CA2144441C - Dexpanthenol-containing plaster for the transdermal application of steroid hormones - Google Patents
Dexpanthenol-containing plaster for the transdermal application of steroid hormones Download PDFInfo
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- CA2144441C CA2144441C CA002144441A CA2144441A CA2144441C CA 2144441 C CA2144441 C CA 2144441C CA 002144441 A CA002144441 A CA 002144441A CA 2144441 A CA2144441 A CA 2144441A CA 2144441 C CA2144441 C CA 2144441C
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Abstract
A self adhesive plaster for the transdermal application of steroid hormones with a backing impermeable to active agents, an adhesive layer containing the active agent and a protective layer removable before the application of the plaster to the skin, in which the active agent-containing adhesive layer contains a hot-melt adhesive with a processing temperature of between 60 and 100°C and dexpanthenol in a concentration of 15 to 25 wt.%.
Description
!.
PLASTER FOR THE TRANSDERMAL APPLICATION OF STEROID HOR-MONES, CONTAINING DEXPANTHENOL
D E S C R I P T I O N
The invention relates to a self-adhesive plaster for the transdermal application of systemically active steroid hor-mones, comprising an active substance-impermeable backing layer, an active substance-containing pressure-sensitive adhesive layer and a removable protective layer covering said pressure-sensitive adhesive layer prior to application to the skin.
Active substance plasters as therapeutic systems (TTS) are self-adhesive devices to be applied to the skin, having a defined application surface and releasing one or more drugs contained therein to the human or animal body in a control-led manner as to time and amount.
However, it is a prerequisite for transdermal active sub-stance absorption, that the active substance in the galenic formulation be provided in a form permitting its absorption by the skin, which means that the active substance must be at least partially dissolved in the formulation. The steroid hormones, and in particular the active substance estradiol, which among the substances of this group is the one most thoroughly tested for transdermal administration, are known to exhibit only a very low solubility in those formulations which are commonly suitable for transdermal active substance release and are commonly used for this purpose. In such formulations, wherein as base polymers for example polyacrylates or polyisobutylenes are utilized, generally recrystallisation of the active substance occurs during storage of the plaster, which alters the release be-haviour and thus the resorption behaviour.
In principle, there is a possibility to maintain the solu-bility of the active substance during storage and to prevent recristallisation by employing solubilizers.
In estradiol TTS which have been available on the market under the trademark ~~Estraderm~~, estradiol and ethanol are administered as solvents for estradiol in a plaster formu-lation containing the active substance solution in a bag (EP 0 285 563). Disadvantages of this plaster are for once its complicated structure and complicated, costly manufac-ture, and secondly the fact that in particular in the case of application over a period of several days skin irrita-tions may occur caused by the solubilizer ethanol.
In transdermal therapeutic systems of common construction -comprising single-layered, self-adhesive active substance matrices, for example - the use of solubilizers at a con-centration which is at least equal to that required results in loss of cohesion, i.e. in the matrices becoming ~~mushy~~.
This especially applies to dexpanthenol, a liquid which is highly viscous at room temperature and which in common for-mulations has a highly softening effect, even at compara-tively low concentrations. EP 0 380 989 describes dexpan-thenol as a penetration auxiliary substance in the trans-dermal administration of systemically effective, pharmaceu-tic active substances. It is stated to be a particular ad-vantage of the use of dexpanthenol that dexpanthenol does not only have a penetration enhancing effect but also sup-presses or reduces the skin irritating influence of active substances and auxiliary substances.
PLASTER FOR THE TRANSDERMAL APPLICATION OF STEROID HOR-MONES, CONTAINING DEXPANTHENOL
D E S C R I P T I O N
The invention relates to a self-adhesive plaster for the transdermal application of systemically active steroid hor-mones, comprising an active substance-impermeable backing layer, an active substance-containing pressure-sensitive adhesive layer and a removable protective layer covering said pressure-sensitive adhesive layer prior to application to the skin.
Active substance plasters as therapeutic systems (TTS) are self-adhesive devices to be applied to the skin, having a defined application surface and releasing one or more drugs contained therein to the human or animal body in a control-led manner as to time and amount.
However, it is a prerequisite for transdermal active sub-stance absorption, that the active substance in the galenic formulation be provided in a form permitting its absorption by the skin, which means that the active substance must be at least partially dissolved in the formulation. The steroid hormones, and in particular the active substance estradiol, which among the substances of this group is the one most thoroughly tested for transdermal administration, are known to exhibit only a very low solubility in those formulations which are commonly suitable for transdermal active substance release and are commonly used for this purpose. In such formulations, wherein as base polymers for example polyacrylates or polyisobutylenes are utilized, generally recrystallisation of the active substance occurs during storage of the plaster, which alters the release be-haviour and thus the resorption behaviour.
In principle, there is a possibility to maintain the solu-bility of the active substance during storage and to prevent recristallisation by employing solubilizers.
In estradiol TTS which have been available on the market under the trademark ~~Estraderm~~, estradiol and ethanol are administered as solvents for estradiol in a plaster formu-lation containing the active substance solution in a bag (EP 0 285 563). Disadvantages of this plaster are for once its complicated structure and complicated, costly manufac-ture, and secondly the fact that in particular in the case of application over a period of several days skin irrita-tions may occur caused by the solubilizer ethanol.
In transdermal therapeutic systems of common construction -comprising single-layered, self-adhesive active substance matrices, for example - the use of solubilizers at a con-centration which is at least equal to that required results in loss of cohesion, i.e. in the matrices becoming ~~mushy~~.
This especially applies to dexpanthenol, a liquid which is highly viscous at room temperature and which in common for-mulations has a highly softening effect, even at compara-tively low concentrations. EP 0 380 989 describes dexpan-thenol as a penetration auxiliary substance in the trans-dermal administration of systemically effective, pharmaceu-tic active substances. It is stated to be a particular ad-vantage of the use of dexpanthenol that dexpanthenol does not only have a penetration enhancing effect but also sup-presses or reduces the skin irritating influence of active substances and auxiliary substances.
In addition, tests carried out by the applicant of the present application have shown that dexpanthenol is a good solvent and a good solubilizer for steroid hormones.
It was thus the object of the present invention to provide an application of steroid hormones for a plaster for trans-dermal formulation permitting incorporation into the for-mulation of dexpanthenol at concentrations not below those required for solubilization while avoiding both loss of cohesion and deliquescence of the active substance-containing plaster component during application.
Surprisingly, this object was achieved in that the active substance-containing pressure-sensitive layer contains a presse-sensitive hot melt adhesive with a processing tempe-rature of 60 to 100 °C, and a portion of dexpanthenol of from 15 to 25%-wt.
Since, commonly, formulations for the transdermal applica-tion of systemically active steroid hormones contain the respective steroid hormone, e.g. estradiol, at a con-centration of 1 to 2%, and considering the respective sat-uration solubility of the steroid hormone in dexpanthenol, a portion of at least 15%-wt. of dexpanthenol is required in order to reliably prevent crystallization of the active substance in the formulation. Despite expectations to the contrary, it is possible to achieve such a concentration of dexpanthenol in an active-substance-containing formulation for transdermal application while avoiding the loss of in-ner cohesion of the pressure-sensitive adhesive formula-tion, if a pressure-sensitive hot melt adhesive having a processing temperature of 60 to 100 °C is selected.
Pressure-sensitive hot melt adhesives are solid, ther-moplastic formulations, substantially containing substances 2~4~~4~
It was thus the object of the present invention to provide an application of steroid hormones for a plaster for trans-dermal formulation permitting incorporation into the for-mulation of dexpanthenol at concentrations not below those required for solubilization while avoiding both loss of cohesion and deliquescence of the active substance-containing plaster component during application.
Surprisingly, this object was achieved in that the active substance-containing pressure-sensitive layer contains a presse-sensitive hot melt adhesive with a processing tempe-rature of 60 to 100 °C, and a portion of dexpanthenol of from 15 to 25%-wt.
Since, commonly, formulations for the transdermal applica-tion of systemically active steroid hormones contain the respective steroid hormone, e.g. estradiol, at a con-centration of 1 to 2%, and considering the respective sat-uration solubility of the steroid hormone in dexpanthenol, a portion of at least 15%-wt. of dexpanthenol is required in order to reliably prevent crystallization of the active substance in the formulation. Despite expectations to the contrary, it is possible to achieve such a concentration of dexpanthenol in an active-substance-containing formulation for transdermal application while avoiding the loss of in-ner cohesion of the pressure-sensitive adhesive formula-tion, if a pressure-sensitive hot melt adhesive having a processing temperature of 60 to 100 °C is selected.
Pressure-sensitive hot melt adhesives are solid, ther-moplastic formulations, substantially containing substances 2~4~~4~
of the group consisting of polymers, resins, fillers and ageing protecting agents.
For this purpose, homopolymers, copolymers or block poly-mers, such as polyamides, polyesters, polycaprolactames, polycaprolactones, ethylene-vinylacetate copolymers (EVA), ethylene-ethylacrylate copolymers (EEA), polyvinyl ethers, poly(meth)acrylates, polyvinyl acetales, polyvinyl acetates, styrene-butadiene block polymers, isoprene block polymers, polyurethanes, ethylcellulose, cellulose acetate butyrate, synthetic rubbers (e. g. neoprene rubber), polyisobutylene, butyl rubber, acrylonitrile butadiene co-polymers, epoxide resins, melamine resins, phenol-formal-dehyde resins and resorcinol formaldehyde resins may be used as polymers, it being also possible to use, inter alia, the following modified resins: hydrogenated colophony, polymerized colophony, dimerized resin acids, disproportionated colophony, methyl esters of colophony, glycerin esters of hydrogenated colophony, methyl esters of hydrogenated colophony, pental esters, triethylene glycol esters of hydrogenated colophony, hydroabietyl alcohol arid its derivatives, glycerin esters, di-triol esters arid pental esters of resin acids, pental esters of polymerized colophony, pental esters of dimerized colophony, glycerin esters of dimerized colophony, esters of malefic acid-modified or phenol-modified colophony, aromatic and aliphatic hydrocarbon resins, hydrogenated resins, polyter-pene resins, modified terpene resins, waxes, low-molecular polyethylene and polypropylene, alkyl-styrene copolymers.
In addition, fillers may be admixed, such as titanium di-oxide, magnesium dioxide, zinc oxide and silicon dioxide, as well as ageing protecting agents, such as tocopherol, substituted phenols, hydroguinones, pyrocatechines and aro-matic amines.
~~4~~~~.
For this purpose, homopolymers, copolymers or block poly-mers, such as polyamides, polyesters, polycaprolactames, polycaprolactones, ethylene-vinylacetate copolymers (EVA), ethylene-ethylacrylate copolymers (EEA), polyvinyl ethers, poly(meth)acrylates, polyvinyl acetales, polyvinyl acetates, styrene-butadiene block polymers, isoprene block polymers, polyurethanes, ethylcellulose, cellulose acetate butyrate, synthetic rubbers (e. g. neoprene rubber), polyisobutylene, butyl rubber, acrylonitrile butadiene co-polymers, epoxide resins, melamine resins, phenol-formal-dehyde resins and resorcinol formaldehyde resins may be used as polymers, it being also possible to use, inter alia, the following modified resins: hydrogenated colophony, polymerized colophony, dimerized resin acids, disproportionated colophony, methyl esters of colophony, glycerin esters of hydrogenated colophony, methyl esters of hydrogenated colophony, pental esters, triethylene glycol esters of hydrogenated colophony, hydroabietyl alcohol arid its derivatives, glycerin esters, di-triol esters arid pental esters of resin acids, pental esters of polymerized colophony, pental esters of dimerized colophony, glycerin esters of dimerized colophony, esters of malefic acid-modified or phenol-modified colophony, aromatic and aliphatic hydrocarbon resins, hydrogenated resins, polyter-pene resins, modified terpene resins, waxes, low-molecular polyethylene and polypropylene, alkyl-styrene copolymers.
In addition, fillers may be admixed, such as titanium di-oxide, magnesium dioxide, zinc oxide and silicon dioxide, as well as ageing protecting agents, such as tocopherol, substituted phenols, hydroguinones, pyrocatechines and aro-matic amines.
~~4~~~~.
Pressure-sensitive hot melt adhesives of the kind mentioned above are processed at temperatures of between 60 and 100 °C in melted condition and solidify while forming ad-hesive and cohesive forces; the cohesive forces generally decrease with decreasing softening temperatures of the pressure-sensitive hot melt adhesives.
The softening temperature is in particular reduced by so-called plasticizers, which also include dexpanthenol, whereby, generally, low concentrations of plasticizers already result in a marked loss of cohesion. As already mentioned above, the plasticizer dexpanthenol, sur-prisingly, can be incorporated into pressure-sensitive hot melt formulations in unusually high concentrations, where-by the above-mentioned loss of cohesion has not been ob-served. However, the plasticizer absorption capacity of a pressure-sensitive hot melt formulation according to the present invention having a processing temperature of bet-ween 60 and 100 °C is limited as well.
Where the dexpanthenol portion is above 25~-wt., in the beforementioned pressure-sensitive hot melt adhesives too a reduction of the melt temperature occurs within a range near the body temperature so that, upon application of such formulations to the skin, unwanted softening occurs.
When formulating active substance-containing pressure-sen-sitive hot melt adhesives for the transdermal application of systemically active steroid hormones, the temperatures required for the manufacture and processing of the press-ure-sensitive hot melt adhesive must be kept within a range which precludes unwanted changes in the steroid hormone or in other formulation components. The temperature stability of the known steroid hormones is quite good at temperatures of below 100 °C, so that a pressure-sensitive hot melt for-~~~~4~
The softening temperature is in particular reduced by so-called plasticizers, which also include dexpanthenol, whereby, generally, low concentrations of plasticizers already result in a marked loss of cohesion. As already mentioned above, the plasticizer dexpanthenol, sur-prisingly, can be incorporated into pressure-sensitive hot melt formulations in unusually high concentrations, where-by the above-mentioned loss of cohesion has not been ob-served. However, the plasticizer absorption capacity of a pressure-sensitive hot melt formulation according to the present invention having a processing temperature of bet-ween 60 and 100 °C is limited as well.
Where the dexpanthenol portion is above 25~-wt., in the beforementioned pressure-sensitive hot melt adhesives too a reduction of the melt temperature occurs within a range near the body temperature so that, upon application of such formulations to the skin, unwanted softening occurs.
When formulating active substance-containing pressure-sen-sitive hot melt adhesives for the transdermal application of systemically active steroid hormones, the temperatures required for the manufacture and processing of the press-ure-sensitive hot melt adhesive must be kept within a range which precludes unwanted changes in the steroid hormone or in other formulation components. The temperature stability of the known steroid hormones is quite good at temperatures of below 100 °C, so that a pressure-sensitive hot melt for-~~~~4~
mulation for steroid hormones ideally exhibits a processing temperature of below 100 °C. On the other hand, the proces-sing temperature should be above 60 °C in order to attain a sufficient cohesion of the pressure-sensitive hot melt adhesive after cooling down.
A pressure-sensitive hot melt adhesive that is particularly suited to meet the requirements with regard to processing temperature (60 to 100 °C), cohesion of the formulation (max. 25%-wt. dexpanthenol) and solubility of the steroid hormone (at least 15% dexpanthenol) is a dexpanthenol-containing pressure-sensitive hot melt adhesive having the following composition:
to 30%-wt. of ethylene-vinylacetate copolymer having a vinyl acetate content of 28%
to 45%-wt. flexible resin having a melt vis-cosity of below 10 Pa~s at 60 °C
10 to 30%-wt. aliphatic hydrocarbon resin having a melt viscosity above 10 Pa~s at 100 °C
15 to 25%-wt. dexpanthenol 0.1 to 10%-wt. steroid hormone 0 to 5%-wt. filler 0 to 5%-wt. ageing protecting agent.
A pressure-sensitive hot melt adhesive formulation of the above-mentioned composition may also contain 16.7%-wt. ethylene-vinylacetate copolymer having a vinylacetate content of 28%
35.8%-wt. hydroabietyl alcohol 23.2%-wt. polyalkadiene (chain length of the monomer C, to CS ) 21.6%-wt. dexpanthenol 0.7%-wt. silicon dioxide 2.0%-wt. estradiol.
If this formulation, after melting and homogenizing at a temperature of, for example, 90 °C, is spread onto a car-rier material, a homogeneous, transparent film is obtained, wherein even 12 months after preparation no estradiol crys-talls will be found in microscopic examinations.
If a pressure-sensitive hot melt adhesive formulation of the same composition, however, without the addition of dex-panthenol, is prepared, the active substance estradiol, which is to be incorporated, cannot be completely dis-solved. After spreading and cooling of the pressure-sen-sitive hot melt adhesive, crystallisation of the active substance from the oversaturated solution quickly occurs, as well as continuing crystalline growth, especially in those places where crystalls are already present which have not dissolved in the melt.
The above-described example, on the one hand, illustrates the fact that dexpanthenol is particularly suited for solubilization in those cases where steroid hormones are to be dissolved in pressure-sensitive hot melt adhesives - g _ having a processing temperature of 60 to 100 °C; on the other hand, the example shows the ability of dexpanthenol to stabilize the state of the oversaturated solution of steroid hormones in the pressure-sensitive hot melt ad-hesive and to prevent recrystallization of the steroid hormone and thus the destabilization of the system.
Systemically active steroid hormones according to the present invention may be estrogens, for example. These include the most effective one of the natural estrogens, 17-!3-estradiol, as well as esters, ethers or ethinyl com-pounds of estradiol, such as - estradiol (1713)-17-butyryl acetate, - estradiol 17-i3-cipionate, - estradiol 3,17-$-dienantate, - estradiol 3,17-!3-dipropionate, - estradiol enantate, - estradiol 3-hydrogen sulfate (sodium salt), - estradiol 17-i3-(3-phenylpropionate), - estradiol undecylate, - estradiol valerate, - estradiol 17-(oxohexonate), - epimestrol, - quinestrol, - quinestradol, - ethinyl estradiol, - fosferol, as well as - estratriol.
In addition, systemically active steroid hormones according to the invention may be progestagens, such as:
- lynestrenol, - norethisterone, _ g -- hydroxyprogesterone, - progesterone, - medroxyprogesterone, - gestonorone, - dydrogesterone, - chloromadinone, - allylestrenol, - megestrol, - medrogestone.
