EP0693932A4 - Procedes et compositions pour induire une separation de phase des deux couches lipidiques de l'epithelium - Google Patents

Procedes et compositions pour induire une separation de phase des deux couches lipidiques de l'epithelium

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Publication number
EP0693932A4
EP0693932A4 EP94911673A EP94911673A EP0693932A4 EP 0693932 A4 EP0693932 A4 EP 0693932A4 EP 94911673 A EP94911673 A EP 94911673A EP 94911673 A EP94911673 A EP 94911673A EP 0693932 A4 EP0693932 A4 EP 0693932A4
Authority
EP
European Patent Office
Prior art keywords
group
composition according
epithelial
epicholesterol
cholesterol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP94911673A
Other languages
German (de)
English (en)
Other versions
EP0693932A1 (fr
Inventor
Peter M Elias
Carl R Thornfeldt
Stephen Grayson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California
DMK Pharmaceuticals Corp
Original Assignee
University of California
Cellegy Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of California, Cellegy Pharmaceuticals Inc filed Critical University of California
Priority claimed from PCT/US1994/003085 external-priority patent/WO1994021271A1/fr
Publication of EP0693932A1 publication Critical patent/EP0693932A1/fr
Publication of EP0693932A4 publication Critical patent/EP0693932A4/fr
Ceased legal-status Critical Current

Links

Definitions

  • This invention relates to a method for enhancing permeation of topically administered physiologically active agents by inducing phase separation of stratum corneum intercellular lipid bilayers in epidermis and keratinized mucous membrane.
  • epithelia The major function of epithelia, including the stratum corneum of epidermis and of keratinizing mucous membranes, is to prevent the excessive loss of bodily fluids. If the epithelial barrier function is disrupted or perturbed, it stimulates a variety of metabolic changes in the epidermis and mucous membranes leading to repair of the barrier defect. While the barrier is beneficial for protection against damage from ultraviolet radiation, desiccation, chemical, frictional, and blunt trauma, it also impedes the percutaneous and transmucosal penetration of topically applied medicaments of potential benefit to the host.
  • the epithelial barrier resides in a system of multuayered lipid bilayers that exist throughout the stratum corneum and keratinized mucous membrane intercellular spaces.
  • These lipid bilayers in the stratum corneum contain three major lipid components: ceramides, free fatty acids, and cholesterol, present in an approximately equimolar ratio and, in addition, a small, but critical, quantity of acylceramides.
  • These lipid bilayers in the keratinized mucous membrane contain glucosylceramide instead of ceramide and acylceramide.
  • Typical solvents or detergents alter the physical properties of intercellular membrane bilayers.
  • solvents or detergents include dimethylsulfoxide (DMSO), oleyl alcohol (OA), propylene glycol, methyl pyrrolidone and AZONE ® (dodecyl azyl cycloheptan 2-one).
  • DMSO dimethylsulfoxide
  • OA oleyl alcohol
  • propylene glycol propylene glycol
  • methyl pyrrolidone methyl pyrrolidone
  • AZONE ® dodecyl azyl cycloheptan 2-one
  • 4,177,267 discloses topical steroid compositions containing dimethylsulfoxide as an epithelial penetration enhancer. It is generally believed that many of these epithelial penetration enhancers fluidize the polar head group (e.g., DMSO) and/or nonpolar tail group (e.g., OA) domains within the membrane bilayers. Yet, some compounds with significant fluidizing effect have been shown to be incapable of substantially increasing epithelial permeability. While these methods typically enhance penetration of certain compounds by three- to five ⁇ fold, these methods are only relatively effective for smaller lipophilic and amphiphathic molecules. Hydrophilic compounds such as proteins or peptides do not penetrate in pharmaceutically useful quantities through the epithelia by most of these methods.
  • This invention is based on the finding that the phase separation of stratum corneum and mucous membrane intercellular lipid bilayers can be induced by several mechanisms, and that the epithelial penetration of a given physiological- ly active substance can occur and/or be substantially improved once such intercellular phase separation has been affected.
  • this invention provides a method for inducing phase separation of epithelial intercellular lipid bilayers in a host in need of topical administration of a physiologically active substance delivered percutaneously or transdermally, which comprises applying to the skin or mucosa of the host an effective amount of an intercellular phase-separating agent.
  • this invention provides a topical composition for inducing phase separation of stratum corneum intercellular lipid bilayers of the epidermis and of the keratinized mucous membrane in a host in need of topical administration of a physiologically active substance delivered percutaneously or transdermally, which comprises an effective amount of an intercellular phase- separating agent, together with a physiologically acceptable carrier delivered percutaneously or transdermally.
  • this invention provides a method for enhancing the percutaneous, transmucosal and transdermal penetration of a physiologically active substance in a host in need of topical administration of the substance, which comprises applying to the skin or mucosa of the host an effective amount of an intercellular phase-separating agent.
  • FIGURE 1 shows TEWL when animals were treated with acetone followed by HEPES with variable pHs.
  • FIGURE 2 shows TEWL when animals were treated with acetone followed by PIPES with variable pHs.
  • FIGURE 3 shows TEWL when animals were treated with acetone followed by sodium phosphate with variable pHs.
  • FIGURE 4 shows TEWL when animals were treated with acetone followed by DCCD.
  • FIGURE 5 shows TEWL when animals were treated with acetone followed by
  • FIGURE 6 shows TEWL when animals were treated with acetone followed by DCCD.
  • FIGURE 7 shows TEWL when animals were treated with acetone followed by NEM, NBD-chloride or BAF.
  • Intercellular phase separation occurs when the capacity of the multuayered lipid bilayers to take up excess quantities of exogenous lipids or other fluidizing molecules is exceeded. As a result, spaces form when the multuayered lipid bilayers are pushed apart or to one side, thus, separating them within the intercellular spaces. These spaces extend and coalesce until significant spaces are present within and between the lipid bilayers within the intercellular spaces (i.e., phase separation), thus, disrupting barrier integrity.
  • phase separation can be induced by any one or more of the following mechanisms:
  • the method of this invention principally employs an effective amount of one or more of these epithelial intercellular phase separating agents.
  • an intercellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epicellular phase separating agent means any compound which would fall within the above-referenced categories.
  • epidermal sterols, esters and salts thereof includes, among others, cholesterol, cholesterol sulfate, and cholesteryl sulfate.
  • an effective amount means that the amount of th intercellular separating agent is applied topically in sufficient quantities t induce phase separation and to enhance epithelial permeation of a given physiologically active substance to a desired degree in the skin or vasculature.
  • the amount can vary according to the effectiveness of each phase separating agent, the depth of cutaneous penetration, the age, and response of th individual host, etc. More importantly, the amount should be determined based on the skin or mucosa penetration efficiency of a physiologically active substance when the substance is administered together with a phase- separating agent.
  • the required quantity to be employed in this invention can be determined readily by those skilled in the art.
  • penetration enhancement or “permeation enhancement” as used herein relates to an increase in the permeability of the epithelium to physiologically active substance; i.e., so as to increase the rate at which th substance permeates through the epithelial barrier.
  • the substance may b targeted to remain within any of the subjacent layers of the skin or mucosa o may later enter the bloodstream of a host.
  • the term "host” includes humans and non-human mammals.
  • Non-human mammals of particular interest are domesticated species such a dogs, cats, monkeys, cows, horses, llamas, sheep, pigs, and goats.
  • the term "physiologically active substance” is intended to encompass any substance that will produce a physiological response when topically administered to a host.
  • the terms include therapeutic or prophylactic agents in all major therapeutic/prophylactic areas of medicine as well as nutrients, cofactors, and xenobiotics.
  • Suitable substances include, but are not restricted to, antifungals such as amphotericin B, griseofulvin, miconazole, ketoconazole, tioconazole, itraconazole, and fluconazole; antibacterials such as penicillins, cephalosporins, tetracyclines, aminoglycosides, erythromicin, gentamicins, polymyxin B; anti-cancer agents such as 5-fluorouracil, bleomycin, methotrexate, hydroxyurea; anti- inflammatories such as glucocorticoids, including hydrocortisone, colchicine; nonsteroidal antiinflammatory agents including ibuprofen, indomethacin, and piroxicam; antioxidants, such as tocopherols, carotenoids, metal chelators, ubiquinones, or phytate; antihypertensive agents such as prazosin, verapamil, nifedipine, and dilti
  • Cytokines include tumor necrosis factors, the interleukins, growth factors, colony stimulating factors, and interferons.Other useful drugs, in approved commercially available formulations, and their recommended dosages are listed in the annual publication of the Physicians' Desk Reference, published by Medical Economics Company, a division of Litton Industries, Inc.
  • More than one physiologically active substance may be included, if desired, in the topical composition of this invention.
  • the active substance will be present in the composition in an amount sufficient to provide the desired physiological effect with no apparent toxicity to the host.
  • the appropriate dosage level of the physiologically active substance without the use of the intercellular phase-separating agents of the present invention, are known to one skilled in the art. These conventional dosage levels correspond to the upper range of dosage levels for compositions, including a physiologically active substance and an intercellular phase-separating agent. However, because the delivery of the active substance is enhanced by the intercellular phase separation agents of this invention, dosage levels significantly lower than a conventional dosage level may be used with success.
  • the active substance will be present in the composition in an amount from about 0.0001 % to about 60%, more preferably about 0.01 % to about 20% by weight of the total composition depending upon the particular substance employed.
  • the amount of the intercellular phase separating agent present in the composition will depend on a number of factors. However, generally the amount will range from about 0.01 to about 25% by weight of the total composition, with levels of from about 0.05 to about 10% being preferred.
  • the intercellular phase-separating agents useful in the compositions and methods of the present invention include any epithelial sterol, esters, salts, or precursors thereof and nonphysiologic analogs thereof. Cholesterol accounts for 20-25% of the stratum corneum lipids by weight.
