CA2114537A1 - Transdermal therapeutic systems - Google Patents
Transdermal therapeutic systemsInfo
- Publication number
- CA2114537A1 CA2114537A1 CA002114537A CA2114537A CA2114537A1 CA 2114537 A1 CA2114537 A1 CA 2114537A1 CA 002114537 A CA002114537 A CA 002114537A CA 2114537 A CA2114537 A CA 2114537A CA 2114537 A1 CA2114537 A1 CA 2114537A1
- Authority
- CA
- Canada
- Prior art keywords
- transdermal therapeutic
- penetration enhancer
- therapeutic systems
- polar
- systems according
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Abstract
ABSTRACT
Described are transdermal therapuetic systems characterized in that they contain, in an adhesive matrix containing an active substance, a polar penetration enhancer and a non-polar penetration enhancer which is insoluble in the polar penetration enhancer.
Described are transdermal therapuetic systems characterized in that they contain, in an adhesive matrix containing an active substance, a polar penetration enhancer and a non-polar penetration enhancer which is insoluble in the polar penetration enhancer.
Description
~ 1 211~-~37 ~ ~:
Tra~sdermal Therapeutic ~ystems The invention relates to transdermal therapeutic systems, Which are characterized in that they contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the polar enhancer.
As is known, transdermal therapeutic systems (TTS) are patche~ containing an active ingredient built up in multiple layers, which are attached to the skin and which continuously deliver their active ingredient percutaneously over a longer period. To reach a therapeutically sufficient penetration rate of the active ingredient through the skin, it is necessary in most case~ to provide the transdermal therapeutic systems with penetration enhancers in addition to the active ingredient.
Transdermal therapeutic systems, which contain a combination of a polar penetration enhancer and a nonpolar penetration enhancer, are previously known. ;
But according to the known prior art, the combination ¢apability of the different penetration enhancers required that they either can be mixed with one another or that they are processed separately (for example, by layers in different matrices). (W0-A 90/~4397; EP-A 0305026 and EP-A 0272987).
It has now been found that it is surprisingly possible to produce transdermal therapeutic systems, which contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the 21~ j3~ :
polar enhancer, without a separation of the components resulting during the production process.
The thus produced transdermal therapeutic systems according to the invention have several advantages relative to comparable systems, which in a matrix contain either only one polar penetration enhancer or only one nonpolar penetration enhancer:
l. The use of combined penetration enhancers often produces an unexpectedly great increase of the penetration rate of the active ingredient.
Tra~sdermal Therapeutic ~ystems The invention relates to transdermal therapeutic systems, Which are characterized in that they contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the polar enhancer.
As is known, transdermal therapeutic systems (TTS) are patche~ containing an active ingredient built up in multiple layers, which are attached to the skin and which continuously deliver their active ingredient percutaneously over a longer period. To reach a therapeutically sufficient penetration rate of the active ingredient through the skin, it is necessary in most case~ to provide the transdermal therapeutic systems with penetration enhancers in addition to the active ingredient.
Transdermal therapeutic systems, which contain a combination of a polar penetration enhancer and a nonpolar penetration enhancer, are previously known. ;
But according to the known prior art, the combination ¢apability of the different penetration enhancers required that they either can be mixed with one another or that they are processed separately (for example, by layers in different matrices). (W0-A 90/~4397; EP-A 0305026 and EP-A 0272987).
It has now been found that it is surprisingly possible to produce transdermal therapeutic systems, which contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the 21~ j3~ :
polar enhancer, without a separation of the components resulting during the production process.
The thus produced transdermal therapeutic systems according to the invention have several advantages relative to comparable systems, which in a matrix contain either only one polar penetration enhancer or only one nonpolar penetration enhancer:
l. The use of combined penetration enhancers often produces an unexpectedly great increase of the penetration rate of the active ingredient.
2. The use of the special combination often results in that the upper load limits of the individual penetration enhancers can be exceeded.
3. Poor adhesion of the system to the skin, as it is observed in transdermal systems which are loaded with a polar penetration enhancer to the upper load limit, is not observed in the systems according to the invention.
4. Patch residues, as they are often observed after the administration of systems that contain nonpolar penetration enhancers, do not occur.
Overall, the adhesive properties of the transdermal systems are improved by the combination according to the invention and their wearing comfort increases by buffering of the moisture during the wearing.
As the adhesive forming the matrix, the system according to the invention preferably contains a commercially available adhesive (Pharmaceutical Technology, 1989, pp. 126-138). Such adhesives are, for example, polyacrylate adhesives of the ~ 3 ~1t~ 7 Durotak~R) type (National Starch Company), Sichello~R) type (Sichelwerke [Sickle Factory]3 or Gelva~R) type (Monsanto Company), synthetic rubber adhesive of Adhesin~R) type (Henkel KG) or silicone adhesive of X7 type (Dow Corning Corp.) As polar penetration enhancers, the transdermal systems according to the invention contain urea or a multivalent alcohol with preferably 2 to 6 carbon atoms. Such polyols are, for example, 1,2-ethanediol, 1,3-propanediol, glycerol, sorbitol, mannitol, dulcitol or especially 1,2-propanediol. In the finished matrix, the concentration of polar penetration enhancer is preferably 5 to 25% by weight relative to the total weight of the matrix.
As nonpolar penetration enhancers, the transdermal system according to the invention preferably contains a fatty acid ester with at least 8 carbon atoms.
Fatty acid esters, which are suitable for the process according to the invention are, for example, those of lauric acid, myristic acid, palmitic acid, isopalmitic acid, stearic acid and isostearic acid, CUch as, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, sec-butyl ester, isobutyl ester, tert-butyl ester or glycerol ester.
Such pharmaceutically common fatty acid esters are, for example, methyl myristate, ethyl myristate, propyl myristate, methyl laurate, ethyl laurate, propyl laurate, isopropyl laurate, methyl oleate, ethyl oleate, propyl oleate, isopropyl oleate and isopropyl palmitate and especially isopropyl myristate.
Certainly, high-boiling liquid hydrocarbons with at least ~ ;
4 ~ 37 ~ ~
carbon atoms and mixtures of these hydrocarbons, such as liquid paraffin or terpenoid hydrocarbons, such as ~-pinene, d-limonene, 3-carene, myrcene, camphene, bisabolene or squalene, alcohols with at least 8 carbon atoms, such as, for example, alkanols, myristyl alcohol or stearyl alcohol or sterines, such as -cholesterol and also fatty acids with at least 8 carbon atoms, such as stearic acid, palmitic acid, oleic acid, should also be suita~le for the production of the transdermal systems according to the invention. There are not yet any attempts that relate to ;~
this.
~ he nonpolar penetration enhancer is preferably metered so that its concentration in the ~inished matrix is 1 to 15% by weight relative to the latter.
Active ingredients which are suitable for the production of the transdermal systems according to the invention are preferably those that are poorly soluble in water or insoluble. Suitable, for example, are steroid hormones, such as:
Progestationally active steroid hormones, such as, for example, 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregn-4-en-20yl-3-one (clevonorgestrel), 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregna-4~15-dien-20yn-3-one (=gestodene) or 13-ethyl-17~-hydroxy- -11-methylene-18,19-dinor-17~-pregn-4-en-20yn (=desorgestrel), estrogenically active steroid hormones, 3-hydroxy-1,3,5-(10)-estrat~ien-17-one (=estrone), 1,3,5(10)-estratriene-3,17~-diol (=estradiol) or 1,9-nor-17~-pregna-1,3,5(10)-trien-20yn-3,17 diol (=ethinylestradiol).
:
21~ 37 Androgenically active steroid hormones, such as 17~-hydroxy-4 androsten-3-one (=testosterone) and its esters~or 17~-hydroxy-l~-methyl-5~-androsten-3-one (=mesterolone).
Antiandrogenically active steroid hormones, such as 17 acetoxy-6-chloro-l~r2~-dihydro-3H-cyclopropa[l~2]-pregna-l~4~6 triene-3,20-dione (=cypoterone acetate).
Corticoids, such as 11~,17a,21-trihydroxy-4-pregnene-3,20-dione (chydrocortisone), 11~,17~,21-trihydroxy-1,4-pregnadiene-3,20-dione (=prednisolone), 11~,17~,21-trihydroxy-6~-methyl-1,4-pregnatriene-3,20-dione (=methyl prednisolone) and 6~-fluoro-11~,21-dihydroxy-16~-methyl-1,4-pregnadiene-3,20-dione (~diflucortolone) and its esters.
Suitable active ingredients are further~
Ergoline derivatives, such as lisuride [=3-(9,10-didehydro-6-methyl-8a-ergolinyl)-1,1-diethylurea], bromolisuride t=3-(2-bromo-9~lo-dehydro-6-methyl-8a-ergolinyl-l~l-diethylurea]~
terguride t=3-(6-methyl-8~-ergolinyl~ diethylurea] and proterguride t=3-(6-propyl-8~-ergolinyl)-1,1-diethylurea].
Antihypertensive agents, such as 7~-acetylthio-17-hydroxy-3-oxo-4-pregnene-21-carboxylic acid-~-lactone (=spironolactone) and 7~-acetylthio-15~,16~-methylene-3-oxo-17~-pregna-1,4-diene-21,17-carbolactone (=mespirenone).
Anticoagulants, such as 5~[hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(lH)-pentalenylidene)]-pentanoic acid (~iloprost) or (Z)-7-[(lR,2R,3R,5R)-5-chloro-3-hydroxy-2-[(E)-(3R)-3-hydroxy-4,4-dimethyl-l-octenyl]-cyclopentyl]-5-heptenoic acid (=nocloprost).
`\
2 ~ 3 7 Psychopharmaceutical agents, such as 4-(3-cyclopentyloxy-4-methoxy-phenyl-2-pyrrolidone (=rolipram) and 7-chloro-1,3-dihydro-l-methyl-s-phenyl-2H-1,4-benzodiazepin-2-one (=diazepam).
Organic nitro compounds, such as nitroglycerine or isosorbide dinitrate t=l,4,3,6-dianhydro-D-glucitol-dinitrate].
Beta-blockers, such as propanolol ~ [(l-methylethyl)-amino]-3-~l-naphthyloxy-2-propanolol}r mepindolol ~=i-[(l-methylethyl)-amino]-3-~(2-methyl-lH-inol-4-yl)-oxy]-2-propanol~
and carazolol ~=2-(sH-carbazol-4-yloxy)-3-t(l-methethyl)-amino]
2-propanol}.
Carotenoids, such as ~-carotene and ~-carotene.
~-Carbolines are another group, as they are described, for ; ;~
example, in European Patent Applications 234,173 and 239,667. As ~-carbolines, there can be mentioned, for example, 6-benzoyloxy-4-methoxymethyl-~-carboline-3-carboxylic acid-isopropylester . . .
~-becarnil) and 5-(4-chlorophenoxy)-4-methoxymethyl-~-carboline-3-carboxylic acid-isopropylester (=Cl-PHOCIP~.
Also worth mentioning are analgesics, such as, for example, salicylic acid, glycol salicylate, methyl salicylate, 7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol (=morphine), 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6-one (oxycodone), (-)-(R)-6-(dimethylaminol-4,4-diphenyl-3-heptanone (=levomethadone) or 3,4,5,6-tetrahydro-5-methyl-1-phenyl-lH-2,5-benzoxacin (=nefopam).
Finally, nicotine, clonidine and scopolamine can be mentioned as suitable active ingredients.
: .
~' ,'.:'.
3~1 It is plausible that ~he transdermal systems according to -the invention can also contain mixtures of these-active ingredients.
The optimal concentration of the active ingredient in the transdermal therapeutic systems according to the invention is, of course, dependent on the type of active ingredient, its effectiveness, the type of penetration enhancer, the adhesive used, etc., and must be determined in the individual case by the preliminary tests familiar to the galenic specialist. Usually, he will proportion the active ingredient so that its concentration in the finished matrix is 0.1 to 10% by weight ~ `
relative to the latter.
The transdermal therapeutic systems according to the invention are pre*erably constituted so that they consist of a top coating impermeable to the penetration enhancer and optlonally also to water, an adhesive matrix containing an active ingredient adhering to the top coating, which contains polar and nonpolar penetration enhancers, and a removable protective layer.
This simplest form of a transdermal therapeutic system, which i5 designated as an adhesive matrix-TTS, can be produced in the way that a solution of adhesive is mixed in a low-boiling solvent with the active ingredient or active ingredient mixture, the polar and the nonpolar penetration enhancer, the mixture is applied in sheets to a top coating impermeable to the penetration enhancer and optionally also to water, the volatile solvent is removed by heating and the obtained product is covered with a removable protective layer.
--~ 8 211~1~37 Suitable solvents for dissolving the adhesive are, for example, low-boiling alcohols, such as methanol~ ethanol or isopropanol, low-boiling ketones, such as acetone, low-boiling hydrocarbons, such as hexane, or low-boiling esters, such as ethyl acetate as well as their mixtures.
This process can be performed in the way that a solution or : .
suspension of the active ingredient, the penetration enhancer and -~
the adhesive in a volatile solvent are spread on a flat, impermeable top coating and after the drying at about 60C to 90C are provided with a removable protective layer.
As protective layers, all films are suitable which are usually used with adhesive in transdermal therapeutic systems.
Such films are, for example, siliconized or coated with fluoropolymer.
As a top coating, for example, 10 to 100 ~m thick films made oP polyethylene, PVC, PVDC or their copolymers or polyesters can be used alternatively pigmented or metallized. The pharmaceutical agent layer applied upon this preferably has a thickness of 20 to 500 ~m. The active ingredients are delivered preferably over an area of 5 to 100 cm2.
It is obvious to one skilled in the art that the transdermal therapeutic systems according to the invention can also be con~igured significantly more complex than the already mentioned simple matrix systems. (Yie W. Chien: "Transdermal Controlled Systemic Medications," Marcel Dekker, Inc., New York and Basel, 1987, Dr. Richard Baker: "Analysis of Transdermal Drug Delivery Patents 1934 to 1984" and "Analysis of Recent Transdermal ,. .. .
2 ~ 3 7 Delivery Patents, 1984-1986 and Enhancers," Membrane Technology Research, 1030 Hamilton Court, Menlo Park, CA 94025 (415) 328-2228). But this should generally provide no significant ~.
advantages of the systems whatsoever, which warrant the increased ~ ~:
expense in their production.
The following embodiment is used to explain the invention in -more detail:
~ ~ 10 2 ~ 3 r~ :
Example 1 -To 100 g of a 50% by weight solution of silicone adhesive X7-4~02 (manufacturer: Dow Corning Comp.) in hexane are added in succession 3.00 g of 17~-estradiol 6.00 g of 1,2-propanediol and ~ `
1.00 g of isopropyl myristate.
The cloudy mass which forms is then rolled in a high-grade steel vessel to remove existing gas bubbles.
The mass that is largely free of gas bubbles is applied to a fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over-roll coating device in the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. Then, it is laminated with a polyester cover film ~Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patche6 of 5 cm2, 10 cm2 and 20 cm2 areas and packed in ;~`
aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.
Exam~le 2 To 100 g of a 50% by weight solution of acrylate adhesive Gelva~R) (manufacturer: Monsanto Comp.) in ethyl acetate are added ' i"' 2 1 ~ 7 ~ ~
in succession 3.00 g of 17~-estradiol -6.00 g of micronized urea, dispersed in hexane and -3.00 g of isopropyl myristate.
The cloudy mass which forms is then rolled in a high-grade steel vessel to remove existing gas bubbles.
The mass that is largely free of gas bubbles is applied to a fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over~roll coating device ln the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. ~hen, it is laminated with a polyester cover film (Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patches of 5 cm2, 10 cm2 and 20 cm2 area and packed in aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.
Example 3 To 100 g of a 50% by weight solution of silicone adhesive X7-4502 (manufacturer: Dow Corning Comp.) in hexane are added in succession 3.00 g of 17~-estradiol 5.00 g of micronized urea, dispersed in hexane and 2.00 g of isopropyl myristate.
- ' ~
~-` 2 1 t ~ 7 ~ .
The cloudy mass which forms is then rolled in a high-grade steel ~ ;
vessel to remove existing gas bubbles. -The mass that is largely free of gas bubbles is applied to a -. .
fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over-roll coating -device in the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. Then, it is laminated with a polyester cover film (Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patches of 5 cm2, lO cm2 and 20 cm2 areas and packed in --aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.
, .
.~
- " ,.. ~ .~
Overall, the adhesive properties of the transdermal systems are improved by the combination according to the invention and their wearing comfort increases by buffering of the moisture during the wearing.
As the adhesive forming the matrix, the system according to the invention preferably contains a commercially available adhesive (Pharmaceutical Technology, 1989, pp. 126-138). Such adhesives are, for example, polyacrylate adhesives of the ~ 3 ~1t~ 7 Durotak~R) type (National Starch Company), Sichello~R) type (Sichelwerke [Sickle Factory]3 or Gelva~R) type (Monsanto Company), synthetic rubber adhesive of Adhesin~R) type (Henkel KG) or silicone adhesive of X7 type (Dow Corning Corp.) As polar penetration enhancers, the transdermal systems according to the invention contain urea or a multivalent alcohol with preferably 2 to 6 carbon atoms. Such polyols are, for example, 1,2-ethanediol, 1,3-propanediol, glycerol, sorbitol, mannitol, dulcitol or especially 1,2-propanediol. In the finished matrix, the concentration of polar penetration enhancer is preferably 5 to 25% by weight relative to the total weight of the matrix.
As nonpolar penetration enhancers, the transdermal system according to the invention preferably contains a fatty acid ester with at least 8 carbon atoms.
