• 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 invention relates to a multilayer pharmaceutical formulation containing layers with various active ingredient content, a water-impermeable layer applied thereon and an adhesive layer ensuring the fixation to the body surface of the pharmaceutical formulation, which comprises: a silicone rubber layer directly contacting with the skin surface and ensuring the zero order kinetics of the dissolution of the active ingredient; as well as a multilaminated silicone rubber matrix comprising one or more layer(s) with various active ingredient content.
    公开号:SU1760968A3
    申请号:SU894613605
    申请日:1989-02-21
    公开日:1992-09-07
    发明作者:Надь Йожеф；Шаламон Ференц；Вагнер Оден
    申请人:Биогал Дьедьсердьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    This invention relates to medicine, in particular, to transdermal therapeutic agents based on siloxane rubber and methods for their preparation.
    The aim of the invention is to increase the bioavailability of the drug substance, expressed in a more uniform removal and transdermal means and simplify the method of obtaining this tool.
    The transdermal agent is a multi-layer system consisting of a water-impermeable adhesive layer that provides fixation of the agent to the skin and a matrix based on siloxane rubber consisting of 2-6 layers containing the medicinal substance. The thickness of each layer is 0.1-1.5 mm. The layer of the matrix in contact with the skin, do not obsess the medicinal substance, at least one of the other layers contains up to 0% of the medicinal substance.
    The transdermal therapeutic effect is shown in fig. 1, where A is a silicone silicone rubber, which ensures the dissolution of the active component with zero order kinetics; Bp is a multi-layer silicone rubber matrix, comprising layers (1-5) with different contents of the active component; C is luminium foil or a layer of another acceptable waterproof foil; D is an adherent layer that ensures the fixation of the composition on the surface of the body.
    A transdermal therapeutic agent is a multilayer system consisting of layers of silicone rubber of various thickness and with different content of active ingredient. Such a system is provided with a waterproof layer, usually a layer of aluminum foil over the layers of silicone rubber and an adhesive layer that adheres to the skin surface. The first layer with a thickness of 0.1-1.5 mm of the pharmaceutical composition in contact with the skin surface does not contain the active component (symbol A in Fig. 1), is tightly bound to subsequent layers with different content of the active component, resulting in kinetics of zero order dissolution in the entire layered system.
    In the compositions, various drugs can be used as the active component, for example, cardiovascular, smemasolitic, anorectogenic (appetite suppressant), antidiabetic agents, as well as drugs that affect the hormonal system.
    According to the invention, a multilayer system is formed by polymerizing individual layers of a matrix one on another.
    Depending on the active component of the system, layer A can be obtained by polycondensation a layer of different thickness, for example 0.1-1.5 mm, at different temperatures, for example 15-70 ° C, preferably at 25-60 ° C of the mixture obtained, for example, from various polydimethylsiloxane-a, (W-diols or their mixtures using various crosslinking catalysts (including polycondensation) (hereinafter abbreviated KS) in an amount of 0.1-1.5%, preferably 5-10%. As a catalyst or The main component of the catalyst is trisfunctional methyl derivative. Ilan having communication SI-N and / or Si-O is typically metiltritsiklogeksila- minosilan, as a main component
    catalysts use tetraalkoxysilane, tetraethoxysilane, tetramethoxysilane, and the like. and a catalytic mixture containing a dialkyltin salt with a long chain fatty acid, preferably dibutyl tin laurate, is used as an initiator. In the case of polysiloxane polymers containing alkyl (SpNzn-n), aryl (CeHs, СеНбСНа) alkenyl) or -H groups and having reactive
    5 groups (OH, H, vinyl, etc.) or monofunctional groups (CH3) s (CH3) 2CH2-CH SIO-, etc.) as terminal fragments (hereinafter PSP), the process is carried out in such a way that the thickness of the layer A that forms
    0 as a result of polyaddition under the action of salts of noble metals or complexes of noble metals (hereinafter referred to as BM-type catalysts), used in an amount of 1-100 ppm, is 0.1-1.5
    5 mm and polyaddition are carried out at a temperature of 15 ° C-70 ° C.
    The first Bi layer, containing the active ingredients, is applied onto the obtained layer A. The Bi layer is obtained by polymerization at a temperature of 15-70 ° C, preferably 15-50 ° C, of a homogenized mixture prepared from the active component as such or in a diluted form in solid or a liquid diluent (for example, in lactose, glucose, aerosil, etc.) and from PDDS and PSP as the main material used in an amount of 0.5-20%, preferably 0.5-4%, with a catalyst KS - or BM-type. Upon receipt of polycondensation by the BI layer, the amount of the KS-type catalyst is 0.1-15%, preferably 5-10%, and the curing temperature is 15-70 ° C, preferably 20-50 ° C.
    When using the polylaris5 method, the amount of BM-type catalyst may be 1-100 ppm, and the method can be carried out at a temperature of 15- 70 ° C, preferably 20-60 ° C.
    Depending on the nature and properties
    0 of the active component, the breakage of Bp is applied to the polymerized layers of Bp-1 in the manner described above with a sequentially increasing content of the active component in the range of 15-25% of the content of the active component in the Bn-i layer.
    As the base material, a CPAP or PSP with a layer thickness of 0.1-1 mm, containing no active component and 0.01-15%, preferably 5-8%, KS type catalyst or 1-100 ppm is applied to the last layer B preferably 20 ppm of the catalyst, BM type and after applying a waterproof layer, preferably aluminum foil, at a temperature of 15-70 ° C, preferably 25-30 ° C, polymerization is carried out. Finally, a sticky layer is bonded to the waterproof layer to ensure adhesion of the agent to the skin. Example 1.
    a) A mixture containing 60% dimethylpolysiloxane-a, o) -diol with a viscosity of 50000 mPa and 35% of the same product with a viscosity of 1000 mPa is homogenized for 2 minutes with vigorous stirring, then 5% is added to the polymer mixture catalyst Wacker T-5, stirring continued for another 2 minutes. The resulting homogeneous mixture is stretched into a layer with a thickness of 0.5 mm using appropriate equipment and cured for 3 hours at 40 ° C (layer A).
    b) A mixture containing 50% dimethylpoly-silox-a, a) -diol with a viscosity of 5,000 mPa and 25% of the same product with a viscosity of 1,000 mPa is homogenized for 2 minutes with vigorous stirring, then 20% lactose diethyl is added in portions - containing 10% nitrbglycerol, the mixture is slowly stirred for 5 minutes, and after adding 5% Wacker T-5 catalyst, the homogenization is continued for another 5 minutes. The resulting mass is stretched on layer A using the appropriate equipment into a layer with a thickness of 0.5 mm, after which it is stitched for 3 hours at 40 ° C (Bi layer).
    c) a layer of 35% dimethylpolysiloxane-a, a co-diol with a viscosity of 5000 mPa, 20% of the same product with a viscosity of 1000 mPa, 40% lactose trituration containing 10% nitroglycerin, and 5% of the catalyst Wacker T-5, a layer of Ba with a thickness of 1 mm sew 3 hours at 40 ° C.
    d) Homogeneous mixture obtained by method c) from 30% dimethylpolyxyloxane, O) -diol with a viscosity of 5000 mPa, 15% of the same product with a viscosity of 1000 mPa, and also 50.% lactose trituration; containing 10% nitroglycerin and 5% Wacker T-5 catalyst. layer 1 mm thick is applied on the surface of the layered matrix A + Bi + 62, and then sewed for 3 hours at 40 ° C into the coat.
    e) A layer consisting of 95% dimethyl-poly-siloxane-a, co-diol with a viscosity of 1000 mPa and 5% of a Wacker T-5 catalyst is applied with a thickness of 0.1 mm on the Vz layer of the matrix consisting of the Vz layer consisting of layers of A + Bi + 62 + Bz, then coated with thin aluminum foil and stitched for 3 hours at 40 ° C.
    f) An adhesive layer of textile material is applied to the layer of aluminum foil, which protrudes to the limits of the polymer matrix and ensures that the composition 5 sticks to the skin.
    PRI mme R 2. The sequence of obtaining funds, as in example 1. except:
    a) Layer A is 1 mm thick, contains 50 dimethyl polysiloxane-a, co-di 0 ol with a viscosity of 50,000 mPa, 45% of the same product with a viscosity of 5,000 mPa, and 5% of the Wacker T-5 catalyst. The polymerization was carried out for 90 minutes at 60 ° C.
    b) The thickness of the Bi layer is 1 mm and it contains 5–70% dimethyl polysiloxane a, a co-diol with
    a viscosity of 50,000 mPa and 20% of the same product with a viscosity of 5,000 mPa, as well as 5% sodium phenobarbital and 5% of a Wacker T-5 catalyst. Polymerization are 3 hours 0 at 40 ° C.
    c) The thickness of the B2 layer is 1 mm and Pts contains 70% dimethylpolysiloxane-i, and) -diol with a viscosity of 50,000, 17% of the same product with a viscosity of 5,000 mPa, 8% phenobarbital per 5 three, and also 5% of the catalyst Wacker T- five. The polymerization is carried out for 3 hours at 40 ° C.
    d) The VC layer is 1 and contains 70% dimethylpolysiloxane-a, e; J-diol with a viscosity of 50,000 mPa. 13% of the same product
    0 with a viscosity of 5000 mPa, 12% sodium phenobarbital and 5% of a Wacker 1-5 catalyst. The polymerization is carried out for 3 hours at 40 ° C.
    Layers C and D are prepared as in Example 1 d and e.
    5 EXAMPLE 3. The sequence of operation is carried out as in Example 1, except:
    a) Layer A with a thickness of 1 mm consists of two component silicone rubber of the Wacker 3003/50 type (capable of entering into a polyaddition reaction) as the base material, components A and B of which are homogenized in a ratio of 50:50. Polymerization are 25 minutes at 70 ° C.
    b) Layer B1 with a thickness of 1 mm, it consists of 5 35% dimethyl polysiloxane- #, nd-diol with
    viscosity is 50000 mPa, 40% of the same product with viscosity of 5000 mPa, 20% lakhtoznoy three-. with 40% isosorbcidinitrate as the active component, and 0 also 5% as a Wacker T-5 catalyst. The polymerization is carried out for 3 hours at 40 ° C.
    c) Layer B2 0.5 mm thickness contains 25% dimethylpolysiloxane-a, and a -diol with a viscosity of 50,000 mPa, 30% of the same product
    5 with a viscosity of 5000 mPa, 40% lactose trituration, comprising 40% isosorbidine nitrate as the active component, and also 5% Wacler T-5 catalyst. The polymerization is carried out for 3 hours at 40 ° C.
    d) Vz layer with a thickness of 0.5 mm and it contains 20% dimethylpolysiloxane, a U-diol with a viscosity of 50,000 mPa, 30% of the same product with a viscosity of 5,000 mPa, 45% lactose trituration, including as the active component isosorbidine nitrate, as well as 5% of the catalyst Wackeg T-5, the polymerization is carried out for 3 hours at 40 ° C.
    Layers C and D are prepared as described in Example 1e and e.
    PRI me R 4. As in example 1, except that:
    a) Layer A 0.25 mm thick contains as a base material two-component silicone rubber of the Wacker 3003/50 type, components A and B of which are homogenized in a ratio of 50:50. Polymerization lead 30 minutes at 70 ° C.
    b) The Bi layer contains two-component Wacker 3003/50 silicone rubber as the base material, components A and B of which are homogenized in the ratio of 33:35, after which 30% crushed O-acetylsalicylic acid is added. At the end of the homogenization, the mixture is stretched to a thickness of 1.5 mm on layer A. The polymerization is carried out for 1 hour at 50 ° C.
    c) The Ba layer is 1.5 mm thick and contains components A and B of silicone rubber of the Wacker 3003/50 type in a ratio of 30%: 30% as the base material and 40% of crushed O-acetylsalicylic acid. The polymerization is carried out for 1 hour at 50 ° C.
    Layers C and D are prepared as in Example 1 d and e.
    PRI me R 5.
    a) By 30 May. parts of the auxiliary material, polymethylsiloxane oil with a viscosity of 100 mPa, add a mixture of 2 wt. parts of absolute ethanol and 0.25 mass. parts of ostradiol, after which the whole mass is homogenized with 13 mass parts of colloidal silicon dioxide. Then 39.75 wt.% Is added to it. part of a mixture of methylcyclohexylaminosilane and dibutyl-on-dilaurate in a mass ratio of 99: 1 as a catalyst, the mixture is stirred for 3 minutes, a layer of 0.5 mm is formed from it and subjected to crosslinking at room temperature for 30 minutes (layer A).
    b) Mixed as component A are polysiloxane with terminal functional vinyl groups and viscosity of 14,000 MPa, and as component B is a poly-siloxane polymer with terminal functional methyl groups and a viscosity of 1000 MPa in a mass ratio of 9: 1, 97.249 masses, this homogenized blends sew with 0.001 May. platinum
    complex catalyst. A mixture of 0.75 May is then added to the mixture. parts of estradiol and 2 May. parts of absolute ethanol, stirring is continued for another 2 minutes, after which the resulting mixture is applied to the prepared stage. a) a layer thickness of 0.8 mm and subjected. crosslinked at room temperature for 90 minutes.
    The layer obtained in this way after curing is covered with PVC with a film and a layer ensuring its fixation on the skin.
    The catalyst (pre-complexed connection of the plate) required for the polyaddition in examples 3 and 4 is contained in one of the components of silicone rubber manufactured by Wackrt Chemie GmbH of the Federal Republic of Germany.
    0 The process of isolating a drug from a transdermal therapeutic agent was investigated using a Keshary-chum diffusion cell (see Drug Development Industrial Pharmacy
    5 10/6, p. 883-913, 1984). In the measurements made, the sample surface was 3.14 cm2, the liquid was an isotonic sodium chloride solution with a volume of 10 ml and a temperature of 37 ° C. Sample volume 1 ml.
    The content in the sample of the active component is determined by UV absorption using a VSV 2-P instrument (Carl Zeis, Jena). Nitroglycerin is determined at 207 nm with a layer thickness of 2 mm relative to
    5 isotonic solution of sodium chloride. Isosorbidinitrate is determined at 2200 nm with a layer thickness of 2 mm relative to distilled water.
    The results of studies on the allocation of drugs are presented in Fig. 2
    权利要求:
    Claims (1)
    [1]
    As can be seen from fig. 2 and 3, under the experimental conditions used, the transdermal means evenly excreted the drug substance within 24 hours. The invention The method of obtaining a transdermal therapeutic agent by applying to the waterproof layer an adhesive
    A layer of a matrix based on silicone rubber containing a medicinal substance, characterized in that. In order to simplify the process and increase the bioavailability of the drug substance, the matrix is obtained by successive layering and curing of 2-6 layers of siloxane rubber with a skin thickness of up to a layer of 0.1-1.5 mm; their mixtures with
    viscosity 1000-50000 MPa and / or polyaddition reactions of polysiloxane polymers or their mixtures with various alkyl (CnH2n + i), aryl (SbNb. SbNSH2), alkenyl () or hydroxy (H-) g groups and terminal pe - by action-capable groups (СНз) -510, (СНз) 2-СН25Ю) in the presence of 0.001-15% by weight of the catalyst - salt or complex0
    Compound of all layers, except the layer in contact with the skin, before curing, up to 40% by weight of the drug substance is added without or mixed with a liquid diluent-lactose, glucose and / or colloidal silicon oxide, and curing is carried out at 15-70 ° C.
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    引用文献:
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    US4031894A|1975-12-08|1977-06-28|Alza Corporation|Bandage for transdermally administering scopolamine to prevent nausea|
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    优先权:
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