  • the intercellular phase-separating agents can be biosynthetic precursors of the epithelial sterols. Preferred precursors include squalene, 7-dehydrocholesterol, lanosterol, desmosterol, zymosterol, cholesterol sulfate, and cholesterol esters.
  • the intercellular phase-separating agents can be inactive synthetic (nonphysiologic) analogs of the epithelial sphingolipids including stearylamine and sterols, esters, and salts and precursors thereof, including epicholesterol and cholesterol phosphate.
  • This embodiment also comprises combination of two or more of these anlogs combined with a synthetic fatty acid analog such as transvaccenic acid.
  • the intercellular phase separating agents can be biological pH modifiers.
  • biological pH modifiers includes both physiologically acceptable buffers, proton pump inhibitors, and granule secretion inhibitors. Suitable buffers act as a proton acceptor in vivo. Tris(hydroxymethyl) aminomethyl maleate (often referred to as TRIS), (N-[2-
  • HEPES Hydroxyethyl] piperazine-N'-[2-ethanesulfonic acid]) (often referred to as HEPES), piperazine-N,N'-bis[2-ethanesulfonic acid (often referred to as PIPES), morpholine sulfonic acid (often referred to as MES) and 1 ,4-piperazine- diethanesulfonic acid are preferred.
  • PIPES piperazine-N,N'-bis[2-ethanesulfonic acid
  • MES morpholine sulfonic acid
  • 1 ,4-piperazine- diethanesulfonic acid are preferred.
  • TRIS, HEPES, and MES are most preferred.
  • Other organic amines such as tri(hydroxymethyl)aminomethane (THA), 2,4,6-trimethylpyridine and 2-amino-2-methyl-1 ,3-propanediol can be used.
  • Suitable proton pump inhibitors include ionophores such as monensin, lasalocid, chloroquine, nigericin, valinomycin, gramicidin D, and salinomycin.
  • Other preferred proton pump inhibitors are n-ethyimaleimide (NEM), N,N'- dicyclohexylcarbodiimide (DCCD), NBD-chloride, and bafilomycin (BAF) A-, or
  • the drugs tend to accumulate in cellular lysosomes and cause skin irritation.
  • This invention is applicable not only to the weak base drugs as taught in U.S. Patent No. 5,130,139, but also to non-irritating drugs outside the scope thereof.
  • the use of the biological pH modifiers is particularly useful for the penetration enhancement of non-irritating drugs of therapeutical value.
  • the "proton pump inhibitors” block the delivery to and/or confine proton equivalents to the intercellular spaces, thus precluding the intercellular pH from lowering.
  • Glucocerebrosides and phospholipids are converted to ceramides and free fatty acids, respectively, by enzymatic hydrolysis in the acidic environment of the stratum corneum. In mucous membranes, phospholipids are converted to free fatty acids by this mechanism. At a pH of 6.0 or higher, this enzymatic hydrolysis ceases, which leaves the non-metabolized lipid precursors intact. The accumulation of these precursor molecules leads to phase separation.
  • the correct final proportion of free fatty acids, ceramides or glucosylceramides, and cholesterol, required for the formation of lipid bilayer structures that mediate epithelial barrier function, will not be generated.
  • An effective amount of the biological buffers to be included in the composition of this invention should be sufficient to bring the intercellular pH of the epithelium to greater than 6.0.
  • Topical treatment regimens comprise applying the composition directly to the skin or mucosa, i.e., at the application site, from one to several times daily.
  • Any one of the above-indicated intercellular phase separating agents permits the significantly improved topical application of the physiologically active substance in terms of epithelial permeation.
  • more than one intercellular phase-separating agent can be co-applied to the skin or mucosa of a host in a combined formulation. Alternatively, they can be applied concurrently as separate formulations if such combination synergistically enhances percutaneous or transmucosal absorp ⁇ tion.
  • one agent can be applied before or after application of the other agent(s) provided that the time interval between the two (or three) is not too lengthy, i.e., not more than a few hours.
  • the physiologically active substance can be co-administered to the host with the topical compositions which contain one or more of the intercellular phase separating agents. Alternatively, the active substance may be administered after application of the topical composition. It is, however, for convenience to the host and the prescribing physician who prescribe medicaments to use the physiologically active agent and the intercellular phase separating agents as a single composition formulation.
  • the single or combined intercellular phase separating agent is applied to the skin or mucosa in combination with a physiologically acceptable carrier.
  • the carrier may comprise any one of conventional topical formulation bases such as those described in Remington's
  • Preferred penetration-enhancing compounds include 1- dodecylazacycloheptan-2-one (AZONE ® ) (Stoughton, Arch. Dermatol., 1982, 118), DMSO, propylene glycol, oleyl alcohol, and methyl pyrrolidone.
  • the use level of the additional penetration-enhancing compounds is not significantly different from that of the intercellular phase-separating agents, and is in the range of from about 0.1 to about 10% and preferably about 1.0% to about 5.0% by weight of the topical composition.
  • Additional ingredients may be added to the topical composition, as long as they are pharmaceutically acceptable and not deleterious to the epithelial cells or their function. Further, they should not adversely affect the epithelial penetration efficiency of the above-noted intercellular phase separating agents, and should not cause deterioration in the stability of the composition.
  • fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, preservatives, buffering agents, and the like may be present.
  • the pH of the topical composition of this invention may be adjusted to a physiologically acceptable range of from about 6.0 to about 9.0 by adding buffering agents thereto in order for the composition to be physiologically compatible with the skin.
  • topical compositions of this invention to enhance epithelial penetration of a physiologically active substance at the desired site of a host is determined by their ability to induce intercellular phase separation.
  • the enhanced permeation effected through the use of the enhancer composi- tion of this invention can be observed by measuring the rate of diffusion of th e active agent through animal or human epithelium using a diffusion cell apparatus or the Fourier transform infrared spectroscopy (FTIR) technique known to one skilled in the art.
  • FTIR Fourier transform infrared spectroscopy
  • a lotion may be formulated as follows to contain about 0.1% to 2.0% estradiol valerate:
  • An ointment may be formulated to contain 0.2% indomethacin:
  • a cream may be formulated as follows to contain about 0.1% nifedipine:
  • a suppository formulation may be prepared as follows to contain about 0.5% oxymorphone:
  • mice were treated with acetone on one flank to produce TEWL readings between 2.0 and 8.0 mg/cm 2 /hr.
  • the mice were injected with chloral hydrate to immobilize them, and the flanks were immersed in buffers, at 37°C, of varying pH (e.g., pH 5.5, 7.4 and 8.5).
  • the buffers 10 mM HEPES, 10 mM PIPES, and 100 mM sodium phosphate included 280 mosmolar sucrose.
  • the TEWL 0 time point was taken soon after acetone treatment when the treated flank returned to ambient temperature (approximately 10 minutes with gentle heating). Time points at 2 and 5 hours were taken after immersion.
  • Proton-pump inhibitors N.N'-dicyclohexylcarbodiimide (DCCD); 1-10 mM); N- ethyl maleimide (NEM; 1 mM); 7-chloro-4-nitrobenz-2-oxa-1 ,3-diazole (NBD Cl; 1 mM) and bafilomycin A-, (10 ⁇ M) were prepared in vehicle (i.e., 70% propylene glycol, 30% ethanol). Flanks of hairless mice were pre-treated for 30 minutes to 1 hour with drug or vehicle alone before breaking the barrier with acetone. TEWL readings were taken at various time points as described above, followed by additional treatments with drug or vehicle.
  • the DCCD- override study included immersion of flanks in HEPES buffer at pH 5.5 or 7.4 after the pre-treatment with either drug or vehicle and after breaking the barrier with either acetone or by tape stripping.
  • lipid mixture or vehicle-propylene glycol; ethanol, 7:3 vols.
  • barrier recovery occurs normally whether LA or PA are used in the three component mixture with cholesterol and ceramide, when the complex precursor CholPA is substituted for Choi, barrier recovery is delayed significantly (combination 6).
  • TEWL trans-epidermal water loss
  • mice were kept under anesthesia until the harvest of tissue samples and then sacrificed. At time zero, the tested drug delivery compound listed in Tables 2, 3 and 4 below was applied to the whole treated flank of each mouse.
  • the treated skin was cut off, the subcutaneous fat was removed, and the whole skin was placed into vial #7 to which 1 ml of tissue solubilizer was added, and the mixture was allowed to digest overnight at 55°C.
  • the corpse was digested in 100 ml of saponification mix at 55 ⁇ C overnight.
  • EXAMPLE 9 Applying the pH buffer TRIS alone at cutaneous surface physiologic pH 5.5 very significantly (p ⁇ 0.001 ) increased lidocaine delivery and also significantly increased water permeability as shown in Table 2. HEPES alone in a single
  • Brefeldin A is a molecule that inhibits "proton" granule migration and exocytosis, resulting in the same stratum corneum effects as a proton pump inhibitor.
  • HEPES (pH 7.4) + Brefeldin A 3 20mM/ 637 ⁇ 61 ⁇ .001 0.43 ⁇ 0.13 0.159 21.91 ⁇ 1.01 ⁇ . 0 0.1
  • phase separation of the stratum corneum membrane bilayers was induced by application of one or two inactive synthetic analogs of the critical lipids in a propylene glycol/ethanol vehicle, as shown by very significantly increased delivery of lidocaine.
  • Table 4 the two combinations of epicholesterol with either transvaccenic acid or stearyl amine produced very significantly increased lidocaine delivery, while epicholesterol alone significantly increased its delivery.
  • Epicholesterol with transvaccenic acid significantly increased water permeability as well.
  • epicholesterol + transvaccenic acid 4 2.0/1.0 124 ⁇ 36 ⁇ .017 0.93 ⁇ 14 ⁇ .0001 71.31 ⁇ 4.18 ⁇ .0
  • epicholesterol 3 2.0 397 ⁇ 55 >.2 0.24 ⁇ 0.05 .004 11.40 ⁇ 1.98 >.2 stearylamine + epicholesterol 4 2.0/0.5 238 ⁇ 38 >.2 1.01 ⁇ 0.18 ⁇ .0001 59.36 ⁇ 5.65 ⁇ .0

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP94911673A 1993-03-19 1994-03-21 Procedes et compositions pour induire une separation de phase des deux couches lipidiques de l'epithelium Ceased EP0693932A4 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3380793A 1993-03-19 1993-03-19
US3381193A 1993-03-19 1993-03-19
US33811 1993-03-19
PCT/US1994/003085 WO1994021271A1 (fr) 1993-03-19 1994-03-21 Procedes et compositions pour induire une separation de phase des deux couches lipidiques de l'epithelium

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EP0693932A1 EP0693932A1 (fr) 1996-01-31
EP0693932A4 true EP0693932A4 (fr) 2000-06-14

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EP94911673A Ceased EP0693932A4 (fr) 1993-03-19 1994-03-21 Procedes et compositions pour induire une separation de phase des deux couches lipidiques de l'epithelium
EP94913927A Withdrawn EP0764017A4 (fr) 1993-03-19 1994-03-21 Procedes et compositions permettant d'induire une separation de phase dans des doubles couches lipidiques epitheliales

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EP94913927A Withdrawn EP0764017A4 (fr) 1993-03-19 1994-03-21 Procedes et compositions permettant d'induire une separation de phase dans des doubles couches lipidiques epitheliales

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Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
EP2233128A1 (fr) * 2009-03-25 2010-09-29 Cognis IP Management GmbH Composition cosmétique

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1051461A (en) * 1963-11-04 1966-12-14 Gillette Co Dermatologic composition
GB1070593A (en) * 1962-12-26 1967-06-01 Olin Mathieson Ophthalmic ointment composition and the preparation thereof
US4420474A (en) * 1979-10-15 1983-12-13 E. R. Squibb & Sons, Inc. Synergistic antifungal compositions
DE3325506A1 (de) * 1983-07-15 1985-01-24 Manfred 7700 Singen Reichle Salbe
JPH03153634A (ja) * 1989-11-09 1991-07-01 Shiseido Co Ltd 経皮吸収促進剤及び皮膚外用剤
US5120545A (en) * 1990-08-03 1992-06-09 Alza Corporation Reduction or prevention of sensitization to drugs

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1070593A (en) * 1962-12-26 1967-06-01 Olin Mathieson Ophthalmic ointment composition and the preparation thereof
GB1051461A (en) * 1963-11-04 1966-12-14 Gillette Co Dermatologic composition
US4420474A (en) * 1979-10-15 1983-12-13 E. R. Squibb & Sons, Inc. Synergistic antifungal compositions
DE3325506A1 (de) * 1983-07-15 1985-01-24 Manfred 7700 Singen Reichle Salbe
JPH03153634A (ja) * 1989-11-09 1991-07-01 Shiseido Co Ltd 経皮吸収促進剤及び皮膚外用剤
US5120545A (en) * 1990-08-03 1992-06-09 Alza Corporation Reduction or prevention of sensitization to drugs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FRANSSON L -A ET AL: "EFFECTS OF CYCLOHEXIMIDE, BREFELDIN A, SURAMIN, HEPARIN AND PRIMAQUINE ON PROTEOGLYCAN AND GLYCOSAMINOGLYCAN BIOSYNTHESIS IN HUMAN EMBRYONIC SKIN FIBROBLASTS", BIOCHIMICA ET BIOPHYSICA ACTA,NL,AMSTERDAM, vol. 1137, no. 3, 17 November 1992 (1992-11-17), pages 287 - 297, XP000573708, ISSN: 0006-3002 *
PATENT ABSTRACTS OF JAPAN vol. 015, no. 377 (C - 0870) 24 September 1991 (1991-09-24) *
See also references of WO9421271A1 *

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EP0764017A4 (fr) 1997-08-06
EP0764017A1 (fr) 1997-03-26
EP0693932A1 (fr) 1996-01-31

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