Agent and method for transdermal delivery of oestrogen

FIELD: chemistry.

SUBSTANCE: invention relates to medicine. Described are transdermal oestrogen delivery systems which include a polymer matrix and oestrogen. Also described are methods of producing and using said systems.

EFFECT: transdermal oestrogen delivery systems have a smaller active surface area without detriment to daily dosage of oestrogen.

16 cl, 1 dwg, 1 ex

 

The technical FIELD

[0001] the Described compositions and methods for transdermal delivery of estrogen.

PRIOR art

[0002] the Present invention generally relates to the transdermal delivery systems of drugs and in particular to the transdermal delivery systems of drugs for delivery of estrogen. Application of the transdermal system, such as a patch, comprising a pressure-sensitive adhesive material containing the drug, as a means of drug delivery through the skin is well known. However, there remains a need in the transdermal delivery systems of drugs for delivery of certain medications, such as estrogen, and in particular, there remains a need in the transdermal delivery systems of drugs smaller with desirable pharmacokinetic parameters.

[0003] Transdermal delivery system (adhesive bandages) as dosage form have been the subject of numerous patent applications in the last 25 years, which has resulted in a large number of patents, despite the relatively small number of commercial products. For those working in this area, the relatively small number of commercial products is not surprising. Although managerial, economic the market difficulties play a role in limiting the number of products on the market, development of transdermal delivery systems, which has desirable physical and pharmacokinetic parameters that satisfy the requirements of the doctor and the patient remains more challenging. The parameters that should be considered when developing a commercial product, may include: solubility of drug substance stability (for example, taking into account the interaction with other components and/or with the environment), the delivery of therapeutic amounts of drug at the desired speed of delivery over the estimated period of use, a sufficient degree of adhesion to the anatomical site overlay, integrity (e.g., minimum twisting, wrinkling, delamination and offset) in conjunction with minimal discomfort, irritation and sensitization both during application and after removal of plaster, and a minimal residual amount of adhesive substance (or other components) after removing the pads. In addition, the size can be important, both for production and from the point of view of the patient, as well as the appearance may be set for the patient. Can be important also physical aspects of manufacturing and production in developing a commercial product (for example, compliance and cost of materials, equipment and labor) is confirming the analytical methods required for regulatory compliance.

[0004] Among other physical parameters, which take into account when developing a commercial transdermal delivery of medicinal substance, the size (for example, the surface area in place of the overlay) is often determined and limited by other physical and pharmacokinetic requirements such as the desired rate of drug delivery and daily dosage. In General, it is easier to develop a relatively "large" transdermal delivery of medicinal substance, which will ensure the delivery of a drug in a given therapeutic level over the estimated period of treatment than to develop transdermal delivery of medicinal substance in a smaller size, which will still have acceptable pharmacokinetic properties. However, since the size directly affects the cost (e.g., cost components, the cost of packaging materials, the cost of equipment for manufacturing and production, labor costs relative to product yield per unit of working time, etc), and because patients usually prefer small system large (as for aesthetic reasons, and the sight of comfort, because the lower surface of the poses which enables you to use a less aggressive adhesive substances), there is a need in the transdermal delivery systems of drugs a smaller size.

A BRIEF description of the INVENTION

[0005] In accordance with one embodiment, the present invention provides transdermal delivery of medicinal substance, which includes a layer containing the drug, which defines the area of the active surface, and also includes a polymer matrix containing estradiol, and said system includes more than 0.156 mg/cm2estradiol and provides a stream of estradiol in excess of 0.01 mg/cm2/day, based on the area of the active surface. In some embodiments, the implementation of the specified polymer matrix contains a combination of polymers, including acrylic adhesive, silicone adhesive or soluble polyvinylpyrrolidone (PVP). In some embodiments, the implementation of the specified polymer matrix contains about 2-25% by weight acrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25% by weight soluble PVP, about 5-15% of the substances contributing to the penetration, and about 0.1-10% by weight of estradiol (all values refer to the total dry weight of the polymer matrix). In some embodiments, the implementation of the specified polymer matrix comprises about 20% by weight acrylic adhesive, about 56.9% by weight of silico the new adhesive, about 7.5% by weight soluble PVP, about 6.0% by weight olejowego alcohol, about 8.0% by weight of dipropyleneglycol and about 1.6% by weight of estradiol. In some embodiments, the implementation of these acrylic adhesive and silicone adhesive are present in a ratio from about 1:2 to about 1:6, based on the total weight of the above acrylic and silicone adhesives.

[0006] In some embodiments, the implementation of the substance which assists the penetration includes alerby alcohol or dipropyleneglycol, or both.

[0007] In some embodiments, the implementation of the specified polymer matrix includes a number of estradiol sufficient to deliver a therapeutically effective amount of estradiol over a period of time selected from the group consisting of: at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. In some embodiments, the implementation of the specified polymer matrix includes a number of seconds, delivering doses of estradiol selected from the group consisting of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day.

[0008] In some embodiments, the implementation of the specified polymer matrix has a lot of top layer more than about 10 mg/cm2. In some embodiments, the implement is placed the polymer matrix has a weight of a coating layer, selected from the group consisting of about 12.5 mg/cm2and about 15 mg/cm2.

[0009] In some embodiments, the implementation of the system has an area of active surface, which is approximately 60% of the size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2and delivers a daily dose of estradiol, approximately 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.

[0010] In accordance with some of the options for implementation, the present invention provides a transdermal system drug delivery, comprising a polymer matrix which contains estradiol, and this system has an area of active surface constituting about 60% of the size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2and delivers a daily dose of estradiol, approximately 0.025, 0.0,375, 0.05, 0.075 and 0.1 mg/day, respectively.

[0011] According to some variants of implementation, the present invention provides a method for injection of estradiol, comprising applying to the skin or mucosa of a subject who needs it, transdermal delivery of medicinal substance described in this document, for example, transdermal delivery of medicinal substance, which includes a layer containing a medicine which defines the area of the active surface, and also includes a polymer matrix containing estradiol, and this system contains more than 0.156 mg/cm2estradiol and provides a stream of estradiol in excess of 0.01 mg/cm2/day, based on the area of the active surface. In some embodiments, the implementation of this system has an area of active surface, which is approximately 60% of the size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2that is enough to deliver a daily dose of estradiol, approximately 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.

[0012] In accordance with some of the options for implementation, the present invention provides a method of manufacturing a transdermal delivery system drug substance for introduction of estrogen, including the formation of a polymeric matrix containing an estrogen and a mixture of polymers, including acrylic adhesive, silicone adhesive and soluble PVP, and application of polymer matrix on the protective layer so that this system contains more than 0.156 mg/cm2estradiol. In some embodiments, the implementation of the system has an area of active surface constituting about 60% of the size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm2. In some embodiments, the implementation of the specified polymer matrix comprises approx the RNO 20% by weight acrylic adhesive, approximately 56.9% by weight silicone adhesive, about 7.5% by weight soluble PVP, about 6.0% by weight olejowego alcohol, about 8.0% by weight of dipropyleneglycol and about 1.6% by weight of estradiol. In some embodiments, the implementation of the polymeric matrix is applied on a substrate with the weight of the coating layer is more than about 10 mg/cm2. In some embodiments, the implementation of the mass of the top layer of the specified polymer matrix selected from the group consisting of about 12.5 and about 15 mg/cm2.

BRIEF DESCRIPTION of FIGURES

[0013] figure 1 shows the flow of estradiol (µg/cm2per hour) over time (0-81 hours) of transdermal delivery systems according to the present invention (R&•), compared with the Vivelle-Dot® (♦).

DETAILED description of the INVENTION

[0014] In the field of technology relating to transdermal delivery systems, there is a problem associated with the need to consider many different competing factors in developing a commercial product, which has, for example, as clinical efficacy and acceptable properties when wearing, and it is acceptable for patients. For example, selecting the size of the transdermal delivery system, it is necessary to find a balance between factors that determine a smaller size (for example, lower cost, improved adhesi the basic properties and superior appearance and factors for which preferred the larger size (for example, the adjusted delivery rate (flow) and daily dose). The market offers product options Vivelle-Dot® (manufactured by Noven Pharmaceutcials Inc.) for transdermal delivery of estradiol with five different areas of the active surface (2.5, 3.75, 5.0, 7.5 and 10.0 cm2), each of which delivers a different daily doses of medication (0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively). Each of the products Vivelle-Dot® contains 0.156 mg/cm2seconds.

[0015] In accordance with some of the options for implementation, the present invention provides a transdermal delivery system of drugs for transdermal delivery of estrogen, which have a smaller area of the active surface than the system Vivelle-Dot®, but provide a daily dose, which is approximately equal to the dose products Vivelle-Dot® or higher. For example, the present invention comprises a transdermal delivery system of drugs, which provide a daily dose, which correspond approximately to the product of the Vivelle-Dot®, but with a smaller system size. The possibility of obtaining a system of smaller size without compromising daily dosage is a significant advantage.

[0016] the Applicants unexpectedly discovered that increasing the coating weight of the adhesive layer containing l is carstvo, increases the flow per unit area, and this has allowed the development of transdermal delivery systems of drugs, having a smaller size, which provide comparable daily doses. This result was unexpected because usually the mass of the top layer is chosen to control the duration of delivery, and, according to the General view, it does not affect the speed of delivery. Thus, although this technology is known to increase the mass of the top layer to ensure delivery for a long period of time, still no information about that by increasing the mass of the coating layer can improve the speed of delivery or flow, which allows to develop a system of smaller size while maintaining the doses.

[0017] In accordance with certain of its aspects, the present invention provides a transdermal system drug delivery and methods for transdermal delivery of estrogen. In some embodiments, the implementation of these systems show an increased flow compared with other known drugs containing estrogen (for example, Vivelle-Dot®, production Noven Pharmaceutcials Inc.), and, thus, is characterized by increased delivery of drug per unit area. For example, in some embodiments, the implementation specified the system shows a flow greater than the flow of 0.01 mg/cm2/day, typical products Vivelle-Dot®, for example, flow, approximately 1.25 times (including from 1.125 to 1.375, for example 1.25), approximately 1.33 times (including from 1.197 to 1.463, for example 1.33), about 1.5 times (including from 1.35 to 1.65, for example 1.5), approximately 1.67 times (including from 1.503 to 1.837, for example 1.67), approximately 1.75 times (including from 1.575 to 1.925, for example 1.75), approximately 2 times (including from 1.8 to 2.2, for example, 2), approximately 3 times (including from 2.7 to 3.3, for example 3), approximately 4 times (including from 3.6 to 4.4, example 4) or approximately 5 times (including from 4.5 to 5.5, for example, 5) is greater than the number of products Vivelle-Dot®. In some embodiments, the implementation of the mass of the top layer of this system is higher than in other known means containing estrogen. For example, in some embodiments, the implementation of the mass of the top layer of the system is such that the amount of estradiol per unit area greater than 0.156 mg/cm2estradiol, which is present in the products Vivelle-Dot®, for example the weight of the shell is approximately 1.25 times (including from 1.125 to 1.375, for example 1.25), approximately 1.33 times (including from 1.197 to 1.463, for example 1.33), about 1.5 times (including from 1.35 to 1.65, for example 1.5), approximately 1.67 times (including from 1.503 to 1.837, for example 1.67), approximately 1.75 times (including from 1.575 to 1.925, for example 1.75), approximately 2 times the (including from 1.8 to 2.2, for example 2), or approximately 3 times (including from 2.7 to 3.3, for example, 3) is greater than the mass of the top layer of products Vivelle-Dot®, or more. Thus, in accordance with some aspects, the present invention allows to use the means of smaller to achieve a comparable level of drug delivery.

DEFINITION

[0018] as Used in the text of scientific and technical terms have common values, according to the understanding of a person skilled in the art to which the present invention relates, unless otherwise noted. In the description links to numerous ways well known to the average person skilled in the art. The publications and other materials that reveal these known methods, referenced, fully incorporated in the present description, as if they were presented as a whole. When implementing the present invention can use any suitable materials and/or methods, well known to the average person skilled in the art. Nevertheless describes the specific materials and methods. Materials, reagents and the like, referenced in the following description and examples, can be obtained from commercial sources, unless otherwise indicated.

[0019] as Used in the text form of the singular include both single and multiple objects, if direct is not specified, they represent only a single object.

[0020] the Term "about" and use in General intervals, regardless of whether characterized they term "about"indicates that the implied number is not limited to a particular specified number, and means spacing, essentially located within the specified ranges and included in the scope of the present invention. Used in the text, the term "about" is understandable to the average person skilled in the art, and to some degree it varies, depending on the context where it is used. In cases where the value of this term is not obvious to the average specialist taking into account the context in which it is used, "about" means plus or minus 10% of a specific value.

[0021] In this text, the phrase "substantially free from"usually means that the described composition (e.g., transdermal delivery system drug substance, the polymer matrix, and the like) includes less than about 5%, less than about 3%, or less than about 1% excluded component by weight based on the total weight of the considered composition.

[0022] In this text, "subject" means any animal that is in need of drug therapy, including humans. For example, the subject may experience a condition or a risk we get the condition which can be treated or prevented with estrogen, or can't take estrogen to maintain health.

[0023] In this description, the phrase "therapeutically effective amount" and "therapeutic level" means such dosage or concentration of the drug in the blood plasma of the subject, respectively, which provide the specific pharmacological response for which the drug is administered to a subject in need of such treatment. It should be emphasized that therapeutically effective amount or a therapeutic level of medication may not always be effective in the treatment described in this document, conditions/diseases, even though such dosage is deemed therapeutically effective amount among specialists in this field of technology. Examples of dosages, the number of delivered drug, a therapeutically effective amount of therapeutic levels, for convenience only use the following in relation to adults. Specialists in this field will be able to change these quantities in accordance with standard practice, to the extent that this is necessary for the treatment of a specific subject and/or condition/illness.

[0024] In this text area of the active surface" means the surface area of the layer containing the drug, in transdimensional of drug delivery.

[0025] In this text the term "weight of a coating layer" refers to the weight of the layer containing the drug, per unit area of the active surface of the transdermal system of drug delivery.

[0026] In this text "estrogen" includes estrogen steroids, such as estradiol (17-β-estradiol, estradiol benzoate, estradiol 17-β-cypionate, estropipate, equilenin, equilin, estriol, estrone, ethinyl estradiol, conjugated estrogens, esterified estrogens, and mixtures thereof.

[0027] In the text "flow" (also called "penetration rate") is defined as the absorption of drug substances through the skin or mucous membrane and is described by the first law of diffusion Fika:

J=-D(dCm/dx),

where J is the flux in g/cm2/sec, D is the diffusion coefficient of drug substances through the skin or mucous in cm2/sec, and dCm/dx is the concentration gradient of drug substance in the skin or mucous membrane.

[0028] In this text the term "transdermal" refers to the delivery, the introduction or application of medicine through direct contact with skin or mucous membranes. Such delivery methods, the introduction or application also known as dermal, transdermal, cresselia and transbukkalno. In this text the term "dermal" includes the skin and mucous membranes, including the oral mucosa floor of the STI, cheeks, nose, and rectal and vaginal.

[0029] In this text the term "transdermal system drug delivery" refers to the system (e.g., means)that contains a composition that releases estrogen when applying to the skin or any other surface, above). Transdermal system drug delivery may include a protective layer, the layer containing the drug, and the outer cover film. In some embodiments, the implementation of the specified transdermal system drug delivery is an essentially non-aqueous solid form, is able to fit snugly to the surface with which it comes into contact with, and capable of maintaining the contact in such a way as to facilitate topical application without undesirable physiological reactions, and without appreciable destruction of the system when in contact with water during local application to the patient. In this area known in the art and many such commercially available system, such as plasters for transdermal drug delivery. As described below, in one embodiment, the specified transdermal system drug delivery includes containing the drug polymer matrix comprising a pressure-sensitive adhesive material or bioadhesive the first material, and adapted for direct application to the skin of the user (e.g., subject). In other embodiments, implementation of the polymeric matrix is non-adhesive and can be equipped with various adhesive means (for example, a separate adhesive layer) for application and adhesion to the skin of the user.

[0030] In this text, "polymer matrix" refers to polymer compositions containing one or more medication. In some embodiments, the implementation of the matrix comprises a pressure-sensitive adhesive polymer or bioadhesive polymer. In other embodiments, the implementation of this matrix does not contain a pressure-sensitive adhesive polymer or bioadhesive polymer. In this text, the polymer is "adhesive"if it itself has adhesive properties, or if it acts as an adhesive when adding amplifiers adhesion, plasticizers, agents, cross-linking or other additives. Thus, in some embodiments, implementation of the present invention the polymeric matrix comprises a pressure-sensitive adhesive polymer or bioadhesive polymer, which is dissolved or dispersed estrogen. The specified polymer matrix may also include one or more of any of the amplifiers adhesion, plasticizers, agents, cross-linking or other is an optional component, described in this document. U.S. patent No. 6024976 describes a mixture of polymers which can be used in transdermal systems described in this document. The entire contents of U.S. patent No. 6024976 entirely included in the present description by reference.

[0031] In this text the term "pressure sensitive adhesive" refers to a viscoelastic material, which instantly adheres to most substrates with the imposition of even a weak pressure and remains permanently tacky. The polymer is a pressure-sensitive material in the meaning of the term used in this text, if it itself has the properties of a pressure-sensitive material, or acts as a pressure-sensitive material when making amplifiers adhesion, plasticizers or other additives.

[0032] the Term "pressure sensitive adhesive" also includes mixtures of different polymers and mixtures of polymers, such as polyisobutylene (PIB), with different molecular weight, and each resulting mixture is pressure-sensitive adhesive. In the latter case, polymers with lower molecular weight in the mixture is not considered to be "amplifiers adhesion", since that term refers to additives that are different from the polymers to which they are added, on other grounds, in addition to molecular mA the son.

[0033] In some embodiments, the implementation of the polymeric matrix is a pressure-sensitive adhesive at room temperature and possesses other desirable characteristics, adhesive substances used in the field of transdermal drug delivery. Such characteristics include: good adhesion to the skin; the possibility of detachment or removal by any other means, without substantial injury to the skin; the preservation of stickiness during aging of the material, etc. In some embodiments, the implementation of the specified polymer matrix has a glass transition temperature (Tg), measured using a differential scanning calorimeter, in the range of from about -70°C. to 0°C.

[0034] In this text the term "pressure-sensitive adhesive based on rubber" refers to a viscoelastic material having the properties of a pressure-sensitive adhesive containing at least one natural or synthetic elastomeric polymer.

[0035] In some embodiments, the implementation of the specified transdermal delivery system drug substance includes one or more additional layers such as one or more additional layers of a polymeric matrix, or one or more adhesive layers, through which this transdermal delivery system drug prophetic the STV is attached to the skin of the user. In other embodiments, implementation of the specified transdermal system drug delivery represents a single whole, this implies that it includes a single layer of a polymeric matrix containing pressure-sensitive adhesive or bioadhesive material, which is dissolved or dispersed drug substance, and does not contain a membrane that controls the speed.

[0036] the Transdermal delivery system of medicinal substance may include a protective layer or film that is impermeable to the drug. In some embodiments, the implementation of the protective layer is adjacent to one surface of the layer of polymer matrix. The protective layer, if present, protects the layer of polymer matrix (and any other layers present) from the environment and prevents loss medications and/or release of other components in the environment during application. Materials that can be used as protective layers, are well known in the art and may include films of polyesters, polyethylene, vinyl acetate resins, copolymers of ethylene/vinyl acetate, polyvinyl chloride, polyurethane and the like, a metal foil, non-woven fabric, cloth and commercially available laminates. Standard protective layer has a thickness in the range from 2 to 1000 micrometer is.

[0037] the Transdermal system of drug delivery may include coating film, usually adjacent to the opposite side of the system, relative to the protective layer. Top film, if present, is removed from the system before use to release the layer of polymer matrix and/or the adhesive before local application. Materials suitable as the cover film, well known in the art and include commercially available products of the company Dow Coming Corporation, called Bio-Release® and Syl-off® 7610 and 3M's 1022 Scotch Pak.

[0038] as Used in this description, the term "executed as a single unit" transdermal delivery of medicinal substance may include a protective layer and/or coating film.

[0039] In accordance with some of the options for implementation of the present invention transdermal delivery system of medicinal substance layer includes a polymeric matrix containing a drug, which includes a mixture of a pressure-sensitive adhesive material including one or more of: acrylic polymer, silicone polymer and/or soluble PVP, for example, a mixture of a pressure-sensitive adhesive material including an acrylic polymer and a silicone polymer; an acrylic polymer and soluble PVP; silicone is a polymer and soluble PVP; or acrylic polymer, silicone polymer and soluble PVP.

Acrylic polymers

[0040] the Term "acrylic polymer" is used herein in the value adopted in the art, equivalent to the concepts of "polyacrylate", "polyacrylic polymer and an acrylic adhesive. The polymers are acrylic-based can be any of the homopolymers, copolymers, terpolymers etc. of various acrylic acids or esters. In some embodiments, the implementation of the polymers are acrylic-based adhesive polymers. In other embodiments, implementation of the polymers, acrylic-based act as adhesives adding amplifiers adhesion, plasticizers, agents, cross-linking or other additives. The term "acrylic polymer" may include any combination of one or more acrylic polymers, described herein, for example one or more homopolymers, copolymers, terpolymers and/or multipolymer.

[0041] the Acrylic polymer may include homopolymers and/or may include copolymers, terpolymers and/or multipolymer. For example, the acrylic polymer may represent any of the homopolymers, copolymers, terpolymers etc. of various acrylic acids. In some embodiments, the implementation of the specified acrylic polymer is from about 2% to approx the RNO 95% by weight content of the polymers specified in the polymeric matrix, including from about 3% to 90% and from about 5% to 85%, for example from 2% to 95%, from 3% to 90% and from 5% to 85%. In some embodiments, the implementation of the number and type of acrylic polymer depends on the type and quantity of estrogen.

[0042] the Acrylic polymers that can be used when implementing the present invention in practice, include polymers of one or more monomers of acrylic acid and other monomers capable of copolymerization. Acrylic polymers also include copolymers of alkylacrylate and/or methacrylates and/or copolymerizing secondary monomers or monomers with functional groups. There are also combinations of polymers, acrylic-based, based on their functional groups. The polymers are acrylic-based functional groups include copolymers and terpolymer containing, in addition to non-functional Monomeric units, additional monomers with free functional groups. These monomers may be monofunctional or polyfunctional. As is known in the art, varying the number of each type of the added monomers, you can change the binding properties of the final acrylic polymer. In some embodiments, the implementation of the acrylic polymer has at least 50% by weight of acrylate or alkylacrylate monomers from 0 to 20% from functional monomers, copolymerizing with acrylate, and from 0 to 40% of other monomers.

[0043] Acrylate monomers that can be used include one or more of: acrylic acid and methacrylic acid and alkylacrylate or methacrylic esters such as methyl acrylate, acrylate, propylacetate, amylacetate, butyl acrylate, butylmethacrylate, hexidecimal, vexillarius, heptylamine, octylacrylate, nasolacrimal, 2-ethylbutylamine, 2-ethylbutylamine, isooctadecyl, isooctylphenyl, 2-hexyl acrylate, 2-ethylhexylacrylate, dellaquila, decylmethacrylate, dodecylamine, dodecylammonium, tridecylamine, tridecylamine, glycidylmethacrylate and the corresponding methacrylic esters.

[0044] non-Functional polymers, acrylic-based can include one or more polymers, acrylic-based, not containing or containing no free functional groups.

[0045] Functional monomers, copolymerisate with the above alkylacrylate or methacrylates that can be used include one or more of: acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethylacrylate, hydroxypropylmethacrylate, acrylamide, dimethylacrylamide, Acrylonitrile, dimethylaminoethylacrylate, dimethylaminoethylmethacrylate is a, tert-butylmethacrylate, tert-butylmethacrylate, ethoxyethylacetate and ethoxyethylacetate.

[0046] In this text the term "functional monomers or group" means a typical monomer units in the polymers are acrylic-based, contain reactive chemical groups that directly modify these polymers are acrylic-based or which provide a site for subsequent chemical reactions. Examples of functional groups include: carboxyl, epoxypropyl, hydroxyl, sulfoxyl and the amino group. The polymers are acrylic-based functional groups contain, in addition to non-functional Monomeric units described above, additional monomer units bearing available functional groups. These monomers may be monofunctional or polyfunctional. Typical functional groups include carboxyl group, a hydroxy-group, amino group, aminogroup, epoxypropyl etc. Typical carboxyl functional monomers include acrylic acid, methacrylic acid, taconova acid, maleic acid and crotonic acid. Typical hydroxyl functional monomers include 2-hydroxyethylmethacrylate, 2-hydroxyethylacrylate, hydroxyethylacrylate, hydroxyethylmethacrylate, hydroxyethylacrylate, hydroxic methacrylat, hydroxypropylamino, hydroxypropylmethacrylate, hydroxyethylacrylate, hydroxyethylmethacrylate, hydroxynitriles, hydroxynicotinate, hydroxyanthranilate, hydroxypaclitaxel. As indicated above, in some embodiments, the implementation of any one of the specified one or more acrylic polymers do not contain functional groups.

[0047] further details and examples of the acrylic adhesive materials suitable in the practice of the present invention described in the literature: Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp.396-456 (D.Satas, ed.). Van Nostrand Reinhold, New York (1989); "Acrylic and Methacrylic Ester Polymers," Polymer Science and Engineering. Vol.1, 2nd ed., pp 234-268, John Wiley & Sons, (1984); U.S. patent No. 4390520 and U.S. patent No. 4994267; the contents of each of these sources directly and fully incorporated into the present description by reference.

[0048] Suitable acrylic polymers include commercially available pressure-sensitive adhesive materials, such as one or more adhesives, acrylic-based, commercially available under the trademarks DURO-SO®, manufactured by National Starch and Chemical Corporation, Bridgewater, new Jersey (e.g., DURO-TAK® 87-2287, -4098, -2852, -2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085, -9088 and 73-9301). Other suitable acrylic adhesives include products commercially available under t the commodity mark EUDRAGIT®, production Roehm Pharma GmbH, Darmstadt, Germany, as well as the production Cytec Surface Specialties, St. Louis, Missouri under the trademarks GELVA® Multipolymer Solution (for example, GELVA® 2480, 788, 737, 263, 1430, 1753, 1151, 2450, 2495, 3067, 3071, 3087 and 3235). For example, you can apply hydroxy-functional adhesive substances with reactive functional IT-group in the polymer chain. Non-limiting examples of this type of adhesive materials, commercially available, include GELVA® 737, 788, and 1151, and DURO-TAK® 87-2287, -4287, -2510 and-2516. As stated above, you can use any one or more acrylic polymers.

Silicone polymers

[0049] the Term "polymer-based silicone (silicone polymer)is used in equal value with the terms of the siloxane, polysiloxane and silicones used in this text and accepted in the art. Suitable polymer is a silicone-based can also be a pressure-sensitive adhesive material. Thus, in some embodiments, the implementation polymer is a silicone-based adhesive is a polymer. In other embodiments, the realization of polymer-based silicone acts as an adhesive when adding amplifiers adhesion, plasticizers, agents, cross-linking or other additives. You can apply any of the methods in this text, silicone polymer, or a combination of two or more is polimerov.

[0050] Suitable polysiloxanes include silicone pressure-sensitive adhesive materials on the basis of two main components: (i) a polymer or rubber, and (ii) a resin that increases the stickiness. Polysiloxane adhesive can be obtained by cross-linking of the rubber, usually of high molecular weight polydiorganosiloxane, with resin, with the formation of three-dimensional silicate structure, using the condensation reaction in a suitable volatile organic solvent such as ethyl acetate or heptane. The ratio of resin to polymer can be chosen so as to modify the physical properties of the polysiloxane adhesives (Sobieski, et al., "Silicone Pressure Sensitive Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp.508-517 (D.Satas, ed.), VanNostrand Reinhold, New York (1989)).

[0051] Examples of polymers, silicone-based adhesives are (for example, able to stick to the plot in the local application), including pressure-sensitive adhesives. Illustrative examples of polymers, silicone-based, having a lower concentration of silanol groups include: adhesives based on silicone (and polysiloxane adhesive substance with terminal reactive groups), for example, described in U.S. patent number Re. 35474 and U.S. patent No. 6337086, the contents of which are fully incorporated into the present description by reference; commercially available from Dow Corning Corpration (Dow Coming Corporation, Medical Products, Midland, Michigan), a series of products BIO-PSA® 7-4100, -4200 and -4300; and hypoallergenic pressure-sensitive adhesives obtained by the use of a compatible volatile organic solvent (such as ethyl acetate or heptane), which are available on the market under the name BIO-PSA®series 7-4400, -4500 and-4600.

[0052] further details and examples of the silicone pressure-sensitive adhesives that can be used are described in this document polymer matrices and compositions and methods contained in the following U.S. patents No.:4591622; 4584355; 4585836 and 4655767, the contents of each of which is uniquely and fully incorporated into the present description by reference. It should be borne in mind that also provides the use of silicone fluids in polymer matrices and methods described in this document.

[0053] In some embodiments, the implementation of polysiloxane is from about 9% to 97% of the content of polymers in the polymer matrix, including from about 8% to 97% and from about 14% to 94%, for example, from about 9% to 97%, from 8% to 97% and from 14% to 94%.

Soluble PVP

[0054] In some embodiments, the implementation of the polymeric matrix comprises a soluble PVP. It was found that soluble PVP is highly effective in preventing crystallization of drug substances, such as estradiol, transder the existing system of drug delivery adhesion type. Soluble PVP can also modulate the speed of the percutaneous penetration of drugs. You can use any of the features described in this document soluble PVP, or any combination of two or more.

[0055] the Term "PVP", or "polyvinylpyrrolidone", refers to a polymer, as a rule, either a homopolymer or a copolymer containing N-vinyl pyrrolidone as a Monomeric unit. Typically, the polymers PVP are PVP homopolymer and a copolymer of vinyl acetate and vinylpyrrolidone. Homopolymer PVP known in the pharmaceutical industry under various names, including povidone (Povidone, polyvidone (Polyvidone), polyvidone (Polyvidonum), soluble polyvidone (Polyvidonum soluble) and poly(1-vinyl-2-pyrrolidone). The copolymer is a vinyl acetate-vinyl pyrrolidone known in the pharmaceutical industry as Copolyvidon, Copolyvidone and Copolyvidonum. In cases where you use the term "soluble" with respect to PVP, we mean that the polymer is soluble in water, does not contain in General a significant cross-links and has a molecular weight of less than about 2000000. In the General case, see: Buhler, KOLLIDON.RTM.: POLYVINYLPRYRROLIDONE FOR THE PHARMACEUTICAL INDUSTRY, BASF Aktiengesellschaft (1992).

[0056] the Number and type of soluble PVP may depend on the amount and type of present of estrogen, as well as the type of adhesive material, but it can easily be determined during rationalexpectations procedures. As a rule, the PVP is present in an amount of about from 1% to 20% by weight, preferably from about 5% to 15% by weight based on the total weight of the polymer matrix. However, the content of PVP can be higher than 20%, for example up to 40%, depending on the specific drug and the desired characteristics of the specified polymer mixture. Soluble PVP may have a molecular weight from about 2000 to 1100000, including from 5,000 to 100,000, and from 7000 to 54,000. In some embodiments, the implementation of soluble PVP has a molecular weight of from about 17000 90000, for example, from about 17000 60000, including 17,000 to 17,000 90,000 and up to 60,000.

[0057] In some embodiments, the implementation of the specified polymer matrix comprises a soluble PVP with a pressure-sensitive adhesive based on rubber and polyacrylate polymer, for example a combination of acrylic polymer, polysiloxane and soluble PVP. In some embodiments, the implementation of a combination of pick up so as to affect the rate of drug delivery. In particular, it is possible to select a variety of polymers, including soluble polyvinylpyrrolidone, possibly with different parameters of solubility for the drug substance and not miscible with each other, in order to obtain the desired solubility of the drug substance in the above polymeric matrix (which allows control of the funds, the maximum concentration of drug substance in the system) and to vary the delivery of drug substances through the skin.

[0058] the Content of each polymer component, for example the content of the polymer, acrylic-based and polymer based on silicone, you can choose to change the saturation concentration of drug substance in the specified polymeric matrix, with the purpose of influencing the speed of delivery specified medicinal substances from the system and through the skin. In some embodiments, the implementation uses a polymer acrylic-based and polymer-based silicone in a weight ratio of from about 2:98 to 96:4, including from about 2:98 to 90:10, and from about 2:98 to 86:14, for example from 2:98 to 96:4, from 2:98 to 90:10 and from 2:98 to 86:14.

[0059] the Content of estrogen in the weight of the transdermal system of drug delivery is typically from about 0.1 to 50%, including from about 0.1 to 40%, and from about 0.3 to 30%, for example from 0.1 to 50%, from 0.1 to 40% and from 0.3% to 30% (all values are determined based on the total weight of the specified polymer matrix). In some embodiments, the implementation of estrogen is a estradiol is present in the amount of approximately from 0.1 to 10%, including from about 0.1 to 5%, for example from 0.1 to 10% and from 0.1 to 5% (all values are determined based on the total weight of the specified polymer matrix). Regardless of whether high or low loading of estrogen in the transdermal delivery system Le is artenova substances, you can find the composition of the pressure-sensitive adhesive so as to provide acceptable characteristics of the adhesive substance in relation to displacement, stickiness and bundles.

Additional components

[0060] the Transdermal delivery system of the medicinal substance can include one or more of the following components.

[0061] In one embodiment, the polymeric matrix comprises one or more of the substances that promote penetration. "A substance that promotes penetration", as it is known, is an agent that accelerates the delivery of drug substances through the skin. Such agents can also be called a: accelerators, adjuvants, and sorption promoters, and together they are marked in the text as "amplifiers". This class of agents includes agents with different mechanisms of action, including those that possess the function of improving percutaneous absorption, for example, by changing the ability of the stratum corneum to hold moisture, softening the skin, improving the permeability of the skin, and act as agents promoting penetration or as agents contributing to the disclosure of the hair follicle, or by changing the condition of the skin, including the boundary layer.

[0062] Examples of substances that promote the penetration include, without limitation, polyhydric alcohols, such as di is propylenglycol, propylene glycol and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and alerby ether; ether esters of acids, such as isopropylated; urea and urea derivatives such as allantoin which affect the ability of keratin to hold moisture; polar solvents such as dimethylphenylphosphine, metiletilketoksim, dimethylacrylamide, dodecylpyridinium, isosorbid, dimethylacetamide, dimethylsulfoxide, decelerated and dimethylformamide, affect keratin permeability; salicylic acid which softens the keratin; amino acids which are substances that promote infiltration; benzylsuccinic, which is a substance that promotes disclosure of the hair follicle; high molecular weight aliphatic surfactants such as salts laurylsulphate acid, which change the surface state of the skin and injected drugs. Other agents include oleic and linoleic acid, ascorbic acid, panthenol, bottled hydroxytoluene, tocopherol, tocopherylacetate, tocopherylacetate, Propylaea and isopropyl.

[0063] In one embodiment, the substance which assists the penetration is alerby alcohol. In another embodiment, the substance, sposobem the criterion penetration, is a glycol, such as dipropyleneglycol, propylene glycol, butyleneglycol or polyethylene glycol. In other embodiments, implementation of the substance which assists the penetration includes a mixture of at least two substances that promote penetration. For example, a substance that promotes penetration may include alerby alcohol and one or more polyhydric alcohols, for example glycerol, dipropyleneglycol, butyleneglycol, propylene glycol. For example, a substance that promotes penetration may include alerby alcohol and dipropyleneglycol.

[0064] In some embodiments, the implementation of the substance which assists the penetration, is used in an amount of about up to 30% of the dry weight of the specified polymer matrix (including up to values from 27% to 33%, for example, up to 30%), approximately up to 20% (including up to values between 18% to 22%, for example up to 20%); approximately up to 10% (including up to values ranging from 9% to 11%, for example up to 10% by weight), or about up up to 5% (including up to values from 4.5 to 5.5%, for example 5%) by weight, based on the dry weight of the polymer matrix. In some embodiments, the implementation of the substance which assists the penetration, is used in an amount of about 5% to 15%, including from 4.5 to 16.5%, for example from 5% to 15%. In some embodiments, the implementation of a substance that promotes p is unknowing, includes a mixture of olejowego alcohol and dipropyleneglycol in total amount to approximately 14%, including from 12.6% to 15.4%, for example 14% by weight of the polymer matrix. The polymer matrix may additionally include various thickeners, fillers and other additives or components for use in the transdermal delivery systems of drugs known.

[0065] the Amount of estrogen that is included in the specified polymer matrix may vary depending on the specific medicinal substance, the desired therapeutic effect and the period of time during which the system must provide therapy. For most drugs the passage of drugs through the skin is the stage that limits the speed of delivery. The minimum number of medicinal substance is selected based on the amount of medicine that passes through the skin over a period of time during which the system must provide therapy. In some embodiments, the implementation of a system for transdermal delivery of estrogen used in the period of about 1 day, about 3 days, about 7 days or more. Thus, in one embodiment, this system includes such a number of medicinal substance (e.g., estradiol), which is about especial delivery of therapeutically effective amounts of drugs during the period from 1 day to 3 days, 7 days or more, including: within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or more. In some embodiments, the implementation of a therapeutically effective amount of estradiol is in the range of about 0.025-0.1 mg/day (including from 0.0225 to 0.11 mg/day, for example, from 0.025 to 0.1 mg/day), for example about 0.025 (including from 0.0225 to 0.0275, for example, 0.025); about 0.0375 (including from 0.03375 to 0.04125, for example, 0.0375); about 0.05 (including from 0.045 to 0.055, for example, 0.05); approximately 0.075 (including from 0.0675 to 0.0825, for example, 0.075); and about 0.1 (including from 0.09 to 0.11, for example, 0.1) mg/day. Thus, in some embodiments, the implementation of the specified transdermal system drug delivery includes this number of seconds, which provides transportation to and from at least about 0.025 mg to at least about 0.1 mg of estradiol per day (including from 0.0225 to 0.11 mg/day, for example, from 0.025 to 0.1 mg/day). In some embodiments, the implementation of this system of drug delivery includes this number of seconds, which delivers from about 0.025 mg to 0.1 mg of estradiol per day (including from 0.0225 to 0.11 mg/day, for example, from 0.025 to 0.1 mg/day), for example, about 0.025 (including from 0.0225 to 0.0275, for example, 0.025); about 0.0375 (including 0.03375 to 0.04125, for example, 0.0375); about 0.05 (including from 0.045 to 0.055, for example, 0.05); approximately 0.075 (including from 0.0675 to 0.0825, n the example, 0.075); and about 0.1 (including from 0.09 to 0.11, for example, 0.1) mg/day. As noted above, in some embodiments, the implementation of these speeds are provided during the application period, of at least about 1 day, including at least about 3 days, and at least about 7 days, for example at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. For example, the transdermal system of drug delivery may include from at least about 0.39 mg to at least about 1.56 mg estradiol (including from 0.351 to 1.716 mg, for example, from 0.39 to 1.56), for example, about 0.39 mg (including from 0.351 to 0.429 mg, 0.39 for example mg), approximately 0.585 mg (including from 0.5265 to 0.6435 mg, for example, 0.585 mg), about 0.78 mg (including from 0.702 to 0.858 mg, for example, 0.78), about 1.17 mg (including from 1.053 to 1.287 mg, for example, 1.17 mg); and about 1.56 mg (including from 1.404 to 1.716 mg, for example, 1.56 mg). In some embodiments, the implementation of the transdermal system drug delivery includes fewer estradiol, compared with the product Vivelle-Dot®, but provides a comparable level of drug delivery. For example, in some embodiments, the implementation of the transdermal delivery system of drug substances according to the present which the invention may contain about 1.44 mg (including from 1.296 to 1.584 mg, for example 1.44 mg), or about 1.2 mg (including from 1.08 to 1.32 mg, for example, 1.2 mg) of estradiol on 6 cm2means, and to provide the level of drug delivery, comparable with the product Vivelle-Dot®, which contains about 1.56 mg of estradiol per 10 cm2tools.

[0066] In some embodiments, the implementation of the system according to the present invention includes a polymer matrix comprising a polymer of an acrylic base in an amount of about 1 to about 70% by weight, including from about 2 to about 25% by weight, based on the dry weight of the polymer matrix, for example 2-25% by weight of polymer are acrylic-based.

[0067] In some embodiments, the implementation of this system includes a polymer matrix that includes the amount of silicone polymer comprising from about 5 to 70% by weight, including from about 45 to 70% by weight, based on the dry weight of the polymer matrix, for example 45-70% by weight silicone polymer.

[0068] In some embodiments, the implementation of this system includes a polymer matrix containing a number of soluble PVP in the range of about 1 to 30% by weight, including from about 2 to 25% by weight, based on the dry weight of the polymer matrix, for example 2-25% by weight soluble PVP.

[0069] In some embodiments, the implementation of this system includes a polymer matrix containing the number of lilboo alcohol in the range of about 1 to about 10% by weight, including from about 4 to 8% by weight, based on the dry weight of the polymer matrix, for example 4-8% by weight olejowego alcohol.

[0070] In some embodiments, the implementation of this system includes a polymer matrix containing the number of dipropyleneglycol within about 1 to 10% by weight, including from about 5% to 10% by weight, based on the dry weight of the specified polymer matrix, for example 5-10% by weight of dipropyleneglycol.

[0071] In some embodiments, the implementation of the polymer matrix according to the present invention includes about 2-25% by weight acrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25% by weight soluble PVP, about 5-15% of the substances contributing to the penetration, and about 0.1-10% by weight of estradiol (all values expressed on the basis of the dry weight of the specified polymer matrix). In some embodiments, the implementation of the specified polymer matrix contains about 20% (including 18% to 22%, for example, 20%) by weight acrylic adhesive, about 56.9% (including from 51.21% to 62.59%, for example, 56.9%) by weight silicone adhesive, about 7.5% (including from 6.75% to 8.25%, for example, 7.5%) by weight soluble PVP, about 6.0% (including from 5.4% to 6.6%, for example, 6.0%) by weight olejowego alcohol; about 8.0% (including from 7.2% to 8.8%, for example, 8.0%) by weight of dipropyleneglycol; and about 1.6% (including from 1.44% to 1.76%, for example, 1.6%) by weight of estradiol.

[0072] In kotoryj options exercise of acrylic adhesive and silicone adhesive are present in a ratio from about 1:2 up to no more than 1:7, for example, up to 1:6, based on the weight of the above acrylic and silicone adhesive substances. For example, in some embodiments, the implementation of these acrylic adhesive and silicone adhesive are present in a ratio of about 1:2, 1:3, 1:4, 1:5 or 1:6, based on the weight of the above acrylic and silicone adhesive substances. In some embodiments, the implementation of the acrylic adhesive and silicone adhesive are present in a ratio of 1:2.8, based on the weight of the above acrylic and silicone adhesives.

[0073] As described above, in those embodiments of the implementation, where the polymer matrix comprises a pressure-sensitive adhesive or bioadhesive material specified polymer matrix can perform the function of the adhesive parts of the system (for example, funds in the form of a tank) or may constitute one or more layers of the multilayer system. In another embodiment, the specified polymer matrix comprising a pressure-sensitive adhesive or bioadhesive material dissolved or dispersed therein the drug can be a tool, made as one whole. In those versions of the implementation, where the polymer matrix does not contain adhesive, but instead, for example, polymer contains a reservoir of medicinal substance, it can be used in combination with one or more adhesi the different layers, or the surrounding adhesive part that is well known to specialists in this field of technology.

[0074] In some embodiments, the implementation of this system essentially consists of a layer of the polymer matrix. The phrase "consists essentially of a layer of polymer matrix" means that the system does not contain any other layers that affect the delivery of medicinal substance, such as additional controlling the speed of the polymer layer, controlling the speed of the membrane or layer is a reservoir of medicinal substance. However, it should be understood that the system consisting essentially of a layer of a polymeric matrix can include a protective layer and/or coating film.

[0075] As discussed above, in some embodiments, the implementation of this system provides a greater flow than other known products containing estrogen (for example, Vivelle-Dot®, the production of Noven. Pharmaceutcials Inc.), and therefore are characterized by increased delivery of medicinal substance per unit area of the active surface. For example, in some embodiments, the implementation of this system provides a flow greater than 0.01 mg/cm2/day, typical products Vivelle-Dot®, for example, a thread that is about 1.25 times (including from 1.125 to 1.375, for example, 1.25), approximately 1.33 times (including from 1.197 to 1.463, for example, 1.33), CA is approximately 1.5 times (including from 1.35 to 1.65, for example, 1.5), approximately 1.67 times (including from 1.503 to 1.837, for example, 1.67), approximately 1.75 times (including from 1.575 to 1.925, for example, 1.75), approximately 2 times (including from 1.8 to 2.2, for example, 2), approximately 3 times (including from 2.7 to 3.3, for example, 3), approximately 4 times (including from 3.6 to 4.4, for example, 4 or about 5 times (including from 4.5 to 5.5, for example, 5) more than the product stream Vivelle-Dot®. In some embodiments, the implementation of the system provide the thread that approximately 1.67 times (including from 1.503 to 1.837 times, for example, 1.67 times greater than that of products Vivelle-Dot®, for example, a flow of approximately 0.0167 mg/cm2/day (including from 0.01503 to 0.01837 mg/cm2/day, for example, 0.0167 mg/cm2/day).

[0076] In some embodiments, the implementation of the system according to the present invention have a large mass of the top layer than other known products containing estrogen. For example, in some embodiments, the implementation of these systems have such a mass of a coating layer, the amount of estradiol per unit area of the active surface is more than 0.156 mg/cm2estradiol, which have products Vivelle-Dot®, for example the mass of the top layer, approximately 1.25 times (including from 1.125 to 1.375, for example, 1.25), approximately 1.33 times (including from 1.197 to 1.463, for example, 1.33), approximately 1.5 times the (including from 1.35 to 1.65, for example, 1.5), approximately 1.67 times (including from 1.503 to 1.837, for example, 1.67), approximately 1.75 times (including from 1.575 to 1.925, for example, 1.75), approximately 2 times (including from 1.8 to 2.2, for example, 2), or approximately 3 times (including from 2.7 to 3.3, for example, 3) greater than the mass of the top layer for the products Vivelle-Dot® or more. In some embodiments, the implementation of the system according to the present invention have a mass of a coating layer, which is approximately 1.25 times the mass of the top layer of products Vivelle-Dot®, for example, weight of a coating layer, comprising approximately 12.5 mg/cm2(including from 11.25 to 13.75 mg/cm2for example, 12.5 mg/cm2). In some other embodiments, the implementation of the system are the mass of the top layer, which is approximately 1.5 times greater than the mass of the top layer of products Vivelle-Dot®, for example, weight of a coating layer, comprising approximately 15 mg/cm2(including from 13.5 to 16.5 mg/cm2for example 15 mg/cm2).

[0077] These systems can be of various shapes and sizes, suitable for transdermal application. In some embodiments, the implementation of the system are smaller than the products Vivelle-Dot®, but provide comparable daily doses. For example, these systems may have an area of active surface constituting 0.9, 0.8, 0.7, 0.75, 0.66, 0.6, 0.5, 0.4, 0.33, 0.3, 0.25, 0.2, or 0.1 from p is Asadi active surface of the product Vivelle-Dot®. In some embodiments, the implementation of the system has an area of active surface constituting approximately 60% (including from 54% to 66%, for example 60%) of the amount of product Vivelle-Dot®, for example, approximately 60% (including from 54% to 66%, for example, 60%) of 2.5. 3.75, 5.0, 7.5 or 10.0 cm2and delivers a daily dose of estradiol comparable to the dose for the relevant product Vivelle-Dot®. In one embodiment, this system has an area of active surface approximately 6 cm (including from 5.4 to 6.6 cm2for example, 6 cm2and delivers a daily dose of estradiol comparable to those for product Vivelle-Dot® 10 cm2for example, approximately 0.1 mg/day (including from 0.09 to 1.1 mg/day, for example, 1 mg/day).

[0078] the Polymer matrix, described in this document can be obtained by methods known in the art. The polymer matrix can be embedded in a system according to the present invention by methods known in the art. For example, the polymer matrix can be applied to the protective layer and the coating film by methods known in the art, and to mould with the receipt of sizes and shapes suitable for use.

[0079] for Example, after the polymer matrix is formed, it is possible to enter into contact with the support layer, for example by a layer of epithelial p is Enki or protective layer, in any manner known to the person skilled in the art. Such methods include coating calandrinia, a coating of hot melt coating from a solution, etc.

[0080] for Example, the specified polymer matrix can be obtained by mixing the polymer matrix, causing the matrix material to the substrate, for example a protective layer or coating film, and removal of all residual solvents. Estrogen can be added at any stage. In one embodiment, all components of the polymer matrix, including estrogen, are mixed together. In another embodiment, all components of the specified polymer matrix, in addition to estrogen, mix together, and then estrogen is dissolved or dispersed in the mixture. The order of stages, the number of ingredients, as well as the intensity and time of shaking or mixing can be determined and optimized practitioners. The following is a General example of the method shown in the context of a specific variant implementation, including acrylic polymer, polysiloxane and soluble PVP.

Appropriate amounts of soluble PVP, solvent(s), amplifier(s) and organic(s), solvent(s) (e.g., toluene) are combined and thoroughly mixed in a vessel.

Next, the mixture was added estrogen and spend shake up the ex long while specified drugs will not be evenly distributed in the mixture.

Then add the appropriate amount of polysiloxane and acrylic polymers to the mixture containing the drug, and mix thoroughly.

Preparation of dosage forms next comes down to the process of coating, in which the mixture is applied on an outer protective film so that it formed a layer with a controlled, predetermined thickness. The product is coated then passed through the drying chamber in order to remove all volatile solvents remaining from the manufacturing process. Dried coating film, the product is then combined with the substrate material, wound into rolls and stored.

System of a suitable size and shape and then cut out the stamp from the roll of material and then Packed.

[0081] Similar methods can be used in the manufacture of systems that includes various components, described in this document. In the art there are other ways, which are suitable for the manufacture of the systems described in this document.

[0082] Some embodiments of provide a method for making transdermal drug delivery-estrogen, such as estradiol, by overlaying system described in this paper is e, on the skin or mucous membrane of a subject who needs it. In some embodiments, the implementation of this system includes estradiol, and the system put in for a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, or at least about 7 days, for example 1, 2, 3, 4, 5, 6 or 7 days. In some embodiments, the implementation of this method allows to provide therapeutic levels of estrogen in the specified subject during the period of use. As indicated above, the usual dosage is in the range from at least about 0.025 mg to at least about 0.1 mg of estradiol per day, for example, from about 0.025 mg to 0.1 mg of estradiol per day (including 0.0225 to 0.11 mg/day, for example, from 0.025 to 0.1 mg/day), for example approximately 0.025 (including from 0.0225 to 0.0275, for example, 0.025); approximately 0.0375 (including from 0.03375 to 0.04125, for example, 0.0375); approximately 0.05 (including from 0.045 to 0.055, for example, 0.05); approximately 0.075 (including from 0.0675 to 0.0825, for example, 0.075); and approximately 0.1 (including from 0.09 to 0.11, for example, 0.1) mg/day.

[0083] it is Understood that the described embodiments of unconstraining. Thus, for example, any of the aspects, the sign is or components of the present invention, specifically described, can be combined with one or more of any other aspects, characteristics, or features, as specifically described. All such combinations and permutations are considered part of the present invention.

[0084] the Following specific examples are given to illustrate the transdermal delivery systems drug and polymer matrices, described in this document. Understood that these examples in no way limit the scope of the present invention. Other aspects of the invention obvious to a person skilled in the art to which the present invention relates.

EXAMPLE 1

[0085] Preparing polymeric matrix of the following composition:

Acrylic adhesive20%
Silicone adhesive56.9%
Povidone (PVP)7.5%
Alerby alcohol6.0%
Dipropyleneglycol, USP8.0%
Estradiol1.6%

(all values expressed in %represent the percentage content in % by weight from the dry weight of the whole on kernou matrix)

[0086] the Polymer matrix was applied to the coating film, thus the mass of the top layer was 12.5 (•) or 15 (▲) mg/cm2.

[0087] Conducted a study of the permeability of human cadaver skin with the aim of quantifying the effective penetration through the stratum corneum. The stratum corneum was obtained from split, frozen samples cadaver skin using separation by heating. Of the multilayer material cut samples with a diameter of 5/16 inch in four copies and reinforced by 1/2-inch pre-cut fragments of the stratum corneum. These samples were then placed in a modified diffusion cell Franz. The receptor compartment was filled with 7.5 ml of 0.9% NaCl and 0.01% NaN3in deionized water. The cell was kept at a constant temperature of 32°C and were stirring on a magnetic stirrer at about 300 rpm at specific points In time were selected samples of the receptor phase with the complete replacement of the receptor phase. These quantitative samples were evaluated using high-performance liquid chromatography (HPLC)using a Waters instrument HPLC. Used column C-8 (15 cm×4.6 mm) with a particle size of 5 μm (HYPERSIL, production MetaChem Technologies, Inc., TORRANCE, Calif.) at 50°C (temperature of the columns).

[0088] figure 1 shows the flow of estradiol (ág/cm /h) over time (0-81 hours) from transderma is lnyh delivery systems according to the present invention (▲& •)compared to the Vivelle-Dot® (♦).

[0089] the Results show that the system according to the present invention are characterized by a greater magnitude of flow, compared with the product Vivelle-Dot®, and allow therapeutic daily dose, despite their much smaller size.

1. Monolithic transdermal system drug delivery, including containing the medicinal substance layer comprising a polymer matrix containing 2-25% by weight acrylic adhesive, 45-70% by weight silicone adhesive, 2-25% by weight soluble polyvinylpyrrolidone, 5-15% of the substances contributing to the penetration, and 0.1-10% by weight of estradiol, where all these values are calculated on the total dry weight of the specified polymer matrix, and this system contains more than 0,156 mg/cm2estradiol and provides a stream of estradiol than 0.01 mg/cm2/day, based on the surface area of the layer containing the medicinal substance.

2. The transdermal system of drug delivery according to claim 1, characterized in that the specified substance that promotes penetration, includes alerby alcohol.

3. The transdermal system of drug delivery according to claim 1, characterized in that the specified substance that promotes penetration, includes dipropyleneglycol.

4. Transderma the other system of drug delivery according to claim 1, characterized in that the specified substance that promotes penetration, includes alerby alcohol and dipropyleneglycol.

5. The transdermal system of drug delivery according to claim 1, characterized in that the said acrylic adhesive and silicone adhesive are present in a ratio from about 1:2 to about 1:6, based on the total weight of the above acrylic and silicone adhesives.

6. The transdermal system of drug delivery according to claim 1, characterized in that the polymer matrix comprises a number of estradiol, effective to deliver a therapeutically effective amount of estradiol over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days.

7. The transdermal system of drug delivery according to claim 1, characterized in that the polymer matrix comprises a number of estradiol, effective to deliver doses of estradiol selected from the group consisting of approximately 0.025, 0,0375, 0,05, of 0.075 and 0.1 mg/day.

8. The transdermal system of drug delivery according to claim 1, characterized in that the polymer matrix has a lot of top layer of more than about 0 mg/cm 2.

9. Transdermal delivery system for the drug substance of claim 8, characterized in that the polymer matrix has a weight of a coating layer selected from the group consisting of about 12.5 and about 15 mg/cm2.

10. The transdermal system of drug delivery according to claim 1, characterized in that the surface layer containing the medicinal substance, approximately 60% of the size selected from the group consisting of 2,5, 3,75, of 5.0, 7.5 and 10.0 cm2and delivers a daily dose of estradiol, which constitutes approximately 0.025, 0,0375, 0,05, of 0.075 and 0.1 mg/day, respectively.

11. Monolithic transdermal system drug delivery, comprising a polymer matrix containing 2-25% by weight acrylic adhesive, 45-70% by weight silicone adhesive, 2-25% by weight soluble polyvinylpyrrolidone, 5-15% of the substances contributing to the penetration, and 0.1-10% by weight of estradiol, where all these values are calculated on the total dry weight of the specified polymer matrix, and the surface area of the specified polymer matrix is about 60% of the size selected from the group consisting of 2,5, 3,75, of 5.0, 7.5 and 10.0 cm2and delivers a daily dose of estradiol, which constitutes approximately 0.025, 0,0375, 0,05, of 0.075 and 0.1 mg/day, respectively.

12. The method of introducing östra Iola, comprising applying to the skin or mucosa in need thereof of a subject a transdermal delivery system drug substance according to any one of claims 1 to 11.

13. A method of manufacturing a monolithic transdermal delivery of medicinal substance for injection of estradiol, including the formation of a polymeric matrix containing 2-25% by weight acrylic adhesive, 45-70% by weight silicone adhesive, 2-25% by weight soluble polyvinylpyrrolidone, 5-15% of the substances contributing to the penetration, and 0.1-10% by weight of estradiol, where all these values are calculated on the total dry weight of the specified polymer matrix, and applying the specified polymer matrix on the substrate layer so that said system includes more than 0,156 mg/cm2seconds.

14. Method according to item 13, characterized in that the polymer matrix has a surface area of approximately 60% of the size selected from the group consisting of 2,5, 3,75, of 5.0, 7.5 and 10.0 cm2.

15. Method according to item 13, wherein the specified polymer matrix is applied to the substrate layer with the weight of the coating layer is more than about 10 mg/cm2.

16. Method according to item 15, characterized in that the mass of a coating layer of a polymeric matrix selected from the group consisting of about 12.5 and about 15 mg/cm2.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to the application of a solid medicinal product, which is heated under the impact of an alternating magnetic field, for further therapeutic treatment after surgical ablation of tumours and cancerous ulcers. The medicinal product represents a surgical implant, presented in the form of a physiologically acceptable fabric, sponge or film. The medicinal product contains magnetic particles, which generate heat when excited by an impact of the alternating magnetic field, and in this way, heat the medicinal product.

EFFECT: invention ensures considerable improvement of further treatment after operation on cancerous tumour in comparison with chemotherapy.

21 cl, 14 ex

FIELD: medicine.

SUBSTANCE: what is described is a dressing for treating skin conditions and relieving symptoms of skin conditions accompanying blood protein exudation, or for absorbing blood proteins transuding onto the skin.

EFFECT: using the dressing for clearance of waste proteins secreted onto the skin.

8 cl, 22 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: material consists of several layers: an inner layer is made from chitosan nanofibres/superfine fibres, and an outside layer are used as an electrical forming substrate and exercise the protective function. The chitosan layer is made from herbal or mixed herbal and animal chitosan and can contain antibiotic. The multilayer material can contain at least one more layer of biopolymer nanofibres/superfine fibres electroformed of cellulose diacetate or gelatin. The three-layer material with the chitosan layer of the nanofibres/superfine fibres is applicable for local wound and burn healing.

EFFECT: material resistance to mechanical stress.

15 cl, 4 dwg, 8 ex

FIELD: packaging industry.

SUBSTANCE: invention relates to a package in which the adhesive tape is packaged, which has a layer of adhesive agent on the substrate. The package 10 for the self-adhesive adhesive tape comprises the adhesive tape 14 having a substrate 18 and the adhesive agent layer 12, provided on one surface of the substrate 18, and comprises a release sheet 16 is attached with the ability to release to the adhesive agent layer 12. The release sheet 16 is folded along a predetermined fold line with the adhesive tape 14 so that the adhesive agent layer faces outwardly and the folded adhesive tape 14 is sealed inside the folded release sheet 16.

EFFECT: according to this configuration, the traditionally occurring package separate from the release sheet can be eliminated; moreover, when the release sheet 16 is opened as detaching of the release sheet 16 from the adhesive agent layer 12 of the adhesive tape 14, half of the adhesive agent layer 12 is opened making the process of applying to the area for applying simple.

18 cl, 15 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine. Described is a composition for transcutaneous delivery, in particular, ionophoretic transcutaneous delivery of at least one cationic active substance or its salt, with the composition containing the said at least one cationic active substance or its salts, at least one polyamine and/or polyamine salt, water or water dissolving mixture and optionally one or several additives.

EFFECT: described is application of the claimed composition as a component of transcutaneous plaster or ion-phoretic transcutaneous plaster and application of the claimed composition in a method of transcutaneous or ionophoretic introduction of cationic active substances and in a method of determining in vitro properties of permeability through the skin, containing an active substance of the ionophoretic composition.

26 cl, 1 tbl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and can be used in need of the delivery of therapeutic compositions for local application, including for local analgesic therapy. That is ensured by a system comprising a container having a first chamber with a therapeutic composition for local application with at least one active ingredient, and a second chamber containing a coating composition. The composition for local application and the coating composition is dispensed through a valve and supplied through one nozzle gradually. The delivery can be also gradual by dispensing the composition for local application by pressing a first release button, while the coating composition is dispensed from the system by pressing a second release button.

EFFECT: invention provides the most convenient delivery of the therapeutic compositions ensured by the gradual release of the two compositions having different consistence through the same nozzle.

22 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and represents a self-degradable transdermal therapeutic system (TTS) containing at least one active ingredient, at least one agent disabling the active substance with the agent representing a solid substance or a paste, at least one release agent between the active substance and the agent disabling the active substance; the release agent represents a liquid-permeable and solid-impermeable layer, a mobile phase and at least one mechanical agent for perforating at least one adjacent layer of the TTS; the perforation agent has a dull outline and an acute or pointed area inside; when the TTS is released after the use, the perforation agent degrades the release agent between the release agent and the agent disabling the active ingredient thereby it enables the mobile phase supplied onto the agent disabling the active ingredient and enabling the contact of the active ingredient with the agent disabling the active ingredient, while the active ingredient is degraded by this contact.

EFFECT: device enables reducing a risk of undesired release of the preparation in transportation, provides the prolonged storage.

12 cl

FIELD: medicine.