Dexpanthenol-containing plasters for the transdermal appli-cation of systemically active steroid hormones wherein the active substance-releasing part contains pressure-sensitive hot melt adhesives may be construed according to any plaster construction known to those skilled in the art, for example according to the matrix system or the membrane sys-tem.
A membrane system comprises at least 5 members: a flexible backing layer, an active substance-containing pressure-sen-sitive hot melt adhesive, a membrane for controlling the active substance release, an adhesive layer laminated on the membrane for fixing the system to the skin, as well as a removable protective layer covering the skin-facing, ad-hesive surface of the plaster.
A matrix system in its most simple form comprises three members: a flexible backing layer, an active substance-con-taining pressure-sensitive hot melt adhesive and a re-movable protective layer covering the skin-facing, adhesive surface of the plaster.
Suitable backing layer materials are, for example, poly-ester, polyamide, polyethylene, polypropylene, poly-urethane, polyvinylchloride, both as single-layered films and as sandwich films in combinations of films of different orics of. these plastics. These ~tlms may also be aluminised or laminated with an al.umituum foil.
Suitable materials fur the removable protective layer are, for example, polyesce;r, polyethylene and. pvlypropylcne, as well as paper materials coated with these tnaterials and optionally aluminised or lam.inatcd with an aluminium foil. 1n addition, the frlrns or paper materials are coated with silicone in order to render them detachable.
The active substance-releasing pressure-sensitive hot melt adhesive may be pxesent in one or several layers. In fUe individual layers, different auxiliaries or different acrivc substance concentrations arc used in order to ensure that the active substance is released in such a manner as is required .far application, and as cannot be achieved, fur example, by using single-layered StruCturcs.
The present invention provides a process for the rnartufaeh.ire of a plaster according to the ~eatures described hereinbelow;
a) resin portions oi'thc fotznul.ation are mc:ltcd at approx. 60 to 200°C, b) palyrners are slowly stirred into the melt until a clear melt is obtained, c) subsequently or simultane4usly, auxiliaries and/or filicrs are slowly stirred into the mass until a laornogeneous distribution is obtained (melt A), l.9Ull2ll-31$7UI
TUO REn #c518361 b v. I
d) in a separate stirring vessel dexpanthenol is melted at 50 °C; estradiol is slowly stirred into the melt in portions until a clear solution is obtained (melt 8) e) melt s is slowly stirred into melt A until a homogene-ous mixture is obtained, f) using a knife coating technique, the pressure-sensitive hot melt adhesive is thereafter spread at 60 to 100 °C
onto a siliconized polyester protective layer (thick-ness 30 to 250 Vim) such that a weight per area of 80 to 500 g/m2, preferably 150 to 260 g/ms, results; after cooling down, a backing layer of polyester (thickness 6 to 100 ~tm) is laminated onto the pressure-sensitive hot melt adhesive, g) subseguently, plasters having a thickness of 10 cms are punched out.
The processing of the active substance-releasing pressure-sensitive adhesive layer containing pressure-sensitive hot melt adhesives with a processing temperature of between 60 and 100 °C, may be carried out employing known procedures such as extrusion, casting, roll coating, knife coating, spray coating, or a printing process.
Ethylene-vinylacetate copolymer 17,7 g 16,7 g comprising 289s vinyl acetate Dexpanthenol 15,9 g 21,6 g Hydroabietyl alcohol 38,9 g 35,8 g Polyalkadiene 24,7 g 23,2 g (monomer chain length C, to CS) i Silicon dioxide 0,7 g 0,7 g Ethylcellulose 0,7 g Estradiol 1,4 g 2,0 g 100,0 g 100,0 g Weight per area of the active substance-free pressure-sensi-tive adhesive layer (g/m~) 230 231 Active substance content 2,80 4,24 of the plaster (mg/10 cmZ) Penetration of mouse skin (~,g/10 cma ) 8 h 33 38 24 h 91 113 48 h 257 340 In vitro release (paddle over disc;
~..t,g/10 cm2 ) 4 h 116 194 24 h 430 752 The manufacture of the plasters according to the formu-lation examples 1 and 2 is carried out such that, for example, hydroabietyl alcohol is melted at 90 °C. Ethylene-vinylacetate copolymer and polyalkadiene are slowly stirred into the melt until it becomes clear. Thereafter, silicon dioxide and, in example 1, ethylcellulose are slowly stirred into the mass, until a homogeneous distribution is obtained (melt A).
Dexpanthenol is melted at 50 °C in a separate stirring ves-sel. Estradiol is slowly and in portions stirred into the melt until a clear solution is obtained (melt B).
Melt B is slowly stirred into melt A until a homogeneous distribution is obtained.
Using a knife coating process, the pressure-sensitive hot melt adhesive is spread onto a siliconized polyester protective layer (thickness 100 ~.t,m) such that a weight per area of 230 g/mz is obtained. After cooling down, a poly-ester backing layer (thickness 15 E.lm) is laminated onto the pressure-sensitive hot melt adhesive.
Subsequently plasters having an area of 10 cma are punched out.
Examinations of these plasters with regard to penetration through excised mouse skin and in-vitro release have shown that the plaster according to the invention ensures optimum penetration values while preventing the occurence of crys-tallization.
A pressure-sensitive hot melt adhesive that is particularly suited to meet the requirements with regard to processing temperature (60 to 100 °C), cohesion of the formulation (max. 25%-wt. dexpanthenol) and solubility of the steroid hormone (at least 15% dexpanthenol) is a dexpanthenol-containing pressure-sensitive hot melt adhesive having the following composition:
to 30%-wt. of ethylene-vinylacetate copolymer having a vinyl acetate content of 28%
to 45%-wt. flexible resin having a melt vis-cosity of below 10 Pa~s at 60 °C
10 to 30%-wt. aliphatic hydrocarbon resin having a melt viscosity above 10 Pa~s at 100 °C
15 to 25%-wt. dexpanthenol 0.1 to 10%-wt. steroid hormone 0 to 5%-wt. filler 0 to 5%-wt. ageing protecting agent.
A pressure-sensitive hot melt adhesive formulation of the above-mentioned composition may also contain 16.7%-wt. ethylene-vinylacetate copolymer having a vinylacetate content of 28%
35.8%-wt. hydroabietyl alcohol 23.2%-wt. polyalkadiene (chain length of the monomer C, to CS ) 21.6%-wt. dexpanthenol 0.7%-wt. silicon dioxide 2.0%-wt. estradiol.
