RU2172171C2 - Pressure-sensitive sticky composition (options) and method of preparation thereof, method for transdermal injection of therapeutic substance and device for implementation thereof - Google Patents

Abstract

FIELD: pharmaceutical substances. SUBSTANCE: composition contains mixture of polymers influencing solubility of therapeutic substance and velocity of its release from preparation. In particular, polymers are mutually unmixable and include soluble polyvinylpyrrolidone, which can increase concentration of therapeutic substance in mixture to desired maximum. EFFECT: essentially reduced dimensions of device needed for achieving therapeutic levels and simultaneously saved desired properties regarding release of therapeutic substance and adhesiveness. 44 cl, 11 dwg, 21 tbl, 33 ex

Description

 This invention mainly relates to systems for transdermal drug delivery, more specifically to a preparation for transdermal use of drugs, which use a mixture of polymers to affect the solubility of the drug and its release rate from the composition. More specifically, the invention relates to a composition of polymers desirably immiscible, including soluble polyvinylpyrrolidone (PVP), which can increase the concentration of drug substance in the mixture to the desired maximum, thereby significantly reducing the size of the device needed to achieve therapeutic levels while maintaining the required drug release and adhesion properties.

State of the art
The use of a transdermal preparation, for example, a pressure sensitive adhesive containing a medicament, a medicinal substance or other biologically active substance, as a means of controlled delivery of a drug released and delivered through the skin at a certain constant speed is well known. Thus, drug delivery devices are known in which the medicament is included in a carrier, such as a polymer matrix and / or a pressure sensitive adhesive preparation. The pressure sensitive adhesive should adhere firmly to the skin and not impede the migration of the drug from the carrier through the skin and bloodstream of the patient.

 The concentration of drug substance in monolithic systems for percutaneous delivery can vary greatly depending on the drug substance and polymers used. Low concentrations of the drug in the adhesive can lead to difficulties in achieving an acceptable release rate. High drug concentrations, on the other hand, often affect the adhesive properties of adhesives and tend to promote crystallization. Crystallization can occur because most drugs that pass through the skin, to one degree or another, do not show noticeable solubility or suspendibility in pressure sensitive adhesives.

 In preparations for transdermal administration of drugs, the presence of crystals (drugs and / or other components) is usually undesirable. If the drug substance is presented in crystalline form, it is inaccessible to exit the system and, therefore, unsuitable for use. Moreover, although the crystals of the drug substance may first dissolve and then exit the device, this process usually limits the speed and leads to a decrease in the rate of penetration through the skin.

 Simple diffusion models of the penetration of drugs through the skin suggest that these penetration rates depend on the concentration, that is, they depend on the amount of the substance and on the degree of saturation of the pressure-sensitive adhesive preparation with it. Although polyacrylate adhesives have a high degree of affinity for many drugs and thus tend to dissolve them in themselves at higher concentrations than rubber adhesives, when they are only used as pressure sensitive adhesives, it is difficult to achieve acceptable penetration rates and the manifestation of adhesive properties . The minimum concentration at which a pressure-sensitive adhesive is saturated with a drug to maximize permeability can be achieved by mixing a rubber adhesive in which the drugs do not dissolve or dissolve poorly into a polyacrylate adhesive. However, a decrease in solubility and an increase in the degree of supersaturation of the drug substance in such a composite polymer system creates favorable conditions for crystallization of the drug substance.

 High concentrations of dissolved active ingredient can be used to increase the intake of the active ingredient through the skin, as is often reported in publications on so-called oversaturated systems.

 The size and distribution of crystals thus become important parameters that must be controlled in order to achieve maximum drug release. However, these parameters are usually difficult to control. The inability to control the size and distribution of crystals can affect the products of production and their appearance means that the production process is not controlled. More importantly, the presence of large crystals, especially in excessive amounts, can be harmful to transdermal adhesive preparations. Crystals on the surface of a pressure-sensitive adhesive system can lead to a decrease in adhesion. Moreover, crystals from the surface may come in direct contact with the skin, which may cause irritation.

 Soluble PVP is known as a crystallization inhibitor for the preparation of transdermal preparations. However, PVP reduces or at a sufficiently high concentration violates acceptable penetration rates for the release of the therapeutic level of the drug substance and the adhesive properties of pressure sensitive adhesives. Schering AG EPO Patent Publication No. WO 93/08793, an application of October 21, 1992 entitled "Transdermal Therapeutic Systems Containing Crystallization Inhibitors", describes PVP as a crystallization inhibitor in a single polymer adhesive system. US 5,252,334 describes the use of PVP in a monopolymer adhesive system without an amplifier.

 Noven Pharmaceuticals, Inc. PCT US 92/05297, application of June 22, 1992, and entitled "Solubility Parameter Based on the Drug Release System and Method for Correcting the Saturation of the Drug Substance": describes a monolithic pressure-sensitive transdermal adhesive system comprising two different polymers . Rubber having a lower solubility tends to decrease the solubility of the drug in the pressure-sensitive adhesive, thereby lowering the concentration of the soluble drug.

 None of the patent publications disclose that by adding rubber to a drug substance in the composition of the polyacrylate adhesive, the transdermal penetration rate may increase as a result of an increase in the degree of saturation, namely, saturation or oversaturation of the system with the drug substance. However, this increase in saturation can lead to crystallization of the drug. Also, these patents and patent publications do not report that the increased penetration rate should not be sacrificed in order to minimize the crystallization phenomenon or that the crystallization problem could be solved by adding soluble PVP in an amount sufficient to dissolve all drug substance to a supersaturated concentration in the composite polymer adhesive mixture while maintaining the release of therapeutic levels of the drug substance, as well as the adhesive properties of the prep rata.

 SUMMARY OF THE INVENTION

 It has now been found that soluble PVP can be used in a composite polymer adhesive system in a narrow concentration range in order to dissolve drug substances in amounts close to the quantities that can be dissolved in a polymer system consisting of only one polyacrylate; soluble PVP allows pressure-sensitive adhesive systemic mixture to maintain the required ability to adhesion.

 The foregoing and other objects have been achieved using the present invention by incorporating soluble PVP in a mixture of at least two polymers. Soluble PVP allows for increased drug saturation of a pressure sensitive adhesive. The amount of soluble PVP used should be sufficient to dissolve the drug, while avoiding undesirable crystallization, significantly reducing the penetration rate of the drug or the adhesive characteristics of the drug. A mixture of at least two polymers is described in PCT US 92/05297, reference to the patent cited above.

 In accordance with one aspect of the present invention, an improved pressure-sensitive adhesive preparation includes: (1) rubber adhesive, (2) polyacrylate, (3) drug, and (4) soluble PVP.

 The term “supersaturated” as used with respect to a drug substance means that the amount of drug substance exceeds its degree of solubility or the ability to form dispersions in a composite polymer adhesive system in which there is no soluble PVP.

 The term "polyvinylpyrrolidone" or "PVP" refers to a polymer, both a homopolymer and a copolymer containing N-vinylpyrrolidone as one of the monomers. Typical PVP polymers are homopolymer PVPs and copolymers containing vinyl acetate and vinylpyrrolidone. Homopolymer PVPs are known in the pharmaceutical industry under various names, including the international name poly (1-vinyl-2-pyrrolidone) and the trade names Povidone, Polyvidone, Polyvidonum and Polyvidonume. The vinyl acetate / vinylpyrrolidone copolymer is known in the pharmaceutical industry as Copolyvidon, Copolyvidone and Copolyvidonum. Suitable PVP polymers are those sold under the Kollidon trademark of BASF AG, Ludwigshafen, Germany. Preferred polymers are Kollidon 17PF, 25, 30, 90 and VA 64.

The term “soluble” with respect to PVP means that the polymer is soluble in water, as a rule, has no strong cross-links and has a molecular weight of less than about 2,000,000. General information can be found in Buhler, Kollidon ^® : POLYVINILPIRROLIDONE FOR THE PHARMACEUTICAL INDUSTRY, BASF AG (1992).

 Although PVP can increase the solubility or dispersibility of drugs in a composite polymer adhesive system, increasing the amount of PVP leads to a decrease in the expiration of the drug substance, as well as the ability of the system to adhere. Thus, the selected amount of soluble PVP should be sufficient to dissolve the entire drug substance, but insufficient to substantially prevent the outflow of the drug substance from the system. This amount of drug substance can be experimentally determined, but, as a rule, the mass ratio of drug substance and PVP is from 1:10 to 10: 1, preferably from 1: 5 to 5: 1 and optimally from 1: 3 to 3: 1.

 The most preferred embodiment of the invention includes mixtures containing a rubber adhesive and soluble PVP, where polysiloxane acts as rubber.

 Polysiloxane is predominantly part of a pressure-sensitive drug in an amount of from 9 to 97%, and polyacrylate is present mainly in an amount of up to 95%. The preferred ratio of polyacrylate and rubber is from 2: 98 to 96: 4, more preferably from 2:98 to 86:14. The optimum ratio of rubber and polyacrylate is one that allows the highest concentration of the drug substance necessary to achieve approximately zero order kinetics, having a sufficient amount of soluble PVP to dissolve the entire drug substance without adversely affecting the adhesive properties of the pressure-sensitive adhesive preparation or speed drug release from the drug.

 In a pressure-sensitive preparation, soluble PVP is preferably present in an amount varying from 1 to 20% of the total weight of the preparation, in that mass ratio with the drug substance as indicated above. The minimum is the amount of added soluble PVP that is needed to increase the solubility of the drug in the ternary system compared to the solubility of the drug in the binary system, but without rubber. In other words, the amount of soluble PVP is sufficient to dissolve the entire drug substance present in an amount that would exceed its solubility in a composition containing a rubber adhesive with polyacrylate, but without soluble PVP. This amount can be determined experimentally by dissolving the desired amount of drug in the polyacrylate and then dissolving the desired amount of rubber, and then a sufficient amount of soluble PVP to dissolve the drug. The actual amount used will depend on the system and can be determined experimentally by adding enough PVP to the mixture to at least compensate for the decrease in drug solubility resulting from the addition of rubber to the polyacrylate.

 The maximum amount of soluble PVP added is that amount that allows a therapeutic amount of a drug substance to be released from the system, mainly with an approximate zero order of kinetics, and does not significantly reduce the adhesiveness of the system needed for percutaneous use. This amount can also be determined experimentally by measuring the rates of expiration or percutaneous penetration from the system and measuring the adhesive properties of the system.

 The pressure sensitive adhesive composition of this invention is a mixture of preferably from 9 to 97% and optimally from 14 to 94% by weight of rubber, from 5 to 85% acrylate, and preferably from 1 to 20%, more preferably from 3 to 15% and optimally from 5 to 15% soluble PVP.

 The multi-component polymer adhesive system is comprised of from 50 to 99% pressure sensitive adhesive composition. The multiple polymer adhesive system combines with the drug substance in an amount of from 0.1 to 50%, optimally from 0.3 to 30% by weight of the pressure sensitive adhesive composition. Additional additives such as cosolvents for the drug substance (up to 30%) and enhancers (up to 20%) can be included in the overall composition.

In preferred embodiments, the drug substance is a steroid, such as estrogen, or progestogens, or a combination thereof. In other embodiments, the drug substance may be a β ₂ -adrenergic agonist, such as albuterol, or a cardioactive agent, such as nitroglycerin. In other embodiments, the drug is a cholinergic agent such as pilocarpine, antipsychotic like haloperidol, a tranquilizer / sedative like alpazolam, or anesthetics or analgesics. It has also recently been discovered that medicinal substances acting on the central nervous system, such as nicotine and selegiline, can be used percutaneously within the framework of this study.

 The pressure sensitive adhesive composition may further include enhancers, fillers, cosolvents known for use in transdermally drug-releasing compositions.

Brief Description of the Drawings
The entire invention is set forth in the following description in accordance with the accompanying drawings, in which:
FIG. 1 is a schematic illustration of a monolithic device for transdermal delivery of a drug substance according to this invention;
FIG. 2 is a graph of diffusion coefficient versus net solubility parameter;
FIG. 3 shows the average flow of estradiol from two compositions containing soluble PVP:
FIG. 4 shows the penetration of estradiol through the human epidermis from compositions containing PVP according to this invention;
FIG. 5 shows penetration through the human epidermis of norethindrone from a composition of this invention containing estradiol and soluble PVP;
FIG. Figure 6 shows the average intake of estradiol and norethindrone acetate from the composition of this invention containing various concentrations of soluble PVP;
FIG. 7 shows the effect of soluble PVP on the penetration of estradiol through the human epidermis;
FIG. 8 shows the cumulative penetration of estradiol and norethindrone acetate from the composition of this invention containing various concentrations of soluble PVP:
FIG. 9 shows the effect of the concentration of soluble PVP on the passage of estradiol and norethindrone acetate through the human epidermis from the composition of this invention; and
FIG. 10 shows the effect of soluble PVP on the average flow of estradiol and norethindrone acetate from the composition of this invention containing various concentrations of soluble PVP.

Information confirming the possibility of carrying out the invention
The invention relates to a pressure sensitive adhesive composition comprising a mixture of at least two polymers, soluble PVP and a drug substance. A mixture of at least two polymers is referred to herein as a composite polymer adhesive system. The term “mixture” is used to mean that there is no or practically no chemical reaction or cross-linking (in addition to simple H bonds) between different polymers in the composition of the multiple polymer adhesive system.

 As mentioned here, the term “pressure sensitive adhesive” refers to a viscoelastic material that instantly adheres to most substrates under very low pressure and also maintains a constant tack. A polymer is a pressure sensitive adhesive as used herein if it has the properties of a pressure sensitive adhesive in itself or acts as a pressure sensitive adhesive when mixed together with tackifiers, plasticizers or other additives. The term “pressure sensitive adhesive” also applies to mixtures of various polymers and polymer blends such as polyisobutylene (PIB) having different molecular weights; the resulting mixtures are pressure sensitive adhesive. In the latter case, polymers of lower molecular weight in the composition of the mixture are not considered as “tackifiers”, since this term is reserved for additives that differ not only in molecular weight from the polymers to which they are added.

 The term “rubber” as used herein means a viscoelastic material having pressure sensitive adhesive properties and containing at least one natural or synthetic highly elastic polymer. Natural rubbers include polysiloxane, polyisobutylene and natural rubber.

 As used herein, the term “drug substance” and its equivalents, “biologically active agent” and “medicament” mean a very broad meaning, as they include any therapeutic, prophylactic and / or pharmacological or physiological agents or a mixture of them that, upon entry into a living organism, produce the desired usually a beneficial effect.

 More specifically, any drug substance capable of inducing a pharmacological response, both local and systemic, whether it is inherently a therapeutic, diagnostic or prophylactic agent in plants or animals, is included in the consideration of this invention. Also included in the scope of the invention are biologically active agents such as pesticides, repellents, sun protectants, cosmetics, etc. It should be noted that medicinal substances and / or biologically active agents can be used individually or in a mixture of two or more similar substances in quantities sufficient to prevent, suspend, diagnose or cure the disease or for any other conditions, depending from need.

 Medicinal substances are used in a "pharmacologically effective amount." This term implies that the concentration of the drug substance is such that in the composition of the composition it reaches a therapeutic level of drug release during the time during which it must be used, preferably with a zero order of kinetics. This release depends on a large number of variable factors, including the drug substance, the period of time during which the individual dose is applied, the rate of expiration of the drug substance from the system, and a number of other variable factors. The amount of drug substance required can be determined experimentally, based on the flow rate of the drug substance through the system and through the skin, with and without the use of enhancers. Having established the desired flow rate, the creation of a system for percutaneous use occurs in such a way that the release rate over a period of time of therapeutic use will be at least equal to the flow rate. Of course, the active area of the transdermal system also affects the release of the drug from the system.

 The term “oversaturated” amount is mentioned in the work. A supersaturated amount is necessary in order to increase the concentration of solute in the system. Soluble PVP is thus necessary for dissolving a drug substance in a system that is otherwise oversaturated.

 Typically, therapeutic amounts of a drug can be obtained from preparations containing from 0.1 to 50% of the drug. However, the composition of this invention is very useful for drugs that are used in relatively low concentrations, especially from 0.3 to 30% of the drug as a whole.

 Soluble PVP is used in an amount effective to dissolve the drug substance. This amount is higher than that required to dissolve the drug in identical rubber-free formulations. However, the maximum amount of soluble PVP should not be higher than the amount that can support the release of therapeutic doses of a drug substance, preferably with a zero order kinetics, and which can maintain the adhesive properties of a pressure-sensitive transdermal adhesive preparation. An example is a steroid, such as 17 β-estradiol or norethindrone acetate, which is soluble in a conventional polyacrylate pressure sensitive adhesive at an approximate concentration of 2 to 4% in the absence of PVP, although, as noted in PCT N WO 93/08793 of 12 October 1992, a crystallization tendency is observed in the absence of PVP and intensifies at room temperature and normal atmospheric pressure. The inventors of the present invention have found that adding rubber to the mixture reduces the solubility of the steroid in polyacrylate in proportion to the amount of rubber added. Thus, for a system containing polyacrylate and rubber, a sufficient amount of PVP should be used as a solvent to compensate for the loss of solubility caused by the introduction of rubber. Moreover, only a minimal amount of soluble PVP should be added to the pressure-sensitive adhesive preparation, since increased amounts of PVP will result in the loss of acceptable penetration rates to release the drug to a therapeutic level and provide the desired adhesive properties.

 This invention was developed from the discovery that the rate of transdermal penetration of a drug substance coming from a pressure-sensitive adhesive system can be selectively varied by adjusting the solubility of the drug substance in the system. The term “percutaneous penetration rate” as used herein means the rate at which a drug passes through the skin. It is known from the prior art that the rate of release of a drug substance from a carrier may or may not affect the rate of percutaneous penetration.

 Formation of a mixture of composite polymers results in an adhesive system having the characteristic “pure solubility index”, the selection of which provides favorable selective modulation of the release rate of the drug substance by adjusting the solubility of the drug substance in the composite polymer adhesive system.

 The solubility parameter, also referred to herein as “PR”, is disclosed as the sum of all intermolecular attractive forces that are empirically related to the mutual solubility of many chemicals. A general discussion of solubility parameters can be found in Vaughan's article “Using Solubility Paramerters in Cosmetics Formulation”, J. Soc. Cosmet. Chem., V. 36, p. 319-333 (1985).

The composite polymer adhesive system is preferably prepared in such a way that it exhibits the properties of a pressure sensitive adhesive at room temperature and has other desirable characteristics of adhesives used in the practice of transdermal use of drugs. Such characteristics include good adhesion to the skin, the ability to tear off or another method of removal without causing noticeable injury to the skin, maintaining stickiness as it ages, etc. In General, the composite polymer adhesive system should have a glass transition temperature (T _g ), measured using a differential scanning calorimeter and ranging from -70 to 0 ^o C.

 The term "acrylic polymer" is used here in the same way as in other works, as an interchangeable concept with polyacrylate, polyacrylic and acrylic adhesive. Acrylic-based polymer and silicone-based polymer are preferred in a weight ratio, respectively, of from about 2: 98 to 96: 4, more preferably from about 2:98 to 90:10, even more preferably from about 2:98 to 86: 14. The amount of acrylic-based polymer (hereinafter referred to broadly as polyacrylate) and silicone-based polymer (hereinafter referred to broadly as polysiloxane) is chosen to modify the saturation concentration of the drug substance in the triple composite polymer adhesive system to affect the rate of release of the drug substance from system and its passage through the skin.

 In particularly improved uses for the invention, polyacrylate is present in an amount of 5-85% by weight of the total pressure sensitive adhesive preparation, and polyisobutylene is present in an amount of 14-94% of the total weight of the drug. In another preferred embodiment, polyisobutylene is present in an amount of 10-90% of the total weight of the preparation, and polyacrylate is present in an amount of 5-95% of the total weight of the preparation.

 The preferred concentration of the drug substance in the pressure-sensitive adhesive preparation is from 0.1 to 50%, more preferably from 0.1 to 40% and optimally from 0.3 to 30%, these percentages are based on the total weight of the pressure-sensitive adhesive preparation. The invention is especially useful for drugs used in low concentrations, for example 10, 5 or even 3 wt.% Of the drug. Regardless of whether the transdermal preparation is highly saturated or low saturated with a drug substance, the pressure-sensitive adhesive system of this invention can be formulated to maintain acceptable adhesive properties such as adhesiveness, shear ability and tearing ability.

 In the practice of the preferred embodiments of the invention, the polyacrylate can be represented by any homopolymers, copolymers, ternary copolymers and the like of various acrylic acids. In such preferred applications, the polyacrylate composition preferably occupies up to about 95% of the total weight of the pressure sensitive adhesive preparation, more preferably from 3 to 90% and optimally from 5 to 85%, the amount of polyacrylate is dependent on the amount and type of drug used.

 Polyacrylates useful for use in this invention are polymers of one or more acrylic acid monomers and other copolymerizable monomers. Polyacrylates also include copolymers of alkyl acrylates and / or methacrylates and / or secondary monomers capable of copolymerization, or monomers with functional groups. By varying the amount of added monomers of each type, the adhesion ability of the resulting acrylate can be changed, as is known from practice. Typically, a polyacrylate contains at least 50% acrylate or alkyl acrylate monomer, from 0 to 20% functional monomer capable of copolymerization with acrylate, and from 0 to 40% of other monomers.

 Other details and examples of acrylic adhesives that can be used according to this invention are described in Satas, "Acrylic Adhesives", Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., Pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).

 Suitable acrylic adhesives are commercially available and include polyacrylate adhesives sold under the trademarks Duro-Tak 80-1194, 80-196, 80-1197, 2287, 2516 and 2852 sold by National Starch and Chemical Corporation, Bridgewater, New Jersey. Other suitable acrylic adhesives are sold under the trademarks Gelva-Multipolymer Solution GMS 737, 788, 1151 and 1430 (Monsanto; St. Louis, MO).

 Rubber adhesives useful in the practice of this invention include hydrocarbon polymers such as natural and synthetic polyisoprene, polybutylene and polyisobutylene, styrene / butadiene polymers, styrene-isoprene-styrene bonded copolymers, hydrocarbon polymers such as butyl rubber, halogen-containing polymers polyacrylonitrile, teflon, polyvinyl chloride, polyvinylidene chloride and polychloropien, and polysiloxanes and their other copolymers.

 Suitable polysiloxanes include silicone pressure sensitive adhesives based on two main components: a polymer or elastomer and a tackifying resin. A polysiloxane adhesive is usually prepared by structuring an elastomer, typically a high molecular weight polydiorganosiloxane with a resin, to obtain a three-dimensional siloxane structure through a condensation reaction in a suitable organic solvent. The ratio of resin to elastomer is the most important factor that can be varied to change the physical properties of polysiloxane adhesives. Sobieski et al., "Silicole Pressure-Sensitive Adhesives" Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., Pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).

 Further details and examples of silicone pressure-sensitive adhesives that can be used according to this invention are described in the following US patents: 4591622, 4584355, 4585836, 4655767.

 Suitable silicone pressure sensitive adhesives are commercially available and include silicone adhesives sold under the trademark BIO-PSA X7-3027, X7-4203, Q7-4503, X7-4603, X7-4301, X7-4303, X7-4919, X7- 2685 and X7-3122 Dow Corning Corporation, Medical Products, Midland, Michigan. BIO-PSA X7-4203, X7-4301 and X7-4303, in particular, are suitable for use in compositions containing medicinal substances with amine functional groups, such as albuterol.

 In the practice of this invention, the polysiloxane content is preferably from 9 to 97% of the total weight of the pressure sensitive adhesive preparation, more preferably from 12 to 90% and optimally from 14 to 94%.

Medicines that can be mainly used in this invention. These drugs include the categories and types of drugs listed on ther-5 through ther-29 pages in the Merck Index, 11th Edition of Merck & Co. Rahway, NJ 1989. Examples of drugs for which a new transdermal system of the invention can be used, however, the list can be expanded:
1. β-adrenergic agonists, such as Albuterol, Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Denopamine, Dioxetedrine, Dopexamine, Ephedrine, Epinephrine, Etaphedrine, Ethylnorephenolopterolophenolopteroloperolenoproloterophenoloteroplenoperoloteroplenoperoloteroplenoperoloteroplenoperoloteroplenoperoloteroplenoperolenoprotherolophenolophenoloterophenoloterophenoloterophenoloterophenolot , Methoxyphenamine, Oxyfedrine, Pirbuterol, Prenalterol, Prokaterol, Protokyolol, Reproterol, Rimiterol, Ritodrin, Soterenol, Terbuterol and Xamoterol.

 2. Beta-blockers, such as Acebutolol, Alprenolol, Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, Bevantolol, Bisoprolol, Bopindolol, Bucumolol, Befetolol, Cedololol, Bolololololololololololololololol , Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol, Indenolol, Labetalol, Levobunolol, Mepindolol, Metipranalol, Metoprolol, Moprolol, Nadoxolol, Nifenalol, Nipradolol, Polololololololololololololololololololololololololololololololololololololololololololololol Timolol, Toliprolol and Xibenolol.

 3. Analgesics such as chlorobutanol; drugs such as Alfentanil, Allylprodine, Alphaprodine, Anileridine, Benzylmorphine, Bezitramide, Buprenorphine, Butorphanol, Clonitazene, Codeine, Codeine Methyl Bromide, Codeine Phosphate, Codeine Sulfate, Dimedine Dimedine Dimedine Dimedine Dimedine Dimedine Dimedine, , Dimepheptanol, Dimethylthiambutene, Dioxaphetyl Butyrate, Dipipanone, Eptazocine, Ethoheptazine, Ethylmethylthiambutene, Ethylmorphine, Etonitazene, Fentanyl, Hydrocodone, Hydromorphone, Hydroxypethidine, Isomethadone, Ketobemidone, Levorphanol, Lofentanil, Meperidine, Meptazinol, Metazocine, Methadone Hydrochloride, Metopon, Morphine, derivatives Morphine, Myrophine, Nalbuphine, Narceine, Nicomorphine, Norlevorphanol, Normethadone, Normorphine, Norpipanone, Opium, Oxycodone, Oxymorphone, Papaveretum, Pentazoci m, Phenadoxone, Phenazocine, Pheoperidine, Piminodine, Piritramide, Ptoheptazine, Promedol, Properidine, Propiram, Propoxyphene, Sufentanil and Tilidine and non-narcotic substances such as Acetaminophen, Acetylsalicylsalicyicacacid and Alcl.

 4. Antianginal drugs, such as Acebutolol, Alprenolol, Aminodoron, Amlodipine, Arotinolol, Atenolol, Bepridil, Bevantolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, Bupranolol, Celozol, Carozolol, Calvedolol, Clozemololololololololololol, Cartololololol, Carolololol, Cartolololol Gallopamil, Imolamine, Indenolol, Isosorbide dinitrate, Isradipine, Limaprost, Mepindolol, Metoprolol, Molsidomin, Nadolol, Nicardipine, Nifedipine, Nifenalol, Nilvadipine, Nipradilol, Olsolipolitholololololololololololololololololololololololololololololololololololololololololitololinolitolitolitolitolitolitolit Propranolol, Sotalol, Terodiline, Timolol, Toliprolol and Verapamil.

 5. Antiarrhythmic drugs such as Acebutol, Acecaine, Adenosine, Aymalin, Alprenolol, Amiodarone, Amoproxan, Aprindine, Arotinolol, Atenolol, Bevantolol, Bretylium Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunobololol, Bunobrololol Carazolol, Carteolol, Cifenline, Cloranolol, Disopyramide, Encainide, Esmolol, Flecainide, Gallopamil, Hydroquinidine, Indecainide, Indenolol, Ipratropium bromide, Lidocaine, Lorajolololine, Metrolinoline, Metrolinoline, Metrolinoline, Metrolinoline, Metrolinoline, Metrolinoline, Metrolinol, Merolentoline , Pirmenol, Practolol, Prajmaline, Procainamide hydrochloride, Pronethalol, Propafenone, Propranolol, Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol, Timolol, Tocainide, Verapamil, Viquidil and Xibenolol .

6. Antidepressants, including:
Bicyclic such as Binedaline, Caroxazone, Citalopram, Dimethazan, Indalpin, Fencamine, Indeloxazine Hydrochloride, Nefopam, Nomifensine, Oxitriptan, Oxypertine, Paroxetine, Sertraline, Thiazesim, Trazodon and Zometapine:
Hydrazides / hydrazines such as Benmoxine, lproclozide, lproniazid, Isocarboxazid, Nialamide, Octamoxin and Phenelzine;
Pyrrolidones, such as Cotinine, Rolicyprine and Rolipram;
Tetracyclic such as Maprotiline, Metralindole, Mianserin and Oxaprotiline.

 Tricyclics such as Adinazolam, Amitriptyline, Amitriptylinoxide, Amoxapine, Butriptyline, Clomipramine, Demexiptiline, Desipramine, Dibenzepin, Dimetracrine, Dothiepin, Doxepin, Fluacizine, Opipramine, Imipramine Nindolipin, Nipolipen, Indipin, Nipolipin, Nolefin, Nolefin, Nolefin, Nolefen, Nipolipin, Nipolipen, Melipramine, Amipramine , Pizotyline, Propizepine, Protriptyline, Quinupramine, Tianeptine, and Trimipramine, and others, such as Adrafinil, Benactyzine, Bupropion, Butacetin, Deanol, Deanol Aceglumate, Deanol Acetamidobenzoate, Фефолетин, Фетолетінетет, Ipeteridamin, Foxaradi Hypercinin, Levophacetoperane, Medifoxamine, Minaprine, Moclobemide, Oxaflozane, Piberaline, Prolintane, Pyrisuccideanol, Rubidium chloride, Sulpiride, Sultopride, Teniloxazine, Thozalinone, Tofenacin, Toloxatone, Tranylcypromhan, , Viloxazine and Zimeldine.

 7. Antiestrogens such as Delmadinone Acetate, Ethamoxytriphetol, Tamoxifen, and Toremifene.

 8. Antigonadotropins, such as Danazole, Gestrinone and Paroxipropion.

9. Antihypertensive drugs, including:
Arylethanolamine derivatives such as Amosulalol, Bufuralol, Dilevalol, Labetalol, Pronethalol, Sotalol, Sulfinalol;
Aryloxypropanolamine derivatives such as Acebutolol, Alprenolol, Arotinolol, Atenolol, Betaxolol, Bevantolol, Bisoprolol, Bopindolol, Bunitrolol, Bupranolol, Butofilolol, Carazololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololol , Nipradilol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Talinolol, Tetraolol, Timolol and Toliprolol;
Benzothiadiazine derivatives such as Althiazide, Bendroflumethiazide, Benzthiazide, Benzylhydrochlorothiazide, Buthiazide, Chlorothiazide, Chlorthalidone, Cyclopenthiazide, Cyclothiazide, Diazoxide, Epithiazide, Ethiazide, Fenquizone, Hydrochlorothiazide, Hydroflumethiazide, Methylclothiazide, Meticrane, Metolazone, Paraflutizide, Polythiazide, Tetrachlormethiazide and Trichlormethia:
N-carboxylalkyl derivatives (peptide / lactam) such as Alacepril, Captopril, Cilazapril, Delapril, Enalapril, Enalaprilat, Fosinopril, Lisinopril, Moveltipril, Perindopril, Quinapril, Ramipril;
Dihydropyridine derivatives such as Amlodipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nisoldipine, Nitrendipine;
Guanidine derivatives such as Bethanidine, Debrisoquin, Guanabenz, Guanacline, Guanadrel, Guanazodine, Guanethidine, Guanfacine, Guanochlor, Guanoxabenz and Guanoxan;
Hydrazines and phthalazines such as Budralazine, Cadralazine, Dihydralazine, Endralazine, Hydracarbazine, Hydralazine, Pheniprazine, Pildralazine, Todralazine;
Imidazole derivatives such as Clonidine, Lofexidine, Phentolamine, Tiamenidine, Tolonidine:
Compounds of quaternary ammonium salts Azamethonoium Bromide, Chlorisondamine Chloride, Hexamethonium, Pentacynium Bis (methyl sulfate), Pentamethonium Bromide, Pentolinium Tartate, Phenactopinium Chloride and Trimethidiunum Methosulfate:
Quinazoline derivatives such as Alfuzolin, Bunazosin, Doxazosin, Prazosin, Terazosin, Trimazosin;
Reserpine derivatives such as Bietaserpine, Deserpidine, Rescinamine, Reserpine and Syrosingopine;
Sulfonamide derivatives such as Ambuside, Clopamide, Furosemide, Indapamide, Quinethazone, Tripamide and Xipamide; and
others, such as Aymaline, γ-Aminobutyric acid, Bufeniode, Chlorthalidone, Cicletaine, Ciclosidomine, Cryptenamine Tannates, Fenoldopam, Flosequinan, Indoramin, Ketanserin, Metbutamate, Mecamylamine, Methyldolone Mineral Pyrone, Methylazone Mineral Pyrone , Pempidine, Pinacidil, Piperoxan, Primaperone, Protoveratrines, Raubasine, Rescimetol, Rilmenidene, Saralasin, Sodium Nitroprusside, Ticrynafen, Trimethaphan Camsylate, Tyrosinase and Urapidil.

10. Anti-inflammatory medicinal substances (non-steroidal nature), including:
Amino acrylic carboxylic acid derivatives such as Enfenamic Acid, Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, Niflumic Acid, Talniflumate, Terofnamate and Tolfenamic Acid:
Derivatives of aryl acetic acid such as Acemetacin, Alclofenac, Amfenac, Bufexamac, Cinmetacin, Clopirac, Diclofenac Sodium, Etodolac, Felbinac, Fenclofenac, Fenclorac, Fenclozicacin, Icolecececinacen, Iclucecenecin, Acin , Proglumetacin, Sulindac, Tiaramide, Tolmetin and Zomepirac:
Arylbutyric acid derivatives such as Bumadison, Butibufen, Fenbufen and Xenbucin;
Derivatives of arylcarboxylic acids such as Clidanac, Ketorolac and Tinoridine;
Derivatives of arylpropionic acid such as Alminoprofen, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, lbuproxam, Indoprofen, Ketoprofen, Loxoprofen, Acroprofen, Poprofrofen, Paprofrofen, Paprofrofen, Paprofrofen, Oxoprofen, Paprofen, Paprofen, Paprofen, Paprofen, Oxoprofen, Paprofen, Paprofen, Paprofen ;
Pyrazoles such as Difenamizole and Epirizole;
Pyrozolones such as Apazone, Benzpiperylon, Feprazone, Mofebutazone, Morazone, Oxyphenbutazone, Phenybutazone, Pipebuzone, Propyphenazone, Ramifenazone, Suxibuzone and Thiazolinobutazone;
Derivatives of salicylic acid, such as Acetaminosalol, Aspirin, Benorylate, Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate, Fendosal, Gentisic Acid, Salicylate glycol, Imidazole Salicylate, Salicylate, Salicylate, Calcium salicylate, Salizylate, Amylate Phenyl Salicylate, Salacetamide, Salicylamine O-Acetic Acid, Salicyl Sulfuric Acid, Salsalate and Sulfasalazine;
Thiazine carboxamides such as Droxicam, Isoxicam, Piroxicam and Tenoxicam: and
others such as epsilon-Acetamidocaproic Acid, S-Adenosylmethionine, 3-Amino-4-hydroxybutyric Acid, Amixetrine, Bendazac, Benzydamine, Bucolome, Difenpiramide, Ditazol, Emorfazone, Guaiazulene, Nabumelone Oxone, Parate Peroxidone, Nabumelone Oxone, Nabumelone Oxone Pifoxime, Proquazone, Proxazole and Tenidap.

11. Antitumor drugs, including:
2-aminolevulinic acid and alkylating agents, including:
Alkyl sulfonates such as Busulfan, Improsulfan and Piposulfan;
Azaridines such as Benzodepa, Carboquone, Meturedepa and Uredepa;
Ethyleneimines and methylmelamines such as Altretamine, Triethylene melamine, Triethylene phosphoramide, Triethylene thiophosphoramide, and Trimethylolmelamine;
Nitrogen mustards such as Chlorambucil, Chlornaphazine, Cholophosphamide, Estramustine, lfosfamide, Mechlorethamine, Mechlorethamine Oxide Hydrochloride, Melphalan, Novembichin, Phenesterine, Prednimustine, Trofosfamide and Uracilard;
Nitrosoureas such as Carmustine, Chlorozotocin, Fotemustine, Lomustine, Nimustine and Ranimustine; and
others, such as Dacarbazine, Mannomustine, Mitobronitol, Mitolactol and Pipobroman;
Antibiotics such as Aklacinomycin, Actinomycin F ₁ , Anthramycin, Azaserin, Bleomycin, Cactinomycin, Carubicin, Carzinophilin, Chromomycin, Dactinomycin, Daunorubicin, 6-Diazo-5-oxo-L-norleucine, Ecorubicin, Doricubin, Morbicin, Doxorubicin Nogalamycin, Olivimycins, Peplomycin, Plicamycin, Porfiromycin, Puromycin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Zinostatin and Zorubicin;
Antimetabolites, including:
Folic acid analogues such as Denopterin, Methotrexate, Pteropterin and Trimetrexate;
Purine analogs such as Fludarabine, 6-Mercapturin, Thiamiprine and Thioguanaine; and
Pyrimidine analogs such as Ancitabine, Azacitidine, Azauridine, Carmofur, Cytarabine, Doxifluridine, Enocitabine, Floxuridine, Fluorocil and Tagafur;
Enzymes such as L-Asparaginase; and
other medicinal substances, such as Aceglatone, Amsacrine, Bestrabucil, Bisantrene, Carboplatin, Cisplatin, Defofamide, Demecolcine, Diaziquone, Elfornithine, Elliptinium Acetate, Etoglucid, Etoposide, Gallium nitrate,
Hydroxyurea, α Interferon, β Interferon, γ-interferon, Interleukin-2, Lentinan, Lonidamine, Mitoguazone, Mitoxantrone , Mopidamol, Nitracrine, Pentostatin, Phenamet, pirarubicin, Podophyllinic Acid, 2-Ethythydrazide, procarbazine PSK ^®, Razoxane, Sizofiran , Spirogermanium, Taxol, Teniposide, Tenuazonic Acid, Triaziquone, 2.2 '. 2 '' - Trichlorotriethylamine, Urethan, Vinblastine, Vincristine and Vindesine;
Antitumor hormone medications, including:
Androgens such as Calusterone, Dromostanolone Propionate, Epitiostanol, Mepitiostane and Testolactone:
Adrenal cortical inhibitors such as Aminoglutetimide, Mitotane, and Trilostane:
Antiandrogens such as Flutamide and Nilutamide; and
Antiestrogens such as Tamoxifen and Toremifene.

 12. Agents for treating Parkinson’s disease, such as Amantadine, Benserazide, Bietanautine, Biperiden, Bromocriptine, Bidupine, Carbidopa, Deprenyl, Dexetimide, Diethazine, Droxidopa, Ethopropazine, Ethylbenzididegine, Piridine, Peroxidum, Peptidin, Hydax, Pyramide, Peroxidine Tigloidine and trihexyphenidyl hydrochloride.

 13. Agents that inhibit prostatic hypertrophy, such as Gestonoroncapronate, Mepartricin, Oxendolone, and Proscar.

14. Antipsychotics, including: Butyrophenones, such as Benperidol, Bromperidol, Droperidol, Fluanisone, Haloperidol, Melperone, Moperone, Pipamperone, Sniperone, Timiperone and Trifluperidol;
Phenothiazines, such as Acetophenazine, Butaperazine, Carphenazine, Chlorproethazine, Chlorpromazine, Clospirazine, Cyamemazine, Dixyrazine, Fluphenazine, Imiclopazine, Mepazine, Nesoridazine, Phenazine, Methoxyazazine, Pefazine, Oxofazine, Oxofazine, Sulforidazine, Thiopropazate, Thioridazine, Trifluoperazin and Triflupromazine:
Thioxatenes such as Chlorprothixen, Clopenthixol, Flupentixol and Thiothixene:
other tricyclic compounds such as Bezquinamide, Carpipramin, Clocapramine, Clomacran, Clothiapine, Clozapine, Opipramol, Prothipendyl, Tetrabenazine and Zotepine; and
other remedies such as Alizapride, Amisulpride, Buramate, Fluspirylene, Molindone, Penfluridol, Pimozide, Spirilene and Sulpiride.

 15. Antispasmodic drugs, such as Alibendol, Ambucetamide, Aminopromazine, Apoatropine, Bevonium Methyl Sulfate, Bietamiverine, Butaverine, Butropium Bromide, N-Butyl Scopolammonium Bromide, Caroverine, Cimetropium Bromide, Cinnamedbromideideroidomeriodi, Hydromide Diisopromine , Octamylamine, Octaverine, Pentapiperide, Phenamacide Hydrochloride, Phloroglucinol, Pinaverium Bromide, Piperilate, Pipoxolan Hydrochloride, Pramiverin, Prifinium Bromide, Properidine, Propivane, Propyromazine, Prozapine, Racefemine, Rolytolidid, Rocolidid, e, Sultroponium, Tiemonium Iodide, Tiquizium Bromide, Tiropramide, Trepibutone, Tricromyl, Trifolium, Trimebutine, N, N-1-Trimethyl-3,3-diphenylpropylamine, Tropenzile, Trospium Chloride and Xenytropium Bromide.

16. Tranquilizers, including:
Arylpiperazines such as Buspirone, Gepirone and Ipsapirone;
Derivatives of benzodiazepine, such as Alprazolam, Bromazepam, Camazepam, Chlordiazepoxide, Clobazam, Clorazepate, Chotiazepam, Cloxazolam, Diazepam, Ethyl Loflazepate, Etizolam, Fluidazamazamepamazame, Flutazazamazame, Flutazazamepamazam, Flutazazam, Klazazam, Flutazazam Oxazepam, Oxazolam, Pinazepam, Prazepam and Tofisopam;
Carbamates such as Cyclarbamate, Emylcamate, Hydroxyphenamate, meprobamate, Phenprobamate and Tybamate; and
others, such as Alpidem, Benzoctamine, Captodiamine, Chlormezanone, Etifoxine, Fluoresone, Glutamic acid, Hydroxyzine, Mecloralurea, Mephenoxalone, Oxanamide, Phenaglycodol, Suriclone.

 17. Calcium regulators such as Calcifediol, Calcitonin, Calcitriol, Clodronic acid, Dihydrotachysterol, Eicatonin, Ethidronic acid, lpriflavone, Pamidronic Acid, Parathyroid Hormone and Teriparatide Acetate.

 18. Heart rate regulators, such as Acephillin, Acetyldigoxin, 2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, Buclasdesine, Cerberoside, Camphotamide, Convallatoxin, Coumarin, Denopamine, Digitoxin, Digitalis, Dobital, Ditital, Dobital , Dopexamin, Enoximone, Erythrophleine, Fenalcomine, Gitalin, Gitoksin, Glycocyamine, Heptaminol, Hydrastinine, lbopamine, Lanotodises, Metamivam, Milrinone, Neriifolin, Oleandrin, Ouabain, Oxyfedrin, Prenalterinolinolin, Orenifrolinolin, Prillaridolinolinolin, Prolinearolinolinolin, Probinarolinolinolin, Probinarolinolinolin, Prolarinolinolin, Prolarinolinolin, Prolarinolinolin, Prorenalinolin, Prolarinolinolin, Orenohydrin, and Xamoterol.

 19. Chelating agents such as Deferozmine, Ditiocarb Sodium, Edetate Calcium Disodium, Edetate Disodium, Edeate Sodium, Edetate Trisodium, Penicillamine, Pentetate Calcium Trisodium, Pentectic Acid, Succimer and Trientine.

 20. Dopamine receptor agonists such as bromocriptine, Dopexamine, Fenoldopam, lbopamine, Lisuride, Naxagolide and Pergolide.

 21. Inducers of liver enzymes such as Flumecinol.

22. Estrogens, including:
Non-sterile androgens such as Benzestrol, Broparoestrol, Chlortrianisen, Dienestrol, Diethylstilbestrol, Diethylstilbestrol Diproprionate, Dimestrol, Fosfestrol, Hexestrol, Methallenestril and Methestrol; and
Steroidal estrogens such as Colpormon, Estrogen-conjugated hormones, Equilenin, Equilin, Estradiol, Estradiol benzoate, Estradiol 17 β-Cypionate, Estriol, Estron, Ethinyl estradiol, Mestranol, Moxestrol, Mytatrienediol Quin.

 23. Glucocorticoids, such as 21-Acetoxyprefnenolone, Aalclometasone, Algestone, Amicinonide, Beclomethasone, Betamethasone, Budesonide, Chloroprednisone, Clobetasol, Blovetasone, Corticosterolone Done, Cloprednol, Corticosterone Defolezone, Defolon, Cloprednol Difluprednate, Enoxolone, Fluazacort, Flucloronide, Flumehtasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorometholone, Fluperolone acetate, Fluprednidene acetate, Fluprednisolone, Flurandrenolide, Formocortal, Halcinonide, Halometasone, Halopredone acetate, Hydrocortamate, Hydrocortisone, Hydrocortisone acetate, Hydrocortisone Phosphate, Hydrocortisone 21-Sodium Succinate, Hydrocortisone Tebutate, Mazipredone, Medrysone, Meprednisone, Methyolprednisolone, Mometasone Furoate, Parameth asone, Prednicarbate, Prednisolone, Prednisolone 21-diethylaminoacetate, Prednisone sodium phosphate, Prednisolone sodium succinate, Prednisolone 21-m-sulfobenzoate, Prednisolone 21-Stearoylglycolate, Prednisolone Tebutate, Prednisalone 21-trimethylthenylnitnenitnitnylnitnenitnitnyltnyltnyltnylnate, Prednisolone, Prednisolone , Tixocortal, Triamcinolone, Triamcinolone Acetonide, Triamcinolon Benetonide and Triamcinolone Hexacetonide.

 24. Mineralcorticoids such as Aldosterone, Deoxycorticosterone, Deoxycorticosterone Acetate and Fludrocortisone.

 25. Monoamine oxidase inhibitors such as Deprenyl, lproclozide, lproniazid, Isocarboxazid, Moclobemide, Octomoxin, Pargyline, Phenelzine, Phenoxypropazine, Pivalylbenzhydrazine, Prodipine, Toloxatone and Tranylcypromine.

 26. Skeletal muscle relaxants such as Alfoqualone, Alcuronium, Atracurium Besylate, Baclofen, Benzoctamine, Benzoquinonium Chloride, C-Calebassine, Carisoprodol, Chlormezanone, Chlorphenzameblozen, Chlorproethazome, Chlorproethazome, Chlorproethazome, Chlorproethazome, Chlorproethazome, Chlorproethazome, Chlorproethazome Epiresone, Fazaddinium bromide, Flumetramide, Gallamine Triethiodide, Hexacarbacholine bromide, Hexafluorenium bromide, ldrocilamide, Lauexium Methyl Sulfate, Leptodactyline, Memantine, Mephenesin, Mephenoxalone, Metaxalone, Methocarbamol, Metocurine Iodide, Nimetazepam, Orphenadrine, Pancuronium bromide, Phenprobamate, Phenyramidol, Pipekury bromide , Promoxolane, Quinine Sulfate, Styramate, Succinylcholine Bromide, Succinylcholine Chloride, Succinylcholine Iodine, Suxethonium Bromide, Tetrazepam, Thiocolchicoside, Tizanisidine, Tolperisone, Tubokurarin Chloe Eid, Vecuronium Bromide and Zoxolamine.

 27. Drug antagonists such as Amiphenazole, Cyclazocine, Levallorphan, Nadide, Nalmfene, Nalorphine, Nalorphine, Dinicotinate, Naloxone and Naltrexone.

 28. Progesterones, such as Allylestinol, Anageston, Chlormadinone Acetate, Delmadinone Acetate, Demegestone, Desogestrel, Dimethisterone, Dydrogesterone, Ethisterone, Ethynodiol, Flurogestone Acetate, Metro-17-hydrometer-Captone, 17 Gestonorone-Capone -hydroxyprogesterone, 17α-hydroxygesterone caproate, Lynestrenol, Medrogestone, Medroxyprogesterone, Megestrol Acetate, Melengestrol, Norethindrone, Norethynodrel, Norgesterone, Norgestimate, Progesterone, Progestone, Questone, Quinone, Norestone, Tregin, Norginestone, Tregin, Norin

29. Vasodilators (coronary) such as Amotriphene, Bendazol, Benfurodil Hemisuccinate, Benziodarone, Chloacizine, Chromonar, Clobenfurol, Clonitrate, Dilazep, Dipyridamole, Droprenilamine, Efloxate, Erythritol, Erythrityl Tetranitrate, Etafenone, Fendiline, Floredil, Ganglefene, Hexestrol Bis ( beta-diethylaminoethyl ether), Hexobendine, ltramin Tosylate, Khellin, Lidoflazin, Mannitol hexanitrate, Medibazine, Nicorandil, Nitroglycerin, Pentaerythritol Tetranitrate, Pentrinitrol, Perhexiline, Pimefylline, Tridylitrin, Prenylitrin, Prenyltrin , and
vasodilators (peripheral), such as Aluminum nicotinate, Bametan, Bencyclane, Betahistine, Bradykinin, Brovincamine, Bufoniode, Buflomedil, Butalamine, Cetiedil, Ciclonicate, Cinepazide, Cinnarizine, Elicisopilin, Fliniden, Flinidin, Dichloidenfilin, Dicloidilofen, Dicloidilofen, Dicloidilofin, Niacinate, Isoxsuprine, Kallidin, Kallikrein, Moxisylyte, Nafronyl, Nicametate, Nicergoline, Nicofuranose, Nicotinyl Alcohol, Nylidrin, Pentifylline, Pentoxifylline, Piribedil, Protaglandin E ₁ , Sulostidil and Xanthinal.

 30. Benzodiazepine antagonists such as Flumazenil.

31. Bronchodilators, including:
Derivatives of ephedrine, such as Albuterol, Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Dioxethedrine, Ephedrine, Epiniphrine, Eprozinol, Etafedrine, Ethyinorepinephrine, Fenoterol, Hexoprenaline, Isoetharine, Moproterolyn, Proterolyn, Poloterolyn, Iteroterolyn , Reproterol, Rimiterol, Soterenol, Terbutaline and Tulobuterol;
Quaternary ammonium salts such as Bevonium Methyl Sulfate, Clutropium Bromide, Ipratropium bromide and Oxitropium Bromide;
Xanthine derivatives such as Acefylline, Acefylline Piperazine, Ambuphylline, Aminophylline, Bamifylline, choline Theophyllinate, Doxofylline, Diphilin, Enprofylline, Etamiphyllin, Theofylline, Guaithylline, Proxyobomy and
others, such as Fenspiride, Medibazine, Methoxyphenanime and Tretoquinol.

 Medicinal substances and their mixtures can be presented in the composition in various forms, depending on in which form the optimal release is achieved. As for medicinal substances, they can be in the form of a base or acid, or in the form of salts, esters, or any other derivatives that meet pharmacological criteria, or as components of molecular complexes.

 The amount of drug substance included in the composition varies depending on the specific drug substance, the desired therapeutic effect and the length of time during which treatment is carried out. For most drugs, penetration through the skin is a step that limits the rate of release. Therefore, the amount of drug substance and its release rate, as a rule, are selected in such a way as to ensure transdermal delivery with zero ordinal dependence time for a prolonged period of time. The minimum amount of drug substance in the system is selected based on the amount of drug substance that passes through the skin during the time during which this device can provide treatment. Normally, the amount of drug substance in the system can vary from 0.1 to 50% and optimally, for lower doses of the drug substance from 0.3 to 30%.

 It is obvious that the composition for the transdermal use of the drug should also include agents that are known to accelerate the penetration of the drug through the skin. These agents were referred to as skin permeability enhancers, catalysts, adjuvants, sorption promoters, and are referred to herein under the general term “enhancers”. This class of agents includes substances with different mechanisms of action, including those in which the action is to improve the solubility and diffusion ability of drugs in the composition of the composite polymer, and those substances that improve percutaneous absorption, for example, by changing the ability of the skin layer to hold moisture, softening the skin, improving skin permeability, acting as auxiliary factors of permeability or openers of hair follicles or changing the structure of the skin, including the boundary layer . Some of these agents have more than one mechanism of action, but essentially they enhance the release of the drug. The amplifier can be included in the drug release system at a concentration of up to about 20%. If the amplifier is turned on, then its preferred concentration is from about 1 to 10%. Examples of enhancers are polyhydric alcohols, such as dipropylene glycol, propylene glycol and polyethylene glycol, which enhance the solubility of drugs: liquid oils such as olive oil, squalene and lanolin: polyethylene glycol ethers and fatty esters such as cetyl ether and oleoyl ether: fatty acid esters, such as isopropyl myristate, which enhance the ability of drugs to diffuse; fatty acid alcohols such as oleoyl alcohol; urea and urea derivatives such as allantoin, which affect the ability of keratin to retain moisture; polar solvents such as dimethyl decyl phosphoxide, methyloctyl sulfoxide, dimethyl lauryl amide, dodecyl pyrrolidone, isosorbitol, dimethyl acetonide, dimethyl sulfoxide, decyl methyl sulfoxide and dimethyl formamide, which affect the permeability of keratin; salicylic acid, which softens keratin; amino acids that promote permeability; benzyl nicotinate, which opens the hair follicles; high molecular weight aliphatic surfactants, such as lauryl sulfate salts, which alter the surface structure of the skin and the supply of drug substances. Other substances include oleic and linolinic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, isopropyl palmitate, oleamide, polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl oleyl ether under the trade names Brij 30, 93 and 97 by ICI Americas, Inc., and polysorbent 20 sold under the trade name Tween 20 by ICI Americas, Inc.

 In major embodiments of the invention, a plasticizer or tackifier is included in the formulation to improve the adhesive properties of the pressure-sensitive adhesive formulation. The tackifier is extremely useful in combinations where the drug does not plasticize the polymer. Suitable known tackifying agents for this purpose are: (1) aliphatic hydrocarbons; (2) mixed aliphatic and aromatic hydrocarbons; (3) aromatic hydrocarbons; (4) substituted aromatic hydrocarbons; (5) hydrogenated esters; (6) polyterpenes; and (7) hydrogenated wood resin or rosin. It is desirable that the agent used for stickiness is mixed with a mixture of polymers. In a preferred embodiment, the tackifying agent is a silicone fluid (e.g. 360 Medical Fluid, available from Dow Corning Corporation, Midland, MI) or mineral oil. Silicone fluid is effective for mixtures containing polysiloxane as the main component. In other embodiments, for example, using synthetic rubber as the main component, the preferred tackifier is mineral oil. Acrylics can provide tack in combination with oleates, oleic acid, oleyl alcohol and other fatty acid derived agents.

 Some drugs, such as the vasodilator nitroglycerin, act as plasticizers, since they are largely soluble in the polymers in the system. If the drug molecules are poorly soluble in the polymer system, a co-solvent for the drug and polymer can be added. Co-solvents such as lecithin, retinol derivatives, tocopherol, dipropylene glycol, triacetin, propylene glycol, saturated and unsaturated fatty acids, mineral oil, silicone fluid, alcohols, butyl benzophthalate and the like are useful in the use of the present invention, depending on the solubility of the drug substance in the compound polymer adhesive system.

 Thus, the best drugs for the combination of rubber and polyacrylate are the following (see table. 1).

 The compositions of this invention can be further equipped with various hardeners, fillers and other known additives for use in devices for percutaneous delivery of medicinal substances. If the drug tends to absorb moisture, for example when lecithin is used as a co-solvent, hydrophilic substances are especially useful. One option for a successfully used hydrophilic substance is clay. It has been found that the addition of clay improves the adhesive properties of the transdermal delivery formulations without decreasing the release rate of the drug substance. Suitable clays for this purpose include kaolinites, such as baolinite, anauxite, dikkit and nakrit, montmorillonites, such as montmorillonite, bentonite, berdellite and montronite, illites / muscovites, such as illithi glauconite, chlorites, galsulfite, such as metabolloisite, allophan and aluminosilicate clays.

 In the device of this invention, pressure-sensitive adhesive preparations can be used as an adhesive part of any transdermal drug device (eg, reservoir), or it can be an adhesive monolithic device. Of course, the principles of the present invention can still be applied to those embodiments in which the transdermal drug delivery composition is not pressure sensitive adhesive and includes a drug reservoir.

 In FIG. 1 is a schematic illustration of a monolithic adhesive device 10 according to the invention. The percutaneous drug delivery device includes a monolithic body of composition 11 of a certain geometric shape with a protective release pad 12 on one side of the monolithic body of composition 11 and a back layer 13 located on the other side. Removing the release liner 12 exposes the pressure-sensitive composite polymer adhesive preparation, which acts as the matrix carrier of the drug substance and at the same time as the means by which the device is used by the patient.

The device, or individual unit dosage, of the present invention can be manufactured by any previously known method. After the skin preparation is formulated, it can be brought into contact with the back layer using any of the known methods. Such technologies include coating by knurling, hot fusion, solution coating, and the like. Of course, the supporting materials are well known and can be represented by plastic films of polyethylene, vinyl acetate resins, polyester, polypropylene, BAREX ^R , ethylene / vinyl acetate copolymers, polyvinyl chloride, polyurethane and other similar substances, metal foil, non-woven fabrics, fabrics, their joint extrusion or layering and industrially manufactured laminated materials. Supporting materials typically have a thickness of from 2 to 1000 microns, and typically a skin preparation is applied to the supporting material in a layer of a thickness of about 12 to 250 microns.

Suitable release pads are also well known and are commercially available from Release International under the name Bio-Release ^R gasket and Syl-off ^R 7610 gasket. In preferred embodiments of the invention in which polysiloxane is part of the composite polymer adhesive system, the release liner should be compatible with the silicone adhesive. 3M's 1022 ScotchPak is an example of a suitable commercially available gasket.

The configuration of the transdermal device of the present invention can be of any shape or size, if desired or desired. For example, a single dose may be applied to an area of 1 to 200 cm ² . Preferred sizes are from 5 to 60 cm ² .

 In the preparation method according to this invention, a plurality of polymers having different solubility parameters are mixed (but do not chemically interact and do not crosslink) with soluble PVP to obtain a pressure-sensitive adhesive composition that controls the supply of the drug substance contained therein to and through the epidermis. As a result of mixing the polymers, the saturating concentration of the drug substance in the polymer system is regulated, and thus it becomes possible to selectively change the rate of transdermal drug delivery. The term “blending” certainly embraces the selection of suitable polymer components and their proportions to achieve the desired effect.

 In a preferred embodiment of the invention, a transdermal drug delivery device is prepared by mixing soluble PVP, polyacrylate, polysiloxane, a drug, a co-solvent (cosolvents) and, if desired, a tackifying agent in a specific volatile solvent (s), then the mixture is cast, and volatile solvent (s) are removed by evaporation in order to obtain a film.

 A number of suitable volatile solvents include, but are not limited to, alcohols such as isopropanol and ethanol: aromatics such as xylenes and toluene: aliphatic substances such as hexane, cyclohexane and heptane; and alkanoic acid esters such as ethyl acetate or butyl acetate.

An exemplary general manufacturing method is as follows:
1. The required amounts of soluble PVP, solvent (s), enhancer (s) (eg, toluene) are combined and thoroughly mixed in a container.

 2. Then add the drug substance to the mixture and mix until the mixture is homogeneous.

 3. The required amounts of polysiloxane and polyacrylate are then added to the drug mixture and mixed thoroughly.

 4. Then, the composition is subjected to the application procedure, in which they cover the protective release pad, while controlling a certain thickness of the formed layer. The applied product is then passed through an oven in order to remove all volatile solvents used in the process.

 5. The dried product on the release pad is then combined with support material and wound into rolls for preservation.

 6. “Devices” are cut from the roll according to the template in accordance with the required size and shape and then packaged.

The sequence of stages, the number of ingredients, the amount and time of shaking or mixing can be important process variables, which depends on the specifics of the polymers, drugs, cosolvents and enhancers used in the composition. These factors can be selected by specialists who need to consider that the product must be uniform in quality. It is believed that a number of other methods, including a change in the sequence of steps, can be applied and will give the desired results. In addition to changing forms, dosage may also vary. The surface area is from 1 to 200 cm ² , preferred sizes: 5, 10, 15, 20, 30 and 60 cm ² .

 The molecular weight of said PVP is from about 2,000 to 1,100,000, more preferably from 2,000 to 1,000,000, more preferably from 5,000 to 100,000, and the best option is from 7,000 to 54,000.

 A preferred embodiment includes soluble PVP with pressure-sensitive adhesive rubber and polyacrylate. Most preferred mixtures include mixtures of polyacrylate, polysiloxane and soluble PVP.

 Soluble PVP has been shown to be highly effective for dissolving drugs in the transdermal systems of the adhesive type of drugs of the present invention. In particular, soluble PVP has proven useful in maintaining the norethindrone acetate system (NEA) and the NEA / estradiol system in a state that is almost completely free of crystals. Other specific medicinal substances for which soluble PVP is very useful according to this invention are albuterol, estradiol, haloperidol and alprazolam.

 The amount and type of dissolved PVP required in the aforementioned advantageous embodiment depends on the amount and type of drug present in the adhesive, and equally on the type of adhesive. For example, the addition of a rubber adhesive to a mixture of a drug substance and a polyacrylate adhesive causes a decrease in the solubility of the drug substance and its subsequent crystallization as a result of excessive saturation. However, adding soluble PVP to the mixture may increase the apparent solubility of the substance. In other words, the presence of a rubber adhesive reduces the saturation of the mixture with a dissolved drug substance, and the presence of soluble PVP compensates for this negative effect.

 Accordingly, the optimal concentration of soluble PVP in the transdermal drug delivery system is equal to the amount of soluble PVP sufficient to compensate for the decrease in solubility of the drug caused by the rubber adhesive. Optimal concentrations of soluble PVP can easily be determined using a simple experiment. Typically, PVP is present in an amount of about 1 to 20%, more preferably about 3 to 15%, and optimally about 5 to 15%.

 For example, for norethindrone acetate (NEA), the optimal concentration of soluble PVP is a concentration of 10%, which has been shown to inhibit the formation of NEA crystals without undesirable effects on the flow of NEA from a multiple polymer adhesive system (polyacrylate / polysiloxane). For estradiol, the inclusion of 5 - 10% soluble PVP in the composition not only increases the flow of estradiol, but also increases the total amount of estradiol passing through the skin. In the case of albuterol, the optimal concentration (as shown) is approximately 5%.

 Significant amounts of soluble PVP can cause a decrease in drug intake. For example, when PVP is present in amounts greater than about 20% by weight, NETA penetration begins to decrease.

 The soluble PVP used according to the invention is dissolved together with one or more additional polymeric materials of the inventive mixture.

 The type and amount of soluble PVP can also have a significant effect on the adhesive properties of the final product. In adhesives with high binding properties, it is advantageous to include soluble PVP with a lower molecular weight, while soluble PVP with a higher molecular weight is preferred in weakly binding adhesives.

 The following examples include, by way of illustration, pressure-sensitive adhesive compositions and transdermal drug release devices and methods for preparing such within the scope of this invention. These examples in no way limit the scope of the invention.

 The following commercially available adhesives were used in mixtures comprising composite polymer adhesive systems in the examples: "Duro-Tak 80-1194, 80-1196, 80-1054, 80-1074, 80-1058, 80-2434, 80-1070, 80- 6172, 80-1197, 87-2287, 87-2516 and 87-2852 "are trademarks of National Starch and Chemical Corporation, Bridgewater, New Jersey for acrylic adhesives (polyacrylates) dissolved in organic solvents.

 "BIO-PSA X7-3027, X7- 4919, X7-2685, X7-3122, X7-4603, X7-4301, X7-4303, Q7-4503, Q7- 4501 and Q7-4502" are trademarks of Dow Coming Corporation, Medical Products, Midland, Michigan for silicone adhesives (polysiloxanes) dissolved in organic solvents. BIO-PSA X7-4303 is particularly suitable for use in formulations containing amine functional drugs, such as albuterol and pilocarpine, in the following examples.

 "Gelva-Multipolymer Solution (GMS) 737, 788, 1151, 1753, 1430 and 2480" are trademarks of Mosanto Company, St. Louis, Missouri for acrylic adhesives dissolved in organic solvents.

 "Vistaex LM-LS-LC" is a trademark of the manufacturer Exxon Chemical Company, Houston, Texas for a polyisobutylene polymer with a molecular weight according to Flory from 42.600 to 46.100.

 The above-mentioned polymer adhesives were supplemented or prepared as solutions, where the mass percentage of solid components was as follows and are given in table. 2.

 "360 Medical Fluid" is a trademark of Dow Corning Corporation for liquid polydimethylsiloxane. In certain parts of the invention, 360 Medical Fluid is added as an adhesive to improve the adhesive characteristics of the final product.

EXAMPLE 1
A mixture of estradiol polymers was prepared by combining 1.0 parts of estradiol, 6.0 parts of dipropylene glycol, 8.0 parts of oleic acid, 35.0 parts of toluene, 5.0 parts of polyvinylpyrrolidone (Kollidon 30) and 129.03 parts of polyacrylate adhesive (GMS 737) in an appropriate container and thoroughly mixed until then until the mixture is completely homogeneous. Then 66.67 parts of a polysiloxane adhesive (BIO-PSA Q7-4503) was added and the mixture was thoroughly mixed. In the table. 3 shows the concentration of the ingredients of the final composition on the dry residue after removal of volatile solvents.

In the following examples, the method of Example 1 was applied with the appropriate amounts of starting materials in order to obtain compositions having the following concentrations of ingredients (see table 4)
The penetration of estradiol through the human epidermis in vitro from the systems of Examples 2 and 3 is shown in Figure 3. This graph shows that the formulas of this invention release significantly more estradiol than Estraderm ^R , a commercially available estradiol preparation.

EXAMPLE 4
The estradiol / norethindrone acetate polymer mixture was prepared by combining 0.05 parts of estradiol, 3.0 parts of norethindrone acetate, 4.0 parts of dipropylene glycol, 6.0 parts of oleic acid, 10.0 parts of toluene, 10.0 parts of polyvinylpyrrolidone (Kollidon 30), 1.0 parts of butylated hydroxyanisole and 62.0 g of 7 polyacrylate in an appropriate container and thoroughly mixing until the mixture becomes completely homogeneous. Then 93.0 parts of a polysiloxane adhesive (BIO-PSA Q7-4503) were added and the mixture was thoroughly mixed. In the table. 5 shows the concentration of the ingredients of the final composition by dry weight after removal of volatile solvents.

 In the following examples, the method of example 4 was used with the appropriate amounts of starting materials to obtain compositions with the concentrations of the ingredients given in table. 6.

 The intake of estradiol through the human epidermis in vitro from the systems of examples 4 to 11 (with the amount of estradiol from 0.05% to 1.0%) is shown in Figure 4. This graph demonstrates how wide the amplitude at the end of estradiol achieved using the claims by varying the concentration of estradiol . The flow of norethindrone acetate was not affected by the concentration of estradiol and it remained constant at about 0.8 μg / h; see figure 5.

EXAMPLE 12
The estradiol / norethindrone acetate acetate polymer mixture was prepared by combining 0.2 parts of estradiol, 3.0 parts of norethindrone acetate, 4.0 parts of dipropylene glycol, 6.0 parts of oleic acid, 60.0 parts of toluene, 0.0 parts of polyvinylpyrrolidone (Kollidon 30), 1.0 parts of butylated hydroxyanisole and 64.52 parts of 737 polyacrylate in an appropriate container and thoroughly mixing until the mixture becomes completely homogeneous. Then 93.0 parts of a polysiloxane adhesive (BIO-PSA Q7-4503) were added and the mixture was thoroughly mixed. In the table. 7 shows the concentration of the ingredients of the final composition by dry weight after removal of volatile solvents.

 In the following examples, the method of example 12 was used with the appropriate amounts of starting materials in order to obtain compositions with the concentrations of the ingredients given in table. 8.

 EXAMPLE 15 (see table. 9).

 Figure 6 shows how a system with varying levels of polyvinylpyrrolidone (0-10%) has essentially the same expiration of a drug substance (estradiol or norethindrone acetate): examples 6, 12-14. However, polyvinylpyrrolidone has been found to affect the recrystallization of a drug substance in this system. Thus, crystal formation decreased with increasing concentration of polyvinylpyrrolidone; see table 10.

EXAMPLE 16
An estradiol / norethindrone acetate polymer mixture was prepared by combining 20.0 parts of isosorbide dinitrate, 4.0 parts of dipropylene glycol, 4.0 parts of oleic acid, 10.0 parts of polyvinylpyrrolidone (Kollidon 30) and 67.00 parts of polyacrylate adhesive (Duro-Tak 80-1196) in a suitable container until the mixture has become completely homogeneous. In this example, isosorbide dinitrate is added as a solution in toluene mixed with a polyacrylate adhesive. Then 53.0 parts of the polysiloxane adhesive (BIO-PSA Q7-4503) was added and the mixture was thoroughly mixed. In the table. 11 shows the concentration of the ingredients of the final composition by dry weight after removal of volatile solvents.

EXAMPLE 17
A norethindrone acetate polymer mixture was prepared by combining 3.0 parts of norethindrone acetate, 4.0 parts of dipropylene glycol, 6.0 parts of oleic acid, 60.0 parts of toluene, 10.0 parts of polyvinylpyrrolidone (Kollidon VA 64), 1.0 parts of butylated hydroxyanisole and 64.52 parts of polyacrylate adhesive in 7MS (GMS) and stirring until the mixture is completely homogeneous. Then 95.00 parts of the polysiloxane adhesive (BIO-PSA X7-4603) were added and the mixture was thoroughly mixed. In the table. 12 shows the concentration of the ingredients of the final composition by dry weight after removal of volatile solvents. Although the following options contain 2.0 to 3.0% norethindrone acetate, the preferred amplitude is from about 1 to about 12% by weight.

 In the following examples, the method of example 17 was applied with appropriate amounts of starting materials to obtain compositions with the concentrations of the ingredients given in table. thirteen.

 EXAMPLE 26 (see tab. 14).

EXAMPLE 27
The estradiol-polymer mixture was prepared by mixing 2.0 parts of estradiol, 4.0 parts of dipropylene glycol, 4.0 parts of oleic acid, 3.0 parts of lecithin and 5.0 parts of polyvinylpyrrolidone (Kollidon 17-PF) in an appropriate container and thoroughly mixed until homogeneous. In this example, estradiol was added (as a solution in toluene) with 67.0 parts of polyisobutylene (Vistanex LM-LS-LC). Then 124.0 parts of polysiloxane adhesive (BIO-PSA X7-4301) was added and the mixture was thoroughly mixed. In the table. 15 shows the concentration of the ingredients of the final composition by dry weight after removal of volatile solvents.

In the following examples, the method of example 27 was applied with appropriate amounts of starting materials to obtain compositions with the following concentrations of ingredients:
EXAMPLE 28 (see tab. 16).

 EXAMPLE 29 (see table. 17).

EXAMPLE 30
An estradiol-polymer mixture was prepared by mixing 1.6 parts of estradiol, 6.0 parts of dipropylene glycol, 8.0 parts of oleic acid, 4.8 parts of polyvinylpyrrolidone (Kollidon 30), 50.0 parts of polyacrylate adhesive (GMS 1430), 17.0 parts of A-polysiloxane adhesive (BIO-PSA XI-PS460) and 82.0 parts of polysiloxane B adhesive (BIO-PSA 07-4503) in an appropriate container and mixed well until the mixture is completely homogeneous. In the table. 18 shows the concentration of the ingredients of the final composition by dry weight after removal of volatile solvents.

 In the following examples, the method of example 30 was applied with appropriate amounts of starting materials to obtain compositions with the concentrations of the ingredients given in table. 19, 20, 21.

 EXAMPLE 31 (see table. 19).

 EXAMPLE 32 (see tab. 20).

 EXAMPLE 33 (see tab. 21).

 Although the invention is described in the form of specific examples, specialists can, without violating the scope and meaning of the claimed invention, create additional options. Accordingly, it should be understood that the drawings and description are offered to facilitate understanding of the invention and do not limit its scope.

Claims (42)

1. A pressure-sensitive adhesive composition suitable for use in transdermal drug delivery systems containing a mixture of rubber adhesive, polyacrylate, a therapeutically effective amount of one drug substance, or a mixture of two or more drug substances for percutaneous delivery and soluble polyvinylpyrrolidone, characterized in that it contains components in the following quantitative ratio, wt.% by weight of the entire composition:
Rubber Adhesive - 5 - 97
Polyacrylate - 2 - 85
moreover, the ratio of polyacrylate to rubber adhesive is from 2: 98 to 96: 4,
Medicinal substance - 0.1 - 50
Soluble polyvinylpyrrolidone - 1 - 20
moreover, the ratio of the drug substance to soluble polyvinylpyrrolidone is from 1: 10 to 10: 1, and the amount of soluble polyvinylpyrrolidone is sufficient to dissolve the entire drug substance present in an amount that would exceed its solubility in a composition containing rubber adhesive with polyacrylate, but without soluble polyvinylpyrrolidone .  2. The composition according to claim 1, characterized in that it further comprises an amplifier.  3. The composition according to claim 1, characterized in that it further comprises clay.  4. The composition according to p. 3, characterized in that the clay is a bentonite.  5. The composition according to claim 1 or 2, characterized in that it contains 5 - 94% polysiloxane as a rubber adhesive, 2 - 85% polyacrylate, 1 - 15% polyvinylpyrrolidone, 0 - 20% co-solvent, 0 - 15% amplifier and 0.3 to 30% of the drug substance based on the weight of the entire composition.  6. The composition according to claim 1 or 5, characterized in that the polyvinylpyrrolidone has a molecular weight of from 7000 to 54000.  7. The composition according to claim 6, characterized in that it contains 5 to 10% polyvinylpyrrolidone.  8. The composition according to claim 1, characterized in that the drug substance is selected from the group consisting of fluoxetine, sertraline and paroxetine.  9. The composition according to claim 1, characterized in that the drug substance includes clonidine.  10. The composition according to claim 1, characterized in that the drug substance is selected from the group consisting of bromocriptine, lysuride and pergolide.  11. The composition according to claim 1, characterized in that the drug substance is selected from the group consisting of norgestimate, norgestrel, ethinodiol diacetate and desogestrel.  12. The composition according to claim 1, characterized in that the drug substance is selected from the group consisting of ipsapiron and bushpiron.  13. A composition according to any one of claims 1, 5 or 6, characterized in that the drug substance is selected from the group consisting of enalapril, enalaprillet, fluoxetine, niflumic acid, piroxicam and sertraline.  14. The composition according to one of claims 1, 5 or 6, characterized in that the drug substance is selected from the group consisting of scopolamine, sumatriptan, physostigmine, tetrosterone, methyltestosterone, fluoxymesterone, methylphenidate, loratadine, simvastatin, pravastatin, methimazole and ethidronate. 15. The composition according to one of claims 1, 5 or 6, characterized in that the drug substance is selected from the group comprising steroids, β ₂ -adrenergic agonists and blockers, cardioactive agents, cholinergic agonists, tranquilizers, anesthetics, analgesics, antitumor agents, drugs that act on the central nervous system, vasodilators, drugs for the treatment of Parkinson's disease, antipsychotics and non-steroidal anti-inflammatory drugs.  16. The composition according to p. 15, characterized in that it contains at least two medicinal substances.  17. The composition according to p. 16, characterized in that it contains a mixture of progesterone-like substances and estrogen.  18. The composition according to p. 15, characterized in that the drug substance is selected from the group comprising conjugated estrogen hormones, esterified estrogens, estropipat, 17β-estradiol, equiline, mestranol, estrone, estriol, ethinyl estradiol, diethylstilbestrol, progesterone, 19-norprog norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethinodiol diacetate, norethinodrel, 17α-hydroxyprogesterone, dydrogesterone, dimethisterone, ethinyl estrenol, norg Demegestone, Promegestone Megestrol Acetate, Metaproterenol, Terbutaline, Albuterol, Carbuterol, Rimeterol, Fenoterol, Soterenol, Nidroglycerin, Isosorbite Dinitrate, Isosorbite Mononitrate, Quinidine Sulfate, Procainamide, Bendrofluazinazolidazidiazolidazide, , captopril, clonidine, prazosin, choline, acetylcholine, methacholine, carbazole, betanechol, pilocarpine, muscarin, arecoline, alprazolam, chlordiazepoxide, chlorazeptate, galazepam, oxazepam, prazepam, clonazepam, fluz iazolam, lorazepam, diazepam, thiopropazate, chlorpromazine, triflupromazine, mesoridazine, piperazetazin, thioridazine, acetophenazine, flufenazine, perphenazine, trifluoperazin, chlorprotinquinidinocinidinodinocinidin-dicinodinocinone, dopamine, lidoperidinodinocinone dicinodinocinone bupivacaine, ethidocaine, prilocaine, benzocaine, fentanyl, buprenorphine, codeine, nicotine, papaverine, butorphanol, hydromorphone, oxymorphone, mecamylamine, diclofenac, phenoprofen, flurbiprofen, ibuprofen, ketoprofenamine-pirroxen, naproxen, naproxen, pirroxen, paproxen, naproxen Wai acid, deprenyl, selegiline, buspirone and lisuride.  19. The composition according to 17, characterized in that it contains 70% polysiloxane, 5% polyacrylate, 10% polyvinylpyrrolidone, 3% norethindrone acetate and 0.7% estradiol.  20. The composition according to p. 18, characterized in that it contains 25% polysiloxane, 45% polyacrylate, 10% polyvinylpyrrolidone, 7% alprazolam and 10% enhancer.  21. The composition according to p. 18, characterized in that it contains 60% polysiloxane, 20 - 25% polyacrylate, 10% polyvinylpyrrolidone and 4% norethindrone acetate.  22. The composition according to p. 18, characterized in that it contains 10% polysiloxane, 60% polyacrylate, 5% polyvinylpyrrolidone and 10% albuterol.  23. The composition according to p. 18, characterized in that it contains 5% polysiloxane, 70% polyacrylate, approximately 5% polyvinylpyrrolidone and 10% δ-aminolevulinic acid.  24. The composition according to p. 18, characterized in that it contains 50% polysiloxane, 20% polyacrylate, 10% polyvinylpyrrolidone and 5% fentanyl.  25. The composition according to p. 18, characterized in that it contains 65% polysiloxane, 15% polyacrylate, 5% polyvinylpyrrolidone and 15% nicotine.  26. The composition according to p. 18, characterized in that it contains 65% polysiloxane, 15% polyacrylate, 15% polyvinylpyrrolidone and 15% selegiline.  27. The composition according to p. 18, characterized in that it contains 5% polysiloxane, 60% polyacrylate, 5% polyvinylpyrrolidone and 30% ketoprofen.  28. The composition according to p. 18, characterized in that it contains 60% polysiloxane, 20% polyacrylate, 5% polyvinylpyrrolidone and 2% 17β-estradiol.  29. The composition according to claim 1, characterized in that it contains about 5 to 90% silicone adhesive as a rubber component, about 5 to 85% polyacrylate, about 1 to 20% polyvinylpyrrolidone, and about 1 to 10% clonidine.  30, the composition according to claim 1, characterized in that it contains about 5 to 90% silicone adhesive as a rubber component, about 5 to 70% polyacrylate, about 1 to 15% polyvinylpyrrolidone, and about 5 to 30% methylphenidate.  31. The composition according to claim 1, characterized in that it contains about 5 to 70% silicone adhesive as a rubber component, about 5 to 70% polyacrylate, about 2 to 20% polyvinylpyrrolidone, and about 5 to 30% methylphenidate.  32. The composition according to claim 1, characterized in that it contains about 5 to 75% silicone adhesive as a rubber component, about 10 to 50% polyacrylate, about 5 to 20% polyvinylpyrrolidone, and about 0.5 to 20% terbinafine.  33. The composition according to claim 5, characterized in that it contains about 20 to 75% silicone adhesive as a rubber component, about 5 to 50% polyacrylate, about 5 to 20% polyvinylpyrrolidone, about 5 to 8% dipropylene glycol, about 2 to 6 % oleyl alcohol and approximately 1 to 20% clonazepam.  34. The composition according to claim 5, characterized in that it contains approximately 40 to 85% silicone adhesive as a rubber component, approximately 2.5 to 20% polyacrylate, approximately 5 to 15% polyvinylpyrrolidone, approximately 2 to 10% dipropylene glycol, approximately 2 - 10% oleyl alcohol and approximately 0.5 to 5.0% fludrocortisone acetate.  35. The composition according to claim 5, characterized in that it contains approximately 40 to 70% silicone adhesive as a rubber component, approximately 5 to 30% polyacrylate, approximately 2 to 15% polyvinylpyrrolidone, approximately 0 to 10% dipropylene glycol, approximately 0 to 10 % oleyl alcohol and approximately 1 to 10% estradiol.  36. The composition according to claim 5, characterized in that it contains about 5 to 75% silicone adhesive as a rubber component, about 5 to 75% polyacrylate, about 2 to 25% polyvinylpyrrolidone, about 2 to 25% oleic acid and about 5 to 20% ketoprofen. 37. The composition according to claim 1, characterized in that the polyvinylpyrrolidone has a glass transition temperature of from about 70 to 0 ^o C.  38. The composition according to p. 1, characterized in that as a rubber adhesive it contains rubber. 39. A pressure sensitive adhesive composition suitable for use in transdermal drug delivery systems containing a mixture of rubber adhesive, a therapeutically effective amount of one drug substance, or a mixture of two or more percutaneous drug substances and soluble polyvinylpyrrolidone, characterized in that it contains As a rubber component, the silicone adhesive and components have the following quantitative ratio, wt.% by weight of the total composition:
Silicone adhesive - 5 - 90
Polyvinylpyrrolidone - 1 - 20
Dipropylene glycol - 1 - 25
Oleic acid - 0.5 - 10
Alprazolam - 1 - 10
40. A method of preparing a pressure-sensitive adhesive composition for percutaneous delivery of a medicinal substance by mixing components, characterized in that the rubber adhesive is mixed in an amount of 5 to 97 wt. %, polyacrylate in an amount of 2 to 85 wt.%, and the ratio of polyacrylate to rubber adhesive is from 2: 98 to 96: 4, a therapeutically effective amount of one drug substance or a mixture of two or more drugs for percutaneous delivery, while the drug substance is 0.1 to 50 wt.% By weight of the entire composition, and soluble polyvinylpyrrolidone in an amount of 1 to 20 wt.%, And the ratio of drug to soluble polyvinylpyrrolidone is from 1: 10 to 10: 1, while using such an amount of edible polyvinylpyrrolidone, which is sufficient to dissolve the entire drug substance present in an amount that would exceed its solubility in a composition containing rubber with polyacrylate, but without soluble polyvinylpyrrolidone.  41. The method of percutaneous delivery of a medicinal substance by applying to the skin, characterized in that the composition is used for percutaneous delivery of a medicinal substance, while a mixture consisting of rubber adhesive in an amount of 5 to 97 wt.% Polyacrylate in an amount of 2 to 85 wt. %, and the ratio of polyacrylate to rubber adhesive is from 2 - 98 to 96: 4 therapeutically effective amount of one drug substance or a mixture of two or more drugs for percutaneous delivery, and drug e substance is 0.1 to 50 wt.% by weight of the entire composition, and soluble polyvinylpyrrolidone in an amount of 1 to 20 wt. %, and the ratio of drug to soluble polyvinylpyrrolidone is from 1: 10 to 10: 1, while using such an amount of soluble polyvinylpyrrolidone that is sufficient to dissolve the entire drug substance present in an amount that would exceed its solubility in a composition containing rubber with polyacrylate, but without soluble polyvinylpyrrolidone.  42. A device for percutaneous drug delivery, made in the form of a sheet of a certain geometric shape, characterized in that said sheet contains a composition according to any one of claims 1 to 39.  43. The device according to § 42, characterized in that it is made in the form of an individual dosage unit.  44. The device according to § 42, characterized in that it further includes a supporting material superimposed on one of the surfaces of the composition, and a release pad applied to the surface of the composition from the side opposite to the supporting material, the supporting material being practically impermeable to the drug substance.

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