• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention provides a transdermal therapeutic system for administering sex hormones having an active ingredient impermeable support layer, a pressure-sensitive adhesive polymer matrix connected thereto and containing a skin permeation enhancing substance in addition to sex hormones, and a protective layer that can be separated before application. Wherein the polymer matrix contains, in addition to sex hormone testosterone, a mixture of at least one permeation enhancer from the group consisting of fatty alcohol esters and fatty acid esters, and at least one readily volatile permeate enhancer. Treatment system.
    公开号:KR20030072630A
    申请号:KR10-2003-7010810
    申请日:2002-02-07
    公开日:2003-09-15
    发明作者:프란크 테오발드
    申请人:엘티에스 로만 테라피-시스템 악티엔게젤샤프트；
    IPC主号:
    专利说明:

    Testosterone-containing transdermal treatment system and method for producing the same {TRANSDERMAL THERAPEUTIC SYSTEM CONTAINING TESTOSTERONE AND METHOD FOR THE PRODUCTION THEREOF}
    [2] Testosterone belongs to the group of sex hormones; It is the most powerful natural androgen. The testosterone daily production of an adult male is about 7 mg (equivalent to 24 μmol), and an adult female produces about 10% of the adult male production. In the blood, 98% of testosterone is bound to transport proteins. The serum concentration of testosterone in adult men is 3-10 µg / l, which corresponds to 10-35 nmol / l. When the serum concentration of testosterone in an adult man drops below 10 nmol / l, it is called hypogonadism characterized by incomplete formation or lack of formation of primary or secondary sexual characteristics, or secondary decline. Treatment of hypogonadism caused by a testosterone deficiency consists of a substitution of testosterone.
    [3] Testosterone cannot be administered orally because of its short plasma half-life (about 80 minutes) and its strong first-passmetabolism. Testosterone is generally administered by intramuscular injection in the form of a suitable ester compound.
    [4] On the other hand, testosterone, by its physicochemical properties, has been shown to be suitable for transdermal administration. However, it should be borne in mind that hypogonadism is a disease that is overwhelming to the person concerned and can be diminished from social isolation or the social environment, so care should be taken in a discreet manner as inconspicuous as possible.
    [5] For example, transdermal treatment systems are known that apply to the scrotum. This system often requires pretreatment of the scrotum by hair removal, which affects the user's acceptance and acceptance of this system.
    [6] Another example is a transdermal treatment system that is recognized as a storage system. In this system, testosterone is dissolved in a solvent (eg alcohol). Release of testosterone into the skin is controlled by a control membrane. Such a membrane control system has the advantage of being able to be applied to the skin like any other conventionally known TTS. However, when the membrane is damaged, there is a disadvantage that "dose dumping", ie the contents of the active ingredient reservoir, is delivered to the skin through the damaged membrane in a short period of time, leading to preliminary overdose. In addition, solvents commonly used for the storage of active ingredients such as alcohols, when used in high concentrations in the reservoir, often exhibit skin irritation effects and cause erythema or itching on the application site.
    [1] The present invention relates to a transdermal therapeutic system (TTS) for sex hormone administration, which contains a mixture of testosterone and skin permeation enhancers. The present invention also relates to a method for producing the TTS.
    [7] It is therefore an object of the present invention to provide a transdermal treatment system that can deliver testosterone to the skin continuously and does not have the drawbacks described above.
    [8] The object is that the pressure-sensitive adhesive polymer matrix is at least one permeation enhancer component from the group consisting of testosterone and at least two component mixtures that additionally enhance skin permeation, ie fatty alcohol esters and fatty acid esters, A transdermal therapeutic system (TTS) having the features described in the introduction of claim 1 containing a mixture of at least one highly volatile permeation enhancer component is achieved. According to a preferred embodiment, both the hormone and the permeation additive are homogeneously distributed in the pressure-sensitive adhesive polymer matrix.
    [9] Within the framework of the study underlying the present invention, it was found that any mixture of permeation enhancers (= skin permeation enhancers) had an optimal permeation enhancer effect on testosterone. These are mixtures of at least one fatty alcohol ester and / or fatty acid ester with one or more high volatile component (s). High volatility enhancers include, in particular, isopropylidene glycerol, transcutol (= diethylene glycol monoethyl ether), DEET (= N, N-diethyl-m-tolueneamide), solketal, ethanol In addition to 1,2, propanediol, or other short chain alcohols (e.g., alcohols having 6 or less carbon atoms), menthol and other essential oils or components of essential oils are suitable.
    [10] As the fatty alcohol ester, ethyl oleate is preferably used, and fatty alcohol ester selected from the group consisting of ethyl laurate, ethyl palmitate, ethyl lactate, propyl lactate, propyl palmitate, propyl laurate, propyl oleate, etc. Can be mentioned.
    [11] As the fatty acid ester, those selected from the group of compounds containing ethyl oleate, methyl oleate, methyl laurate, ethyl laurate, methyl adipic acid, ethyl adipic acid and the like are preferably used.
    [12] Permeation enhancer mixtures of the above kind have proved to be particularly suitable in that the relative quantitative ratio of the substance (s) derived from the group comprising fatty alcohol esters and fatty acid esters and the readily volatilized substance (s) is from 1: 2 to 2: 1. It became. The amount of permeate strengthening material (s) that easily volatilizes is preferably 10 to 20% by weight, particularly preferably 15 to 20% by weight, based on the active ingredient matrix. The amount of permeation enhancing material derived from the group comprising fatty alcohol esters and fatty acid esters is preferably 5 to 20% by weight relative to the matrix (ie, nonwoven, support layer and separate protective layer are not considered), Especially preferably, it is 6-10 weight%.
    [13] It has also been found that the skin permeability is further increased by adding nicotinic acid amide to the TTS of the present invention. The concentration of nicotinic acid amide is preferably in the range of 2 to 10% by weight, particularly preferably in the range of 3 to 5% by weight, based on the active ingredient-containing matrix.
    [14] According to a particularly preferred embodiment, the testosterone-containing TTS of the present invention contains 5 to 20% by weight, preferably 6 to 10% by weight of at least one permeation enhancing material from the group comprising fatty alcohol esters and fatty acid esters. At least one component selected from the group consisting of isopropylidene glycerol, DEET, transcutol and short-chain alcohols, in a total concentration of 10 to 20% by weight, preferably 15 to 20% by weight, The nicotinic acid amide is preferably contained in a concentration of 2 to 10% by weight, preferably 3 to 5% by weight. The percentages represent values for the matrix.
    [15] The content of testosterone in the system according to the invention is in the range of 0.1 to 10% by weight, particularly preferably 1 to 5% by weight, based on the matrix. "Tetosterone" is intended to include testosterone esters as well. Examples of testosterone esters specifically include testosterone acetate and testosterone propionate.
    [16] As the pressure-sensitive adhesive matrix, a polymer layer prepared based on pressure-sensitive adhesive polymers derived from the group consisting of polyacrylates is preferably used. Moreover, the coating prepared on the basis of pressure-sensitive adhesive hot-melt adhesives can be preferably used as the pressure-sensitive adhesive matrix. The pressure-sensitive adhesive polymer matrix may further contain auxiliary materials known to those skilled in the art, in addition to the polymers (active), active ingredients and enhancer components. However, the matrix consists substantially of pressure-sensitive adhesive polymers.
    [17] Another useful aspect of the teptosterone containing TTS of the present invention contains an antioxidant or antioxidant combination in an amount of 0.1 to 5% by weight, preferably 0.3 to 1% by weight, based on the active ingredient-containing matrix, respectively. As antioxidants used in testosterone-containing TTS, tocopherol and ascorbyl palmitate are preferable.
    [18] Non-contacting surfaces of the active ingredient-containing polymer matrix are covered with an active ingredient impermeable backing layer in contact with the matrix. As the material of the support layer, polyesters exhibiting particularly high strength such as polyethylene terephthalate and polybutylene terephthalate are most suitable, but polyvinyl chloride, ethylene-vinylacetate copolymers, polyvinylacetate, polyethylene, polypropylene, poly Almost all of skin compatible plastics such as urethane and cellulose derivatives can be suitably used. In each case, an additional layer can be provided in a support layer by vacuum-depositing with metals, such as aluminum, for example. For the detachable protective layer, basically the same material as that used for the support layer can be used, and the protective layer is given peelability by suitable surface treatment such as silicon deposition. In addition, other separate protective layers such as polytetrafluoroethylene treated paper or cellophane (trade name) (cellulose hydrate) can also be used.
    [19] The preparation of the TTS with the active ingredient-containing matrix layer is usually done in the manner of preparing the active ingredient solution or suspension of the adhesive or non-adhesive polymer. This solution or suspension is coated on a carrier material by suitable coating units and then dried to remove the solvent present. However, as in the case of the present invention, when the prepared matrix system contains a component that easily volatilizes, such a method is impossible because the component that evaporates easily evaporates unless otherwise specified. The same problem occurs even when the polymer matrix is prepared from a melt (hot-melt method).
    [20] According to the present invention, this problem is solved by applying a certain amount of the liquid enhancer mixture further containing the active ingredient testosterone to a nonwoven fabric, fabric (eg textile fabric) or carrier film as needed. Such nonwoven, woven or carrier films are not dried. Instead, these pretreated nonwoven, woven or carrier films are each laminated to a polymer matrix layer already prepared and dried. The nonwoven or woven fabric is then contacted with the matrix layer and preferably embedded therein. That is, it becomes one of the matrix components. During storage, diffusion then takes place so that the active and enhancer components are uniformly and homogeneously distributed in the polymer matrix.
    [21] In order to adjust the viscosity to be suitable for carrying out the method according to the present invention, thickeners and gelatinizers may be added to the mixture of permeation enhancers designed with the above-mentioned enhancer solution. Suitable materials for this are preferred materials from the group comprising polyacrylates, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, cellulose and cellulose derivatives.
    [22] Therefore, in a preferred embodiment of the method for producing tetosterone-containing TTS according to the present invention, first, a pressure-sensitive adhesive polymer or polymer mixture solution is coated on a film-like support and then dried to prepare a polymer matrix. In addition, a mixture of at least one permeation enhancer and at least one highly volatile permeate enhancer derived from the group comprising fatty alcohol esters and fatty acid esters is prepared. Testosterone is then added to the mixture to dissolve the testosterone in the mixture. If the hormone has already been added to the pressure-sensitive adhesive matrix polymer, the addition of testosterone may be omitted.
    [23] The viscosity of this liquid enhancer mixture can be adjusted in the manner described above as needed. Subsequently, a mixture containing the permeation enhancer (and testosterone as needed) is applied to the nonwoven fabric or fabric or carrier film. Such a nonwoven, woven or carrier film containing an adjuvant mixture and, if desired, testosterone is laminated to the dried polymer matrix to be bonded to and embedded in the matrix. In general, the nonwoven is located between two polymer layers ("sandwich").
    [24] In the above production method, testosterone may be used in ester form. As testosterone esters, in particular testosterone acetate and testosterone propionate are contemplated.
    [25] The film material suitable for the above-mentioned support layer or the support layer serves as a carrier film, as pointed out. The nonwoven or woven fabric is preferably made as viscose, polyester, polypropylene, polyethylene, polyamide, cellulose, or a combination of these materials.
    [26] The invention is illustrated by the following examples, but the invention is not limited thereto.
    [27] Example 1
    [28] Acrylate matrix1. Testosterone2.00% 2. Durotack (1) 90.70% 3. Al-acetylacetonate0.80% 4. Nicotinamide5.00% 5. Tocopherol0.75% 6. Ascorbyl Palmitate0.75%
    [29] Incremental Enhancer Solution1. Ethyl Olate21.70% 2. Solketal43.40% 3. Plastoid B (2) 27.90% 4. Testosterone7.00%
    [30] The weight per unit area of the acrylate matrix is 120 g / m 2. The weight per unit area of the incremental enhancer solution is 60 g / m 2.
    [31] (1) polyacrylate pressure sensitive adhesive (manufactured by National Starch)
    [32] (2) Copolymers based on methacrylic acid and methacrylic acid methyl esters (manufactured by Rohm GmbH)
    [33] Example 2
    [34] In addition, formulations with the following matrix layer compositions have been found to be particularly suitable.
    [35] Testosterone ............... 3.5 wt%
    [36] Nicotinic acid amide ............ 3.5% by weight
    [37] Polyacrylate .......... 63.0 wt%
    [38] Ethyl Olate .............. 10.0 wt%
    [39] Isopropylidene glycol ...... 20.0 wt%
    [40] (The percentages are for the pressure sensitive adhesive polymer matrix.)
    [41] Testosterone-containing TTS according to the present invention can be usefully applied to alternative treatment of hypogonadism in men. Also suitable for clinical findings and syndromes caused by other testosterone deficiencies (eg, treatment of menopausal syndrome in men (“hormone replacement therapy / HRT” for men)), infertility in men, or treatment of osteoporosis due to androgen deficiency Do.
    [42] In addition, TTS according to the present invention can be applied to the treatment of HIV patients (AIDS) or cancer patients by using the anabolic effect of testosterone, and can also be used for other chronic wasting diseases or disease states including metabolic abnormalities. Applicable to adjuvant therapy.
    [43] Another preferred field of testosterone containing TTS application according to the present invention is the treatment of premenstrual syndrome (PMS) in women.
    权利要求:
    Claims (19)
    [1" claim-type="Currently amended] A transdermal therapeutic system for administering sex hormones having an active ingredient impermeable support layer, a pressure-sensitive adhesive polymer matrix connected thereto and containing a skin permeation enhancer in addition to sex hormones, and a protective layer that can be separated prior to application, wherein the polymer matrix is And, in addition to sex hormone testosterone, a transdermal therapeutic system containing a mixture of at least one permeation enhancer from the group consisting of fatty alcohol esters and fatty acid esters, and at least one readily volatile permeation enhancer.
    [2" claim-type="Currently amended] The method of claim 1,
    In the mixture, the substance (s) from the group consisting of one fatty alcohol ester and the fatty acid ester and the substance (s) from the group consisting of easily volatilizing material of the other are 1: 2 to 2: 1 A transdermal therapeutic system characterized by being present in relative quantitative ratios.
    [3" claim-type="Currently amended] The method according to claim 1 or 2,
    The permeate enhancer (s) portion that easily volatilize is 10-20% by weight, preferably 15-20% by weight relative to the matrix.
    [4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
    Easily volatile permeation enhancer (s) are isopropylideneglycerol, transcutol (= diethylene glycol monoethyl ether), DEET (= N, N-diethyl-m-tolueneamide), ethanol, 1,2-propane A transdermal therapeutic system characterized in that it is selected from the group consisting of diols, short chain alcohols, menthol, essential oils and essential oil components.
    [5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
    Percutaneous treatment characterized in that the part of the permeation enhancing material (s) from the group consisting of fatty alcohol esters and fatty acid esters is preferably 5 to 20% by weight, particularly preferably 6 to 10% by weight relative to the matrix. system.
    [6" claim-type="Currently amended] The method according to any one of claims 1 to 5,
    The system is characterized in that the transdermal therapeutic system contains nicotinic acid amide as another permeation enhancer in a concentration of preferably 2 to 10% by weight, particularly preferably 3 to 5% by weight relative to the matrix.
    [7" claim-type="Currently amended] The method of claim 1,
    At least one permeation enhancer (s) from the group consisting of fatty alcohol esters and fatty acid esters, particularly preferably ethyl oleate, with a total concentration of 5 to 20% by weight, preferably 6 to 10% by weight,
    -At least one easily volatilized permeation enhancer (s) from the group consisting of isopropylidene glycerol, DEET, transcutol and short chain alcohols, in a total concentration of 10-20% by weight, preferably 15-20% by weight, and
    Concentrations of 2 to 10% by weight, preferably 3 to 5% by weight of nicotinic acid amide;
    (The concentration represents the weight for the matrix)
    Percutaneous treatment system, characterized in that it contains.
    [8" claim-type="Currently amended] The method according to any one of claims 1 to 7,
    Percutaneous treatment system, characterized in that the polymer matrix is a matrix based on polyacrylates.
    [9" claim-type="Currently amended] The method according to claim 1, wherein
    And the polymer matrix is a matrix based on pressure-sensitive adhesive hot-melt adhesives.
    [10" claim-type="Currently amended] The method according to any one of claims 1 to 9,
    The polymer matrix comprises the permeation enhancer or has a nonwoven or woven or carrier film impregnated with the permeation enhancer and testosterone, the nonwoven, woven or carrier film is connected to a polymer matrix, preferably a polymer matrix Percutaneous treatment system, characterized in that built in.
    [11" claim-type="Currently amended] The method according to any one of claims 1 to 10,
    A transdermal therapeutic system characterized in that testosterone is present as ester, preferably as testosterone acetate or testosterone propionate.
    [12" claim-type="Currently amended] The method according to any one of claims 1 to 11,
    The percutaneous treatment system, characterized in that the content of testosterone is 1 to 10% by weight, preferably 1 to 5% by weight relative to the matrix.
    [13" claim-type="Currently amended] The method according to any one of claims 1 to 12,
    The system is characterized in that it contains 0.1 to 5% by weight, preferably 0.3 to 1% by weight, based on the matrix, of an antioxidant or a combination of antioxidants, preferably a combination of tocopherol and ascorbyl palmitate. Transdermal treatment system.
    [14" claim-type="Currently amended] The method according to any one of claims 1 to 13,
    The system contains an additive selected from the group consisting of thickeners and gelatinizing agents, preferably from the group consisting of polyacrylates, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, cellulose and cellulose derivatives. Characterized transdermal treatment system.
    [15" claim-type="Currently amended] The method according to any one of claims 1 to 14,
    A transdermal therapeutic system, characterized in that the active ingredient and the permeation enhancer are completely dissolved and homogeneously distributed in the system.
    [16" claim-type="Currently amended] A solution or melt of the pressure-sensitive adhesive polymer or polymer mixture is coated on a film-like support and then dried to prepare a polymer matrix;
    Preparing a mixture of at least one permeate enhancing material from the group consisting of fatty alcohol esters and fatty acid esters and at least one easily volatile permeating enhancer material;
    Testosterone is added to the mixture described above to dissolve the testosterone in the mixture;
    A mixture containing testosterone and a permeation enhancer is applied to a nonwoven or woven or carrier film;
    -Laminating this nonwoven, woven or carrier film on the dried polymer matrix
    A method for producing a transdermal therapeutic system containing testosterone and a permeation enhancer.
    [17" claim-type="Currently amended] A testosterone-containing solution or melt of the pressure-sensitive adhesive polymer or polymer mixture is coated on a film-like support and then dried to prepare a polymer matrix;
    Preparing a mixture of at least one permeate enhancing material from the group consisting of fatty alcohol esters and fatty acid esters and at least one easily volatile permeating enhancer material;
    The permeation enhancing material-containing mixture is applied to a nonwoven, woven or carrier film;
    Laminating this nonwoven, woven or carrier film onto the dried polymer matrix
    A method for producing a transdermal therapeutic system containing testosterone and a permeation enhancer.
    [18" claim-type="Currently amended] The method according to claim 16 or 17,
    To the liquid permeation mixture, at least one viscosity adjusting component is added, and the component is preferably a group consisting of thickeners and gelatinizing agents, particularly preferably polyacrylates, polyethylene glycol, polyvinylpyrrolidone, poly A method for producing a transdermal therapeutic system, characterized in that it is selected from the group comprising vinyl alcohol, cellulose and cellulose derivatives.
    [19" claim-type="Currently amended] The method of claim 1, as a hormone replacement for treating hypogonadism, or as a hormone replacement for testosterone deficiency in elderly men, or as an assimilation agent in the treatment of HIV, or as a treatment for premenstrual syndrome in women. Use of a transdermal treatment system according to any one of the preceding claims.
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    CA2438657A1|2002-08-29|
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    CA2438657C|2010-10-12|
    CN100349571C|2007-11-21|
    AT522205T|2011-09-15|
    DE10107663B4|2004-09-09|
    EP1361869A2|2003-11-19|
    CN1717239A|2006-01-04|
    DE10107663A1|2002-09-05|
    JP2004517965A|2004-06-17|
    WO2002066018A2|2002-08-29|
    JP4851683B2|2012-01-11|
    WO2002066018A3|2003-04-24|
    AU2002247690B2|2006-06-22|
    KR100787545B1|2007-12-21|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-02-19|Priority to DE10107663A
    2001-02-19|Priority to DE10107663.0
    2002-02-07|Application filed by 엘티에스 로만 테라피-시스템 악티엔게젤샤프트
    2002-02-07|Priority to PCT/EP2002/001258
    2003-09-15|Publication of KR20030072630A
    2007-12-21|Application granted
    2007-12-21|Publication of KR100787545B1
    优先权:
    申请号 | 申请日 | 专利标题
    DE10107663A|DE10107663B4|2001-02-19|2001-02-19|Testosterone-containing transdermal therapeutic system, process for its preparation and its use|
    DE10107663.0|2001-02-19|
    PCT/EP2002/001258|WO2002066018A2|2001-02-19|2002-02-07|Transdermal therapeutic system containing testosterone and method for the production thereof|
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