CA2220358A1 - Transdermal therapeutic system (tts) for the administration of testosterone - Google Patents
Transdermal therapeutic system (tts) for the administration of testosterone Download PDFInfo
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- CA2220358A1 CA2220358A1 CA002220358A CA2220358A CA2220358A1 CA 2220358 A1 CA2220358 A1 CA 2220358A1 CA 002220358 A CA002220358 A CA 002220358A CA 2220358 A CA2220358 A CA 2220358A CA 2220358 A1 CA2220358 A1 CA 2220358A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
-
- 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
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gynecology & Obstetrics (AREA)
- Nanotechnology (AREA)
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- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
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- Crystallography & Structural Chemistry (AREA)
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- Diabetes (AREA)
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- Steroid Compounds (AREA)
Abstract
The invention concerns a transdermal therapeutic system for administering testosterone or a testosterone derivative as the active substance.
Description
CA 022203~8 1997-11-06 8th May 1 996/he Our ref.: 8091 International Patent Application based on DE (1) 95 17145.4 Hexal AG
Transdermal therapeutic system (TTS) for the administration of testosterone According to the current state of the art, testosterone and testosterone derivatives are used especially for hormone replacement therapy in men. Other indications, in addition to primary and secondary hypogonadism, are oligozoospermia, impotencia coeundi and premature ejaculation. Tests on the use thereof in the case of osteo-porosis in men are also currently in progress; see, for example, Rapado et a/., in Trends in Osteoporosis, 1 (1989) 1-9.
Owing to a high first-pass effect, testosterone is largely ineffective when administered orally. Accordingly, in replacement therapy there are administered either orally effective esters, such as testosterone undecanoate, or injectable depot preparations, such as testosterone enanthate and testosterone propionate.
Those data yield a number of starting points for a meaningful development of transdermal therapeutic systems (TTS). With such systems, the high doses of active ingredient in oral administration can be avoided, a painful injection is circumvented and the blood level can be better regulated and better matched to the circadian rhythm.
For example, US-A-4 704 282 describes a transdermal therapeutic system having a carrier film (reenforcing means), an active ingredient reservoir and a removablecover film (release liner). The active ingredient reservoir may be in the form of an aqueous or non-aqueous gel or polymer material, the active ingredient therein being dissolved in a concentration that is no greater than the saturation concentration of the active ingredient in the matrix material. The matrix may comprise permeationenhancers. The active ingredient to be administered may, for example, be CA 022203~8 1997-11-06 testosterone. Of course, if testosterone is present in a less than saturated solution in a transdermal therapeutic system, the presence of perrrleation enhancers is indispensable to obtain satisfactory blood levels, see WO-A-9 210 231, page 11, line 33.
US-A-4 849 224 proposes a transdermal therapeutic system in which an active ingredient reservoir is formed by a carrier film (backing foil) and a porous membrane. The active ingredient may be testosterone or a testosterone ester.
Permeation enhancers may be provided in addition to the active ingredient. The useability of that known system is, of course, to be viewed critically insofar as the active ingredient reservoir, which is formed by the laminate of carrier film andmembrane, is to adhere to the skin by means of a ring of adhesive. Since the adhesive is provided in annular form, in effect there is provided a window through which the active ingredient and the permeation enhancer can penetrate through tothe skin via the membrane without the permeation enhancer coming into contact unnecessarily with the adhesive, there being provided additionally annular sealing elements to protect the adhesive. Since only limited adhesion can be obtained with an annular adhesive zone, the size of the known patch is restricted.
WO-A-9 210 231 = EP-A-O 562 041 is based on the prior art of US-A-4 849 224, according to which a ring of adhesive is provided for the adhesion of a transdermal therapeutic system to the skin; see WO-A-9 210 231, page 13, lines 18/19.
Alternatively, a basal adhesive layer underlying the reservoir (separate basal adhesive layer underlaying the reservoir) and also an adhesive coating for the reservoir (adhesive overlay for the reservoir) are proposed. Since, in accordance with that prior art, the use of a permeation enhancer is, however, indispensable for the administration of testosterone, it is not clear how WO-A-9 210 231 seeks to prevent the undesirable penetration of the permeation enhancer into the adhesive if the adhesive is not provided in annular form.