Fatty acid esters, which are suitable for the process according to the invention are, for example, those of lauric acid, myristic acid, palmitic acid, isopalmitic acid, stearic acid and isostearic acid, CUch as, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, sec-butyl ester, isobutyl ester, tert-butyl ester or glycerol ester.
Such pharmaceutically common fatty acid esters are, for example, methyl myristate, ethyl myristate, propyl myristate, methyl laurate, ethyl laurate, propyl laurate, isopropyl laurate, methyl oleate, ethyl oleate, propyl oleate, isopropyl oleate and isopropyl palmitate and especially isopropyl myristate.
Certainly, high-boiling liquid hydrocarbons with at least ~ ;
4 ~ 37 ~ ~
carbon atoms and mixtures of these hydrocarbons, such as liquid paraffin or terpenoid hydrocarbons, such as ~-pinene, d-limonene, 3-carene, myrcene, camphene, bisabolene or squalene, alcohols with at least 8 carbon atoms, such as, for example, alkanols, myristyl alcohol or stearyl alcohol or sterines, such as -cholesterol and also fatty acids with at least 8 carbon atoms, such as stearic acid, palmitic acid, oleic acid, should also be suita~le for the production of the transdermal systems according to the invention. There are not yet any attempts that relate to ;~
this.
~ he nonpolar penetration enhancer is preferably metered so that its concentration in the ~inished matrix is 1 to 15% by weight relative to the latter.
Active ingredients which are suitable for the production of the transdermal systems according to the invention are preferably those that are poorly soluble in water or insoluble. Suitable, for example, are steroid hormones, such as:
Progestationally active steroid hormones, such as, for example, 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregn-4-en-20yl-3-one (clevonorgestrel), 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregna-4~15-dien-20yn-3-one (=gestodene) or 13-ethyl-17~-hydroxy- -11-methylene-18,19-dinor-17~-pregn-4-en-20yn (=desorgestrel), estrogenically active steroid hormones, 3-hydroxy-1,3,5-(10)-estrat~ien-17-one (=estrone), 1,3,5(10)-estratriene-3,17~-diol (=estradiol) or 1,9-nor-17~-pregna-1,3,5(10)-trien-20yn-3,17 diol (=ethinylestradiol).
:
21~ 37 Androgenically active steroid hormones, such as 17~-hydroxy-4 androsten-3-one (=testosterone) and its esters~or 17~-hydroxy-l~-methyl-5~-androsten-3-one (=mesterolone).
Antiandrogenically active steroid hormones, such as 17 acetoxy-6-chloro-l~r2~-dihydro-3H-cyclopropa[l~2]-pregna-l~4~6 triene-3,20-dione (=cypoterone acetate).
Corticoids, such as 11~,17a,21-trihydroxy-4-pregnene-3,20-dione (chydrocortisone), 11~,17~,21-trihydroxy-1,4-pregnadiene-3,20-dione (=prednisolone), 11~,17~,21-trihydroxy-6~-methyl-1,4-pregnatriene-3,20-dione (=methyl prednisolone) and 6~-fluoro-11~,21-dihydroxy-16~-methyl-1,4-pregnadiene-3,20-dione (~diflucortolone) and its esters.
Suitable active ingredients are further~
Ergoline derivatives, such as lisuride [=3-(9,10-didehydro-6-methyl-8a-ergolinyl)-1,1-diethylurea], bromolisuride t=3-(2-bromo-9~lo-dehydro-6-methyl-8a-ergolinyl-l~l-diethylurea]~
terguride t=3-(6-methyl-8~-ergolinyl~ diethylurea] and proterguride t=3-(6-propyl-8~-ergolinyl)-1,1-diethylurea].
Antihypertensive agents, such as 7~-acetylthio-17-hydroxy-3-oxo-4-pregnene-21-carboxylic acid-~-lactone (=spironolactone) and 7~-acetylthio-15~,16~-methylene-3-oxo-17~-pregna-1,4-diene-21,17-carbolactone (=mespirenone).
Anticoagulants, such as 5~[hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(lH)-pentalenylidene)]-pentanoic acid (~iloprost) or (Z)-7-[(lR,2R,3R,5R)-5-chloro-3-hydroxy-2-[(E)-(3R)-3-hydroxy-4,4-dimethyl-l-octenyl]-cyclopentyl]-5-heptenoic acid (=nocloprost).
`\
2 ~ 3 7 Psychopharmaceutical agents, such as 4-(3-cyclopentyloxy-4-methoxy-phenyl-2-pyrrolidone (=rolipram) and 7-chloro-1,3-dihydro-l-methyl-s-phenyl-2H-1,4-benzodiazepin-2-one (=diazepam).
Organic nitro compounds, such as nitroglycerine or isosorbide dinitrate t=l,4,3,6-dianhydro-D-glucitol-dinitrate].
Beta-blockers, such as propanolol ~ [(l-methylethyl)-amino]-3-~l-naphthyloxy-2-propanolol}r mepindolol ~=i-[(l-methylethyl)-amino]-3-~(2-methyl-lH-inol-4-yl)-oxy]-2-propanol~
and carazolol ~=2-(sH-carbazol-4-yloxy)-3-t(l-methethyl)-amino]
2-propanol}.
Carotenoids, such as ~-carotene and ~-carotene.
~-Carbolines are another group, as they are described, for ; ;~
example, in European Patent Applications 234,173 and 239,667. As ~-carbolines, there can be mentioned, for example, 6-benzoyloxy-4-methoxymethyl-~-carboline-3-carboxylic acid-isopropylester . . .
~-becarnil) and 5-(4-chlorophenoxy)-4-methoxymethyl-~-carboline-3-carboxylic acid-isopropylester (=Cl-PHOCIP~.
Also worth mentioning are analgesics, such as, for example, salicylic acid, glycol salicylate, methyl salicylate, 7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol (=morphine), 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6-one (oxycodone), (-)-(R)-6-(dimethylaminol-4,4-diphenyl-3-heptanone (=levomethadone) or 3,4,5,6-tetrahydro-5-methyl-1-phenyl-lH-2,5-benzoxacin (=nefopam).
Finally, nicotine, clonidine and scopolamine can be mentioned as suitable active ingredients.
: .
~' ,'.:'.
3~1 It is plausible that ~he transdermal systems according to -the invention can also contain mixtures of these-active ingredients.
The optimal concentration of the active ingredient in the transdermal therapeutic systems according to the invention is, of course, dependent on the type of active ingredient, its effectiveness, the type of penetration enhancer, the adhesive used, etc., and must be determined in the individual case by the preliminary tests familiar to the galenic specialist. Usually, he will proportion the active ingredient so that its concentration in the finished matrix is 0.1 to 10% by weight ~ `
relative to the latter.
The transdermal therapeutic systems according to the invention are pre*erably constituted so that they consist of a top coating impermeable to the penetration enhancer and optlonally also to water, an adhesive matrix containing an active ingredient adhering to the top coating, which contains polar and nonpolar penetration enhancers, and a removable protective layer.
This simplest form of a transdermal therapeutic system, which i5 designated as an adhesive matrix-TTS, can be produced in the way that a solution of adhesive is mixed in a low-boiling solvent with the active ingredient or active ingredient mixture, the polar and the nonpolar penetration enhancer, the mixture is applied in sheets to a top coating impermeable to the penetration enhancer and optionally also to water, the volatile solvent is removed by heating and the obtained product is covered with a removable protective layer.
--~ 8 211~1~37 Suitable solvents for dissolving the adhesive are, for example, low-boiling alcohols, such as methanol~ ethanol or isopropanol, low-boiling ketones, such as acetone, low-boiling hydrocarbons, such as hexane, or low-boiling esters, such as ethyl acetate as well as their mixtures.
This process can be performed in the way that a solution or : .
suspension of the active ingredient, the penetration enhancer and -~
the adhesive in a volatile solvent are spread on a flat, impermeable top coating and after the drying at about 60C to 90C are provided with a removable protective layer.
As protective layers, all films are suitable which are usually used with adhesive in transdermal therapeutic systems.
Such films are, for example, siliconized or coated with fluoropolymer.
As a top coating, for example, 10 to 100 ~m thick films made oP polyethylene, PVC, PVDC or their copolymers or polyesters can be used alternatively pigmented or metallized. The pharmaceutical agent layer applied upon this preferably has a thickness of 20 to 500 ~m. The active ingredients are delivered preferably over an area of 5 to 100 cm2.
It is obvious to one skilled in the art that the transdermal therapeutic systems according to the invention can also be con~igured significantly more complex than the already mentioned simple matrix systems. (Yie W. Chien: "Transdermal Controlled Systemic Medications," Marcel Dekker, Inc., New York and Basel, 1987, Dr. Richard Baker: "Analysis of Transdermal Drug Delivery Patents 1934 to 1984" and "Analysis of Recent Transdermal ,. .. .
2 ~ 3 7 Delivery Patents, 1984-1986 and Enhancers," Membrane Technology Research, 1030 Hamilton Court, Menlo Park, CA 94025 (415) 328-2228). But this should generally provide no significant ~.
advantages of the systems whatsoever, which warrant the increased ~ ~:
expense in their production.
The following embodiment is used to explain the invention in -more detail:
~ ~ 10 2 ~ 3 r~ :
Example 1 -To 100 g of a 50% by weight solution of silicone adhesive X7-4~02 (manufacturer: Dow Corning Comp.) in hexane are added in succession 3.00 g of 17~-estradiol 6.00 g of 1,2-propanediol and ~ `
1.00 g of isopropyl myristate.
The cloudy mass which forms is then rolled in a high-grade steel vessel to remove existing gas bubbles.
The mass that is largely free of gas bubbles is applied to a fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over-roll coating device in the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. Then, it is laminated with a polyester cover film ~Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patche6 of 5 cm2, 10 cm2 and 20 cm2 areas and packed in ;~`
aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.
Exam~le 2 To 100 g of a 50% by weight solution of acrylate adhesive Gelva~R) (manufacturer: Monsanto Comp.) in ethyl acetate are added ' i"' 2 1 ~ 7 ~ ~
in succession 3.00 g of 17~-estradiol -6.00 g of micronized urea, dispersed in hexane and -3.00 g of isopropyl myristate.
The cloudy mass which forms is then rolled in a high-grade steel vessel to remove existing gas bubbles.
The mass that is largely free of gas bubbles is applied to a fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over~roll coating device ln the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. ~hen, it is laminated with a polyester cover film (Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patches of 5 cm2, 10 cm2 and 20 cm2 area and packed in aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.
Example 3 To 100 g of a 50% by weight solution of silicone adhesive X7-4502 (manufacturer: Dow Corning Comp.) in hexane are added in succession 3.00 g of 17~-estradiol 5.00 g of micronized urea, dispersed in hexane and 2.00 g of isopropyl myristate.
- ' ~
~-` 2 1 t ~ 7 ~ .
The cloudy mass which forms is then rolled in a high-grade steel ~ ;
vessel to remove existing gas bubbles. -The mass that is largely free of gas bubbles is applied to a -. .
fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over-roll coating -device in the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. Then, it is laminated with a polyester cover film (Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patches of 5 cm2, lO cm2 and 20 cm2 areas and packed in --aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.
, .
.~
- " ,.. ~ .~
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Transdermal therapeutic systems, wherein they contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the polar enhancer.
2. Transdermal therapeutic systems according to claim 1, wherein they contain a multivalent alcohol or urea as polar penetration enhancer.
3. Transdermal therapeutic systems according to claim 2, wherein they contain 1,2-propanediol, glycerol, sorbitol, mannitol or dulcitol as multivalent alcohol.
4. Transdermal therapeutic systems according to claims 1 to 3, wherein they contain a hydrocarbon, an alcohol, a fatty acid or a fatty acid ester with at least 8 carbon atoms each as nonpolar penetration enhancer.
5. Transdermal therapeutic systems according to claim 4, wherein they contain isopropyl myristate as fatty acid ester.
6. Transdermal therapeutic systems according to claims 1 to 5, wherein they consist of a top coating impermeable to the penetration enhancer and optionally also to water, an adhesive matrix containing an active ingredient adhering to the top coating, which contains polar and nonpolar penetration enhancers, and a removable protective layer.
7. Process for the production of transdermal therapeutic systems according to claim 6, wherein a solution of adhesive is mixed in a low-boiling solvent with the active ingredient or active ingredient mixture, the polar and the nonpolar penetration enhancer, the mixture is applied in sheets to a top coating impermeable to the penetration enhancer and optionally also to water, the volatile solvent is removed by heating and the obtained product is covered with a removable protective layer.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4125611.5 | 1991-07-30 | ||
DE4125611 | 1991-07-30 | ||
DE4210165A DE4210165A1 (en) | 1991-07-30 | 1992-03-25 | TRANSDERMAL THERAPEUTIC SYSTEMS |
DEP4210165.4 | 1992-03-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2114537A1 true CA2114537A1 (en) | 1993-02-18 |
Family
ID=25906037
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002114537A Abandoned CA2114537A1 (en) | 1991-07-30 | 1992-07-07 | Transdermal therapeutic systems |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0596903B1 (en) |
JP (1) | JPH06509346A (en) |
AT (1) | ATE151985T1 (en) |
AU (1) | AU676826B2 (en) |
CA (1) | CA2114537A1 (en) |
DE (2) | DE4210165A1 (en) |
DK (1) | DK0596903T3 (en) |
ES (1) | ES2103952T3 (en) |
FI (1) | FI940427A (en) |
GR (1) | GR3024097T3 (en) |
HU (1) | HU217215B (en) |
NO (1) | NO307736B1 (en) |
PT (1) | PT100737B (en) |
WO (1) | WO1993002669A1 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7011843B2 (en) | 1997-10-01 | 2006-03-14 | Lts Lohmann-Therapie Systeme Ag | Method for protecting a human being against health impairment by ingestion of a transdermal therapeutic system |
US9066887B2 (en) | 2008-01-30 | 2015-06-30 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system having urea components |
EP2977043A3 (en) * | 2003-08-25 | 2016-04-06 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
US9320705B2 (en) | 2002-10-25 | 2016-04-26 | Foamix Pharmaceuticals Ltd. | Sensation modifying topical composition foam |
US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
US9492412B2 (en) | 2002-10-25 | 2016-11-15 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
US9539208B2 (en) | 2002-10-25 | 2017-01-10 | Foamix Pharmaceuticals Ltd. | Foam prepared from nanoemulsions and uses |
US9549898B2 (en) | 2007-12-07 | 2017-01-24 | Foamix Pharmaceuticals Ltd. | Oil and liquid silicone foamable carriers and formulations |
US9572775B2 (en) | 2009-07-29 | 2017-02-21 | Foamix Pharmaceuticals Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
US9622947B2 (en) | 2002-10-25 | 2017-04-18 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US9636405B2 (en) | 2003-08-04 | 2017-05-02 | Foamix Pharmaceuticals Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
US9662298B2 (en) | 2007-08-07 | 2017-05-30 | Foamix Pharmaceuticals Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
US9675700B2 (en) | 2009-10-02 | 2017-06-13 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US9682021B2 (en) | 2006-11-14 | 2017-06-20 | Foamix Pharmaceuticals Ltd. | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
US9713643B2 (en) | 2002-10-25 | 2017-07-25 | Foamix Pharmaceuticals Ltd. | Foamable carriers |
US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
US9884017B2 (en) | 2009-04-28 | 2018-02-06 | Foamix Pharmaceuticals Ltd. | Foamable vehicles and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
US10322085B2 (en) | 2002-10-25 | 2019-06-18 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US10350166B2 (en) | 2009-07-29 | 2019-07-16 | Foamix Pharmaceuticals Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
US10398641B2 (en) | 2016-09-08 | 2019-09-03 | Foamix Pharmaceuticals Ltd. | Compositions and methods for treating rosacea and acne |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08501529A (en) * | 1992-06-11 | 1996-02-20 | セラテック・インコーポレイテッド | Use of glycerin to alleviate skin-penetrating drug administration |
US5843979A (en) * | 1993-02-25 | 1998-12-01 | Bristol-Myers Squibb Company | Transdermal treatment with mast cell degranulating agents for drug-induced hypersensitivity |
US5460820B1 (en) † | 1993-08-03 | 1999-08-03 | Theratech Inc | Method for providing testosterone and optionally estrogen replacement therapy to women |
DE4332094C2 (en) * | 1993-09-22 | 1995-09-07 | Lohmann Therapie Syst Lts | Active substance plaster which can be produced without solvent and process for its preparation |
DE4405899A1 (en) * | 1994-02-18 | 1995-08-24 | Schering Ag | Agent for transdermal application containing desogestrel |
DE4429667C2 (en) * | 1994-08-20 | 1996-07-11 | Lohmann Therapie Syst Lts | Estradiol TTS with water-binding additives and process for its preparation |
DE69527507T2 (en) * | 1994-11-17 | 2002-11-07 | Toray Industries | TRANSDERMAL ABSORBABLE PREPARATION |
DE19526864A1 (en) * | 1995-07-22 | 1997-01-23 | Labtec Gmbh | Hormone patches |
DE19533089C1 (en) * | 1995-09-07 | 1997-05-22 | Hexal Ag | Tacrine patch |
DE19626621A1 (en) * | 1996-07-02 | 1998-01-08 | Hexal Ag | Plaster for transdermal application of pergolide |
DE19701949A1 (en) * | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermal therapeutic system |
ATE293960T1 (en) * | 1997-02-28 | 2005-05-15 | Minnesota Mining & Mfg | TRANSDERMAL DEVICE FOR ADMINISTRATION OF TESTOSTERONE |
FR2761889B1 (en) * | 1997-04-11 | 1999-12-31 | Oreal | PHARMACEUTICAL, COSMETIC OR DERMO-PHARMACEUTICAL PATCH FOR THE DELIVERY OF SEVERAL ACTIVE COMPOUNDS OF DIFFERENT NATURE |
DE10019171A1 (en) * | 2000-04-07 | 2001-10-18 | Schering Ag | Compositions for use as penetration enhancers in transdermal formulations for highly lipophilic active ingredients |
DE10107663B4 (en) * | 2001-02-19 | 2004-09-09 | Lts Lohmann Therapie-Systeme Ag | Testosterone-containing transdermal therapeutic system, process for its preparation and its use |
JP2010539125A (en) | 2007-09-13 | 2010-12-16 | ビーエーエスエフ ソシエタス・ヨーロピア | Use of hydrophobin polypeptides as penetration enhancers |
MX2011004454A (en) * | 2008-10-31 | 2011-08-15 | Moberg Derma Ab | Topical composition comprising a combination of at least two penetration enhancing agents. |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5855411A (en) * | 1981-09-28 | 1983-04-01 | Nitto Electric Ind Co Ltd | Base material composition and medicinal composition for external use |
EP0224981A3 (en) * | 1985-11-04 | 1988-08-10 | Paco Research Corporation | Nitroglycerin transdermal delivery system |
EP0370220B1 (en) * | 1988-10-27 | 1996-01-10 | Schering Aktiengesellschaft | Gestode composition for transdermal application |
EP0399432B1 (en) * | 1989-05-25 | 1994-06-22 | Takeda Chemical Industries, Ltd. | Transdermal therapeutic composition |
HUT59596A (en) * | 1989-08-17 | 1992-06-29 | Schering Corp | Process for producing transdermal nitroglicerol patches |
AU6712090A (en) * | 1989-10-13 | 1991-05-16 | Watson Laboratories, Inc. | Drug delivery systems and matrix therefor |
AR246186A1 (en) * | 1989-11-17 | 1994-07-29 | Beta Pharm Co | Procedure for manufacturing a device for administering stradiol through the skin. |
-
1992
- 1992-03-25 DE DE4210165A patent/DE4210165A1/en not_active Withdrawn
- 1992-07-07 AU AU22298/92A patent/AU676826B2/en not_active Ceased
- 1992-07-07 DE DE59208408T patent/DE59208408D1/en not_active Expired - Fee Related
- 1992-07-07 AT AT92914236T patent/ATE151985T1/en not_active IP Right Cessation
- 1992-07-07 WO PCT/EP1992/001515 patent/WO1993002669A1/en active IP Right Grant
- 1992-07-07 DK DK92914236.2T patent/DK0596903T3/en active
- 1992-07-07 ES ES92914236T patent/ES2103952T3/en not_active Expired - Lifetime
- 1992-07-07 JP JP5503198A patent/JPH06509346A/en not_active Ceased
- 1992-07-07 HU HU9400253A patent/HU217215B/en not_active IP Right Cessation
- 1992-07-07 EP EP92914236A patent/EP0596903B1/en not_active Expired - Lifetime
- 1992-07-07 CA CA002114537A patent/CA2114537A1/en not_active Abandoned
- 1992-07-29 PT PT100737A patent/PT100737B/en not_active IP Right Cessation
-
1994
- 1994-01-28 NO NO940313A patent/NO307736B1/en unknown
- 1994-01-28 FI FI940427A patent/FI940427A/en unknown
-
1997
- 1997-07-15 GR GR970401748T patent/GR3024097T3/en unknown
Cited By (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7011843B2 (en) | 1997-10-01 | 2006-03-14 | Lts Lohmann-Therapie Systeme Ag | Method for protecting a human being against health impairment by ingestion of a transdermal therapeutic system |
US9713643B2 (en) | 2002-10-25 | 2017-07-25 | Foamix Pharmaceuticals Ltd. | Foamable carriers |
US11033491B2 (en) | 2002-10-25 | 2021-06-15 | Vyne Therapeutics Inc. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US10322085B2 (en) | 2002-10-25 | 2019-06-18 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US10821077B2 (en) | 2002-10-25 | 2020-11-03 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
US9539208B2 (en) | 2002-10-25 | 2017-01-10 | Foamix Pharmaceuticals Ltd. | Foam prepared from nanoemulsions and uses |
US10117812B2 (en) | 2002-10-25 | 2018-11-06 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US9492412B2 (en) | 2002-10-25 | 2016-11-15 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
US9622947B2 (en) | 2002-10-25 | 2017-04-18 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US9320705B2 (en) | 2002-10-25 | 2016-04-26 | Foamix Pharmaceuticals Ltd. | Sensation modifying topical composition foam |
US9636405B2 (en) | 2003-08-04 | 2017-05-02 | Foamix Pharmaceuticals Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
EP2977043A3 (en) * | 2003-08-25 | 2016-04-06 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
US9682021B2 (en) | 2006-11-14 | 2017-06-20 | Foamix Pharmaceuticals Ltd. | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
US11103454B2 (en) | 2007-08-07 | 2021-08-31 | Vyne Therapeutics Inc. | Wax foamable vehicle and pharmaceutical compositions thereof |
US10369102B2 (en) | 2007-08-07 | 2019-08-06 | Foamix Pharmaceuticals Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US9662298B2 (en) | 2007-08-07 | 2017-05-30 | Foamix Pharmaceuticals Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
US11433025B2 (en) | 2007-12-07 | 2022-09-06 | Vyne Therapeutics Inc. | Oil foamable carriers and formulations |
US9549898B2 (en) | 2007-12-07 | 2017-01-24 | Foamix Pharmaceuticals Ltd. | Oil and liquid silicone foamable carriers and formulations |
US9795564B2 (en) | 2007-12-07 | 2017-10-24 | Foamix Pharmaceuticals Ltd. | Oil-based foamable carriers and formulations |
US9066887B2 (en) | 2008-01-30 | 2015-06-30 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system having urea components |
US10213384B2 (en) | 2009-04-28 | 2019-02-26 | Foamix Pharmaceuticals Ltd. | Foamable vehicles and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
US9884017B2 (en) | 2009-04-28 | 2018-02-06 | Foamix Pharmaceuticals Ltd. | Foamable vehicles and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
US10588858B2 (en) | 2009-04-28 | 2020-03-17 | Foamix Pharmaceuticals Ltd. | Foamable vehicles and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
US10363216B2 (en) | 2009-04-28 | 2019-07-30 | Foamix Pharmaceuticals Ltd. | Foamable vehicles and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
US10350166B2 (en) | 2009-07-29 | 2019-07-16 | Foamix Pharmaceuticals Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
US10092588B2 (en) | 2009-07-29 | 2018-10-09 | Foamix Pharmaceuticals Ltd. | Foamable compositions, breakable foams and their uses |
US9572775B2 (en) | 2009-07-29 | 2017-02-21 | Foamix Pharmaceuticals Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
US11219631B2 (en) | 2009-07-29 | 2022-01-11 | Vyne Pharmaceuticals Inc. | Foamable compositions, breakable foams and their uses |
US10517882B2 (en) | 2009-10-02 | 2019-12-31 | Foamix Pharmaceuticals Ltd. | Method for healing of an infected acne lesion without scarring |
US10265404B2 (en) | 2009-10-02 | 2019-04-23 | Foamix Pharmaceuticals Ltd. | Compositions, gels and foams with rheology modulators and uses thereof |
US10029013B2 (en) | 2009-10-02 | 2018-07-24 | Foamix Pharmaceuticals Ltd. | Surfactant-free, water-free formable composition and breakable foams and their uses |
US10213512B2 (en) | 2009-10-02 | 2019-02-26 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10463742B2 (en) | 2009-10-02 | 2019-11-05 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10137200B2 (en) | 2009-10-02 | 2018-11-27 | Foamix Pharmaceuticals Ltd. | Surfactant-free water-free foamable compositions, breakable foams and gels and their uses |
US10086080B2 (en) | 2009-10-02 | 2018-10-02 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10610599B2 (en) | 2009-10-02 | 2020-04-07 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10821187B2 (en) | 2009-10-02 | 2020-11-03 | Foamix Pharmaceuticals Ltd. | Compositions, gels and foams with rheology modulators and uses thereof |
US10322186B2 (en) | 2009-10-02 | 2019-06-18 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10835613B2 (en) | 2009-10-02 | 2020-11-17 | Foamix Pharmaceuticals Ltd. | Compositions, gels and foams with rheology modulators and uses thereof |
US10238746B2 (en) | 2009-10-02 | 2019-03-26 | Foamix Pharmaceuticals Ltd | Surfactant-free water-free foamable compositions, breakable foams and gels and their uses |
US10946101B2 (en) | 2009-10-02 | 2021-03-16 | Vyne Therapeutics Inc. | Surfactant-free water-free foamable compositions, breakable foams and gels and their uses |
US10967063B2 (en) | 2009-10-02 | 2021-04-06 | Vyne Therapeutics Inc. | Surfactant-free, water-free formable composition and breakable foams and their uses |
US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
US9675700B2 (en) | 2009-10-02 | 2017-06-13 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10849847B2 (en) | 2016-09-08 | 2020-12-01 | Foamix Pharamaceuticals Ltd. | Compositions and methods for treating rosacea and acne |
US11324691B2 (en) | 2016-09-08 | 2022-05-10 | Journey Medical Corporation | Compositions and methods for treating rosacea and acne |
US10398641B2 (en) | 2016-09-08 | 2019-09-03 | Foamix Pharmaceuticals Ltd. | Compositions and methods for treating rosacea and acne |
Also Published As
Publication number | Publication date |
---|---|
DK0596903T3 (en) | 1997-11-03 |
EP0596903B1 (en) | 1997-04-23 |
DE59208408D1 (en) | 1997-05-28 |
NO940313L (en) | 1994-01-28 |
DE4210165A1 (en) | 1993-02-04 |
HU9400253D0 (en) | 1994-05-30 |
ATE151985T1 (en) | 1997-05-15 |
PT100737B (en) | 1999-07-30 |
HU217215B (en) | 1999-12-28 |
JPH06509346A (en) | 1994-10-20 |
WO1993002669A1 (en) | 1993-02-18 |
AU676826B2 (en) | 1997-03-27 |
FI940427A0 (en) | 1994-01-28 |
NO940313D0 (en) | 1994-01-28 |
NO307736B1 (en) | 2000-05-22 |
AU2229892A (en) | 1993-03-02 |
PT100737A (en) | 1993-10-29 |
FI940427A (en) | 1994-01-28 |
EP0596903A1 (en) | 1994-05-18 |
ES2103952T3 (en) | 1997-10-01 |
GR3024097T3 (en) | 1997-10-31 |
HUT66125A (en) | 1994-09-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2114537A1 (en) | Transdermal therapeutic systems | |
US5676968A (en) | Transdermal therapeutic systems with crystallization inhibitors | |
CA2120599C (en) | Transdermal therapeutic systems containing crystallization inhibitors | |
US5906830A (en) | Supersaturated transdermal drug delivery systems, and methods for manufacturing the same | |
US5079008A (en) | Transdermal monolith systems | |
FI100456B (en) | Use of an agent intended for transdermal administration of an active substance containing the birth control method | |
US5601839A (en) | Triacetin as a penetration enhancer for transdermal delivery of a basic drug | |
US5985317A (en) | Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents | |
KR100392435B1 (en) | Transdermal Therapy System Containing Sex Steroids | |
JP3523259B2 (en) | Plasters containing volatile active substances that can be produced without solvents | |
US5399355A (en) | Agent for transdermal administration containing ergoline derivatives | |
JPH09501398A (en) | Active ingredient patch | |
JPH07138153A (en) | Percutaneous supply of effective medicine | |
US6013276A (en) | Transdermal matrix system | |
AU758107B2 (en) | Estradiol-containing patch for transdermal administration of hormones | |
WO1997009971A2 (en) | High capacity, superabsorbent drug reservoirs for use in transdermal drug delivery systems | |
WO1995005137A1 (en) | Transdermal delivery system using a combination of permeation enhancers | |
SK608989A3 (en) | The composition for transdermal application with gestodene content | |
MXPA99002039A (en) | Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |