis treatment" or "psoriasis treatment" includes agents capable of treating the symptoms and / or diseases of dandruff, seborrheic dermatitis and psoriasis, respectively. "Effective amount" means an amount effective to treat a disease and / or symptoms associated therewith, preferably from about 0.001 to about 20, preferably from about 0.01 to 20, based on the total weight of the vesicle delivery system and any detergent About 10 and more preferably about 0.01 to about 5.
Examples of useful agents suitable for treating the symptoms and / or diseases of dandruff, seborrheic dermatitis and psoriasis, respectively, include, but are not limited to, the compounds set forth above, and include elubiol, shale oil and derivatives thereof, ketoconazole, coultar, salicylic acid, Particular preference is given to zinc pyrithione, selenium sulfide, hydrocortisone, sulfur, menthol, pramoxin hydrochloride and mixtures thereof.
Another preferred aspect of the present invention is alopecia comprising the topical administration of the above-described composition, wherein the useful agent consists of an effective amount of a hair loss therapeutic agent (eg minoxidil or a mixture thereof), optionally comprising a detergent, to the desired site. The present invention relates to a method for treating hair loss, such as hair loss generated from. As used herein, "hair loss therapeutic agent" should include agents capable of growing hair and / or agents capable of preventing hair loss. "Effective amount" means an amount effective to treat hair loss, preferably in the range of about 0.001 to about 20, preferably about 1 to about 5, based on the total weight of the vesicle delivery system and any detergent Can be.
Examples of useful agents suitable for treating hair loss include, but are not limited to, potassium channel openers or terminal vascular relaxants such as those described in minoxidil, diazoxide, and US Pat. No. 5,244,664, incorporated herein by reference. Such as N * -cyano-N- (tert pentyl) -N'-3-pyridinyl-guanidine ("P-1075"); Vitamins such as vitamin E and vitamin C and derivatives thereof such as vitamin E acetate and vitamin C palmitate; Hormones such as erythropoietin, prostaglandins (eg prostaglandin E1 and prostaglandin F2-alpha); Fatty acids such as oleic acid; Diuretics such as spironolactone; Heat shock protein ("HSP") (eg, HSP 27 and HSP 72); Calcium channel blockers (eg verapamil HCL, nifedipine and diltiazem aylide); Immune inhibitors (eg cyclosporin and Fk-506); 5-alpha-reductase inhibitors such as finasteride; Growth factors such as EGF, IGF and FGF; Transforming growth factor beta; Tumor necrosis factor; Nonsteroidal anti-inflammatory agents such as benoxapropene; Retinoids such as tretinoin; Cytokines such as Il-6, IL-1 alpha and IL-1 beta; Cell adhesion molecules such as ICAM; Glucocorticoids such as betamethasone; Plant extracts such as aloe, clove, ginseng, turmeric, medicinal herbs, oranges, xanthoxylum, serenoa lepen, hypoxis luperi, nettle, pumpkin seeds and rye pollen; Other plant extracts including sandalwood, purple radish roots, chrysanthemums, rosemary, burdock roots and other hair growth promoter activators described in DE 4330597, incorporated herein by reference; Homeopathic preparations such as Kalium Phosphoricum D2, Azadirachta indica D2 and Joborandi D1; Genes for cytokines, growth factors and male baldness; Antifungal agents such as ketoconazole and elubiol; Antibiotics (eg streptomycin); Protein inhibitors (eg cycloheximide); Acetazolamide; Benoxapropene; Cortisone; Diltiazem; Hexachlorobenzene; Hydantoin; Nifedipine; Penicylamine; Phenothiazine; Pinassidyl; Soralene, verapamil; Zidovudine; Alpha-glucosylation routines having one or more of quercetin, isoquercitrin, hesperdine, naringin and methylhesperidine and flavonoids and transglycosidized derivatives thereof described in JP 7002677, incorporated herein by reference, Mixtures thereof.
Preferred hair loss therapeutics include 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide, N'-cyano-N- (tert pentyl) -N'-3-pyridinyl-guanidine , Finasteride, retinoids and derivatives thereof, ketoconazole, elubiol or mixtures thereof.
Another aspect of the invention relates to a method for removing hair comprising topically administering an effective amount of the above-described composition, which may optionally comprise a detergent, wherein the useful agent consists of an effective amount of a hair loss agent to a desired site for removing hair. will be. In a preferred embodiment, the composition contains from about 0.001 to about 20, preferably from about 0.01 to about 5, based on the total weight of the composition.
Examples of useful agents suitable for use in removing hair include, but are not limited to thioglycolate, magnesium thioglycolate, potassium thioglycolate, strontium thioglycolate and mixtures thereof.
Another aspect of the present invention provides a method of hair growth comprising topically administering an effective amount of the above-described composition, which may optionally comprise a detergent, wherein the useful agent consists of an effective amount of a hair growth inhibitor, to a desired site for inhibiting hair growth. It is about a suppression method. In a preferred embodiment, the composition contains from about 0.001 to about 20, preferably from about 0.01 to about 5, hair growth inhibitor based on the total weight of the composition.
Examples of useful agents suitable for use in inhibiting hair growth include serine proteases (eg trypsin); Vitamins such as alpha-tocophenol (vitamin E) and derivatives thereof such as tocophenol acetate and tocophenol palmitate; Tumor therapeutics such as doxorubicin, cyclophosphamide, chlormethine, methotrexate, fluorouracil, vincristine, daunorubicin, bleomycin and hydroxycarbamide; Anticoagulants (eg, heparin, heparinoids, coumaerin, detran and indandione); Thyroid therapeutics such as iodine, thiouracil and carbazole; Lithium and lithium carbonate; Interferons such as interferon alpha, interferon alpha-2a and interferon alpha-2b; Retinoids such as retinol (vitamin A), isotretinoin); Glucocorticoids such as betamethasone and dexamethosone; Agents for treating hyperlipidemia (eg, triparanol and clofibrate); thallium; Mercury; Albendazole; Allopurinol; Amiodarone; Emfetamine; Androgen; Bromocriptine; Butyrophenone; Carbamazepine; Cholestyramine, cimetidine, clofibrate, danazol; Desipramine; Dicyrazine; Ethambutol; Ethionamide; Fluoxetine; Gentamicin, gold salts; Hydantoin; Ibuprofen; Impramine; Immunoglobulins; Indandione; Indomethacin; Intraconazole; Levadopa; Mapprotilin; Methisergid; Metoprolol; Metirapone; Nadolol; Nicotinic acid; Potassium thiocyanate; Propranolol; Pyridostymine; Salicylates; Sulfasalazine; Terfenadine; Thiamphenicol; Thiouracil; Trimetadione; Troparanol; Valproic acid and mixtures thereof.
Preferred hair growth inhibitors include serene proteases, retinol isotretinoin, betamethisone, alpha-tocophenol and derivatives thereof, and mixtures thereof.
Another preferred aspect of the present invention is to treat acne, wherein the useful agent comprises topically administering to the desired site of the skin an effective amount of the above-described composition, each of which comprises an effective amount of an anti-aging agent or anti-aging agent, in the presence or absence of a detergent. And a method of reducing signs of aging, i.e., evidence of wrinkles, fine lines and other optical damage.
Examples of suitable anti-aging agents include, but are not limited to, inorganic sunscreens such as titanium dioxide and zinc oxide; Organic sunscreens such as octylmethyl cinnamates and derivatives thereof; Retinol; Vitamins such as vitamin E, vitamin A, vitamin C, vitamin B and derivatives thereof such as vitamin E acetate, vitamin C palmitate, and the like; Beta carotene, alpha hydroxy acids (e.g. glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, alpha-hydroxyisocaproic acid, atrolic acid, Alpha-hydroxyisovaleric acid, ethyl pyruvate, galacturonic acid, glucopheronic acid, glucopetono 1,4-lactone, gluconic acid, gluconolactone, glucuronic acid, glucuronolactone, glycolic acid, iso Antioxidants including propyl pyruvate, methyl pyruvate, muxic acid, pyruvic acid, sakaric acid, sakaric acid 1,4-lactone, tartaric acid and tartronic acid); Beta hydroxy acids such as beta-hydroxybutyric acid, beta-phenyl-lactic acid, beta-phenylpyruvic acid; Plant extracts (e.g. green tea, soybeans, thistle, algae, aloe, angelica, bitter orange, coffee, golden thread, grapefruit, hollen, firewood, pearl bark, citrus root, mulberry, peony, brown root, nice, safflower And mixtures thereof.
Preferred anti-aging agents include retinoids, antioxidants, alpha-hydroxy acids and beta-hydroxy acids, with retinol and tretinoin being most preferred.
Suitable amounts of anti-aging agents are from about 0.01 to about 10, preferably from about 0.04 to about 5, based on the total weight of the vesicle delivery system and any detergent.
Examples of suitable acne therapeutics include, but are not limited to, topical retinoids (tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, retinol); Salicylic acid; Benzoyl peroxide; Resorcinol; Antibiotics (eg tetracycline and isomers thereof, erythromycin) and anti-inflammatory agents (eg ibuprofen, naproxen, hetpropene); Plant extracts (e.g. alnus, amica, artemisia capillaris, asia sarum root, bus, calendula, chamomile, knidium, compressor, fennel, gall bladder, hawthorn, triticale, daegyo, jujube, kiwi , Licorice, magnolia, olive, peppermint, red filodendron, salvia, sasa coniferous); Imidazoles such as ketoconazole and elubiol and in Gollnick, H et al. 196 (1) Dermatology Sebaceous Glands, Acne and Related Disorders, 119-157 (1998). The compounds described, and mixtures thereof.
Preferred acne treatments include retinol, elubiol, antibiotics and salicylic acid, with retinol and tretinoin being most preferred.
Suitable amounts of acne therapeutic agents include from about 0.01 to about 10, preferably from about 0.04 to about 5, based on the total weight of the vesicle delivery system and any detergent.
Another preferred aspect of the present invention relates to a method of bleaching the skin, comprising topically administering the above-described follicular delivery system to a desired site of the skin containing an effective amount of a bleaching agent and any detergent. Suitable effective amounts of bleaching agents include from about 0.01 to about 10, preferably from about 0.04 to about 5, based on the total weight of the vesicle delivery system and any detergent.
Examples of suitable bleaches include, but are not limited to, retinoids (eg, retinol); Kojic acid and derivatives thereof such as kojic acid dipalmitate; Hydroquinone and its derivatives such as arbutin; Transsecsamic acid; Vitamins such as niacin, vitamin C and derivatives thereof; Azelaic acid; Placertia; licorice; Extracts such as chamomile and green tea and mixtures thereof, with kojic acid and hydroquinone being preferred.
Also included within the scope of this invention are instructions for their use and kits consisting of vesicle delivery systems, any useful agent and any detergent. In one aspect, the kit may consist of some or all of the instructions forming the vesicle delivery system packaged separately or in a premixed mixture and instructions describing penetration of the delivery system. In another embodiment, such kits may further comprise useful agents and / or detergents in which the useful agents are ie premixed with a vesicle delivery system component or detergent, or provided in a separate container.
The preferred size of liposome vesicles (except for useful agents) in the vesicle delivery system may range from about 50 to about 5000 nm, with about 100 to about 3000 nm being preferred. One skilled in the art can modify the size of the liposome vesicles without undue experimentation, such as reduction via ultrasound. Ultrasonic processes are well known in the art and are described, for example, in Betageri, GV, et al., "Preparation of Liposomes", Liposome Drug Delivery System, 11 (1993). It is described in Alternatively, the size of liposomes can be determined as described in Martin, FJ, "Pharmaceutical Manufacturing of Liposomes", Specialized Drug Delivery Systems: Manufacturing and Production Technology, 267-316 (1990), incorporated herein by reference. The liposomes can be extruded and / or made more uniform through a series of straight chain containing polycarbonate membranes that change the pore diameter at high pressure (eg, about 250 psi).
The vesicle delivery system containing the encapsulated useful agent and mixed with the detergent is exposed to accelerated stability conditions with temperatures of 4 ° C., 30 ° C., 40 ° C. and 50 ° C. for about 1 month, and the integrity of the aged vesicle bilayer is achieved. Particles, as described, for example, in Betageri, GV, et al. 1993 "Preparation of Liposomes", in Liposome Drug Delivery Systems, Lanncaster PA: Technomic Publishing Co, Inc. pp. 33-34. When evaluated via size analysis and freeze-broken electron microscopy, it was unexpectedly found that the properties of the detergent were modified to such an extent that they did not destroy the vesicles or their bilayers as they do in other vesicle containing formulations known in the art. Thus, it has been surprisingly found that compositions of the present invention containing vesicle delivery systems, useful agents and detergents not only remain stable under accelerated aging conditions, but also retain their multilayer lamellar structure despite mixing with detergents. .
Unexpectedly, to determine the amount of incorporation of useful agents in a vesicle delivery system before and after mixing with a detergent, see, for example, Dowton, SM et al., 1993 "Infuence of liposomal composition on topical delivery of encapsulated. After use of size exclusion chromatography as described in cyclosporin A 1. An in vitro study using hairless mouse skin, "STP Pharma Sci., 3, 404-407" Or when inserted into a bilayer structure, the vesicles have also been found to be able to better maintain useful formulations in accelerated aging than compositions present outside of the vesicles, even when mixed with detergent base detergents again.
The inventors have also found that compositions composed of unexpectedly useful formulations, detergents, and vesicle delivery systems are more efficient than similar vesicle-free compositions for depositing and delivering useful formulations into and over the skin, hair, and follicular branch units. Surprisingly, these new vesicle cleaning formulations have been found to substantially target hair and pores, as opposed to targeting the stratum corneum lipid domains, when delivering useful agents to skin, hair and hair follicle lines.
It is described that the present invention is suitably carried out in the absence of specific components or steps not specifically described herein. Some examples are given below to re-explain the nature of the invention and how to do it. However, the present invention should not be considered as being limited to the detailed description thereof.
Example
Example 1 Preparation of Vesicular Delivery System
Table 1 describes eight vesicle delivery systems for use in the following examples. Table 2 provides a simple and general description of each vesicle delivery system.
Formulation of vesicle delivery system Formulation # (F #)One2345678 Geological phase Glyceryl Distearate40.9140.9138.5933.1333.1340.9138.5933.13 cholesterol13.6413.6412.8611.0411.0413.6412.8611.04 Polyoxyethylene-10-stearyl ether36.3636.3634.3129.4429.4436.3634.3129.44 Cationic Lipids ^* 005.6619.0319.0305.6619.03 Hydrophobic surfactant elubiol ^** 9.099.098.587.367.369.098.587.36 gun100100100100100100100100 Aqueous phase Zinc pyrithione08.578.5708.57000 Salicylic acid0000025.0725.0725.07 Deionized water10091.4391.4310091.4374.9374.9374.93 gun100100100100100100100100
Di (soylylethyl) hydroxyethylmonium methosulfate (DSHM)
** dichlorophenyl imidazoledioxolane
General description of the vesicle delivery system from Table A Formulation NumberExplanation OneNonionic Liposomes with Elrubiol 2Nonionic Liposomes with Elrubiol and Zinc Pyrithione (ZPT) 3Low cation / nonionic liposomes with elrubiol and ZPT 4High cation / nonionic liposomes with elrubiol 5High cation / nonionic liposomes with elrubiol and ZPT 6Nonionic Liposomes with Elrubiol and Salicylic Acid 7Low cation / nonionic liposomes with elrubiol and salicylic acid 8High cation / nonionic liposomes with elrubiol and salicylic acid
Each of these systems is made by mixing the appropriate amount of lipid in a beaker at 75 ° C. until the lipid melts. The resulting melt is then added to a syringe, which is preheated in a water bath to 75 ° C. The second syringe containing the appropriate amount of hydrophilic component is preheated in a water bath to 70 ° C. The two syringes are then connected via a 3-way metal stop cock. The ratio of aqueous phase to lipid phase is about 70:30, or 7 ml aqueous phase to 3 ml lipid phase. After injecting the hydrophilic component into the lipid phase syringe, the resulting mixture is rapidly mixed back and forth several times between the two syringes until the component is cooled to about 25-30 ° C.
Example 2: Preparation of Liposomal-Anionic / Amphoteric Shampoo Compositions
A shampoo is prepared consisting of the following ingredients as set forth in Table 3:
Anionic / Amphoteric Shampoo Premix CTFAsolidTrade nameproducer 1. Sodium Laureth Sulfate4.750Sulfochem NAChemron Corporation 2. Sodium Lauryl Sulfate6.100Sulfochem SLX-RChemron Corporation 3.TEA Lauryl Sulfate7.700Sulfochem TLS-55Chemron Corporation 4. Acrylate / Aminoacrylate C10-30 Alkyl PEG-20 Itaconate0.900Structure PlusNational Starch and Chemical Corporation 5. Methylparaben0.240Methyl ParaseptNipa Hardwicke Inc. 6. Propylparaben0.060Nipasol MNipa Hardwicke Inc. 7. Cocamide MEA6.000Monamid CMAUniquema 8. Glycol Distearate1.500EDGS VAGoldschmidt Chemical Corporation 9. Polyquaternium-70.288Merquat 550Calgon corporation 10.imidazolidinyl urea0.600Germall 115International specialty products 11. Spices0.600FragranceBush boake allen 12. Cocamidopropyl Betaine2.100Chembetaine CGFChemron Corporation 13. Citric Acid0.185Citric AnhydrideHoffman La Roche Inc. 14. Deionized Water68.977 gun100.000
<Preparation of Shampoo Premix>
3/4 of deionized water (component 14) is added to the vessel. After combining components 1-4 with mixing for about 5 minutes or until clearing, the resulting mixture is heated to 70 ° C. with mixing at 500 rpm for about 20 minutes. Components 5 to 8 are added thereto in turn under mixing under constant conditions. After cooling the mixture to 45 ° C., the remaining components 9-12 are added in turn with mixing for 20 minutes at 500 rpm. After adjusting the pH of the mixture to 6.5 ± 0.5 using citric acid (component 13), the mixture is continued to mix at 500 rpm until the mixture is about 25 to 30 ° C. Residual amount of deionized water is added to the final volume and mixed at 500 rpm until homogeneous.
<Preparation of vesicle delivery system preliminary mixture>
F # 2, the vesicle delivery system of Example 1, was prepared according to the method described in Example 1.
<Production of a Shampoo Containing a Follicle Delivery System>
2 ml of the vesicle delivery system premix F # 2 produced from Example 1 was added to 10 ml of the shampoo premix, gently and suitably in a Caframo mixer at 20 ° C. for 20-30 minutes or until homogeneous. Stir.
Final preparation of the premix in a novel anionic / amphoteric shampoo containing a vesicle delivery system ingredientweight Shampoo premix83.33 Liposome premix16.67 gun100.00
Example 3: Preparation of Liposome-Anionic / Amphoteric / Nonionic Shampoo Compositions
A shampoo consisting of the following ingredients set forth in Table 5 is prepared:
Amphoteric shampoo premix formulation INCIsolidTrade nameproducer 1.Sodium C14-16 Olefin Sulfonate6.80Bio-Terge AS-40Stepan company 2. Alkyl Polyglucoside2.50Plantaren 2000Henkel Corporation 3. Salicylic Acid2.50Salicylic Acid USPNipa Hardwicke Inc. 4. Sodium Cocampopropionate1.40Monateric CA-35Uniquema 5. Linoleamidopropyl PG Dimonium Chloride0.15Phospholipid EFAUniquema 6. Dimethicone Copolyol0.50Abil B 8852Goldschmidt Chemical Corporation 7. Dimethicone Copolyol0.30Abil B 88183Goldschmidt Chemical Corporation 8. Cocamidopropyl Betaine7.50Tegobetaine EGoldschmidt Chemical Corporation 9. Polyquiternium-70.30Merquat 550Calgon corporation 10. Spices0.25FragranceBush boake allen 11.citric acid0.15Citric AnhydrideHoffman La Roche Inc. 12. Deionized Water77.293 gun99.650
<Preparation of Shampoo Premix>
After deionized water (component 12) is quantitatively added to the vessel, components 1 and 2 are added thereto in turn while mixing at about 500 rpm in a capramo mixer. The salicylic acid (component 3) is then added while the mixture is mixed at 500 rpm for 20 minutes under constant temperature. After all the salicylic acid is dissolved, the mixture is mixed under constant conditions while citric acid is added. Add ingredients 4-9 sequentially and mix for 20 minutes under constant conditions. After cooling the mixture to 45 ° C., fragrance is added thereto (component 10). An additional amount of citric acid is added to adjust the pH to about 4.0 ± 0.4. The resulting mixture is continuously mixed at 500 rpm until the final batch temperature is about 25-30 ° C.
<Production of vesicle delivery system>
Liposomal F # 2 of Example 1 is prepared according to the method described in Example 1.
<Production of a Shampoo Containing a Follicle Delivery System>
2 ml of liposome F # 2 resulting from Example 1 are added to 10 ml of the shampoo premix, mixing at 500 rpm in a capramo mixer for 20-30 minutes at 30 ° C. or until homogeneous.
Final preparation of the premix in a novel anionic / amphoteric / nonionic shampoo containing a vesicle delivery system ingredientweight Shampoo premix83.33 Liposome premix16.67 gun100.00
Example 4 Preparation of Liposomal-Anionic / Amphoteric Shampoo Compositions
Prepare a shampoo consisting of the following ingredients set forth in Table 7:
Amphoteric / Amphoteric Shampoo Premix Formulation INCIsolidTrade nameproducer 1.Sodium C14-16 Olefin Sulfonate12.000Bio-Terge AS-40Stepan company 2. Sodium Citrate0.600Sodium citrate dianhydrideHaarman and Reimer Corporation 3. Structure plus1.200Salicylic Acid USPNipa Hardwicke Inc. 4. Salicylic Acid3.600Monateric CA-35Uniquema 5. Linoleamidopropyl PG Dimonium Chloride1.440Phospholipid EFAUniquema 6. Cocamidopropyl Betaine10.410Tegobetaine EGoldschmidt Chemical Corporation 7. Hexylene Glycol0.360Hexylene glycolFischer scientific 8.Polyquaternium-220.960Merquat 280Calgon corporation 9. Citric Acid0.054Citric AnhydrideHoffman La Roche Inc. 10. Deionized Water69.736 gun100.360
<Preparation of Shampoo Premix>
After deionized water (component 10) is added to the vessel, components 2, 3 and 4 are added in turn with mixing at 500 rpm until homogeneous in the capramo mixer. The mixture is then heated to about 70 ° C. under constant conditions. Salicylic acid (component 6) is added thereto under certain conditions. After the salicylic acid has dissolved, the mixture is cooled and components 7-10 are added thereto in turn with mixing at 500 rpm for 20 minutes. After adjusting the pH of the mixture to about 4.0 ± 0.2 with citric acid (component 11), the resulting mixture is mixed under constant conditions and cooled to 25-30 ° C.
<Preparation of vesicle delivery system preliminary mixture>
F # 2, the vesicle delivery system of Example 1, was prepared according to the method described in Example 1.
<Production of a Shampoo Containing a Follicle Delivery System>
2 ml of the vesicle delivery system premix F # 2 produced from Example 1 are added to 10 ml of the shampoo premix, mixing at 500 rpm in a capramo mixer for 20-30 minutes at 30 ° C. or until homogeneous.
Final preparation of premix in novel anionic / amphoteric liposome-shampoo ingredientweight Shampoo premix83.33 Liposome premix16.67 gun100.00
Example 5: Measurement of Skin Penetration
Experiments are conducted to determine the deposition of active agents from various shampoo compositions and liposome-shampoo compositions onto the skin. In order to measure the penetration of the active agent, an in vitro skin penetration study is performed using an unembedded Franz diffusion chamber.
The skin of a human body cut to 400 μm with a microtome is placed in a Franz diffusion cell containing a receptor medium consisting of citrate phosphate buffer. The receptor dose is 5 ml and the cell surface area is 0.636 cm 2. Receptor compartments are maintained at 37 ° C. during the experiment.
In the tube, 50 μl of each formulation as shown in Tables 9 and 11 is diluted with 50 μl of 37 ° C. water. This solution is then rubbed onto the epidermal surface of the skin placed for 15 seconds and held there for 5 minutes. The solution is then washed three times with 37 ° C. water from the surface and then rubbed twice with a dry cotton cloth. 24 hours after topical administration of the formulation, the skin surface is washed three times with a cotton rag soaked with methanol and rubbed three times with three dry cotton rags. After the skin is removed from the diffusion cell, the epidermis and dermis are separated and cut, placed in separate vials containing methanol extract and sonicated for 30 minutes in a sonicator. After sonicating the epidermis, dermis and mop, each sonicated sample is analyzed using Waters HPLC. Penetration of the active agent into the skin is calculated based on the dose of the active agent and the amount of active agent in each erubiol delivered to the epidermis or dermis per surface area. The results are shown in Table 9 below.
Levels of erubiol in epidermis and dermis after topical administration FormulationepidermisdermisMass balanceTotal skin deliveryAmt (㎍ / ㎠) Amt (㎍ / ㎠) Amt (㎍ / ㎠)Anion / Amphoteric Base (Control) (Example 2) (A)0.359 ± 0.270.0963 ± 0.070.128 ± 0.020.0344 ± 0.006109.9 ± 4.80.487 ± 0.290.131 ± 0.08 Anionic / Amphoteric Substrate + Nonionic Liposomes (Example 2, Liposomes: Table 1, F # 2) (B)1.409 ± 0.690.3213 ± 0.160.200 ± 0.070.046 ± 0.016109.4 ± 4.81.609 ± 0.750.367 ± 0.17 Anionic / Amphoteric Substrate + High Cationic / Nonionic Liposomes (Example 2, Liposomes; Table 1, F # 5) (C)2.745 ± 0.480.5908 ± 0.070.197 ± 0.070.0425 ± 0.01103.9 ± 0.62.963 ± 0.510.638 ± 0.11
Statistical significance of elrubiol penetration into the epidermis as indicated by the p-value measured by the Student's t-test ^* Formulationp-value Anionic / amphoteric substrate (A) + nonionic liposomes versus anionic / amphoteric + cationic / nonionic liposomes (C)One Tail = 0.027 Two Tail = 0.055 Anionic / Amphoteric Substrate (A) vs. Anionic / Amphoteric Substrate + Nonionic Liposome (B)One Tail = 0.048 Two Tail = 0.096 Anionic / Amphoteric Substrates (A) Large Anionic / Amphoteric Substrates + Cationic / Nonionic Liposomes (C)One Tail = 0.001 Two Tail = 0.003
* p-value> 0.05 is not significantly different.
Based on the results in Tables 9 and 10, it can be seen from this sample that a control formulation containing only a cleaning substrate (Formulation A) delivered 0.0963 of the dose of erubiol to the epidermis. Surprisingly, however, when incorporating a formulation containing a target nonionic vesicle delivery system into the cleaning shampoo substrate (Formulation B), the elubiol delivered to the epidermis increased to 0.3213, resulting in a 3.3-fold increase in delivery rate. When incorporating a cationic / nonionic vesicle delivery system into the cleaning substrate (Formulation C), surprisingly, the erubiol penetration into the epidermis increased again to 0.5908, 6.1 times higher than for Control Formula A. The level of erubiol found in the dermis does not differ significantly between the three formulations.
From this sample, a mixture of erubiols containing a cleaning shampoo base and a nonionic vesicle delivery system or a cationic / nonionic delivery system is compared to a mixture of erubiol and the base alone, which is the It can also be seen that delivery is performed well. Thus, the compositions of the present invention provide an effective method of controlling the delivery of hydrophobic active agents to the skin, regardless of the detergent.
Levels of erubiol in the epidermis after topical administration of various amphoteric shampoo formulationsCompositionEpidermis of Applied DoseEpidermal volume per surface area (㎍ / ㎠)Mass balance DAnionic / Amphoteric / Nonionic Substrates (Example 3)0.0042 ± 0.0010.012 ± 0.00101.7 ± 3.5 EAnionic / amphoteric / nonionic substrates + nonionic liposomes (Example 3, liposomes: Table 1, F # 1)0.3471 ± 0.1821.018 ± 0.43093.5 ± 3.4 FAnionic / amphoteric / nonionic substrates plus cationic / nonionic liposomes (Example 3, liposomes: Table 1, F # 4)0.1571 ± 0.0280.426 ± 0.078106.6 ± 6.5
Statistical Significance of Elrubiol Penetration as Shown by the p-Value Measured by Student's t-Test ^* Formulationepidermis Anionic / Amphiphilic / Nonionic Substrate (D) Large Anionic / Amphiphilic / Nonionic Substrate + Nonionic Liposome (E)One Tail = 0.040 Two Tail = 0.080 Anionic / Amphiphilic / Nonionic Substrate (D) Large Anionic / Amphiphilic / Nonionic Substrate + Cationic / Nonionic Liposome (F)One Tail = 0.000 Two Tail = 0.000 Anionic / Amphoteric / Nonionic Substrate + Nonionic Liposomes (E) Large Anionic / Amphoteric / Nonionic Substrate + Cationic / Nonionic Liposomes (F)One Tail = 0.083 Two Tail = 0.165
* p-value> 0.05 is not important.
Based on the data presented in Tables 11 and 12, it can also be seen from this sample that a control formulation containing only a cleaning substrate (Formulation D) delivered only 0.0042 of the dose of erubiol to the epidermis. Surprisingly, however, when incorporating a formulation containing a target nonionic vesicle delivery system into the cleaning shampoo substrate (Formulation E), the elubiol delivered to the epidermis increased to 0.3471, resulting in a nearly 83-fold increase in delivery rate. . When incorporating a cationic / nonionic vesicle delivery system into the cleaning substrate (Formulation F), surprisingly, the erubiol penetration into the epidermis increased to 0.1571, 37 times higher than for Control Formula D. None of the tested formulations found levels of erubiol in the dermis.
As shown in Tables 11 and 12, from this sample, a mixture of elubiol, a nonionic and cationic / nonionic vesicle delivery system consisting of three different forms of surfactant and a cleaning shampoo substrate, was prepared Compared to the mixture, it can be seen that the delivery of erubiol to the target site, the epidermis, is performed well. Thus, the compositions of the present invention provide an effective method of controlling the delivery of hydrophobic actives to the skin.
Example 6: Inflow Measurement of Formulations
The influx of erubiol into the vesicles is measured using size exclusion chromatography on a Sephadex G-75 column. A detailed description of this method can be found in Dowton, SM, et al. 1993 "Influence of liposomal composition on topiclal delivery of encapsulated cyclosporin A 1. An in vitro study using hairless mouse skin", STP Pharma Sci., 3, 404-407).
The liposome formulations resulting from Examples 1, 2 and 3 are tested for erubiol inflow under accelerated stability conditions. The following formulations were prepared according to the examples described above and then left in a stability chamber at 50 ° C. for 2 or 4 weeks. Tables 13 and 14 show the influx of active agent for each formulation tested.
Inflow studies of various shampoo formulations under stability (compositions produced from Examples 1 and 2) CompositionStability conditionsInflow rate () Nonionic Liposomes (Example 1, Table 1 F # 1)2 weeks at 50 ° C99.13 0.87 97.75 2.25 Anionic / Amphoteric Shampoo + Low Cationic / Nonionic Liposomes (Example 2, Liposomes of Table 1, F # 2)2 weeks at 50 ° C98.93 1.07 97.53 2.47 Anionic / Amphoteric Shampoo + High Cationic / Nonionic Liposomes (Example 2, Liposomes of Table 1, F # 5)2 weeks at 50 ° C99.10 0.90 98.34 1.66
Inflow studies of various liposome-amphoteric formulations under stability (compositions generated from Examples 1 and 3) CompositionStability conditionsInflow rate () Anionic / amphoteric / nonionic substrates + nonionic liposomes (Example 3, Table 1, F # 1)4 weeks at 50 ° C99.13 0.87 97.51 2.49 Anionic / Amphoteric / Nonionic Substrate + Low Cation / Nonionic Liposomes (Example 3, Liposomes in Table 1, F # 3)4 weeks at 50 ° C98.93 1.07 98.62 1.38 Amphoteric substrate + high cationic / nonionic liposomes (Example 3, liposomes in Table 1, F # 4)4 weeks at 50 ° C99.98 0.02 99.91 0.09
It can be seen that the vesicles were destroyed and the erubiol was released from the release of at least 10 erubiols for 4 weeks under accelerated stability conditions. From this example, it can be seen that the vesicles containing erubiol are stable regardless of the vesicle composition and the cleaning system composition.
Example 7: Particle Size Analysis
After preparing the compositions according to Examples 1 to 3, the particle sizes of the resulting formulations were analyzed by inserting 1 ml of a 10-fold dilution of each formulation into the NICOMP 370 submicron particle analyzer using power laser light scattering. The results are shown in Table 15 below, from which the size range can be determined based on the number-weight average diameter of the vesicles in the composition. The analyzer cannot accurately detect particles that are in the range of vesicles less than 30 nm (detection limit is 20 nm) and larger than 30 μm (30,000 nm).
The results of the particle size data are also shown in Tables 15 to 21 below.
Particle Size Distribution of Various Liposome Formulations (Initial) FormulationDistributionSize range (nm)Number distributionDuring Population (Based on #) Nonionic Liposomes + Elubiol (Example 1: Table 1, F # 1)Three types167.9 ± 20.2 (25.1) 1065 ± 123.4 (16.3) 20458 ± 1981 (58.6)156.5 ± 15.71032.6 ± 94.519910.4 ± 124.999.7 0.3 0.0 Cationic / nonionic liposomes + elubiol (Example 1: Table 1, F # 4)Three types238.0 ± 37.6 (17.6) 812.4 ± 115.8 (42.1) 5430.8 ± 520.2 (40.3)206.3 ± 31.4781.6 ± 96.35297.2 ± 435.189.010.70 Nonionic Liposome + Elubiol & ZPT (Example 1: Table 1, F # 2)Three types109.9 ± 6.0 (18.9) 214.4 ± 26.9 (32.5) 803.7 ± 124.7 (48.6)107.2 ± 6.7199.6 ± 21.1769.4 ± 104.490.3 9.4 0.3 Cationic / Nonionic Liposome + Elubiol & ZPT (Example 1: Table 1, F # 5)Two types1549 ± 195.1 (15.1) 26880 ± 2775 (84.9)225.2 ± 20.61465.5 ± 228.426359 ± 230996.8 3.1 0.1
Particle Size Distribution of Nonionic Liposomal-Anionic / Amphoteric Shampoo Compositions Under Accelerated Conditions (Example 2, Liposomes: Table 1, F # 2) Term and conditionDistributionSize range (nm)Number distributionDuring Population (Based on #) EarlyThree types355.9 ± 3307 (8.5) 3307 ± 382 (26.5) 26841 ± 2774 (65.0)347.8 ± 42.93158.2 ± 375.926327 ± 231396.4 3.5 0.1 4 weeks at 50 ℃Two types806.0 ± 116.1 (16.9) 6903.8 ± 929.5 (83.1)775.4 ± 94.46381.8 ± 105593.4 6.6
Particle Size Distribution of Low Cationic / Nonionic Liposomal-Anionic / Amphoteric Shampoo Compositions Under Accelerated Conditions (Example 2, Liposomes: Table 1, F # 3) Term and conditionDistributionSize range (nm)Number distributionDuring Population (Based on #) EarlyTwo types702.1 ± 108.1 (13.3) 7304 ± 1118.8 (86.7)676.8 ± 80.77018.9 ± 125693.9 6.1 4 weeks at 50 ℃Three types464.3 ± 46.1 (6.6) 3397 ± 569.5 (41.6) 26843 ± 2798 (51.8)450.2 ± 54.73258.9 ± 415.326316 ± 213690.6 9.2 0.2
Particle Size Distribution of High Cationic / Nonionic Liposomal-Anionic / Amphoteric Shampoo Compositions Under Accelerated Conditions (Example 2, Liposomes: Table 1, F # 5) Term and conditionDistributionSize range (nm)Number distributionDuring Population (Based on #) EarlyTwo types794.5 ± 121.4 (23.9) 7796.2 ± 1000 (76.1)106.3 ± 0.0765.6 ± 77.77285.9 ± 0.099.5 0.5 0 4 weeks at 50 ℃Two types1250.9 ± 160.7 (22.0) 22090 ± 2587 (78.0)117.2 ± 18.521236 ± 314998.9 1.1
Particle Size Distribution of High Cationic / Nonionic Liposome-Anionic / Amphoteric / Nonionic Shampoo Compositions Under Accelerated Conditions (Example 3, Liposomes: Table 1, F # 4) ConditionDistributionSize range (nm)Number distributionDuring Population (Based on #) EarlyOne type113.5 ± 12.0 (100)107.7 ± 10.0100.0 4 weeks at 50 ℃Three types14.0 ± 1.7 (1.2) 109.7 ± 16.8 (49.5) 496.1 ± 73.8 (49.3)12.8 ± 1.393.8 ± 41.10100
Particle Size Distribution of Low Cationic / Nonionic Liposome-Anionic / Amphoteric / Nonionic Shampoo Compositions Under Accelerated Conditions (Example 3, Liposomes: Table 1, F # 7) ConditionDistributionSize range (nm)Number distributionDuring Population (Based on #) EarlyThree types111.3 ± 6.5 (8.5) 306.2 ± 37.6 (12.8) 1928.2 ± 240.4 (78.6)108.1 ± 6.9292.3 ± 29.51855.8 ± 222.198.1 1.7 0.2 2 weeks at 50 ℃Three types11.5 ± 1.5 (1.0) 22.9 ± 2.6 (3.3) 124.6 ± 19.6 (95.7)10.9 ± 0.921.0 ± 2.1107.6 ± 57.20 6.094.0 4 weeks at 50 ℃Two types70.5 ± 11.3 (15.5) 249.7 ± 35.2 (84.5)59.7 ± 8.5214.1 ± 28.40.699.4
As shown in the table above, the particle size of the vesicles ranges from 0.1 to 1 μm. The vesicles are believed to be stable upon accelerated aging with respect to size if at least 90 of the vesicles are 0.1-1 μm in size.
The table also shows the range of different particle sizes for different liposomes and liposome-cleaning systems. The size of the vesicles proved relatively constant even if some vesicles doubled in size for two weeks at 50 ° C. and four weeks at 50 ° C. as shown in Table 20. However, this change may be due to the effects caused by the aggregation of 2-3 vesicles generated from sampling of vesicles from the vessel or from van der Waals forces. In addition, the vesicles were complete, but the laser proved indistinguishable between two vesicles located very close to each other. Instability and destruction of vesicles is also demonstrated when the particle size increases by at least three times or when the size changes by at least about ten times, ie from 100 nm to 1000 nm.
From this example, it can be seen that in addition to being mixed with the detergent substrate, the particle size of the vesicle delivery system alone remains relatively constant over time under accelerated storage conditions.
Example 8: Freeze Fracture Microscopy
After the compositions of Examples 1 to 3 were prepared according to the examples described above, they were tested using a freeze-fracture transmission electron microscope (FF-TEM). FF-TEM samples of each formulation are prepared according to the techniques described in chapter 5 of "Low Temperature Microscopy and Analysis" by Patrick Echlin (1992), which is incorporated herein by reference. The sample is crushed at low temperature and etched at -150 ° C to remove the surface layer of water.
Freeze fracture photomicrographs of samples prepared from the compositions of Examples 1-3 are shown in FIGS. 1, 2, 3 and 4, respectively.
The photomicrograph of FIG. 3 is considered a sample prepared from the composition of Example 1 containing only nonionic liposomes. From these photomicrographs, it can be seen that the presence of large bilayer structures ranging in size from 100 to 400 nm is stable when the product is stored for 4 weeks at 50 ° C.
The photomicrograph of FIG. 2 is considered a sample prepared from the composition of Example 2 containing a nonionic liposome in the cleaning substrate. Light micrographs show the presence of complete vesicles with many bilayers.
The photomicrograph of FIG. 3 is considered a sample prepared from the composition of Example 2 containing a cationic / nonionic liposome in the cleaning substrate. From FIG. 3, it was demonstrated that the addition of the cationic component to the vesicle bilayer did not destroy the vesicles.
Overview of observations from freeze fracture micrographs FormulationObservation Liposome-shampoo (Example 2), initialMany well-distributed complete liposomes with many bilayers 2 weeks at 50 ℃Many well-distributed complete liposomes with many bilayers 4 weeks at 50 ℃Many well-distributed complete liposomes with many bilayersLiposome Shampoo (Example 3)Well distributed complete liposome 2 weeks at 50 ℃Less liposomes, aggregation of liposomes 4 weeks at 50 ℃Well distributed liposomes, some small crystalline structure
This example shows that the vesicles remain completely under accelerated aging storage conditions. This result is surprising because, according to the teachings known in the art, the interaction of the vesicles with the detergent cleaning substrate is believed to induce destruction of the vesicles.
Example 9: Scanning Electron Microscopy of Hair
Scanning electron microscopy (SEM) was performed on various cleaning systems containing the vesicle delivery system shown in Example 2 and the "Head & Shoulders" shampoo (US formulation, (L) FW8050) manufactured by the Procter & Gamble. It is used to examine the hair to compare the deposition of solids on individual hair fibers after shampooing. All of these cleaning systems contain zinc pyrithione in the form of crystals ranging in size from submicrons to microns.
The original hair area (6-7 g total weight) is washed after applying 0.1 g of each shampoo and the method is repeated a total of 10 times for each shampoo. Each washing cycle consists of a washing step followed by a blow drying until each drying after each washing. Hair is evaluated using Zeiss SEM for portions 1 inch in length taken from the middle and ends of each hair.
5 to 7 show SEM micrographs of washed hair. From these SEM micrographs, the solid deposition capacity of the shampoo in the following order is as follows: liposome-shampoo (Example 2, liposomes: Example 1, Table 1, F # 5) (FIG. 6) &gt; Example 2) (FIG. 5)> Head & Shoulders (FIG. 7).
As shown in FIG. 7, the large amount of solids deposited on the hair treated with the Head & Shoulders formulation consists of particles that are on the order of submicrons to 2 microns and are evenly distributed in the cuticle. Without wishing to be bound by this theory, the solids found in hair shampooed with shampoo base alone (Example 2) and vesicle delivery system-shampoo (Example 2, vesicle: Example 1, Table 1, F # 5) In the case of the matrix and vesicle delivery system-shampoo of elubiol and polyquaternium-7, it is believed to consist of particulates in the additional vesicle components. Thus, the latter formulation was found to bind more uniformly to the keratin compared to the Head & Shoulders formulation. This is because the components bound to the keratin are considered more useful in the treatment of diseases related to hair and scalp due to the excellent deposition of useful agents.
Example 10 Analysis of Treated Hair
For scanning electron microscopy studies, the hair treated as described above in Example 9 is extracted with methanol and then the amount of erubiol retained on and within the hair fibers is measured. In each case the hair is cut into pieces 1.5 cm in length at the middle and end of each set of hair. After weighing the hair from the cut hair and extracting with methanol, they are analyzed using the HPLC technique presented in Example 4. Deposition of active agents on and within the hair fibers is calculated based on the amount of active agent per weight of hair and analyzes the amount of active agent deposited per entire surface of the hair. The diameter of the hair is considered to be 50 μm.
The amount of erubiol retained in the hair fibers after the washing process FormulationAmount of Elrubiol per Hair Weight (µg / gm)The amount of erubiol deposited per μg of hair (μg / cm 2)Total surface area of the analyzed hair (cm 2)# Of analyzed hairs Liposome-shampoo-medium123.690.47542.141793 Liposome-shampoo-terminal196.860.75818.43784 Shampoo base alone, medium12.340.04750.732159 Shampoo base alone, terminal11.220.04624.861058
From the results presented in Table 22, the nonionic cationic cleaning system containing the vesicle delivery system of Example 2 was in the hair fiber and above 10-16 compared to the amount deposited only by the cleaning system of Example 2 alone. It can be seen that Bae elubiol is deposited. This example also shows that after treating the hair with liposome-shampoo (Example 2, Liposomes: Example 1, Table 1, F # 5), a greater amount of erubiol is deposited at the ends compared to the middle of the hair. Shows.
From this example, the addition of the introduced vesicle delivery system to the cleaning substrate composition in addition to the deposition rate achieved by the composition containing only erubiol and the cleaning substrate alone is higher than the hair fibers. It can be seen that the deposition of rubiol is significantly improved.
Example 11: Hair follicle deposition study of hamster ear model
Hair follicular units of hamster ears are described in Plewig and Luderschmidt, J. Invest. Dermatol. 68: 171-176 (1977) and Matias and Orentreich, J. Invest. Dermatol. 81: 43-46, (1983). Since it is known to have anatomical and physiological similarities with human sebaceous glands, a model suitable for examining the degree of deposition and the rate of deposition of clinically potent serum reducing active agents (e.g. to provide.
Male golden Syrian hamsters (12 weeks old) are obtained from Charles River Breeding Laboratories and their androgen-dependent sebaceous glands are left in cages for 14 weeks with 14 hours of light and 10 hours of dark cycles. By maximizing the activity, they adjust their line size. Four hamsters are used for each formulation to be tested. The dosing method consists of treating each ear with 10 μl of the formulation shown in Table 23 below, rubbing with the formulation for 30 seconds and then rinsing the formulation with 5 ml of 37 ° C. water from the ear, a total of two times Repeat. This dosing treatment is performed once a day for 3 days, and the experiment ends 24 hours after the last dose. Each animal is anesthetized with ketamine / xylazine for a total of 1.5 hours during administration (IP injection).
Table 23 below presents the formulations used in the study.
Overview of Formulations and Active Agents Used in Deposition Studies FormulationcodeExample # (F #)Active agent Liposome shampooLS-1Example 2, liposomes; Table 1, F # 4 ^** 0.25Elubiol & 1ZPT ^*Liposome shampooLS-2Example 2, liposomes; Table 1, F # 40.5Elubiol & 1ZPT ^*shampooNLS-3Example 2 (substrate only)0.25Elubiol & 1ZPT ^*shampooNLS-4Example 2 (substrate only)0.5Elubiol & 1ZPT ^*Head & ShouldersHSCommercial product1ZPT T gel-3TG-3Commercial product0.5 Elbiol Liposome shampoo1999Example 30.5 Elbiol
Only elubiol enters the liposome, ZPT is present in the free state in the cleaning substrate. ZPT is obtained from Olin. Thus, the water phase is adjusted to take into account the ZPT addition in the formulation.
** Elrubiol is added at a concentration of 1/2 of F # 4.
Each hamster's ears are incised at their bottom, and excess hair is trimmed with surgical scissors. Then, rub the bottom of the ear several times with a dry rag. The skin surface is then peeled off with scotch tape (# 810, 3M Company, St. Paul, MN) 30 to 50 times to remove the stratum corneum. The clear, glossy appearance indicates that the removal of the stratum corneum is complete. After complete removal of the stratum corneum, each peeled ear is cut to separate the lower and upper ears. The incision method is carefully performed so that cartilage exists between the lower and upper parts of the ear in contact with the lower ear. The lower ear portion is then placed on a glass slide and the hair follicular unit is removed with a surgical mass. Subsequently, removal of the sebaceous glands is confirmed by examining the ears with a Nikon Daphot inverted light microscopy before and after treatment. The absence of hair follicle units is confirmed by the presence of pores in the underlying tissue. Hair follicle units are harvested and analyzed for elrubiol and zinc pyrithione components.
From the table below, it can be seen that the vesicle delivery system containing shampoos (Formulations A and B) deliver significantly more erviol to the follicular line than the shampoo substrate alone (Formulations C and D). The cleaning substrate containing the vesicle delivery system of Example 3 (System 1999 (E)) also delivers 98 times more elubiol into the line than is achieved by the T-Gel 3 substrate alone.
From this example, the most effective composition for delivering elubiol to the follicular branch line is the vesicle delivery system containing the anionic / amphoteric / nonionic substrate of Example 3, followed by elubiol of 0.5 and 0.25, respectively. It can also be seen that the vesicle delivery system contains the anionic / amphoteric substrate of Example 2 for delivering the component.
Levels of erubiol in the hair follicle unit and lower dermis of the hamster's ear after three days of administration FormulationHair follicle unitLower dermisAmt (μg / cm ² ) Amt (μg / cm ² )LS-1 (A)0.088 ± 0.0740.063 ± 0.0530.030 ± 0.0280.022 ± 0.020 LS-2 (B)0.208 ± 0.1150.077 ± 0.0430.037 ± 0.0160.014 ± 0.006 NLS-3 (C)0.001 ± 0.0010.000 ± 0.0010.001 ± 0.000.001 ± 0.000 NLS-4 (D)0000 1999 (E)0.490 ± 0.1030.193 ± 0.0400.049 ± 0.0230.019 ± 0.009 TG-3 (F)0.005 ± 0.0020.002 ± 0.0010.009 ± 0.0020.004 ± 0.001
It can also be seen from this example that similar trends are observed when delivering zinc pyrithione (“ZPT”) in the follicular line. Even if ZPT is not introduced into the vesicles, it is surprisingly found that the incorporation of free ZPT into the vesicles externally improves the transfer of ZPT to the gland.
In addition, it can be seen from this example that the vesicle delivery system-shampoo all performed better than the shampoo lacking the vesicle delivery system in ZPT delivery to the hair follicle line. The shampoos containing the vesicle delivery system of Example 2 (Liposomes: Table 1, F4 ^** ) and Example 2 (Liposomes: Table 1, F4) (see Table 23), respectively, compared to the amount delivered by the Head & Shoulders description, It delivers 1.6 and 3.8 times more ZPT in follicular branch lines.
This example also suggests that the Hean and Shoulders substrate delivers ZPT to the lower dermis, which is usually not a desirable effect because delivery to the dermis can lead to problems of irritation for extended periods of time.
Levels of ZPT in the follicular branch unit and lower dermis after 3 days of administration FormulationHair follicle unitLower dermisVolume / surface area (μg / cm ² ) Volume / surface area (μg / cm ² )LS-10.212 ± 0.0330.039 ± 0.0600 LS-20.090 ± 0.0740.016 ± 0.01400 NLS-30000 NLS-40000 H & S0.056 ± 0.0060.011 ± 0.0010.037 ± 0.0090.007 ± 0.002
In this embodiment, when the vesicle into which the erubiol is introduced is added to the cleaning substrate, the amount of erubiol delivered to the hair follicle gland unit (sebaceous gland and tube) is the erubiol delivered by the erubiol containing cleaning substrate alone It shows a significant increase compared to the amount of ol. In addition, when ZPT is added to such formulations containing follicles with the introduced erubiol, delivery of ZPT to the follicular gland with the vesicle-free formulations containing ZPT with erubiol Increased relative to the amount.
The present invention relates to methods of enhancing transmembrane and / or topical penetration of pharmacologically active substances using not only the compositions used in the present invention but also certain vesicle delivery systems as enhancers and any detergents. Various active agents such as hair growth agents, hair inhibitors, acne treatments, hair loss agents, anti-aging agents and bleaching agents can be effectively delivered to the skin, hair follicles and sebaceous glands using the compositions of the present invention.

权利要求:
Claims (86)
[1" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally, a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer, and
B. A composition for enhancing topical administration of a useful agent, comprising an effective amount of the useful agent.
[2" claim-type="Currently amended] The composition of claim 1, wherein the vesicle delivery system further comprises one or more second double chain lipids and / or one or more second single chain lipids.
[3" claim-type="Currently amended] The composition of claim 1, wherein the total charge of the vesicle delivery system is cationic, nonionic or cationic / nonionic.
[4" claim-type="Currently amended] The composition of claim 1, wherein the first double chain lipid is selected from the group consisting of cationic double chain lipids, nonionic double chain lipids, and mixtures thereof.
[5" claim-type="Currently amended] The composition of claim 1, wherein the first double-chain lipid is present in the composition in an amount greater than about 40, based on the total weight of the vesicle bilayer.
[6" claim-type="Currently amended] The composition of claim 1 wherein the first double chain lipid is a nonionic double chain lipid selected from the group consisting of glyceryl diesters, alkoxylated amides and mixtures thereof.
[7" claim-type="Currently amended] The glyceryl diester of claim 6, wherein the glyceryl diester is glyceryl dilaurate, glyceryl dioleate, glyceryl dimyristate, glyceryl distearate, glyceryl sesoleate, glyceryl stearate lactate and their A composition selected from the group consisting of mixtures.
[8" claim-type="Currently amended] 7. The composition of claim 6, wherein the alkoxylated amide has the structure of formula (I).
Formula 1

In the above formula,
R is an unbranched alkyl group having from about 8 to about 30 carbon atoms,
m is an integer from about 12 to about 24,
b is an integer from about 12 to about 24, provided that the sum of m + b is from about 8 to about 100.
[9" claim-type="Currently amended] The composition of claim 8 wherein the alkoxylated amide is PEG-6 cocoamide.
[10" claim-type="Currently amended] The composition of claim 4, wherein the cationic first double-chain lipid is a cationic lipid containing two unsaturated fatty acid chains having about 10 to about 26 carbon atoms.
[11" claim-type="Currently amended] 11. The method of claim 10, wherein the cationic first double-chain lipids are di (soioylethyl) hydroxyethylmonium methosulfate (DSHM); N- [1- (2,3-Dioleyloxy) propyl] -N, N, N-trimethylammonium bromide (DOTMA); 1,2-dimyristyloxypropyl-N, N-dimethyl-hydroxyethyl ammonium bromide (DMRIE); [N- (N, N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol); Dioctadecyl amidoglysilspermidine (DOGS); Dimethyl dioctadecylammonium bromide (DDAB); Dioleoyl phosphatidylethanolamine (DOPE); 2,3-dioleoyloxy-N- [2- (sperminecarbozamide-O-ethyl] -N, N-dimethyl-propaneaminium trifluoroacetate (DOSPA); 1- [2- (oleic Oiloxy) -ethyl] -2-oleyl-3- (2-hydroxyethyl) imidazolinium chloride (DOTIM); 1,2-dioleoyloxy-3- (trimethylammonio) propane (DOTAP) 1,2-diacyl-3-trimethylammonium propane (TAP); 1,2-diacyl-3-dimethylammonium propane (DAP); quaternary amines such as dicodimonium chloride, quaternary dimethyldiacyl amine A composition selected from the group consisting of fatty acid salts and mixtures thereof.
[12" claim-type="Currently amended] The composition of claim 11, wherein the cationic first double-chain lipid is di (soioylethyl) hydroxyethylmonium methosulfate.
[13" claim-type="Currently amended] The composition of claim 4, wherein the nonionic double chain lipid is present in an amount from about 10 to about 65 based on the total weight of the double chain lipid in the vesicle bilayer.
[14" claim-type="Currently amended] The composition of claim 4, wherein the cationic double chain lipids are present in an amount of from about 1 to about 50, based on the total weight of the double chain lipids in the vesicle bilayer.
[15" claim-type="Currently amended] The composition of claim 4 comprising about 2 to about 30 cationic double chain lipids and about 70 to about 98 nonionic double chain lipids, based on the total weight of the cationic double chain lipids and the nonionic double chain lipids. .
[16" claim-type="Currently amended] The composition of claim 1, wherein the first single chain lipid is selected from the group consisting of nonionic single chain lipids, cationic single chain lipids, and nonionic / cationic single chain lipids.
[17" claim-type="Currently amended] The composition of claim 2, wherein the first single chain lipid and the second single chain lipid are present in the composition in an amount of about 2 to about 30, based on the total weight of the vesicle bilayer.
[18" claim-type="Currently amended] The method of claim 1, wherein the first single-chain lipid is a glyceryl monoester, polyoxyethylene fatty ether, wherein the polyoxyethylene head group has about 2 to about 100 groups, and the fatty acid tail group is about 10 to about 26 carbon atoms), alkoxylated alcohols where the alkoxy groups have about 1 to about 200 carbon atoms and fatty alkyl groups have about 8 to about 30 carbon atoms, alkoxylated alkyl phenols where , Alkoxy groups have about 1 to about 200 carbon atoms, fatty alkyl groups have about 8 to about 30 carbon atoms, polyoxyethylene derivatives of polyol esters, alkoxylated acids, where the alkoxy groups are about 1 To about 200 carbon atoms, and fatty alkyl groups have from about 8 to about 30 carbon atoms) and mixtures thereof.
[19" claim-type="Currently amended] 19. The composition of claim 18, wherein the first single chain lipid is selected from the group consisting of polyoxyethylene fatty ethers, glyceryl monoesters, and mixtures thereof.
[20" claim-type="Currently amended] The method of claim 19, wherein the first single-chain lipid is polyoxyethylene stearyl ether, polyoxyethylene myristyl ether, polyoxyethylene lauryl ether, glyceryl laurate, glyceryl myristate, glyceryl stearate and Is selected from the group consisting of: wherein each ether has from about 5 to about 10 oxyethylene units.
[21" claim-type="Currently amended] The method of claim 1, wherein the cationic single-chain lipids are quaternary trimethylmonoacyl amines, wherein the acyl group has from about 8 to about 30 carbon atoms, stearamidopropyl dimethyl (myristyl acetate) ammonium chloride (quaternium 70 ), Triethylhydrogenated tallow ammonium chloride (quaternium 16), benzalkonium chloride, and derivatives and mixtures thereof.
[22" claim-type="Currently amended] The composition of claim 2, wherein the nonionic single chain lipid is present in the composition in an amount of from about 1 to about 30, based on the total weight of the single chain lipid in the vesicle bilayer.
[23" claim-type="Currently amended] The composition of claim 2, wherein the cationic single chain lipid is present in the composition in an amount from about 1 to about 30 based on the total weight of the single chain lipid in the vesicle bilayer.
[24" claim-type="Currently amended] The composition of claim 2 comprising about 5 to about 20 cationic single chain lipids and about 5 to about 20 nonionic single chain lipids, based on the total weight of cationic single chain lipids and nonionic single chain lipids. .
[25" claim-type="Currently amended] The composition of claim 1, wherein the sterol is selected from the group consisting of phytocholesterol, hydrocortesone, alpha-tocopherol, beta sitosterol, bisabolol, and mixtures thereof.
[26" claim-type="Currently amended] The composition of claim 1 wherein the hydrophilic component is selected from the group consisting of water, polar solvents and mixtures thereof.
[27" claim-type="Currently amended] The formulation of claim 1, wherein the useful formulation is elrubiol, 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide, finasteride, ketoconazole, salicylic acid, zinc pyrithione, coul tar, benzoyl per Oxides, shale oils and derivatives thereof, selenium sulfide, hydrocortisone, sulfur, menthol, pramoxin hydrochloride, tricetylammonium chloride, polyquaternium 10, panthenol, panthenol triacetate, vitamin A and derivatives thereof, vitamin B and derivatives thereof , Vitamin C and derivatives thereof, vitamin D and derivatives thereof, vitamin E and derivatives thereof, vitamin K and derivatives thereof, keratin, lysine, arginine, hydrolyzed wheat protein, hydrolyzed silk protein, octyl methoxycinnamate, oxy Crude selected from the group consisting of benzone, minoxidil, titanium dioxide, zinc dioxide, retinol, erthromycin, tretinoin and mixtures thereof Water.
[28" claim-type="Currently amended] The composition of claim 1, wherein the useful agent is elrubiol, ketoconazole, salicylic acid, and mixtures thereof.
[29" claim-type="Currently amended] The composition of claim 27 wherein the useful agent is mixed with an alpha-hydroxy acid, sulfate-containing compound, or mixtures thereof.
[30" claim-type="Currently amended] The method of claim 1, wherein based on the entire vesicle delivery system,
A. about 40 to about 60 first double chain lipids,
B. about 1 to about 35 first single-chain lipids,
C. about 1 to about 25 sterols and
D. A composition consisting of about 60 to about 99 hydrophilic components.
[31" claim-type="Currently amended] An article composed of the composition of claim 1.
[32" claim-type="Currently amended] 32. The product of the composition of claim 31 wherein the product is a lotion, cream, ointment, mousse, bath, spray, aerosol, patch for skin, gel, soap, tonic, toner, shampoo or mixture thereof.
[33" claim-type="Currently amended] The method of claim 1, wherein the vesicle bilayer is based on the total weight of the vesicle bilayer,
A. glyceryl distearate double chain lipids from about 40 to about 60,
B. about 10 to about 45 polyoxyethylene-10-stearyl ether single chain lipids; and
C. A composition consisting of about 5 to about 45 cholesterol.
[34" claim-type="Currently amended] The method of claim 1, wherein the vesicle bilayer is based on the total weight of the vesicle bilayer,
A. glyceryl distearate double chain lipids from about 25 to about 95,
B. polyoxyethylene-10-stearyl ether single chain lipid, about 1 to about 45,
C. about 1 to about 40 cholesterol and
D. A composition consisting of about 1 to about 45 di (soylylethyl) hydroxyethylmonium methosulfate (DSHM) cationic double chain lipids.
[35" claim-type="Currently amended] The method of claim 1, wherein based on the total weight of the vesicle bilayer,
A. glyceryl dilaurate about 25 to about 60,
B. glyceryl distearate about 5 to about 45,
C. about 1 to about 40 cholesterol,
D. about 5 to about 40 polyoxyethylene-10-stearyl ether and
E. A composition consisting of about 1 to about 45 di (soylylethyl) hydroxyethylmonium methosulfate.
[36" claim-type="Currently amended] The method of claim 1, wherein based on the total weight of the composition,
A. useful formulations from about 0.001 to about 20 and
B. A vesicle delivery system consisting of about 0.06 to about 60.
[37" claim-type="Currently amended] Based on the total weight of the composition,
A) i. At least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii. A vesicle delivery system consisting of a hydrophilic carrier contained in a vesicle bilayer,
B) effective amounts of useful agents and
C) A cleaning composition for enhancing topical administration of a useful formulation comprising a detergent.
[38" claim-type="Currently amended] 38. The cleaning composition of claim 37, wherein the detergent comprises soap, ionic surfactant, nonionic surfactant, cationic surfactant, zwitterionic surfactant, amphoteric surfactant, betaine surfactant, and mixtures thereof.
[39" claim-type="Currently amended] 38. The detergent of claim 37, wherein the detergent is based on the total weight of the detergent,
A. about 0.1 to about 20 anionic surfactant,
B. nonionic surfactant about 0 to about 10,
C. cationic surfactant from about 0 to about 5 and
D. A cleaning composition consisting of about 0.1 to about 15 amphoteric surfactant.
[40" claim-type="Currently amended] The method of claim 39, wherein the detergent is based on the total weight of the surfactant,
A. about 0.5 anionic surfactant selected from the group consisting of sodium C14-16 olefin sulfonate, ammonium lauryl sulfate, sodium trideces sulfate, sodium laureth sulfate, disodium laureth sulfosuccinate and mixtures thereof To about 15,
B. a nonionic surfactant selected from the group consisting of polysorbate 20, cocamide MEA, coconut fatty acid diethanol amide and mixtures thereof about 1 to about 7,
C. about 0 to about 4 cationic surfactants selected from n-acylamidopropyl dimethylamine oxide and
D. A cleaning composition consisting of about 1 to about 10 amphoteric surfactants selected from the group consisting of amidoalkylbetaines, alkyl imidazolines having about 8 to about 18 carbon atoms in the alkyl group, and mixtures thereof.
[41" claim-type="Currently amended] 40. The detergent of claim 39, wherein the detergent is based on the total weight of the detergent:
A. about 50 to about 99 anionic surfactants selected from the group consisting of alkyl sulfates, alkyl ether sulfates and mixtures thereof, wherein the alkyl groups have from about 8 to about 18 carbon atoms;
B. A cleaning composition consisting of about 1 to about 20 cocamidopropyl betaine amphoteric surfactant.
[42" claim-type="Currently amended] The method of claim 39, wherein the detergent is based on the total weight of the surfactant,
A. Anionic surfactants selected from the group consisting of sodium PEG-7 olive oil carboxylate, alkyl sulfates, alkyl ether sulfates, and mixtures thereof, wherein the alkyl groups have from about 8 to about 18 carbon atoms. ,
B. cocamidopropyl betaine amphoteric surfactant from about 1 to about 30 and
C. A cleaning composition consisting of about 2 to about 10 cocamoniumcarbomoyl chloride cationic surfactant.
[43" claim-type="Currently amended] The cleaning composition of claim 39, further comprising a suspending agent.
[44" claim-type="Currently amended] The method of claim 43,
a) acrylate polymers and copolymers thereof,
b) fatty acyl derivatives of which the acyl group is
c) esters of long chain fatty acids, wherein the fatty acid is
d) alkyl dimethylamine oxides having from about 8 to about 18 carbon atoms in the alkyl group,
e) methylvinylether / maleic anhydride copolymer (PVM / MA decadiene crosspolymer) crosslinked with 1,9-decadiene PolyVM / MA,
f) cellulose derivatives,
g) distearyl phthalate amide,
h) di (hydrogenated) tallow phthalate amide,
i) primary amines having fatty alkyl groups of at least 16 carbon atoms,
j) polyacrylic acid,
k) polysaccharide rubber,
l) colloidal clay,
m) colloidal silica and
n) a cleaning composition further comprising a suspending agent selected from the group consisting of mixtures thereof.
Formula 6

Formula 7

In the above formula,
R ₁₀ comprises saturated or unsaturated, substituted or unsubstituted carbon chain having from about 7 to about 21 carbon atoms,
R ₁₁ is an alkyl group having from about 8 to about 30 carbon atoms,
R ₁₂ is an alkyl group having from about 8 to about 30 carbon atoms.
[45" claim-type="Currently amended] The method of claim 44, wherein the carbomer, hydroxyethyl cellulose, methylvinylether / maleic anhydride copolymer (PVM / MA decadiene crosspolymer) crosslinked with 1,9-decadiene PolyVM / MA, acrylate / amino A cleaning composition further comprising a suspending agent selected from the group consisting of acrylate C10-30 alkyl PEG-20 itaconate copolymers and mixtures thereof.
[46" claim-type="Currently amended] 38. The composition of claim 37, based on the total weight of the composition
a) about 1 to about 80 vesicle bilayers,
b) about 0.001 to about 20 useful agents and
c) a composition consisting of about 1 to about 30 detergents.
[47" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. A cleaning composition comprising a detergent.
[48" claim-type="Currently amended] 48. The composition of claim 47, based on the total weight of the composition
a) about 0.5 to about 7 vesicle bilayers and
b) a composition consisting of about 5 to about 25 detergents.
[49" claim-type="Currently amended] A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. A method of enhancing topical administration of a useful formulation, comprising topically administering to a human or animal a composition consisting of an effective amount of the useful formulation.
[50" claim-type="Currently amended] The formulation of claim 49, wherein the useful formulation is elrubiol, 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide, finasteride, ketoconazole, shale oil and derivatives thereof, salicylic acid, zinc pyrithione , Coar tar, benzoyl peroxide and mixtures thereof.
[51" claim-type="Currently amended] The method of claim 49, wherein the composition further comprises a detergent.
[52" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. A method of treating hair loss comprising topically administering a composition consisting of an effective amount of a hair loss therapeutic agent to a desired site for treating hair loss in a human or animal.
[53" claim-type="Currently amended] 51. The method of claim 50, wherein the composition further consists of a detergent.
[54" claim-type="Currently amended] 51. The method of claim 50, wherein the hair loss treatment is minoxidil, N ''-cyano-N- (tert pentyl) -N'-3-pyridinyl-guanidine, diazoxide, vitamin E, vitamin C, vitamin E acetate , Vitamin C palmitate; Erythropoietin; Prostaglandin E1, prostaglandin F2-alpha; Oleic acid; Heat shock protein 27 ("HSP 27"), heat shock protein 72 ("HSP 72"); Verapamil HCL, nifedipine, diltiagemamylide, cyclosporin, Fk-506; Finasteride, 17-beta estradiol, EGF, FGF, benzoxapropene, tretinoin, IL-6, IL-1alpha and IL-1beta ICAM, betamethasone, aloe, clove, ginseng, diurethane, glucose, orange, xanthoxylum , Elrubiol, ketoconazole, zinc pyrithione; Streptomycin; Cycloheximide and mixtures thereof.
[55" claim-type="Currently amended] 54. The method of claim 53, wherein the hair loss treatment is 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide, N "-cyano-N- (tert-pentyl) -N'-3 Pyridinyl-guanidine, retinoids and derivatives thereof, finasteride, minoxidil, ketoconazole or mixtures thereof.
[56" claim-type="Currently amended] 56. The method of claim 55, wherein the hair loss therapeutic agent is mixed with an alpha-hydroxy acid, sulfate containing compound, or mixtures thereof.
[57" claim-type="Currently amended] The method of claim 53, wherein the hair loss therapeutic agent is present in an amount from about 0.001 to about 20 based on the total weight of the composition.
[58" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. A method of inhibiting hair growth, comprising topically administering a composition consisting of an effective amount of a hair growth inhibitor to a desired site for human or animal hair loss.
[59" claim-type="Currently amended] 59. The method of claim 58, wherein the hair growth inhibitor is selected from the group consisting of tumor therapeutics; Anticoagulants; Thyroid drugs; lithium; Lithium carbonate; Interferon; Retinoids; Hyperlipidemia drugs; thallium; Mercury; Albendazole; Allopurinol; Amiodarone; Amphetamine; Androgen; Bromocriptine; Butyrophenone; Carbamazepine; Cholestyramine; Cimetidine; Clofibrate; Danazol; Desipramine; Dicyrazine; Ethambutol; Ethionamide; Fluoxetine; Gentamicin, gold salts; Hydantoin; Ibuprofen; Impramine; Immunoglobulins; Indandione; Indomethacin; Intraconazole; Levadopa; Mapprotilin; Methisergid; Metoprolol; Metirapone; Nadolol; Nicotinic acid; Potassium thiocyanate; Propranolol; Pyridostymine; Salicylates; Sulfasalazine; Terfenadine; Thiamphenicol; Thiouracil; Trimetadione; Troparanol; Valproic acid and mixtures thereof.
[60" claim-type="Currently amended] 59. The method of claim 58, wherein the hair growth inhibitor is serine protease, retinol, isotretinoin, betamethisone, alpha-tocophenol and derivatives thereof, or mixtures thereof.
[61" claim-type="Currently amended] 59. The method of claim 58, wherein the hair growth inhibitor is present in an amount from about 0.001 to about 20, based on the total weight of the composition.
[62" claim-type="Currently amended] 59. The method of claim 58, further comprising a detergent.
[63" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. A method of treating or minimizing the effects of aging, comprising topically administering a composition consisting of an effective amount of an anti-aging active to a desired site of a human or animal.
[64" claim-type="Currently amended] 64. The method of claim 63, wherein the anti-aging active agent is selected from the group consisting of sunscreens, retinoids and derivatives thereof, vitamins and derivatives thereof, antioxidants, hydrocarboxylic acids, plant extracts and mixtures thereof.
[65" claim-type="Currently amended] 64. The method of claim 63, wherein the anti aging active agent is retinol, tretinoin or a mixture thereof.
[66" claim-type="Currently amended] The method of claim 63, wherein the anti-aging active agent is present in an amount from about 0.01 to about 10 based on the total weight of the composition.
[67" claim-type="Currently amended] The method of claim 63, wherein the composition further consists of a detergent.
[68" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. A method of treating acne, comprising topically administering a composition consisting of an effective amount of an acne therapeutic to a desired site of a human or animal.
[69" claim-type="Currently amended] 69. The method of claim 68, wherein the acne treatment is selected from the group consisting of imidazole, retinoid, salicylic acid, benzoyl peroxide, antibiotic, antiandrogen, 5-alpha-reductase isotype, anti-inflammatory agent, plant extract, and mixtures thereof .
[70" claim-type="Currently amended] The method of claim 68, wherein the acne treatment is retinol, elubiol, antibiotics, salicylic acid, or mixtures thereof.
[71" claim-type="Currently amended] The method of claim 68, wherein the anti acne agent is present in an amount from about 0.01 to about 10 based on the total weight of the composition.
[72" claim-type="Currently amended] The method of claim 68, wherein the composition further consists of a detergent.
[73" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. Depigmentation of the skin, comprising topically administering a composition consisting of an effective amount of depigmentation active agent to a desired site of a human or animal.
[74" claim-type="Currently amended] 74. The method of claim 73, wherein the decolorizing active is selected from the group consisting of retinoids and derivatives thereof, kojic acid and derivatives thereof, hydroquinone and derivatives thereof, transsecsamic acid, batamine, azelaic acid, plant extracts, and mixtures thereof. .
[75" claim-type="Currently amended] 74. The method of claim 73, wherein the decolorizing active is kojic acid, retinol, hydroquinone, transsection triacid, or mixtures thereof.
[76" claim-type="Currently amended] The method of claim 73, wherein the bleach activator is present in an amount from about 0.01 to about 10, based on the total weight of the composition.
[77" claim-type="Currently amended] 74. The method of claim 73, wherein the composition further consists of a detergent.
[78" claim-type="Currently amended] A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. Dandruff, seborrheic dermatitis and psoriasis, comprising topically administering to a desired site of a human or animal a composition comprising an effective amount of a useful agent selected from the group consisting of dandruff treatments, seborrheic dermatitis treatments, psoriasis treatments, and mixtures thereof And / or methods of treating the symptoms associated with them.
[79" claim-type="Currently amended] 79. The method of claim 78, wherein the dandruff treatment, seborrheic dermatitis treatment and psoriasis treatment are zinc pyrithione, shale oil and derivatives thereof, selenium sulfide, sulfur, salicylic acid, coultar, povidone-iodine, imidazole (e.g. ketoconazole, dichlorophenyl imide). Dazolodioxalan, clotrimazole, itraconazole, myconazole, klimbazole, thioconazole, sulfonazole, butoconazole, fluconazole, myconazole nitrite and possible stereoisomers and derivatives thereof (e.g., anthraline), Pyroctone olamine (octopyroxox), selenium sulfide, cyclopyroxolamine, psoriasis treatment, vitamin A homologue, corticosteroids and mixtures thereof.
[80" claim-type="Currently amended] 80. The method of claim 79, wherein the dandruff treatment, seborrheic dermatitis treatment and psoriasis treatment are elubiol, ketoconazole, coultar, salicylic acid, zinc pyrithione, selenium sulfide, hydrocortisone, sulfur, menthol, pramoxin hydrochloride, and mixtures thereof. Method selected from the group consisting of:
[81" claim-type="Currently amended] The method of claim 78, wherein the dandruff treatment, seborrheic dermatitis treatment, and psoriasis treatment are present in an amount from about 0.001 to about 20, based on the total weight of the composition.
[82" claim-type="Currently amended] 79. The method of claim 78, wherein the composition further consists of a detergent.
[83" claim-type="Currently amended] Based on the total weight of the composition,
A. i) at least one first double-chain lipid (a); Optionally a vesicle bilayer consisting of at least one first single-chain lipid (b) and at least one sterol (c), and ii) a vesicle delivery system consisting of a hydrophilic carrier contained within the vesicle bilayer;
B. A method of removing hair, comprising topically administering a composition consisting of an effective amount of a hair loss agent to a desired site of a human or animal.
[84" claim-type="Currently amended] 84. The method of claim 83, wherein the hair loss agent is selected from the group consisting of calcium thioglycolate, magnesium thioglycolate, potassium thioglycolate, strontium thioglycolate, and mixtures thereof.
[85" claim-type="Currently amended] 84. The method of claim 83, wherein the hair loss agent is present in an amount from about 0.001 to about 20, based on the total weight of the composition.
[86" claim-type="Currently amended] 86. The method of claim 85, wherein the composition further consists of a detergent.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US9345736B2|2016-05-24|Topical treatment of radiation dermatitis using hamelia patens

---

Ashtikar et al.2016|Transdermal delivery from liposomal formulations–Evolution of the technology over the last three decades

---

EP0963195B1|2002-07-17|Compositions containing an antifungal and a cationic agent

---

US5904932A|1999-05-18|Topical preparation containing a suspension of solid lipid particles

---

AU2004259004B2|2010-04-22|New branched sulfates for use in personal care formulations

---

US6030948A|2000-02-29|Hair regeneration compositions for treatment of alopecia and methods of application related thereto

---

KR100719782B1|2007-05-21|Foaming oil gel compositions

---

KR101951916B1|2019-02-25|Method for producing cosmetic, method for preparing gel for cosmetics, and method for reducing quantity of high-molecular thickener added to starting materials of cosmetic

---

JP3610983B2|2005-01-19|Ascorbyl-phosphoryl-cholesterol

---

EP1391194B1|2008-05-28|Preparation for hair and/or scalp

---

Sinico et al.2005|Liposomes as carriers for dermal delivery of tretinoin: in vitro evaluation of drug permeation and vesicle–skin interaction

---

US8632759B2|2014-01-21|Hair restorer

---

US6762158B2|2004-07-13|Personal care compositions comprising liquid ester mixtures

---

JP3240330B2|2001-12-17|Pharmaceutical and cosmetic preparations containing salts of colanic acid

---

AU2002367171B2|2008-02-21|Combined stable cationic and anionic surfactant compositions

---

KR100394770B1|2003-08-14|Stabilization method of nano-emulsion using tocopheryl derivatives and external application for skin containing the stabilized nano-emulsion

---

EP1663399B1|2010-07-21|Surfactant mixtures for reducing the skin irritant action of cosmetic and/or dermatological compositions

---

KR101364470B1|2014-02-19|Pharmaceutical composition for treating acne

---

JP6248038B2|2017-12-13|Ceramide lamella structure and skin external preparation composition containing the same

---

KR101231914B1|2013-02-08|Cosmetic or dermopharmaceutical composition for reducing the signs of cutaneous ageing

---

TWI257310B|2006-07-01|Topical delivery systems for active agents

---

US5030442A|1991-07-09|Non-crystalline minoxidil composition

---

US5607693A|1997-03-04|Cosmetic or pharmaceutical composition, especially dermatological composition, containing oxyacanthine, intended in particular for stimulating hair growth or retarding hair loss

---

US7262158B1|2007-08-28|Cleansing compositions comprising a liquid silicone and ester mixture

---

US7074747B1|2006-07-11|Cleansing compositions

同族专利:

---

公开号 | 公开日

---

CN1285186A|2001-02-28|

---

US20040091443A1|2004-05-13|

---

CN1216595C|2005-08-31|

---

TWI274588B|2007-03-01|

---

AU3646700A|2000-11-30|

---

BR0002285A|2001-01-23|

---

MXPA00005243A|2003-03-12|

---

US20020102295A1|2002-08-01|

---

CA2309373A1|2000-11-27|

---

JP2001019634A|2001-01-23|

---

EP1060732A3|2001-12-12|

---

EP1060732A2|2000-12-20|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1999-05-27|Priority to US32089499A

---

1999-05-27|Priority to US9/320894

---

2000-05-26|Application filed by 차알스 제이. 메츠, 존슨 앤드 존슨 컨수머 캄파니즈, 인코포레이티드

---

2001-06-15|Publication of KR20010049428A

优先权:

---

申请号 | 申请日 | 专利标题

---

US32089499A| true| 1999-05-27|1999-05-27|

---

US9/320894|1999-05-27|