If this formulation, after melting and homogenizing at a temperature of, for example, 90 °C, is spread onto a car-rier material, a homogeneous, transparent film is obtained, wherein even 12 months after preparation no estradiol crys-talls will be found in microscopic examinations.
If a pressure-sensitive hot melt adhesive formulation of the same composition, however, without the addition of dex-panthenol, is prepared, the active substance estradiol, which is to be incorporated, cannot be completely dis-solved. After spreading and cooling of the pressure-sen-sitive hot melt adhesive, crystallisation of the active substance from the oversaturated solution quickly occurs, as well as continuing crystalline growth, especially in those places where crystalls are already present which have not dissolved in the melt.
The above-described example, on the one hand, illustrates the fact that dexpanthenol is particularly suited for solubilization in those cases where steroid hormones are to be dissolved in pressure-sensitive hot melt adhesives - g _ having a processing temperature of 60 to 100 °C; on the other hand, the example shows the ability of dexpanthenol to stabilize the state of the oversaturated solution of steroid hormones in the pressure-sensitive hot melt ad-hesive and to prevent recrystallization of the steroid hormone and thus the destabilization of the system.
Systemically active steroid hormones according to the present invention may be estrogens, for example. These include the most effective one of the natural estrogens, 17-!3-estradiol, as well as esters, ethers or ethinyl com-pounds of estradiol, such as - estradiol (1713)-17-butyryl acetate, - estradiol 17-i3-cipionate, - estradiol 3,17-$-dienantate, - estradiol 3,17-!3-dipropionate, - estradiol enantate, - estradiol 3-hydrogen sulfate (sodium salt), - estradiol 17-i3-(3-phenylpropionate), - estradiol undecylate, - estradiol valerate, - estradiol 17-(oxohexonate), - epimestrol, - quinestrol, - quinestradol, - ethinyl estradiol, - fosferol, as well as - estratriol.
In addition, systemically active steroid hormones according to the invention may be progestagens, such as:
- lynestrenol, - norethisterone, _ g -- hydroxyprogesterone, - progesterone, - medroxyprogesterone, - gestonorone, - dydrogesterone, - chloromadinone, - allylestrenol, - megestrol, - medrogestone.
Dexpanthenol-containing plasters for the transdermal appli-cation of systemically active steroid hormones wherein the active substance-releasing part contains pressure-sensitive hot melt adhesives may be construed according to any plaster construction known to those skilled in the art, for example according to the matrix system or the membrane sys-tem.
A membrane system comprises at least 5 members: a flexible backing layer, an active substance-containing pressure-sen-sitive hot melt adhesive, a membrane for controlling the active substance release, an adhesive layer laminated on the membrane for fixing the system to the skin, as well as a removable protective layer covering the skin-facing, ad-hesive surface of the plaster.
A matrix system in its most simple form comprises three members: a flexible backing layer, an active substance-con-taining pressure-sensitive hot melt adhesive and a re-movable protective layer covering the skin-facing, adhesive surface of the plaster.
Suitable backing layer materials are, for example, poly-ester, polyamide, polyethylene, polypropylene, poly-urethane, polyvinylchloride, both as single-layered films and as sandwich films in combinations of films of different orics of. these plastics. These ~tlms may also be aluminised or laminated with an al.umituum foil.
Suitable materials fur the removable protective layer are, for example, polyesce;r, polyethylene and. pvlypropylcne, as well as paper materials coated with these tnaterials and optionally aluminised or lam.inatcd with an aluminium foil. 1n addition, the frlrns or paper materials are coated with silicone in order to render them detachable.
The active substance-releasing pressure-sensitive hot melt adhesive may be pxesent in one or several layers. In fUe individual layers, different auxiliaries or different acrivc substance concentrations arc used in order to ensure that the active substance is released in such a manner as is required .far application, and as cannot be achieved, fur example, by using single-layered StruCturcs.
The present invention provides a process for the rnartufaeh.ire of a plaster according to the ~eatures described hereinbelow;
a) resin portions oi'thc fotznul.ation are mc:ltcd at approx. 60 to 200°C, b) palyrners are slowly stirred into the melt until a clear melt is obtained, c) subsequently or simultane4usly, auxiliaries and/or filicrs are slowly stirred into the mass until a laornogeneous distribution is obtained (melt A), l.9Ull2ll-31$7UI
TUO REn #c518361 b v. I
d) in a separate stirring vessel dexpanthenol is melted at 50 °C; estradiol is slowly stirred into the melt in portions until a clear solution is obtained (melt 8) e) melt s is slowly stirred into melt A until a homogene-ous mixture is obtained, f) using a knife coating technique, the pressure-sensitive hot melt adhesive is thereafter spread at 60 to 100 °C
onto a siliconized polyester protective layer (thick-ness 30 to 250 Vim) such that a weight per area of 80 to 500 g/m2, preferably 150 to 260 g/ms, results; after cooling down, a backing layer of polyester (thickness 6 to 100 ~tm) is laminated onto the pressure-sensitive hot melt adhesive, g) subseguently, plasters having a thickness of 10 cms are punched out.
The processing of the active substance-releasing pressure-sensitive adhesive layer containing pressure-sensitive hot melt adhesives with a processing temperature of between 60 and 100 °C, may be carried out employing known procedures such as extrusion, casting, roll coating, knife coating, spray coating, or a printing process.
Ethylene-vinylacetate copolymer 17,7 g 16,7 g comprising 289s vinyl acetate Dexpanthenol 15,9 g 21,6 g Hydroabietyl alcohol 38,9 g 35,8 g Polyalkadiene 24,7 g 23,2 g (monomer chain length C, to CS) i Silicon dioxide 0,7 g 0,7 g Ethylcellulose 0,7 g Estradiol 1,4 g 2,0 g 100,0 g 100,0 g Weight per area of the active substance-free pressure-sensi-tive adhesive layer (g/m~) 230 231 Active substance content 2,80 4,24 of the plaster (mg/10 cmZ) Penetration of mouse skin (~,g/10 cma ) 8 h 33 38 24 h 91 113 48 h 257 340 In vitro release (paddle over disc;
~..t,g/10 cm2 ) 4 h 116 194 24 h 430 752 The manufacture of the plasters according to the formu-lation examples 1 and 2 is carried out such that, for example, hydroabietyl alcohol is melted at 90 °C. Ethylene-vinylacetate copolymer and polyalkadiene are slowly stirred into the melt until it becomes clear. Thereafter, silicon dioxide and, in example 1, ethylcellulose are slowly stirred into the mass, until a homogeneous distribution is obtained (melt A).
Dexpanthenol is melted at 50 °C in a separate stirring ves-sel. Estradiol is slowly and in portions stirred into the melt until a clear solution is obtained (melt B).
Melt B is slowly stirred into melt A until a homogeneous distribution is obtained.
Using a knife coating process, the pressure-sensitive hot melt adhesive is spread onto a siliconized polyester protective layer (thickness 100 ~.t,m) such that a weight per area of 230 g/mz is obtained. After cooling down, a poly-ester backing layer (thickness 15 E.lm) is laminated onto the pressure-sensitive hot melt adhesive.
Subsequently plasters having an area of 10 cma are punched out.
Examinations of these plasters with regard to penetration through excised mouse skin and in-vitro release have shown that the plaster according to the invention ensures optimum penetration values while preventing the occurence of crys-tallization.
Claims
TIDE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A self adhesive plaster for the transdermal application of a systemically active steroid hormone said plaster comprising:
(1) an active substance-impermeable flexible backing layer (2) an active substance reservoir connected to said layer and comprising a pressure-sensitive hot melt adhesive, and (3) a protective layer covering the skin-facing adhesive surface of the plaster and being detachable prior to application of the plaster to the skin, the improvenment wherein the pressure-sensitive adhesive is a pressure-sensitive hot melt adhesive from which an active substance-containing layer is formed by processing at a temperature of between 60° and 100° C. in molten condition, which leads to the formation o:f adhesive and cohesive forces in the process, and wherein the pressure-sensitive hot melt adhesive contains the following components:
i) 10 to 30% by weight ethylene-vinylacetate copolymer;
ii) 15 to 45% by weight flexible resin having a melt viscosity of below 10 Pa~s at 60 °C.
iii) 10 to 30% by weight aliphatic hydrocarbon resin having a melt viscosity above 10 Pa's at 100°C;
iv) 15 to 25% by weight despanthenol;
v) 0.1 to 10%!o by weight steroid hormone;
vi) 0 to 5% a by weight fiber; and vii) 0 to 5% by weight ageing protecting agent, the sun of the percentages of the components being 100.
2. The self adhesive plaster according to claim 1, further comprising a pressure-sensitive adhesive device connected to a membrane for fixing the plaster to the skin.
3. The self adhesive plaster according to claim 1, wherein the steroid hormone is estradiol.
4. The self-adhesive plaster according to claim 1, wherein the pressure-sensitive hot melt adhesive further contains at least one polymer and auxiliary substances.
5. The self adhesive plaster according to claim 4, wherein the at least one auxiliary substance is selected from the group consisting of a flexible resin and a hardened resin.
6. The self-adhesive plaster according to claim 1, wherein the ethylene-vinylacetate copolymer has a vinyl acetate content of 20 to 35% by weight.
7. The self-adhesive plaster according to claim 1, wherein the pressure-sensitive hot melt adhesive is present in one or in several layers of different composition.
8. A process for the production of self adhesive plaster according to claim 1 comprising the steps of:
a) melting the resin portions of the hot melt adhesive at a temperature in the range of from about 60 to 200°C;
b) stirring the ethylene-vinylacetate copolymer into the melted resin until a clear melt is obtained;
c) subsequently or simultaneously adding the filler or ageing protecting agent while stirring, until a homogeneous distribution is obtained (melt A);
d) melting dexpanthenol in a separate stirring vessel at 50 °C and adding steroid hormone in portions while stirring, until a clear solution is obtained (melt B):
e} stirring melt B into melt A, until a homogeneous mixture of pressure-sensitive hot melt adhesive is obtained;
f) spreading the pressure-sensitive hot melt adhesive using a knife coating technique at a temperature in the range of from 60 to 100°C onto a siliconised polyester protective layer having a thickness in the range of from 30 to 250µ, such that a weight per area of from 80 to 500 g/m2 is obtained;
g) after cooling, laminating a backing layer of polyester having a thickness of from 6 to 100 µ onto the pressure-sensitive hot melt adhesive;
and h) subsequently, plasters are punched out 9. The process according to claim 8, wherein the pressure-sensitive hot melt adhesive is spread onto the siliconised polyester protective layer, such that the weight per area is in the range of 150 to 280 g/m2.
10. The process according to claim 8, wherein the steroid hormone is estradiol.
11. A self-adhesive plaster for the transdermal application of systemically active steroid hormones, comprising an active substance-impermeable backing layer, an active substance-containing pressure-sensitive adhesive layer and a removable protective layer covering said adhesive layer prior to application to the skin, characterized in that the active substance-containing pressure-sensitive adhesive layer contains a pressure-sensitive hot melt adhesive which contains as polymer an ethylene-vinylacetate copolymer having a vinyl acetate content of 20 to 35% by weight and which has a processing temperature of between 60 and 100 °C, and dexpanthenol at a concentration of 15 to 25%-wt.
12. The self-adhesive plaster according to claim 11, characterized in that the steroid hormone is estradiol.
13. The self adhesive plaster according to any one of claims 11 to 12, characterized in that the pressure-sensitive hot melt adhesive contains as auxiliary substances flexible resins, hardened resins, fibers and ageing protecting agents.
i4. The self adhesive plaster according to any one of claims 11 to 13, characterized in that the pressure-sensitive hot melt adhesive is composed of the following components:
to 30%-wt. ethylene-vinylacetate copolymer having a vinyl acetate content of 28%
to 45%-wt. flexible resin having a melt viscosity of below 10 Pa~s at 60 °C.
10 to 30%-wt. aliphatic hydrocarbon resin having a melt viscosity above 10 Pa~s at 100 °
15 to 25%-wt. dexpanthenol 0.1 to 10%-wt. steroid hormone 0 to 5%-wt.filler 0 to 5%-wt. ageing protecting agent, whereby the sum of the percentages of the components is 100.
15. The self adhesive plaster according to any one of claims 11 to 14, characterized in that the pressure-sensitive hot melt adhesive is present in one or more layers, whereby the individual layers may be of different composition.
16. The self adhesive plaster according to any one of claims 11 to 15, characterized in that the plaster comprises an active substance-impermeable, flexible backing layer, an active substance reservoir connected thereto which is formed of the pressure-sensitive hot melt adhesive, and, where other controlling mechanisms are not present, a membrane controlling the release of active substance, and optionally a pressure-sensitive adhesive device connected to the membrane for fixing the system to the skin, and a protective layer covering the skin-facing adhesive surface of the plaster and being detachable prior to application of the system.
17. Process for the production of the plaster according to any one of claims 13 to 14, characterized by the following process steps:
a) resin portions of the formulation are melted at a temperature ranging between 60 and 200 °C, b) ethylene-vinylacetate copolymer is slowly stirred into the melt until a clear melt is obtained, c) subsequently or simultaneously, auxiliary substances and/or fillers are slowly added while stirring, until a homogeneous distribution is obtained (melt A), d) in a separate stirring vessel dexpanthenol is melted at 50 °C and steroid hormone is slowly added in portions while stirring, until a clear solution is obtained (melt B), e) melt B is slowly stirred into melt A, until a homogeneous mixture is obtained, f) using a knife coating technique, the pressure-sensitive hot melt adhesive is thereafter spread at 60 to 100 °C onto a siliconised polyester protective layer having a thickness ranging from 30 to 250 µ such that a weight per area of 80 to 500 g/m2 is obtained;
after cooling down, a backing layer of polyester having a thickness ranging from 6 to 100 µ is laminated onto the pressure-sensitive hot melt adhesive, g) subsequently, patches having an area of 10 cm2 are punched out.
18. The self adhesive plaster according to claim 1, wherein the plaster contains a membrane covering the active substance reservoir and which controls the release of the active substance, said membrane being connected to a pressure-sensitive adhesive member for fixation to the skin.
19. A process for the production of self-adhesive plaster according to any one of claims 4 or comprising the steps of:
a) melting resin portions of the hot melt adhesive at a temperature in the range of 60 to 200°C;
b) stirring the ethylene vinylacetate copolymer and the at least one polymer into the melted resin portions until a clear melt is obtained;
c) subsequently or simultaneously adding the auxiliary substances, filler or ageing protecting agent while stirring, until a homogeneous distribution is obtained (melt A);
d) melting dexpanthenol in a separate stirring vessel at 50°C and adding steroid hormone in porfiions while stirring, until a clear solution is obtained (melt B);
e) stirring melt B into melt A, until a homogeneous mixture of pressure-sensitive hot melt adhesive is obtained;
f) spreading the pressure-sensitive hot melt adhesive using a knife coating technique at a temperature in the range of 60 to 100°C onto a siliconised polyester protective layer having a thickness in the range of 30 to 250µ, such that a weight per area of 80 to 500 g/m2 is obtained;
g) after cooling, laminating a backing layer of polyester having a thickness of 6 to 100µ onto the pressure-sensitive hot melt adhesive;
and h) subsequently, plasters are punched out.
20. The process according to claim 19, wherein during step c) one or more auxiliary substances, selected from the group consisting of a flexible resin and a hardened resin, is added.
21. The process according to claim 17 wherein the weight per unit area ranges between 150 to 280 g/m2.
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A self adhesive plaster for the transdermal application of a systemically active steroid hormone said plaster comprising:
(1) an active substance-impermeable flexible backing layer (2) an active substance reservoir connected to said layer and comprising a pressure-sensitive hot melt adhesive, and (3) a protective layer covering the skin-facing adhesive surface of the plaster and being detachable prior to application of the plaster to the skin, the improvenment wherein the pressure-sensitive adhesive is a pressure-sensitive hot melt adhesive from which an active substance-containing layer is formed by processing at a temperature of between 60° and 100° C. in molten condition, which leads to the formation o:f adhesive and cohesive forces in the process, and wherein the pressure-sensitive hot melt adhesive contains the following components:
i) 10 to 30% by weight ethylene-vinylacetate copolymer;
ii) 15 to 45% by weight flexible resin having a melt viscosity of below 10 Pa~s at 60 °C.
iii) 10 to 30% by weight aliphatic hydrocarbon resin having a melt viscosity above 10 Pa's at 100°C;
iv) 15 to 25% by weight despanthenol;
v) 0.1 to 10%!o by weight steroid hormone;
vi) 0 to 5% a by weight fiber; and vii) 0 to 5% by weight ageing protecting agent, the sun of the percentages of the components being 100.
2. The self adhesive plaster according to claim 1, further comprising a pressure-sensitive adhesive device connected to a membrane for fixing the plaster to the skin.
3. The self adhesive plaster according to claim 1, wherein the steroid hormone is estradiol.
4. The self-adhesive plaster according to claim 1, wherein the pressure-sensitive hot melt adhesive further contains at least one polymer and auxiliary substances.
5. The self adhesive plaster according to claim 4, wherein the at least one auxiliary substance is selected from the group consisting of a flexible resin and a hardened resin.
6. The self-adhesive plaster according to claim 1, wherein the ethylene-vinylacetate copolymer has a vinyl acetate content of 20 to 35% by weight.
7. The self-adhesive plaster according to claim 1, wherein the pressure-sensitive hot melt adhesive is present in one or in several layers of different composition.
8. A process for the production of self adhesive plaster according to claim 1 comprising the steps of:
a) melting the resin portions of the hot melt adhesive at a temperature in the range of from about 60 to 200°C;
b) stirring the ethylene-vinylacetate copolymer into the melted resin until a clear melt is obtained;
c) subsequently or simultaneously adding the filler or ageing protecting agent while stirring, until a homogeneous distribution is obtained (melt A);
d) melting dexpanthenol in a separate stirring vessel at 50 °C and adding steroid hormone in portions while stirring, until a clear solution is obtained (melt B):
e} stirring melt B into melt A, until a homogeneous mixture of pressure-sensitive hot melt adhesive is obtained;
f) spreading the pressure-sensitive hot melt adhesive using a knife coating technique at a temperature in the range of from 60 to 100°C onto a siliconised polyester protective layer having a thickness in the range of from 30 to 250µ, such that a weight per area of from 80 to 500 g/m2 is obtained;
g) after cooling, laminating a backing layer of polyester having a thickness of from 6 to 100 µ onto the pressure-sensitive hot melt adhesive;
and h) subsequently, plasters are punched out 9. The process according to claim 8, wherein the pressure-sensitive hot melt adhesive is spread onto the siliconised polyester protective layer, such that the weight per area is in the range of 150 to 280 g/m2.
10. The process according to claim 8, wherein the steroid hormone is estradiol.
11. A self-adhesive plaster for the transdermal application of systemically active steroid hormones, comprising an active substance-impermeable backing layer, an active substance-containing pressure-sensitive adhesive layer and a removable protective layer covering said adhesive layer prior to application to the skin, characterized in that the active substance-containing pressure-sensitive adhesive layer contains a pressure-sensitive hot melt adhesive which contains as polymer an ethylene-vinylacetate copolymer having a vinyl acetate content of 20 to 35% by weight and which has a processing temperature of between 60 and 100 °C, and dexpanthenol at a concentration of 15 to 25%-wt.
12. The self-adhesive plaster according to claim 11, characterized in that the steroid hormone is estradiol.
13. The self adhesive plaster according to any one of claims 11 to 12, characterized in that the pressure-sensitive hot melt adhesive contains as auxiliary substances flexible resins, hardened resins, fibers and ageing protecting agents.
i4. The self adhesive plaster according to any one of claims 11 to 13, characterized in that the pressure-sensitive hot melt adhesive is composed of the following components:
to 30%-wt. ethylene-vinylacetate copolymer having a vinyl acetate content of 28%
to 45%-wt. flexible resin having a melt viscosity of below 10 Pa~s at 60 °C.
10 to 30%-wt. aliphatic hydrocarbon resin having a melt viscosity above 10 Pa~s at 100 °
15 to 25%-wt. dexpanthenol 0.1 to 10%-wt. steroid hormone 0 to 5%-wt.filler 0 to 5%-wt. ageing protecting agent, whereby the sum of the percentages of the components is 100.
15. The self adhesive plaster according to any one of claims 11 to 14, characterized in that the pressure-sensitive hot melt adhesive is present in one or more layers, whereby the individual layers may be of different composition.
16. The self adhesive plaster according to any one of claims 11 to 15, characterized in that the plaster comprises an active substance-impermeable, flexible backing layer, an active substance reservoir connected thereto which is formed of the pressure-sensitive hot melt adhesive, and, where other controlling mechanisms are not present, a membrane controlling the release of active substance, and optionally a pressure-sensitive adhesive device connected to the membrane for fixing the system to the skin, and a protective layer covering the skin-facing adhesive surface of the plaster and being detachable prior to application of the system.
17. Process for the production of the plaster according to any one of claims 13 to 14, characterized by the following process steps:
a) resin portions of the formulation are melted at a temperature ranging between 60 and 200 °C, b) ethylene-vinylacetate copolymer is slowly stirred into the melt until a clear melt is obtained, c) subsequently or simultaneously, auxiliary substances and/or fillers are slowly added while stirring, until a homogeneous distribution is obtained (melt A), d) in a separate stirring vessel dexpanthenol is melted at 50 °C and steroid hormone is slowly added in portions while stirring, until a clear solution is obtained (melt B), e) melt B is slowly stirred into melt A, until a homogeneous mixture is obtained, f) using a knife coating technique, the pressure-sensitive hot melt adhesive is thereafter spread at 60 to 100 °C onto a siliconised polyester protective layer having a thickness ranging from 30 to 250 µ such that a weight per area of 80 to 500 g/m2 is obtained;
after cooling down, a backing layer of polyester having a thickness ranging from 6 to 100 µ is laminated onto the pressure-sensitive hot melt adhesive, g) subsequently, patches having an area of 10 cm2 are punched out.
18. The self adhesive plaster according to claim 1, wherein the plaster contains a membrane covering the active substance reservoir and which controls the release of the active substance, said membrane being connected to a pressure-sensitive adhesive member for fixation to the skin.
19. A process for the production of self-adhesive plaster according to any one of claims 4 or comprising the steps of:
a) melting resin portions of the hot melt adhesive at a temperature in the range of 60 to 200°C;
b) stirring the ethylene vinylacetate copolymer and the at least one polymer into the melted resin portions until a clear melt is obtained;
c) subsequently or simultaneously adding the auxiliary substances, filler or ageing protecting agent while stirring, until a homogeneous distribution is obtained (melt A);
d) melting dexpanthenol in a separate stirring vessel at 50°C and adding steroid hormone in porfiions while stirring, until a clear solution is obtained (melt B);
e) stirring melt B into melt A, until a homogeneous mixture of pressure-sensitive hot melt adhesive is obtained;
f) spreading the pressure-sensitive hot melt adhesive using a knife coating technique at a temperature in the range of 60 to 100°C onto a siliconised polyester protective layer having a thickness in the range of 30 to 250µ, such that a weight per area of 80 to 500 g/m2 is obtained;
g) after cooling, laminating a backing layer of polyester having a thickness of 6 to 100µ onto the pressure-sensitive hot melt adhesive;
and h) subsequently, plasters are punched out.
20. The process according to claim 19, wherein during step c) one or more auxiliary substances, selected from the group consisting of a flexible resin and a hardened resin, is added.
21. The process according to claim 17 wherein the weight per unit area ranges between 150 to 280 g/m2.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4230588A DE4230588C1 (en) | 1992-09-12 | 1992-09-12 | Dexpanthenol-containing plaster for the transdermal application of steroid hormones and process for its production |
| DEP4230588.8 | 1992-09-12 | ||
| PCT/EP1993/002182 WO1994006436A1 (en) | 1992-09-12 | 1993-08-16 | Dexpanthenol-containing plaster for the transdermal application of steroid hormones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2144441A1 CA2144441A1 (en) | 1994-03-31 |
| CA2144441C true CA2144441C (en) | 2005-10-25 |
Family
ID=35311573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002144441A Expired - Lifetime CA2144441C (en) | 1992-09-12 | 1993-08-16 | Dexpanthenol-containing plaster for the transdermal application of steroid hormones |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2144441C (en) |
-
1993
- 1993-08-16 CA CA002144441A patent/CA2144441C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2144441A1 (en) | 1994-03-31 |
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| EEER | Examination request | ||
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