SUBSTANCE: invention represents a composition for the topical delivery of a composition containing a nitrogen oxide donor specified in L-arginine or its derivative; an adverse biophysical medium containing an ionic salt; a stabilisation polymer containing xantham gum; propylene glycol; a polysorbate surfactant containing Polysorbate 20; and ibuprofen and/or an ibuprofen salt, to the individual's skin.

EFFECT: creating the composition possessing temperature stability at high temperatures.

20 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Transdermal medication, which applies intensifier of percutaneous suction, is described. Intensifier of percutaneous suction has ester of sulfosuccinate in its composition or its salt and alkylglycoside or alkylthioglycoside.

EFFECT: described is intensifier of percutaneous suction, which has excellent action of percutaneous suction amplification for broad range of medications, demonstrating at the same time excellent compatibility with substances of glue base.

13 cl, 15 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. There are described compositions for percutaneous administration of physiologically active agents such as drugs or veterinary agents, including a hydrophobic polymer and a solvent.

EFFECT: compositions are characterised by the ultra-high prolonged efficacy ensured by their ability to form the stable skin films.

12 cl, 20 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gynaecology. The method involves the daily transcranial electrical stimulation and drug administration. The transcranial electrical stimulation is characterised by current intensity 1.0÷1.5 mA, 20 - 30 minutes for 10÷15 days. In addition, the patients intakes the phytocomposition 'Myrrasyl-1'. The phytocomposition is taken 15÷20 minutes before meals 2 tablets 2 times a day for 10÷15 days. Thereafter, the phytocomposition 'Myrrasyl-1' is administered daily for 20÷30 days, 1 tablet 2 times a day; the preparation 'Sagenit' is administered before meals 1 tablet a day.

EFFECT: method provides higher clinical effectiveness in the patients suffering the hepatobiliary system by reducing the current intensity during the transcranial electric stimulation.

2 ex, 2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is the use of oestriol for preparing a pharmaceutical composition for vaginal administration for preventing and/or treating urogenital atrophy due to estrogen deficiency in women, wherein said composition is administered so that the patient receives a dose of oestriol 0.3 mg/day or less with this administration being daily or once every two days, once every three days or once a week for at least 3 weeks and a related method for preventing and/or treating. It is shown that the administration of oestriol in a dose of 10 times less than the standard one; it eliminates the state of vaginal atrophy.

EFFECT: invention provides the therapeutic effectiveness similar to the responses to the modern methods of treating, but with greater safety leading to a better quality of life.

14 cl, 10 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition contains as a first active agent, 6β, 7β; 15β, 16β-dimethylenene-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount according to a daily dose after the administration of the composition and making approximately 2 to approximately 4 mg, and as a second active agent, 17a-ethinylestradiol (ethinylestradiol) in an amount according to a daily dose and making approximately 0.01 mg to approximately 0.05 mg together with one or more pharmaceutically acceptable carriers or additives. The composition contains drospirenone applied on inert carrier particles. A method for preparing a pharmaceutical composition involves spraying of the drospirenone and ethinylestradiol solution on the inert carrier particles. The pharmaceutical preparation according to the invention contains a number of separately packed and individually taken daily dosage units of the described compositions in a single package used for oral administration for at least 21 days running with said daily dosage units containing the combination of drospirenone and ethinylestradiol. The composition may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: invention provides higher oral bioavailability of drospirenone.

20 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely obstetrics and gynaecology, and may be used for treating benign hyperplastic processes of the female reproductive system. That is ensured by the introduction of gonadotropin-releasing hormone agonist for 6 months once monthly in a combination with the oral administration of the preparation for hormonal replacement therapy. It is preceded by specifying the initial metabolic, vegetative and gynaecologic status of the patient which along with an age group provides a basis to assess an adequacy of initiating hormonal add-back therapy. If the patient belongs to the age group of under 40 years of age, and in case of observing additional burdening of the metabolic and vegetative status, the introduction of gonadotropin-releasing hormone agonist with no hormonal add-back therapy prescribed. For the purpose of preventing potential negative symptoms, it is combined with underlying prescription of a complex of phytoestrogens and vitamins with required intake of calcium and vitamin D3. Each injection of gonadotropin-releasing hormone agonist, starting with the second one, is followed by clinical assessment of hypestrogenism symptoms and blood chemistry analysis, and if observing hypestrogenism symptoms, additional hormonal add-back therapy is prescribed. If the patient appears to belong to the age of 40 years old and more, and in case of observing the presence of burdened metabolic and vegetative status regardless of the age group, 2 years after the first injection of gonadotropin-releasing hormone agonist, hormonal add-back therapy is started. When selecting the preparation included in the hormonal add-back therapy regimen: there are differentiated: if the patient belongs to a younger group under 35 years of age, a therapeutic add-back preparation is presented by a combine oral contraceptive containing ethinyl estradiol 30 mg and dienogest 2 mg in each tablet. The oral contraceptive is prescribed 1 tablet a day in the continuous regimen which is recommended to be used after termination of the therapeutic course with gonadotropin-releasing hormone agonist if pregnancy prevention is required. If the patient belongs to the age group of 35 years and older, a therapeutic hormonal add-back preparation is presented by a preparation for hormonal replacement therapy containing micronised 17-p estradiol 1 mg and dydrogesterone 5 mg or a preparation containing drospirenone 2 mg instead of dydrogesterone in each tablet 1 tablet a day in the continuous regimen. An initial or underlying tendency to increase of blood pressure, a combined preparation for hormonal replacement therapy containing drospirenone is prescribed. The therapeutic course is followed by recommended administration of the preparation of hormonal replacement therapy if the patient belongs to the age group of 50 years and older in the continuous regimen.

EFFECT: method enables providing an evident therapeutic effect that is manifested in stable elimination of estrogenic deficiency symptoms accompanying gonadotropin-releasing hormone agonist therapy with preserved clinical effectiveness and improved patient's quality of life.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to dentistry, and can be used in orthopedic treatment of women in post-menopausal period in case of complete or partial defects of dentitions by means of removable plate dentures. For this purpose cream "Ovestin" is applied on surface of denture basis in thin uniform 0.5-1.0 mm thick layer. Treatment is carried out daily once during 10 days from the moment of application.

EFFECT: method also ensures reduction of bleeding, keratinisation, improvement of microcirculation in mucosa of denture bed and as a result acceleration of socially-psychological adaptation of said contingent of patients.

2 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted extratriene derivatives of general formula (values of radicals are given in the claim), useful in therapy, especially for treating and/or preventing steroid hormone-dependent disorders which require inhibition of 17β-hydroxysteroid dehydrogenase (17-HSD) enzyme type 1, type 2 and/or type 3, as well as salts thereof, pharmaceutical preparations containing said compounds, as well as methods of producing said compounds.

EFFECT: improved method.

41 cl, 98 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: as a first active agent a pharmaceutical composition contains drospirenone in the amount equal to a daily dose when administering the composition and making 2 to 4 mg, and as a second active agent - ethinylestradiol in the amount equal to a daily dose and making 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives. Drospirenone as a part of the pharmaceutical composition has a particle surface area more than 10000 cm2/g. Preferentially, drospirenone is fine-grained or sprayed from a drospirenone solution by inert carrier particles. The preparation contains a number of separately packed and individually taken daily dosage units in a single package used for oral administration for at least 21 days running with said daily dosage units containing a combination of drospirenone and ethinylestradiol. The preparation may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: combination of drospirenone and ethinylestradiol provides reliable contraceptive activity ensured by the use of a maximum dose of drospirenone which causes no side effects, particularly, excess diuresis.

29 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gynaecology, and is applicable for the purpose of prevention of hormone resistance in endometrial hyperplasia. That is ensured by prescribing a depot synthetic analogue of gonadotrophin releasing hormone by 1 injection on the 1st-2nd day of menstrual cycle once every 28 days. Nine injections in all. It is combined with an oestrogen-gestagen drug by 1 tablet a day starting with the 14th day after the second injection of the gonadotrophin releasing hormone analogue and up to the 28th day after the ninth injection.

EFFECT: method enables prevention of hormone resistance in endometrial hyperplasia.

3 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely to gynecology, and can be used in treatment of patients with climacteric syndrome of various severity degree. Method includes daily carrying out transcranial electric stimulation (TES) of brain protective mechanisms with constant current with intensity 1.5-2.5 mA, duration 20-30 minutes and introduction of medication "Sagenit". After carrying out each third TES session electric encephalogram is registered. If α-rhythm amplitude decreases lower than 30 mcV, TES sessions are not resumed. Treatment is continued by introduction of medication "Femoston 1/10" daily in dose 1 tablet per day during 2-3 weeks until amplitude of α-rhythm is restored above 30 mcV, with further introduction of medication "Sagenit" in dose 1 tablet per day during 2-3 months. If reduction of α-rhythm amplitude does not take place, 9-15 sessions of TES are carried out with the following introduction of medication "Sagenit" daily in dose 1 tablet per day during 20-30 days.

EFFECT: method makes it possible to increase degree of patients' adaptation taking into account individual peculiarities of organism, reduce probability of development of negative side effects in process of climacteric syndrome treatment.

2 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):

wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

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