WO-A-9 503 764, WO-A-9 423 707 and US-A-5 152 997 also describe transdermal therapeutic systems for the administration of testosterone, those systems being reservoir systems in which the active ingredient is present in less than saturated form and in which a permeation accelerator is provided. Those known teachings thus correspond to the prior art as discussed by WO-A-9 210 231, page 11, line 33.
CA 022203~8 1997-11-06 The problem underlying the invention is to provide a transdermal therapeutic system for the administration of testosterone or a testosterone derivative that does not require the use of permeation enhancers and guarantees satisfactory levels of the active ingredient in the blood.
For that purpose, there is proposed according to the invention a transdermal therapeutic system (TTS) for the administration of testosterone or a testosterone derivative as active ingredient, having - a carrier film (backing foil), - a reservoir, - an alcoholic carrier for the active ingredient, - an adhesive layer for contact of the system with the skin, and - a removable cover film (release liner), in which - the system does not comprise a permeation enhancer, - the active ingredient is present in saturation in the carrier for the active ingredient, and - there is provided between the reservoir and the adhesive layer a membrane - which does not control the release of active ingredient, whilst the adhesive layer does control the release of active ingredient.
The invention is based on the surprising observation that a satisfactory level of active ingredient in the blood can be obtained also, or rather especially, when the active ingredient is present in saturation in the carrier for the active ingredient, whereas WO-A-9 210 231 requires undersaturation of the active ingredient.
According to the invention, there may be used as testosterone derivative a testosterone ester, especially testosterone enanthate, testosterone cipionate, testosterone propionate or testosterone undecanoate, or a lower alkyl testosterone, especially methyl testosterone.
The active ingredient may be present in the fomm of a complex with cyclodextrin or cyclodextrin derivatives, especially with ~-cyclodextrin.
CA 022203~8 1997-11-06 The membrane may be a polyethylene or polypropylene membrane.
According to a preferred embodiment, the reservoir is formed by the carrier film and the membrane.
According to the invention, the alcoholic carrier for the active ingredient may be ethanol or a low molecular weight monohydric alcohol, such as isopropanol, or a low molecular weight polyhydric alcohol, for example propylene glycol, or mixtures thereof.
For the adhesive layer according to the invention there may be selected a pressure-sensitive alcohol-resistant adhesive based, for example, on polyurethane, iso-butylene, polyvinyl ether, silicone or acrylate.
The silicone-based adhesive may be a silicone adhesive that is based on two maincomponents: a polymer or adhesive, especially polysiloxane, and a tackifying resin.
The polysiloxane adhesive is usually formulated with a cross-linker for the adhesive, typically a high molecular weight polydiorganosiloxane, and with the resin to yield a three-dimensional silicate structure using an appropriate organic solvent. The admixture of the resin with the polymer is the most important factor for changing the physical properties of the polysiloxane adhesives; see, for example, Sobieski et ~I., "Silicone Pressure Sensitive Adhesives", Handbook of Pressure Sensitive AdhesiveTechnology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1 989).
Suitable pressure-sensitive silicone adhesives are obtainable commercially underthe trade mark BIO-PSA X7.
A further example of a silicone-based pressure-sensitive adhesive is trimethylated silicon dioxide that has been treated with polydimethylsiloxane having terminal trimethylsiloxy groups.
The acrylate-based adhesive may be any homopolymer, copolymer or terpolymer, consisting of various acrylic acid derivatives.
CA 022203~8 1997-11-06 For example, the acrylate polymers may be polymers of one or more monomers of acrylic acids and other copolymerisable monomers. The acrylate polymers may alsocomprise copolymers of alkyl acrylates and/or methacrylates and/or copolymerisable secondary monomers or monomers having functional groups. The cohesive properties of the resulting acrylate polymers can be altered by altering the amount of each type that is added as monomer. Generally, the acrylate polymer consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, from 0 to 20% of a functional monomer, copolymerisable with acrylate, and from 0 to 40% of a different monomer.
Given hereinafter are acrylate monomers that can be used with acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate.
For example, there may be used functional monomers that are copolymerisable withthe above-mentioned acrylates, methacrylates, alkyl acrylates or alkyl methacrylates, for example acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.
Other details and examples of pressure-sensitive acrylates that are suitable for the invention are described in Satas Handbook of Pressure Sensitive Adhesive Technology"Acrylic Adhesives", 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).
Suitable pressure-sensitive acrylates are obtainable commercially.
The transdermal therapeutic system according to the invention may additionally comprise a-tocopherol or an (x-tocopherol derivative and/or a viscosity-increasing agent, such as hydroxypropyl cellulose.
CA 022203~8 1997-11-06 The invention is illustrated hereinafter in greater detail by a Figure and an Example.
According to Figure 1, a transdermal therapeutic system according to the invention may comprise a carrier film (backing foil) (1 ) which may be of slightly convex form, which together with a membrane (3) forms a reservoir (2), the membrane (3) not controlling the release of active ingredient. Applied to the membrane (3), according to Figure 1, is an adhesive layer (5) which controls the release of active ingredient.
That adhesive layer (5) is in turn covered by a cover film (release liner) (6) which is to be removed before administration. According to the Figure, the carrier film (1 ) may be provided with an annular bead (4) which lies on the circumferential edge region of the adhesive layer (5) and is sealed to the membrane (3) in the region of contact.
Example For the adhesive layer there is used a silicone-based pressure-sensitive adhesive (trimethylated silicon dioxide that has been treated with polydimethylsiloxane having terminal trimethylsiloxy groups; layer thickness when dry approximately from 35 to 45 llm; weight per unit surface area approximately from 50 to 60 g/m2). A cover film of PET (thickness approximately 75 llm; weight per unit surface area approximately 100 g/m2) is coated with the silicone adhesive by means of a coating apparatus. A
microporous polyethylene membrane or a microporous polypropylene membrane (heat-sealable; thickness approximately 50 ~,lm; weight per unit surface area approximately 10 g/m2) is then laminated onto the coated cover film to produce alaminate of cover film, adhesive and membrane. The laminate is then welded onto a carrier film of polyester (aluminized with polyolefin sealing layer (heat-sealable);
thickness approximately 70 llm) by means of a sealing machine (having a welding ring) in such a manner that a gap remains for the introduction of an active ingredient solution. The fillable transdermal therapeutic system (empty TTS) is filled, forexample using a Hamilton syringe or a tube pump equipped with a cannula, with the following active ingredient solution:
CA 022203~8 1997-11-06 Composition of the active ingredient solution per TTS:
mg/TTS
testosterone 60.56 96% ethanol 157.18 propylene glycol 48.11 oc-tocopherol 56.78 hydroxypropyl cellulose 5.98 Total 328.61 Filling volume of the reservoir: 360111 Density of the active ingredient solution: 0.91285 g/cm3 Filled amount in the reservoir: 328.6 mg After filling, the filling gap is welded. Filled transdermal therapeutic systems are punched out by means of a punch.
Transdermal therapeutic system (TTS) for the administration of testosterone According to the current state of the art, testosterone and testosterone derivatives are used especially for hormone replacement therapy in men. Other indications, in addition to primary and secondary hypogonadism, are oligozoospermia, impotencia coeundi and premature ejaculation. Tests on the use thereof in the case of osteo-porosis in men are also currently in progress; see, for example, Rapado et a/., in Trends in Osteoporosis, 1 (1989) 1-9.
Owing to a high first-pass effect, testosterone is largely ineffective when administered orally. Accordingly, in replacement therapy there are administered either orally effective esters, such as testosterone undecanoate, or injectable depot preparations, such as testosterone enanthate and testosterone propionate.
Those data yield a number of starting points for a meaningful development of transdermal therapeutic systems (TTS). With such systems, the high doses of active ingredient in oral administration can be avoided, a painful injection is circumvented and the blood level can be better regulated and better matched to the circadian rhythm.
For example, US-A-4 704 282 describes a transdermal therapeutic system having a carrier film (reenforcing means), an active ingredient reservoir and a removablecover film (release liner). The active ingredient reservoir may be in the form of an aqueous or non-aqueous gel or polymer material, the active ingredient therein being dissolved in a concentration that is no greater than the saturation concentration of the active ingredient in the matrix material. The matrix may comprise permeationenhancers. The active ingredient to be administered may, for example, be CA 022203~8 1997-11-06 testosterone. Of course, if testosterone is present in a less than saturated solution in a transdermal therapeutic system, the presence of perrrleation enhancers is indispensable to obtain satisfactory blood levels, see WO-A-9 210 231, page 11, line 33.
US-A-4 849 224 proposes a transdermal therapeutic system in which an active ingredient reservoir is formed by a carrier film (backing foil) and a porous membrane. The active ingredient may be testosterone or a testosterone ester.
Permeation enhancers may be provided in addition to the active ingredient. The useability of that known system is, of course, to be viewed critically insofar as the active ingredient reservoir, which is formed by the laminate of carrier film andmembrane, is to adhere to the skin by means of a ring of adhesive. Since the adhesive is provided in annular form, in effect there is provided a window through which the active ingredient and the permeation enhancer can penetrate through tothe skin via the membrane without the permeation enhancer coming into contact unnecessarily with the adhesive, there being provided additionally annular sealing elements to protect the adhesive. Since only limited adhesion can be obtained with an annular adhesive zone, the size of the known patch is restricted.
WO-A-9 210 231 = EP-A-O 562 041 is based on the prior art of US-A-4 849 224, according to which a ring of adhesive is provided for the adhesion of a transdermal therapeutic system to the skin; see WO-A-9 210 231, page 13, lines 18/19.
Alternatively, a basal adhesive layer underlying the reservoir (separate basal adhesive layer underlaying the reservoir) and also an adhesive coating for the reservoir (adhesive overlay for the reservoir) are proposed. Since, in accordance with that prior art, the use of a permeation enhancer is, however, indispensable for the administration of testosterone, it is not clear how WO-A-9 210 231 seeks to prevent the undesirable penetration of the permeation enhancer into the adhesive if the adhesive is not provided in annular form.
WO-A-9 503 764, WO-A-9 423 707 and US-A-5 152 997 also describe transdermal therapeutic systems for the administration of testosterone, those systems being reservoir systems in which the active ingredient is present in less than saturated form and in which a permeation accelerator is provided. Those known teachings thus correspond to the prior art as discussed by WO-A-9 210 231, page 11, line 33.
CA 022203~8 1997-11-06 The problem underlying the invention is to provide a transdermal therapeutic system for the administration of testosterone or a testosterone derivative that does not require the use of permeation enhancers and guarantees satisfactory levels of the active ingredient in the blood.
For that purpose, there is proposed according to the invention a transdermal therapeutic system (TTS) for the administration of testosterone or a testosterone derivative as active ingredient, having - a carrier film (backing foil), - a reservoir, - an alcoholic carrier for the active ingredient, - an adhesive layer for contact of the system with the skin, and - a removable cover film (release liner), in which - the system does not comprise a permeation enhancer, - the active ingredient is present in saturation in the carrier for the active ingredient, and - there is provided between the reservoir and the adhesive layer a membrane - which does not control the release of active ingredient, whilst the adhesive layer does control the release of active ingredient.
The invention is based on the surprising observation that a satisfactory level of active ingredient in the blood can be obtained also, or rather especially, when the active ingredient is present in saturation in the carrier for the active ingredient, whereas WO-A-9 210 231 requires undersaturation of the active ingredient.
According to the invention, there may be used as testosterone derivative a testosterone ester, especially testosterone enanthate, testosterone cipionate, testosterone propionate or testosterone undecanoate, or a lower alkyl testosterone, especially methyl testosterone.
The active ingredient may be present in the fomm of a complex with cyclodextrin or cyclodextrin derivatives, especially with ~-cyclodextrin.
CA 022203~8 1997-11-06 The membrane may be a polyethylene or polypropylene membrane.
According to a preferred embodiment, the reservoir is formed by the carrier film and the membrane.
According to the invention, the alcoholic carrier for the active ingredient may be ethanol or a low molecular weight monohydric alcohol, such as isopropanol, or a low molecular weight polyhydric alcohol, for example propylene glycol, or mixtures thereof.
For the adhesive layer according to the invention there may be selected a pressure-sensitive alcohol-resistant adhesive based, for example, on polyurethane, iso-butylene, polyvinyl ether, silicone or acrylate.
The silicone-based adhesive may be a silicone adhesive that is based on two maincomponents: a polymer or adhesive, especially polysiloxane, and a tackifying resin.
The polysiloxane adhesive is usually formulated with a cross-linker for the adhesive, typically a high molecular weight polydiorganosiloxane, and with the resin to yield a three-dimensional silicate structure using an appropriate organic solvent. The admixture of the resin with the polymer is the most important factor for changing the physical properties of the polysiloxane adhesives; see, for example, Sobieski et ~I., "Silicone Pressure Sensitive Adhesives", Handbook of Pressure Sensitive AdhesiveTechnology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1 989).
Suitable pressure-sensitive silicone adhesives are obtainable commercially underthe trade mark BIO-PSA X7.
A further example of a silicone-based pressure-sensitive adhesive is trimethylated silicon dioxide that has been treated with polydimethylsiloxane having terminal trimethylsiloxy groups.
The acrylate-based adhesive may be any homopolymer, copolymer or terpolymer, consisting of various acrylic acid derivatives.
CA 022203~8 1997-11-06 For example, the acrylate polymers may be polymers of one or more monomers of acrylic acids and other copolymerisable monomers. The acrylate polymers may alsocomprise copolymers of alkyl acrylates and/or methacrylates and/or copolymerisable secondary monomers or monomers having functional groups. The cohesive properties of the resulting acrylate polymers can be altered by altering the amount of each type that is added as monomer. Generally, the acrylate polymer consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, from 0 to 20% of a functional monomer, copolymerisable with acrylate, and from 0 to 40% of a different monomer.
Given hereinafter are acrylate monomers that can be used with acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate.
For example, there may be used functional monomers that are copolymerisable withthe above-mentioned acrylates, methacrylates, alkyl acrylates or alkyl methacrylates, for example acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.
Other details and examples of pressure-sensitive acrylates that are suitable for the invention are described in Satas Handbook of Pressure Sensitive Adhesive Technology"Acrylic Adhesives", 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).
Suitable pressure-sensitive acrylates are obtainable commercially.
The transdermal therapeutic system according to the invention may additionally comprise a-tocopherol or an (x-tocopherol derivative and/or a viscosity-increasing agent, such as hydroxypropyl cellulose.
CA 022203~8 1997-11-06 The invention is illustrated hereinafter in greater detail by a Figure and an Example.
According to Figure 1, a transdermal therapeutic system according to the invention may comprise a carrier film (backing foil) (1 ) which may be of slightly convex form, which together with a membrane (3) forms a reservoir (2), the membrane (3) not controlling the release of active ingredient. Applied to the membrane (3), according to Figure 1, is an adhesive layer (5) which controls the release of active ingredient.
That adhesive layer (5) is in turn covered by a cover film (release liner) (6) which is to be removed before administration. According to the Figure, the carrier film (1 ) may be provided with an annular bead (4) which lies on the circumferential edge region of the adhesive layer (5) and is sealed to the membrane (3) in the region of contact.
Example For the adhesive layer there is used a silicone-based pressure-sensitive adhesive (trimethylated silicon dioxide that has been treated with polydimethylsiloxane having terminal trimethylsiloxy groups; layer thickness when dry approximately from 35 to 45 llm; weight per unit surface area approximately from 50 to 60 g/m2). A cover film of PET (thickness approximately 75 llm; weight per unit surface area approximately 100 g/m2) is coated with the silicone adhesive by means of a coating apparatus. A
microporous polyethylene membrane or a microporous polypropylene membrane (heat-sealable; thickness approximately 50 ~,lm; weight per unit surface area approximately 10 g/m2) is then laminated onto the coated cover film to produce alaminate of cover film, adhesive and membrane. The laminate is then welded onto a carrier film of polyester (aluminized with polyolefin sealing layer (heat-sealable);
thickness approximately 70 llm) by means of a sealing machine (having a welding ring) in such a manner that a gap remains for the introduction of an active ingredient solution. The fillable transdermal therapeutic system (empty TTS) is filled, forexample using a Hamilton syringe or a tube pump equipped with a cannula, with the following active ingredient solution:
CA 022203~8 1997-11-06 Composition of the active ingredient solution per TTS:
mg/TTS
testosterone 60.56 96% ethanol 157.18 propylene glycol 48.11 oc-tocopherol 56.78 hydroxypropyl cellulose 5.98 Total 328.61 Filling volume of the reservoir: 360111 Density of the active ingredient solution: 0.91285 g/cm3 Filled amount in the reservoir: 328.6 mg After filling, the filling gap is welded. Filled transdermal therapeutic systems are punched out by means of a punch.
Claims (8)
1. Transdermal therapeutic system (TTS) for the administration of testosterone or a testosterone derivative as active ingredient, having - a carrier film (backing foil), - a reservoir, - an alcoholic carrier for the active ingredient, - an adhesive layer for contact of the system with the skin, and - a removable cover film (release liner), in which - the system does not comprise a permeation enhancer apart from the alcoholic carrier for the active ingredient, - the active ingredient is present in saturation in the carrier for the active ingredient, and - there is provided between the reservoir and the adhesive layer a membrane which does not control the release of active ingredient, whilst the adhesive layer does control the release of active ingredient.
2. System according to claim 1, characterised by a testosterone ester, especially testosterone enanthate, testosterone cipionate, testosterone propionate or testosterone undecanoate, or a lower alkyl testosterone, especially methyl testosterone, as testosterone derivative.
3. System according to claim 1 or claim 2, characterised in that the active ingredient is present in the form of a complex with cyclodextrin or a cyclodextrin derivative, especially .beta.-cyclodextrin.
4. System according to any one of the preceding claims, characterised in that the reservoir is formed by the carrier film and the membrane.
5. System according to any one of the preceding claims, characterised by ethanol or a low molecular weight monohydric or polyhydric alcohol, especially propylene glycol, or mixtures thereof, as alcoholic carrier for the active ingredient.
6. System according to any one of the preceding claims, characterised by an adhesive layer of a pressure-sensitive, alcohol-resistant adhesive based on polyurethane, isobutylene, polyvinyl ether, silicone or acrylate.
7. System according to any one of the preceding claims, characterised in that the carrier for the active ingredient additionally comprises .alpha.-tocopherol or an .alpha.-tocopherol derivative.
8. System according to any one of the preceding claims, characterised in that the carrier for the active ingredient additionally comprises a viscosity-increasing agent, such as hydroxypropyl cellulose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19517145.4 | 1995-05-10 | ||
| DE19517145A DE19517145C2 (en) | 1995-05-10 | 1995-05-10 | Transdermal therapeutic system (TTS) for administration of testosterone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2220358A1 true CA2220358A1 (en) | 1996-11-14 |
Family
ID=7761562
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002220358A Abandoned CA2220358A1 (en) | 1995-05-10 | 1996-05-10 | Transdermal therapeutic system (tts) for the administration of testosterone |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0825865B1 (en) |
| JP (1) | JPH11504643A (en) |
| CN (1) | CN1183723A (en) |
| AT (1) | ATE208200T1 (en) |
| AU (1) | AU702710B2 (en) |
| BR (1) | BR9608255A (en) |
| CA (1) | CA2220358A1 (en) |
| CZ (1) | CZ287678B6 (en) |
| DE (2) | DE19517145C2 (en) |
| DK (1) | DK0825865T3 (en) |
| HU (1) | HUP9801130A3 (en) |
| NO (1) | NO975140L (en) |
| NZ (1) | NZ308516A (en) |
| PL (1) | PL323145A1 (en) |
| SK (1) | SK149797A3 (en) |
| WO (1) | WO1996035427A1 (en) |
| ZA (1) | ZA963743B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8173155B2 (en) | 2004-06-01 | 2012-05-08 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive patch |
| US8466138B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US9125816B2 (en) | 2000-08-30 | 2015-09-08 | Besins Healthcare Inc. | Pharmaceutical composition and method for treating hypogonadism |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1429697A (en) * | 1995-12-29 | 1997-07-28 | Cygnus, Inc. | Systems and methods for the transdermal administration of androgenic agents |
| DE69716737T2 (en) * | 1996-07-03 | 2003-03-20 | Alza Corp., Palo Alto | DEVICES FOR DRUG DELIVERY AND MANUFACTURING METHOD |
| US6007837A (en) * | 1996-07-03 | 1999-12-28 | Alza Corporation | Drug delivery devices and process of manufacture |
| DE19646050A1 (en) * | 1996-11-08 | 1998-05-14 | Labtec Gmbh | Transdermal therapeutic system e.g. containing testosterone, melatonin |
| US6174545B1 (en) | 1997-07-01 | 2001-01-16 | Alza Corporation | Drug delivery devices and process of manufacture |
| ES2226394T3 (en) * | 1998-05-22 | 2005-03-16 | Novosis Ag | TRANSDERMAL SYSTEMS CONTAINING ACTIVE SUBSTANCE THAT IS RELEASED CONTROLLED IN TIME. |
| FR2793689B1 (en) * | 1999-05-19 | 2001-08-24 | Pf Medicament | TRANSDERMAL DEVICE FOR THE ADMINISTRATION OF TESTOSTERONE OR A DERIVATIVE THEREOF |
| FR2895679B1 (en) * | 2005-12-29 | 2012-06-08 | Pf Medicament | STABILIZATION OF TESTOSTERONE IN TRANSDERMAL DEVICES |
| CN101480399B (en) * | 2008-09-25 | 2011-10-05 | 宋博 | Application of andrusol in preparing medicament for treating asthenospermia |
| DE102011012712A1 (en) | 2011-03-01 | 2012-09-06 | Frank Lehmann-Horn | Use of aldosterone receptor antagonists for the treatment of female sexual dysfunction |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4286592A (en) * | 1980-02-04 | 1981-09-01 | Alza Corporation | Therapeutic system for administering drugs to the skin |
| US4725439A (en) * | 1984-06-29 | 1988-02-16 | Alza Corporation | Transdermal drug delivery device |
| US4704282A (en) * | 1984-06-29 | 1987-11-03 | Alza Corporation | Transdermal therapeutic system having improved delivery characteristics |
| US4849224A (en) * | 1987-11-12 | 1989-07-18 | Theratech Inc. | Device for administering an active agent to the skin or mucosa |
| GB8804164D0 (en) * | 1988-02-23 | 1988-03-23 | Tucker J M | Bandage for administering physiologically active compound |
| US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US5152997A (en) * | 1990-12-11 | 1992-10-06 | Theratech, Inc. | Method and device for transdermally administering testosterone across nonscrotal skin at therapeutically effective levels |
| MX9202350A (en) * | 1991-05-20 | 1992-11-01 | Alza Corp | SKIN PENETRATION INCREMENTING COMPOSITIONS USING GLYCEROL MONOLINOLEATE. |
| CA2075517C (en) * | 1992-04-01 | 1997-03-11 | John Wick | Transdermal patch incorporating a polymer film incorporated with an active agent |
| ATE184473T1 (en) * | 1992-06-11 | 1999-10-15 | Theratech Inc | USE OF GLYCERINE TO ATTENUATE TRANSDERMAL DRUG ADMINISTRATION |
| EP0695177B1 (en) * | 1993-04-20 | 1998-02-18 | Hexal Ag | Active substance-containing plaster |
| DE4313402A1 (en) * | 1993-04-23 | 1994-10-27 | Hexal Pharma Gmbh | Transdermal preparation of active compound |
| US5460820B1 (en) * | 1993-08-03 | 1999-08-03 | Theratech Inc | Method for providing testosterone and optionally estrogen replacement therapy to women |
-
1995
- 1995-05-10 DE DE19517145A patent/DE19517145C2/en not_active Expired - Fee Related
-
1996
- 1996-05-10 CZ CZ19973512A patent/CZ287678B6/en not_active IP Right Cessation
- 1996-05-10 AU AU58050/96A patent/AU702710B2/en not_active Ceased
- 1996-05-10 DK DK96919765T patent/DK0825865T3/en active
- 1996-05-10 PL PL96323145A patent/PL323145A1/en unknown
- 1996-05-10 NZ NZ308516A patent/NZ308516A/en unknown
- 1996-05-10 SK SK1497-97A patent/SK149797A3/en unknown
- 1996-05-10 CA CA002220358A patent/CA2220358A1/en not_active Abandoned
- 1996-05-10 WO PCT/EP1996/002013 patent/WO1996035427A1/en active IP Right Grant
- 1996-05-10 BR BR9608255A patent/BR9608255A/en not_active Application Discontinuation
- 1996-05-10 HU HU9801130A patent/HUP9801130A3/en unknown
- 1996-05-10 CN CN96193748A patent/CN1183723A/en active Pending
- 1996-05-10 DE DE59608150T patent/DE59608150D1/en not_active Expired - Fee Related
- 1996-05-10 AT AT96919765T patent/ATE208200T1/en not_active IP Right Cessation
- 1996-05-10 EP EP96919765A patent/EP0825865B1/en not_active Expired - Lifetime
- 1996-05-10 ZA ZA963743A patent/ZA963743B/en unknown
- 1996-05-10 JP JP8533786A patent/JPH11504643A/en active Pending
-
1997
- 1997-11-07 NO NO975140A patent/NO975140L/en not_active Application Discontinuation
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9125816B2 (en) | 2000-08-30 | 2015-09-08 | Besins Healthcare Inc. | Pharmaceutical composition and method for treating hypogonadism |
| US9132089B2 (en) | 2000-08-30 | 2015-09-15 | Besins Healthcare Inc. | Pharmaceutical composition and method for treating hypogonadism |
| US8173155B2 (en) | 2004-06-01 | 2012-05-08 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive patch |
| US8466138B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8466137B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8466136B2 (en) | 2005-10-12 | 2013-06-18 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8486925B2 (en) | 2005-10-12 | 2013-07-16 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8729057B2 (en) | 2005-10-12 | 2014-05-20 | Unimed Pharmaeuticals, LLC | Testosterone gel and method of use |
| US8741881B2 (en) | 2005-10-12 | 2014-06-03 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8754070B2 (en) | 2005-10-12 | 2014-06-17 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
| US8759329B2 (en) | 2005-10-12 | 2014-06-24 | Unimed Pharmaceuticals, Llc | Testosterone gel and method of use |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0825865B1 (en) | 2001-11-07 |
| HUP9801130A2 (en) | 1998-08-28 |
| CZ287678B6 (en) | 2001-01-17 |
| BR9608255A (en) | 1999-02-02 |
| ATE208200T1 (en) | 2001-11-15 |
| NO975140L (en) | 1997-11-10 |
| NO975140D0 (en) | 1997-11-07 |
| HUP9801130A3 (en) | 2001-03-28 |
| DE19517145C2 (en) | 2000-02-24 |
| EP0825865A1 (en) | 1998-03-04 |
| ZA963743B (en) | 1996-11-18 |
| NZ308516A (en) | 1999-05-28 |
| AU5805096A (en) | 1996-11-29 |
| SK149797A3 (en) | 1998-05-06 |
| DE19517145C1 (en) | 1996-11-28 |
| DK0825865T3 (en) | 2002-02-18 |
| CZ351297A3 (en) | 1998-03-18 |
| WO1996035427A1 (en) | 1996-11-14 |
| AU702710B2 (en) | 1999-03-04 |
| JPH11504643A (en) | 1999-04-27 |
| CN1183723A (en) | 1998-06-03 |
| PL323145A1 (en) | 1998-03-16 |
| DE59608150D1 (en) | 2001-12-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |