Systemic administration of steroid hormones can generally be carried out by oral means with the aid of suitable dosage forms. However, the bioavailability of oral administration is often reduced because the active ingredient is metabolized in the liver before entering the systemic blood circulation (the so-called "first pass effect"). In addition, there are also special requirements in general for dosage forms for oral administration, since the steroid hormone should be released as uniformly as possible over a prolonged period of time. In order to avoid oral administration of steroid hormones, certain steroid derivatives have been developed which are particularly suitable for injection. In this connection, reference may be made, for example, to patent publications WO 99/67270 and WO 99/67271. Further possibilities include the use of suitable implants for the purpose of sustained administration of steroid hormones and avoiding first-pass effects. Implants for the administration of androgens and their derivatives are disclosed, for example, in the following publications: EP-A970704, WO 97/30656, WO 99/13883, WO 00/28967, US 5,733,565, K.Sundaram et al, Annulas of Medicine, 1993, 25(2), 199; r.a. anderson et al, j.clin.endocrins. & meta.1999, 84(10)3556 and j.suvisaari et al, containment, 1999, 60(5), 299. However, these implants have the following disadvantages: they must be implanted into the patient by surgical intervention by a physician and must be removed again. Such surgical interventions always present a certain risk of infection. In addition, aversion to mood is also prevalent with these administration methods, particularly if other systemic administration methods are available.
In order to avoid the pharmacological disadvantages of oral administration, on the one hand, and the invasive, purely mechanical penetration of the skin by means of medical devices (hypodermic needles, scalpels), on the other hand, methods have been developed by which auxiliary active ingredients are continuously diffused through the skin, and thus enter the systemic blood circulation, over a specific time interval.
The skin represents the largest organ of the human body and has a length of about 20000cm2And receives about one third of the total blood supply of the organism (see y. w. chien, Logics of transgenic Controlled Drug administration. Drug dev. ind. pharm.1983, 9, 497). It mainly plays a protective role: it prevents the invasion of foreign substances and microorganisms and the loss of essential endogenous substances such as water and electrolytes. However, the skin does not form any completely impermeable barrier to foreign substances, so that the active ingredient can be absorbed transdermally by the organism by different methods. Transdermal penetration is primarily affected by the site of administration and the thickness of the stratum corneum, which is the primary barrier to foreign substances. Can be hydrogenatedThe pine of (2) as a model substance absorbed on the surface of the hand, has a reduced absorption degree in the ball of the foot, while the absorption rate through the skin of the posterior auricular region and scrotum is increased by 40 times as compared with the lower arm (see H.Asche, Konzept und Aufbautransmermaler therticische System [ concept and design of transdermal therapeutic System ]]Schweiz [ Switzerland].Rundsch.Med.Prax.，1985，74，3)。
The active ingredient is therefore capable of acting transdermally, but it must diffuse through the epidermis of the skin and leave the blood circulation in sufficient quantities. In this case, the epidermis serves an enhanced barrier function, which is attributed, on the one hand, to the fact that the relevant active ingredient has to pass through the hydrophilic layer and the lipophilic layer in turn and then the hydrophilic layer again, but, on the other hand, the low water content in the stratum corneum also hinders the diffusion of the active ingredient.
The penetration of the stratum corneum, which in most cases is necessary for systemic action as well as for the action of the topically administered active ingredient, takes place both in the intact skin by epicutaneous (in an intracellular or intercellular manner) and by pore (in a glandular or follicular manner) (see k. karzel et al, mecanismen transkulture resource-Pharmakologische und biochemische Aspekte [ mechanism-pharmacological and biochemical aspects of percutaneous absorption ]. arzneim.
Conceptually, penetration of the active ingredient is different from penetration of the active ingredient: penetration refers to the entry of the active ingredient into the skin, whereas penetration refers to the entry of the active ingredient through the skin into the blood stream. For systemic administration of the active ingredient through the blood circulation, osmosis is therefore necessary.
For transdermal administration, patches containing active ingredients have been developed, with the aid of which the active ingredient is able to enter the systemic blood circulation. By diffusion, the active ingredient enters the tissue under the skin and is released into the blood vessels so that it can exert its systemic effect.
However, patches containing active ingredients also have disadvantages: they are applied significantly and visibly to the skin during the period of administration of the active ingredient. In addition, the cover film of the patch also causes a blocking condition. The swelling of the skin caused in this respect may lead to a change in the diffusion profile of the active ingredient. In most types of patches the active ingredient is incompletely released into the skin. The removal of the patch couple causes pain to the patient because the hairs adhered to the adhesive surface of the patch are pulled up together with the roots when the patch is removed. In addition, transdermal patches also have disadvantages: contact adhesives for patients often cause allergies and skin irritation. In addition, repeated application and removal of patches containing active ingredients on the same skin site over time may cause the skin to become red and irritated.
The main drawback of patches containing active ingredients also lies in the fact that their contact surface area on the skin is limited. However, since relatively high plasma concentrations are necessary for many active ingredients to be effective, the latter can only be achieved by administering the active ingredient over a large area of the skin; patches containing active ingredients quickly reached their limits. In particular, when a particular active ingredient exhibits undesirable penetration properties, it can only be compensated by a correspondingly large area of skin contact. In general, sizes in excess of 50cm can be assumed2The patches are only conditionally suitable for use. Because of the limited surface area of the system in patches containing active ingredients, only high performance active ingredients can be used, with active plasma levels in the ng/ml range. For further details, reference may be made, for example, to K.H.Bauer et al, Lehrbuch der pharma zeutischen technology [ textbook of pharmaceutical technology]Wissenschaftliche Verlagsgesellschaftmbh Stuttgart, 1999, 6 th edition.
As an alternative to patches containing active ingredients, gels containing active ingredients have been developed which are applied to the skin and dry on the skin surface in a short time. On the one hand, drying is carried out by evaporation of the solvent, depending on the type of solvent used, but it is also possible that at least a part of the solvent in the gel selectively penetrates directly from the gel into the skin after application of the gel.
Active ingredient-containing gels comprising a polymer matrix differ in that after the gel has dried on the skin, a film consisting of the polymer matrix remains in which the active ingredient and other non-volatile components of the gel are embedded. In the dry state, the polymer matrix controls the diffusion of the active ingredient through the skin and thus makes possible a controlled release to the organism over an extended time interval. The controlled, time-monitored and continuous release of such active ingredients into the blood circulation is particularly desirable for hormones and hormone derivatives, making these active ingredient-containing gels particularly suitable for administering these active ingredients. By bypassing the gastrointestinal tract in the case of transdermal administration, the unfavorable first-pass metabolism is also avoided.
The dosage of the active ingredient can be readily controlled by varying the amount of gel and the surface area to which the gel is applied. Active ingredients with a short biological half-life can in this way prolong the duration of action. In the case of active ingredients with a narrow therapeutic range of action, the side effects are reduced and patient compliance is often better.
The active ingredient-containing gel represents a pure single-phase system. These are semi-solid systems in which a liquid is solidified by a gel matrix former (former). The difference between hydrogel and oleogel depends on whether the liquid forming the gel is water or oil. Hydrogels consist of an aqueous solution of active ingredients substantially solidified in a gel by macromolecular hydrophilic substances. As the gel skeleton former, an organic polymer may be used, and inorganic substances such as bentonite and highly dispersed silica may also be used. Oleogels are oils hardened by a gel matrix former.
Hydrogels differ from ointments in that ointments are formulations that do not contain any aqueous phase. Hydrogels differ from creams in that they do not contain any lipid phase. For further details regarding the definition of hydrogels for other semisolid dosage forms, reference may be made, for example, to K.H.Bauer et al, Lehrbuch der Pharmazeutischen technology, Wissenschaftliche VerlagsgesellschifmbH Stuttgart, 1999, 6 th edition.
Compared with patches containing active ingredients, gels have the advantages: after drying on the skin, only the film formed by the gel component remains, which does not evaporate or penetrate the skin immediately. By drying, a very close contact is created between the outer skin layer and the gel residue and via the liquid gel to the pores and very small protrusions on the skin, which is difficult to achieve with patches containing active ingredients. Stretching of the skin caused by patient movement is not problematic because the gel residue on the full contact surface is elastic and sticky. However, in the case of patches containing active ingredients, this skin stretching often results in undesirable lateral movement of the patch and the outer skin layer contacting surface. The patient does not feel that the active ingredient is absorbed and his mechanical movements are never impaired. The gels can also be applied to the skin over large areas, so that active ingredients which are not suitable for use in patches containing active ingredients can also be administered transdermally. This is a major advantage of gels over patches. After the release of the active ingredient is complete, the film residue remaining on the skin can be washed off with water. Skin irritation is generally less than with transdermal patches, although many hydrogels create problems, particularly because these gels contain a considerable amount of ethanol for improved permeability (about 70% is currently used in hydrogels). High ethanol content is necessary to ensure good permeability, but results in skin irritation.
In addition to compatibility and good permeability, there are special physical requirements for gels containing active ingredients. They must be of a consistency such that they can be easily applied to the skin and have sufficient gel strength to maintain a gel matrix, while volatile components evaporate or enter the skin. The amount of gel per dosage unit that must be applied to the skin is typically 1-5 ml. In the prior art, polyacrylic acid based gels are known to undergo immediate partial liquefaction upon contact with skin. The reason for this is insufficient electrolyte tolerance in these gel systems. This action causes the product to run off or drip off rapidly due to the salts in the water-fat (hydrophilic) membrane on the skin. Particular problems arise if the skin surface contains a high concentration of salt and is wet from perspiration. The inherently problematic administration properties are particularly disadvantageous against the background that in the administration of high-potency steroid hormones, a specific use must be selected according to its purpose. In addition to efficacy, safety (contamination risk) is also important in this regard.
The use of cellulose derivatives as hydrogel formers, which are also known in the prior art, has the disadvantage of a lack of sensory properties and a greater amount of gel former remaining on the skin than polyacrylic acid-based gels. The concentration required to form the gel matrix is 2-3 times higher than that of polyacrylate and produces a so-called "eraser effect" (waving) after application to the skin. These residues are also undesirable for suitable applications of hydrogels for transdermal administration of active ingredients.
US 6,010,716 discloses a pharmaceutical composition for transdermal administration comprising a polymer matrix which dries to form an elastic membrane. The polymer matrix is selected from cellulose polymers or cellulose copolymers or vinylpyrrolidone/vinyl acetate copolymers.
Active ingredients suitable for transdermal therapy by means of hydrogels need to meet a variety of physical and chemical requirements. The molecular weight should be less than 1000gmol-1. The material should be fat-soluble and also exhibit some solubility in aqueous media. Steroids are particularly advantageous from a pharmacological point of view as active ingredients which, due to their physical and chemical properties, are generally suitable for transdermal administration. In this case, they are, in particular, steroids (androgens) having an androgenic action.
In many cases, the addition of a permeation enhancer is necessary in order to achieve a plasma concentration sufficient to function. For this purpose, a number of Penetration Enhancers have been tested, and reference is made, for example, to E.W. Smith et al, Percutaneous pennetration Enhanters, CRC Press, 1995.
Various compositions for transdermal administration of steroid hormones, and certain androgens (particularly testosterone), are known in the art and are disclosed, for example, in WO 96/08255, WO 97/03698, WO97/43989, WO 98/37871, WO 99/13812, WO 00/71133, WO 02/066018 and a.w.meikle et al, j.clin.endocrin. & metab.1992, 74, 623. A common feature of the transdermally administered compositions described in the above publications is that the steroid hormone and at least one penetration enhancer are administered in combination, only to ensure complete penetration of the active ingredient through the skin. As examples of known penetration enhancers for testosterone that are described, mention may be made of fatty acids, fatty acid esters of simple alcohols, fatty acid monoesters of polyvalent alcohols, fatty alcohols and terpenes.
There is a substantial difference between patches containing active ingredients and gels containing active ingredients, and it cannot be concluded that a penetration enhancer suitable for patches containing active ingredients is also suitable for gels containing active ingredients. This is therefore related to the fact that: in addition, active ingredient-containing gels dry after application to the skin, whereas in patches containing active ingredients, a solvent-impermeable backing layer generally prevents drying.
Patches containing active ingredients sometimes contain a gelled core inside them, in which the active ingredient and some adjuvants are embedded. In this connection, reference is made, for example, to patent publication EP-A208395. These gelled cores of patches containing active ingredients are not comparable to gels containing active ingredients, but in this respect they are applied to the skin for the reasons of the above-mentioned properties.
Currently, only those active ingredient-containing gels containing large amounts of ethanol (70% by weight and more) are used in practice, since it is believed that the necessary permeability cannot be achieved with smaller amounts of ethanol. Gels with lower ethanol content have been described but have not been used in practice due to their low permeability. Patients suffer from problems associated with high ethanol content, such as reddening, swelling, and permanent damage and tearing of the skin. In the prior art, one starts from the fact that: lower alkyl alcohols, such as ethanol, increase the mobility of fluids in the stratum corneum or draw lipids from the stratum corneum and thus enhance the penetration of the active ingredient through the skin.
EP-A811381 discloses a gel comprising an estrogen and/or a progestin, a linear primary aliphatic alcohol having from 11 to 19 carbon atoms, a monoalkyl ether of diethylene glycol, an alcohol having from 2 to 4 carbon atoms, ethylene glycol, water, a polymer or copolymer consisting of acrylic acid and a tertiary amine. However, these gels have the disadvantage that the permeability, in particular of the active ingredients, is not entirely satisfactory. The permeability of these formulations can be improved by reduced water content and increased alcohol content, but this does not necessarily result in reduced compatibility.
There is also a problem when using transdermal gels, which is due to the fact that: pharmaceutical compositions in the form of hydrogels often run off after application to the skin, so that the gel matrix necessary for controlled release of the active ingredient is destroyed and possible dripping of the product both reduces patient compliance and increases the likelihood of undue regional or object contamination. These problems occur under normal skin conditions. Hydrogels occur more readily if they are applied to "sweating" skin, and thus with known and commercially available gels, it is desirable that the skin be substantially clean prior to application of the gel. However, if the hydrogel is applied to skin that is not completely free of perspiration, it should preferably remain intact as well.
Treatment with transdermal gels is often a long-term treatment, particularly in the case of steroid administration. The success of these treatments, in addition to the effective administration of the active ingredient (high permeability), the compliance of the patient is also decisive. Complete success of the treatment is also problematic if the patient discontinues the treatment or does not perform the treatment regularly, either because the gel administration is considered too expensive (for example because the skin must be washed in a particular way or the clothes may be contaminated) or because intolerable occurs.
For treatment with transdermal gels, in addition to a high permeability, a permeability which is as linear as possible is advantageous for keeping the level of active ingredient in the blood as stable as possible over a prolonged period of time.
There is thus a need for pharmaceutical compositions suitable for transdermal administration of active ingredients and which exhibit advantages compared to the compositions of the prior art, in particular hydrogels for transdermal administration of active ingredients with very good penetration properties and excellent compatibility (so-called "transdermal gels").
According to the present invention, a hydrogel can be obtained that combines excellent compatibility and outstanding permeability, as defined in the claims. In a preferred embodiment, the hydrogel can also be applied to skin having a significant film of water and fat without causing the hydrogel to run off or drip off quickly.
It has surprisingly been found that by means of a catalyst comprising a carboxylic diester, C2-C4The pharmaceutical composition in the form of a hydrogel of an alkyl alcohol, an active ingredient and a polymer matrix, skin irritation and other side effects can be effectively reduced. At the same time, these compositions give very good results with respect to the penetration characteristics of the different active ingredients.
Pharmaceutical compositions containing carboxylic diesters, in particular propylene carbonate, are known from the prior art.
WO 98/10742 discloses a single phase anhydrous formulation for topical use comprising propylene carbonate, at least one alcohol, ethylene glycol, glycerol and a therapeutically or cosmetically effective ingredient. The composition is completely anhydrous and the active ingredient penetrates the skin rapidly. But is impermeable.
WO 00/41702 discloses an external preparation comprising a 21-alkoxy steroid, propylene carbonate and polyoxyethylene/hardened castor oil. The composition is suitable for topical administration of steroids for the purpose of treating skin disorders, such as chronic or acute eczema, atopic dermatitis, contact dermatitis and psoriasis.
JP 59070612 discloses a gelling ointment base comprising a carboxyvinyl polymer, propylene carbonate, propylene glycol, polyethylene glycol and ethanol. The ointment base may contain isopropyl adipate to enhance penetration of the active ingredient into the skin. Here too, no penetration takes place.
JP 9194396 discloses a composition comprising an antihistamine, an aminoacrylate-based polymer, an acid-soluble polymer and a short-chain ester or ether having a total number of carbon atoms of 4 to 20, such as isopropyl myristate, triacetin-ethylene glycol-mono-n-butyl ether or propylene carbonate. The composition can be used as a matrix for a patch.
US 3924004 discloses a composition for topical use comprising a saturated fatty alcohol having 16 to 24 carbon atoms, propylene carbonate, ethylene glycol, a surfactant, a plasticizer and water. The composition can be used for topical administration of all types of active ingredients, in particular anti-inflammatory corticosteroids. If the composition is free of water, the stability of the composition is improved.
EP-A319555 discloses a transdermal pharmaceutical preparation which has a therapeutic effect and can be applied to the skin in the form of a spray. The formulation comprises a liquid polymer matrix capable of hardening into a flexible film, an active ingredient, a solvent in which the active ingredient is at least partially soluble to control the release of the active ingredient, and a solvent for the matrix that is volatile on the skin. As solvents for controlling the release of the active ingredient, sorbitan polyethylene glycol laurate and/or paraffin and/or medium chain fatty acid diglycerides and/or triglycerides and/or propylene carbonate are disclosed. The preparation is anhydrous.
None of these publications discloses compositions comprising a carboxylic acid diester, C2-C4A pharmaceutical composition in the form of a hydrogel of an alkyl alcohol, an active ingredient and a polymer matrix. Nor does the prior art describe a composition comprising a polymer matrix and C2-C4Use of a carboxylic acid diester (e.g. propylene carbonate) as a penetration enhancer for an active ingredient in a pharmaceutical composition in the form of a hydrogel of an alkyl alcohol.
It has been surprisingly found that when a carboxylic acid diester is used as a penetration enhancer for the active ingredient, C in the composition2-C4The alkyl alcohol content can be kept relatively low without in this case negatively affecting the permeation properties. Particular attention has been given to carboxylic acid diesters in compositions because, after the pharmaceutical composition is administered, water and C2-C4The alkyl alcohol is largely volatilized and enters the skin, while the carboxylic acid diester of lower volatility remains in the polymer matrix with the active ingredient and therefore critically affects the pharmacokinetic properties of the active ingredient.
It has been found that carboxylic diesters have particularly good compatibility and chemical stability, do not generally produce any allergic reactions and do not react with other ingredients contained in the pharmaceutical composition, in particular water and C contained in the hydrogel2-C4The alkyl alcohols interact well. The carboxylic acid diester, water and C in the composition can be selected2-C4Alkyl alcohol in such a proportion by weight that C2-C4The amount of alkyl alcohol and the side effects caused by the latter are minimized, but nevertheless a very good penetration efficacy of the active ingredient is achieved.
The carboxylic acid diesters of the invention are chiral compounds, the latter therefore preferably being in the form of a racemate. However, it is also possible for the compositions according to the invention to contain carboxylic diesters in enantiomerically or diastereomerically enriched form(s).
The molecular weight of the carboxylic acid diester is preferably less than 750gmol-1More preferably less than 500gmol-1And especially less than 250gmol-1. The carboxylic acid diesters preferably contain not more than 12 carbon atoms, but preferably not more than 10, and preferably not more than 7, in particular not more than 5 carbon atoms.
In a preferred embodiment of the invention, the carboxylic acid diester is a compound of the general formula (I)
Wherein R is1And R2Independently of one another is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C4-C6Cycloalkyl radical, C1-C6Heterocycloalkyl, phenyl, C1-C6Heteroaryl, phenyl-C1-C4Alkyl or C2-C10Heteroarylalkyl, wherein the alkyl-, alkenyl-and alkynyl groups may optionally be interrupted in each case up to three times by oxygen and/or sulfur atoms, or R1And R2Independently of one another have one of the above meanings and are connected to one another by a C-C bond. If R is1And R2Linked to each other by a C-C bond, the compound of formula (I) is a cyclic carboxylic diester. In the heterocyclic compounds, C1-C6Heterocycloalkyl-, C1-C6Heteroaryl-and C2-C10Heteroarylalkyl groups may contain 1 to 4 heteroatoms independently selected from N, O and S.
Preferred R1And R2Groups (wherein the alkyl group is optionally interrupted up to three times by oxygen and/or sulfur atoms) are as follows:
C1-C6alkyl groups: -CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、
-CH(CH3)CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2OCH3、
-CH2SCH3、-CH2CH2OCH3、-CH2CH2SCH3、-CH2CH2OCH2CH3、-CH2CH2SCH2CH3and-CH2CH2OCH2CH2OCH2CH3；
C2-C6Alkenyl: -CH ═ CH2、-CH2CH＝CH2、-CH2CH＝CHCH3、-CH(CH3)CH＝CH2and-CH ═ C (CH)3)2；
C2-C6Alkynyl: -C ≡ CH, -CH2C ≡ CH and-CH2C≡CCH3；
C4-C6Cycloalkyl groups: -cyclopentyl and-cyclohexyl;
C1-C6heterocycloalkyl group: -piperidinyl, -morpholinyl, -tetrahydropyranyl and furanyl;
C1-C6heteroaryl group: -pyridyl, -pyrrolyl and-imidazolyl;
phenyl-C1-C4Alkyl groups: -CH2-phenyl, -CH2CH2-phenyl, -CH2CH2O-phenyl, -CH2CH2OCH2-phenyl and-CH2CH2OCH2CH2O-phenyl;
C2-C10heteroarylalkyl group: -CH2-pyridyl, -CH2CH2-pyridyl, -CH2CH2OCH2-a pyridyl group,
-CH2CH2-imidazolyl, -CH2CH2O-imidazolyl and-CH2CH2OCH2-an imidazolyl group.
As preferred R1And R2Groups, which are linked to each other by a C — C bond, the following divalent groups may be mentioned:
-CH2CH2-、-CH＝CH-、-CH(CH3)CH2-、-CH(OCH3)CH2-、-CH(OCH2CH3)CH2-、-CH(CH3)CH(CH3)-、-CH(OCH3)CH(OCH3)-、-CH2CH2CH2-、CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH(CH3)CH2CH(CH3) -and-CH2CH2OCH2CH2-。
As penetration enhancers, the carboxylic acid diester is particularly preferably a compound of the general formula (II):
wherein the index m is a number from 1 to 3, and R3Is hydrogen or C1-C4An alkyl group.
According to the invention, wherein the index m is 1 and R3The carboxylic diesters of the formula (II) which are methyl (propylene carbonate) or hydrogen (ethylene carbonate) are particularly preferred.
Propylene carbonate [ (+ -) -4-methyl-1, 3-dioxolane-2-one]Has a molecular weight of 102gmol-1And a boiling point of 242 ℃. It has two enantiomeric forms. In general, the compositions of the invention may comprise propylene carbonate in the form of the pure R-enantiomer or the S-enantiomer or one of the two enantiomers in enriched form. According to the present invention, it is preferred that the isopropenyl carbonate comprised in the composition is a racemate.
The proportion by weight of the carboxylic acid diester relative to the pharmaceutical composition is preferably 1.0 to 40.0% by weight, more preferably 2.5 to 30.0% by weight, even more preferably 5.0 to 20.0% by weight, in particular 7.5 to 12.5% by weight.
Carboxylic acid diesters are known in the prior art. They can be obtained, for example, by reacting alcohols with phosgene or phosgene derivatives. Propylene carbonate can be obtained technically, for example, by reacting 1, 2-propanediol with phosgene. Many carboxylic acid diesters are commercially available.
According to the invention, the composition preferably comprises C selected from ethanol, n-propanol and isopropanol2-C4An alkyl alcohol. Ethanol is particularly preferred.
C2-C4The proportion by weight of alkyl alcohol in the pharmaceutical composition is preferably from 25.0 to 70.0% by weight, more preferably from 30.0 to 65.0% by weight, even more preferably from 30.0 to 60.0% by weight and in particular from 40.0 to 60.0% by weight.
In a preferred embodiment, the carboxylic acid diester is reacted with C2-C4The relative ratio by weight of the alkyl alcohol is 0.01 to 1.50, preferably 0.08 to 0.80, in particular 0.10 to 0.30.
In a particularly preferred embodiment, the composition of the invention comprises a combination of ethanol and ethylene carbonate or propylene carbonate, wherein the combination of ethanol and propylene carbonate is preferred.
The compositions of the present invention are generally suitable for transdermal administration of a variety of active ingredients; the composition preferably comprises a steroid as an active ingredient.
In a preferred embodiment, the composition of the invention comprises as active ingredient a compound of formula (III)
Wherein
R4Is hydrogen, fluorine, chlorine, C1-C3Alkyl or optionally acetylated hydroxy group, R5、R6、R7、R8、R9、R10And R11Independently of one another, hydrogen or C1-C3Alkyl, the dotted lines are independently of each other optional bonds, and
a and B are each independently of the other a carbonyl group or a group
Wherein X is a hydroxyl group or a carboxylic acid ester thereof having 1 to 8 carbon atoms, and Y is hydrogen or C1-C3An alkyl group. According to the invention, wherein R7、R8And R9Compounds of the formula (III) which are hydrogen are preferred. Compounds of the general formula (III) are known in the prior art. Reference may be made, for example, to the publications DE 1182229, US 3,341,557, US 4,000,273, WO 99/26962, WO 02/48169, Hill et al, Dictionary of Steroids, Chapman and Hall, 1991, Fieser&Fieser, Steroide [ steroids ]]VCH Weinheim, 1961, J.F. Griffin et al, Atlas of Steroid Structure, Plenum Pub Corp, 1984 and G.W.A. Milne, Ashgate handbook of Endocrine Agents and Steroids, Ashgate publishing company, 2000.
In a particularly preferred embodiment, the compositions of the invention comprise, as active ingredient, a compound of formula (IV)
Wherein X is a hydroxyl group or a carboxylic acid ester having 1 to 4 carbon atoms, R4Is hydrogen, fluorine or a hydroxy group, R5And R6Independently of each other, hydrogen, methyl or ethyl, and the dotted line is an optional bond. The compounds of formula (IV) are 19-nor-androgen derivatives, i.e. the methyl group normally contained at the 19-position of the carbon atom is replaced by hydrogen. These steroids are often distinguished by specific pharmacological effects.
The compounds of the general formula (III) or (IV) can be present in pure form or as a mixture of several stereoisomers. The compounds of the formula (III) or (IV) are preferably present in the form of substantially pure stereoisomers, i.e. ee or de values of preferably above 90%, more preferably above 95% and in particular above 99%.
According to the invention, it is particularly preferred if the composition comprises, as active ingredient, a compound of the formula (V)
Wherein R is4Is fluorine or hydrogen and X is a hydroxyl group or an acetate thereof. X is particularly preferably a hydroxyl group.
If R is4Is hydrogen and X is a hydroxyl group, then the compound is 7 alpha-methyl-19-nortestosterone (MENT). If R is4Is hydrogen and the X group of the acetate is a hydroxyl group, then the compound is the corresponding acetate (MENTAc). If R is4Is fluorine and X is a hydroxyl group, then the compound is 7 alpha-methyl-11 beta-fluoro-19-nortestosterone (eF-MENT). If R is4Is fluorine and the X group of the acetate is a hydroxyl group, the compound is the corresponding acetate (eF-MENTAc).
Such compounds are known in the art; reference may be made to Sundaram et al, Annals in medicine, 1993, 25, 199 and WO 2002/59139A 1.
The proportion by weight of the compounds of the general formula (III), (IV) or (V) in the pharmaceutical composition is preferably from 0.001 to 10.0% by weight, more preferably from 0.01 to 5.0% by weight, even more preferably from 0.1 to 2.5% by weight and in particular from 0.5 to 1.0% by weight.
The relative weight ratio of the compound of the formula (III), (IV) or (V) to the carboxylic diester is preferably from 0.0001 to 10, more preferably from 0.005 to 1, and in particular from 0.05 to 0.1.
In a particularly preferred embodiment of the invention, the pharmaceutical composition comprises as active ingredient a compound of the general formula (V) as C2-C4Ethanol as the alkyl alcohol and ethylene carbonate or propylene carbonate as the carboxylic acid diester, wherein a combination of eF-MENT with ethanol and propylene carbonate is particularly preferred.
In a preferred embodiment, the composition of the invention comprises as active ingredient a combination of two or more compounds of formula (III), (IV) or (V).
It is also possible that the composition of the invention comprises as active ingredient one or more active ingredients other than a compound of formula (III), (IV) or (V). As examples of such active ingredients, mention may be made of androgens, antiandrogens, 5 α -reductase inhibitors, estrogen receptor modulators, estrogens, antiestrogens, progestogens, antiprogestins, utero-active substances, m-cholinergic receptor antagonists, prostaglandins or prostaglandin derivatives and/or nicotine.
In a preferred embodiment, the composition of the invention comprises a combination consisting of one or more active ingredients of general formula (III), (IV) or (V) with one or more active ingredients other than a compound of formula (III), (IV) or (V). As examples of active ingredients other than compounds of formula (III), (IV) or (V) there may be mentioned androgens, antiandrogens, 5 α -reductase inhibitors, estrogen receptor modulators, estrogens, antiestrogens, progestogens, antiprogestogens, utero-active substances, m-cholinergic receptor antagonists, prostaglandins or prostaglandin derivatives and/or nicotine.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more androgens. By way of example, MENT, MENTAc, eF-MENT, eF-MENTAc, testosterone propionate, testosterone undecanoate, testosterone heptanoate, mesterone, nandrolone decanoate, chlorostilb acetate or metinolone acetate may be mentioned.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more antiandrogens, such as cyproterone acetate, flutamide or bicalutamide.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more 5 α -reductase inhibitors, such as finasteride or 17 α -estradiol.
In a preferred embodiment, the compositions of the present invention comprise as an active ingredient one or more selective estrogen receptor modulators, such as raloxifene.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more estrogens, such as estradiol, estradiol valerate or estriol.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more conjugated estrogens, estrogen sulfamates or antiestrogens, such as clomiphene or paclitaxel, or partial antiestrogens, such as raloxifene.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more progestogens, such as progesterone, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, chlormadinone acetate, cyproterone acetate, medrogesterone, dydrogesterone, norethindrone acetate, norethindrone heptanoate, levonorgestrel, gestodene, etonogestrel, dienogest, danazol, norgestimate, lynestrenone, desogestrel or drospirenone.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more antiprogestins, such as mifepristone or mesoprogestin (mesoprogestin).
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more utero-active substances, such as oxytocin.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more m-cholinergic receptor antagonists, such as scopolamine.
In a preferred embodiment, the composition of the invention comprises as active ingredient one or more prostaglandins or prostaglandin derivatives, such as alprostadil, gemeprost, dinoprostone, sulprostone, dinoprost, latanoprost or misoprostol.
In a preferred embodiment, the composition of the invention comprises nicotine as active ingredient.
Combinations of two or more of the above active ingredients are also preferred.
The necessary dosages of androgens, antiandrogens, 5 alpha-reductase inhibitors, estrogen receptor modulators, estrogens, antiestrogens, gestagens, antiprogestagens, utero-actives, m-cholinergic receptor antagonists, prostaglandins or prostaglandin derivatives and/or nicotine are known to those skilled in the art. In this respect, reference may be made, for example, to Mutschler Arzneimitelterwirkung-L-ehrbuch der Pharmakologie und Dioxiologicie [ textbook of action of pharmaceutically active agents ], 2001 and W.forth et al, Allgemeine und Spezielle Pharmakologie und Toxikologie [ general and specific pharmacology and toxicology ], B I Wissenschaftsverlag [ scientific Press ]1992, 6 th edition.
In a preferred embodiment, the composition of the invention comprises a combination of several active ingredients selected from the group consisting of androgens and/or antiandrogens and/or 5 α -reductase inhibitors and/or estrogen receptor modulators and/or estrogens and/or antiestrogens and/or gestagens and/or antiprogestagens and/or uterine-active substances and/or m-cholinergic receptor antagonists and/or prostaglandins or prostaglandin derivatives and/or nicotine and/or compounds of the general formulae (III), (IV) and/or (V).
The compositions of the invention preferably comprise additional ingredients as adjuvants.
In a preferred embodiment, the composition comprises cyclomethicone and/or isopropyl myristate as an adjuvant. In the hydrogel, cyclomethicone and isopropyl myristate ensure good spreading on the skin and skin care. In a preferred embodiment, the composition comprises glycerol as an adjuvant. Glycerin acts as a moisturizer for compositions and skin.
In a preferred embodiment, the composition comprises cyclomethicone, isopropyl myristate and glycerol as adjuvants. In their combination, the water and adjuvants are present in the composition in a ratio which gives the composition better compatibility. The concentration of the nutritional aids (cyclomethicone and isopropyl myristate) and the volatility of the cyclomethicone are important because residue of the composition on the skin, which might otherwise be contaminated by the patient coming into contact with the skin of other individuals, should be avoided as much as possible.
As additional adjuvants, polyethylene glycols and/or volatile silicone oils, such as hexamethylcyclotrisiloxane, octamethylcyclotetrasiloxane and/or decamethylcyclopentasiloxane, may be included in the compositions of the invention. As auxiliaries, in addition to water and C2-C4Besides alkyl alcohols, it is also possible to use, for example, the solvents benzyl alcohol, dimethylformamide or dimethyl sulfoxide. Polyvalent alcohols, such as ethylene glycol, propylene glycol, butylene glycol or hexylene glycol, are also preferred. In addition to or instead of glycerol, sorbitol, mannitol, polyethylene glycol and/or polypropylene glycol or copolymers composed of ethylene glycol and propylene glycol can be added in order to prevent the composition from drying out. Glycerol has proven particularly suitable. In addition, the pharmaceutical composition may comprise, for example, dyes, fragrances, antioxidants, surfactants, bactericides, fungicides, complexing agents, cyclodextrins, electrolytes and/or viscosity increasing agents. These auxiliaries are known to the person skilled in the art. For further information, reference may be made, for example, to Fiedler, Lexikon der Hiltstoffe [ auxiliary dictionary]ECU Aulendorf 1996, 4 th edition and Hunnius studieusgabe [ version of the Hunnius textbook]De Gruyter 1993, 7 th edition.
The adjuvant improves the compatibility of the composition to the skin. The relative proportion by weight of the auxiliary agent to the pharmaceutical composition is preferably 0.001 to 15.0% by weight, more preferably 0.01 to 10.0% by weight, even more preferably 0.5 to 5.0% by weight, in particular 1.0 to 4.0% by weight. Particularly preferably 1.0 to 2.0% by weight of cyclomethicone and/or 0.3 to 0.8% by weight of isopropyl myristate and/or 0.5 to 1.5% by weight of glycerol.
The pharmaceutical composition of the present invention is a hydrogel. The water content in the hydrogel is preferably 5.0 to 90.0% by weight, more preferably 10.0 to 70.0% by weight, even more preferably 20.0 to 50.0% by weight, and particularly 25.0 to 40.0% by weight.
C2-C4The relative weight ratio of alkyl alcohol to water is preferably 0.1 to 10.0, more preferably 0.5 to 5.0, even more preferably 1.0 to 3.0, especially 1.8 to 2.2.
In a preferred embodiment of the present invention, the pharmaceutical composition comprises propylene carbonate or ethylene carbonate as the carboxylic acid diester, and C is2-C4An alkyl alcohol, the pharmaceutical composition comprising ethanol. For this case, the pharmaceutical composition preferably comprises 29.0 to 73.0% by weight of ethanol and 5.0 to 50.0% by weight of water, more preferably 34.0 to 68.0% by weight of ethanol and 10.0 to 45.0% by weight of water, even more preferably 39.0 to 63.0% by weight of ethanol and 15.0 to 40.0% by weight of water, particularly preferably 44.0 to 58.0% by weight of ethanol and 20.0 to 35.0% by weight of water, and in particular 54.8 to 57.5% by weight of ethanol and 27.2 to 30.8% by weight of water.
The pH of the pharmaceutical composition of the present invention is preferably 4.5 to 7.5, more preferably 5.0 to 7.0, especially 5.5 to 6.5. For this purpose, buffers such as tris- (hydroxymethyl) -aminomethane, triethanolamine or bases such as diisopropylamine or potassium hydroxide are suitable. In addition, other suitable buffer substances and bases are also known to the person skilled in the art. For further information, reference may be made, for example, to Fiedler, Lexikon der Hilffsstoffe, ECU Aulentorf 1996, 4 th edition and Hunnius studienassgabe, de Gruyter 1993, 7 th edition.
The pharmaceutical compositions of the present invention also comprise a polymer matrix. This polymer matrix contains at least one gel matrix former and optionally one or more thickeners that improve the rheological properties of the composition. With a gel matrix, patient compliance is significantly increased, which is a fundamental advantage of the compositions of the present invention. The balance of the gel properties is important, which is ensured by the composition of the invention. Continuous use of the composition of the invention is usually carried out by the patient, but it does not cause any problems, in particular because it is very easy to reapply the hydrogel to the skin.
Suitable gel matrix formers are known in the art. According to the invention, the polymer matrix preferably contains an acrylic polymer as gel matrix former. The acrylic polymer may be a homopolymer or a copolymer.
The acrylic polymer is a homopolymer, the latter preferably being derived from acrylic acid-C1-C30Alkyl esters or methacrylic acid-C1-C30An alkyl ester.
The acrylic polymer is a copolymer, the latter preferably being derived from acrylic acid, methacrylic acid, acrylic acid-C1-C30Alkyl esters or methacrylic acid-C1-C30A combination of an alkyl ester and one or more vinyl monomers. The vinyl monomer can be acrylic acid, methacrylic acid, acrylic acid-C1-C30Alkyl esters or methacrylic acid-C1-C30Alkyl esters, but it is also possible for the copolymer to contain, for example, styrene, ethylene, propylene, vinyl chloride, 1-dichloroethylene, tetrafluoroethylene, vinyl acetate, vinyl ethers or vinylpyrrolidone.
Acrylic polymers, particularly preferably acrylic acid, methacrylic acid, acrylic acid-C1-C30Alkyl esters and/or methacrylic acid-C1-C30Homopolymers or copolymers obtained by polymerization of alkyl esters.
The acrylic polymer comprised in the composition of the invention may be uncrosslinked or crosslinked. In a preferred embodiment, the composition of the invention comprises a crosslinked acrylic polymer.
The acrylic polymer is an uncrosslinked polymer, the weight average molecular weight M of the acrylic polymerwPreferably from 50000 to 2500000gmol-1More preferably in the range of 100000 to 2000000gmol-1In the range of 500000 to 1500000gmol-1Within the range of (1).
As a gelThe skeleton former, the composition of the invention particularly preferably comprises an acrylic polymer which is a copolymer and is derived from acrylic acid and acrylic acid-C1-C30A mixture of alkyl esters. In a particularly preferred embodiment, these copolymers are crosslinked, for example, with allylpentaerythritol. These crosslinked polymers are known in the art. For example acrylate-C1-C30The alkyl acrylate may be selected from the group consisting ofThe TR1 name is commercially available. This is an acrylate/C10-30 alkyl acrylate crosspolymer.The general chemical structure of TR1 is simplified as follows:
wherein k is 10-30.
The proportion by weight of the gel matrix former in the pharmaceutical composition is preferably from 0.001 to 20.0% by weight, more preferably from 0.005 to 10.0% by weight, even more preferably from 0.01 to 5.0% by weight, in particular from 0.5 to 1.0% by weight.
In addition to the gel matrix former, the polymer matrix of the composition of the invention may comprise other polymers. The latter may act as a thickener. According to the invention, the composition preferably comprises polyacrylic acid as thickener. Polyacrylic acids are commercially available, for example, under the nameAccording to the present invention, there is provided,980 is particularly preferred.
The proportion by weight of polyacrylic acid in the pharmaceutical composition is preferably 0 to 5.0% by weight, more preferably 0.01 to 2.5% by weight, even more preferably 0.1 to 1.0% by weight, in particular 0.3 to 0.5% by weight. In a preferred embodiment of the invention, the composition does not comprise any polyacrylic acid.
In a preferred embodiment of the invention, the polymer matrix comprises, in addition to the gel matrix former, a cellulose derivative as a thickener, but it is also possible that no cellulose derivative is present.
As preferred cellulose derivatives, mention may be made of methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate butyrate, cellulose acetate propionate, hydroxypropyl methyl cellulose acetate succinate and methyl hydroxypropyl cellulose phthalate or mixtures thereof. Ethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose are particularly preferred, in particular ethylcellulose and hydroxypropylcellulose, with hydroxypropylcellulose being most preferred.
Preferred cellulose derivatives according to the invention are compounds having subunits of the general formula (VI)
Wherein R is12、R13、R14、R15、R16And R17In each case independently of one another hydrogen or straight-chain or branched C1-C61An alkyl radical, the carbon chain of which may be interrupted up to 20 times by oxygen atoms and which is optionally substituted by 1 or 2 hydroxy, carboxyl or acyloxy groups, the acyloxy group optionally being derived from C1-C7Carboxylic acid or C1-C7A dicarboxylic acid. R12、R13、R14、R15、R16And R17In each case independently of one another, preferably hydrogen or straight-chain or branched C1-C19Alkyl groups, the carbon chain of which may be interrupted up to 6 times by oxygen atoms and optionally substituted by 1 or 2 hydroxyl groups.
The individual subunits of the general formula (VI) in the cellulose derivatives can be substituted in various ways. The following are therefore possible: for example, in one subunit, R12、R13、R14、R15And R16is-CH2CH3And R is17is-H, and in another subunit, R13、R14、R15、R16And R17is-CH2CH3And R is12is-H.
Preferred cellulose derivatives according to the invention exhibit a high degree of substitution with respect to the hydroxyl groups of the cellulose. The degree of substitution expressed as Molar Substitution (MS) is preferably from 2.0 to 6.0, more preferably from 3.0 to 5.0, and especially from 3.4 to 4.4.
Particularly preferred substituents R12、R13、R14、R15、R16And R17The method comprises the following steps: -H, -CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH2CH2OH、-CH2CH(CH3)OH、-[CH2CH(CH3)O]xH、-CH2CH(CH3)OCH3And- [ CH ]2CH(CH3)O]xCH3Where x can in each case be a number from 2 to 20, preferably from 2 to 6, in particular 2, 3 or 4.
According to the invention, the subunit of the formula (VI) is preferably a subunit of hydroxypropylcellulose, i.e. the group R12、R13、R14、R15、R16And R17Independently of one another, are preferably-H, -CH2CH(CH3) OH or- [ CH ]2CH(CH3)O]xH，Where x is in each case a number from 2 to 20, preferably from 2 to 6. Hydroxypropyl cellulose can be obtained by the following reaction: alkali metal salts of cellulose are reacted with propylene oxide, after which the alkoxy groups are neutralized. If one of the hydroxyl groups of the cellulose does not react with propylene oxide in this reaction, R12、R13、R14、R15、R16Or R17is-H. If in this reaction one of the hydroxyl groups of the cellulose is reacted with an equivalent of propylene oxide, R is12、R13、R14、R15、R16Or R17is-CH2CH(CH3) And (5) OH. If in this reaction one of the hydroxyl groups of the cellulose reacts with one equivalent of propylene oxide and the alkoxide thus produced reacts with the other equivalent of propylene oxide, R12、R13、R14、R15、R16Or R17Is- [ CH2CH(CH3)O]xH. In this case, the index x can be any number, depending on how many equivalents of the oligomerization of propylene oxide are. The index x is preferably a number from 2 to 20, more preferably from 2 to 6, in particular 2, 3 or 4.
R12、R13、R14、R15、R16And R17In each case independently of one another, particularly preferably have one of the following meanings: -H, -CH2CH(CH3)OH、-[CH2CH(CH3)O]2H or- [ CH ]2CH(CH3)O]3H。
According to the invention, the methylcellulose, the hydroxypropylmethylcellulose, the ethylcellulose, in particular the hydroxypropylcellulose, have in each case a Molar Substitution (MS) of from 3.0 to 6.0, more preferably from 3.0 to 5.0, particularly preferably from 3.4 to 4.4.
Preferred cellulose derivatives are known to the person skilled in the art. Ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are commercially available, for example under the namesEXFHF andMH 1000. Particular preference is given according to the inventionHF. For further information, reference may be made, for example, to Fiedler, Lexikon der Hiltstoffe, ECU Aulendorf 1996, 4 th edition and Hunnius studienasusgabe, de Gruyter 1993, 7 th edition. About toFor additional information on hydroxypropyl cellulose of type, reference may be made to Hercules, Aqualon,-Physical and chemical Properties, Produkt-spezification [ product description]，HerculesIncorporated 2001。
Weight average molecular weight M of cellulose derivativewPreferably in the range of 50000 to 2000000gmol-1In the range of 300000 to 1500000gmol is more preferred-1In the range of 750000 to 1250000gmol even more preferred-1In particular in the range from 850000 to 1150000gmol-1Within the range.
The cellulose derivative preferably has a brookfield viscosity of 1000 to 4000mPa, more preferably 1275 to 3500mPa, in particular 1500 to 3000mPa, at a concentration of 1% in water at 25 ℃. Measured with a brookfield viscometer of the LVF type with 4 spindles and 4 speeds, which can cover a range from 0 to 100000 mPa.
The proportion by weight of the cellulose derivative in the pharmaceutical composition is preferably 0 to 5.0% by weight, more preferably 0.01 to 2.5% by weight, even more preferably 0.1 to 1.5% by weight and in particular 0.3 to 1.0% by weight.
According to the invention, the polymer matrix preferably contains polyacrylic acid or cellulose derivatives as a further thickener in addition to the acrylic polymer as gel matrix former. A combination of an acrylic polymer as a gel skeleton former and hydroxypropyl cellulose as a thickener is particularly preferable.
The pharmaceutical compositions of the invention may comprise fatty acids having more than 12 carbon atoms or their esters or fatty alcohol esters derived from these fatty acids or primary amines and/or the C of mono-, di-, tri-or tetraethylene glycols1-C18Alkyl ethers are in particular diethylene glycol monoethyl ether, and/or terpenes. However, these compounds are not essential components of the pharmaceutical composition of the present invention, and the pharmaceutical composition of the present invention is preferably free of these compounds.
In a particularly preferred embodiment, the pharmaceutical composition comprises the following ingredients in the following weight proportions:
TABLE 1
| Composition (I) | The ratio [ weight%] |
| eF-MENT | 0.01-5.0 |
| acrylate/C10-30 alkyl acrylate crosspolymer | 0.1-1.5 |
| Polyacrylic acid | 0-1.0 |
| Cellulose derivatives | 0-2.0 |
| Propylene carbonate | 5.0-20.0 |
| 86% Glycerol | 0.01-5.0 |
| Cyclomethicone | 0.01-5.0 |
| Myristic acid isopropyl ester | 0.01-5.0 |
| Purified water | 20.0-50.0 |
| Ethanol | 30.0-60.0 |
| Tris- (hydroxymethyl) -aminomethane | pH 5-7 |
The pharmaceutical composition of the present invention is suitable as a medicament. The therapeutic indication determines the active ingredient to be administered. The steroid containing formulations according to the invention may be used, for example, for the prevention and/or treatment of different steroid deficiency syndromes. As an exemplary application of the method of the present invention,mention may be made of androgen replacement therapy, contraception, primary and secondary hypogonadism, testicular dysfunction, hair loss, aging, bone loss, muscle atrophy, erectile dysfunction, benign prostatic hypertrophy and prostate cancer. In particular, the pharmaceutical composition comprising MENT, eF-MENT, MENTAc or eF-MENTAc according to the invention is suitable for use in the treatment or prevention of primary and secondary hypogonadism. For pharmacological, physiological and clinical applications of Androgens, reference may be made to Mutschler Arzneimittelwarkung- -Lehrbuch der Pharmakologic und Dioxikologie, 2001, S.Bhasin et al, Pharmacology, Biology, and clinical applications of Androgens: current Status and Future Prospects, John Wiley&Sons, 1st ed., 1996, ch.chawnshang, android and android receiver: mechanisms, Functions, and Clinical Applications, Kluweracademic Publishers, 2002 and M.Carruthers, android Deficiency inter-Aging Male, CRC Press-Parthenon Publishers, 1st Ed.，2002。
The pharmaceutical compositions of the present invention are formulated for systemic administration of the active ingredient by topical application on the skin. The composition may be applied by hand or by spreading on the skin with the aid of a suitable aid, such as a spatula, but it is also possible to apply the composition in the form of a spray on the skin.
The invention also relates to the use of carboxylic acid diesters for improving the transdermal penetration of active ingredients in pharmaceutical compositions in the form of hydrogels, wherein the compositions preferably additionally comprise C2-C4An alkyl alcohol, preferably ethanol, and a polymer matrix. With respect to the preferred components (i.e. with respect to the active ingredient, C)2-C4Alkyl alcohols, carboxylic acid diesters, polymer matrices, adjuvants, buffer substances, etc.) and with regard to the preferred quantitative ratios of these components in the pharmaceutical composition, reference may be made to the above embodiments. The present invention therefore relates to the use of carboxylic acid diesters, preferably of formula (I), more preferably of formula (II), and in particular propylene carbonate, for improving the transdermal penetration of one or more active ingredients in a pharmaceutical composition in the form of a hydrogel, wherein the hydrogel isPreferably comprising a polymer matrix and C2-C4An alkyl alcohol, and preferably as defined above.
According to the present invention, it has also been found, quite surprisingly, that pharmaceutical compositions in the form of hydrogels containing acrylic polymers and cellulose derivatives, if applied to the skin wet by perspiration, do not exhibit the problems of destruction of the gel skeleton and run-off of the gel (antiperspirant compositions). To achieve this effect, the presence of the carboxylic diester in the formulation is not necessary.
According to the invention, such a pharmaceutical composition (antiperspirant composition) comprises an acrylic polymer and a cellulose derivative.
As cellulose derivative, such a pharmaceutical composition (antiperspirant composition) preferably comprises a cellulose derivative as defined above, in particular a compound selected from the group consisting of ethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Ethyl cellulose and hydroxypropyl cellulose are particularly preferred, with hydroxypropyl cellulose being more preferred. The molar substitution of the cellulose derivative is preferably from 2 to 6, more preferably from 3 to 6, especially from 3 to 5, for example from 3.4 to 4.4.
As acrylic polymer, such a pharmaceutical composition (antiperspirant composition) preferably comprises an acrylic polymer as defined above, in particular a homopolymer or copolymer, derived from acrylic acid, methacrylic acid, acrylic acid-C1-C30Alkyl esters and/or methacrylic acid-C1-C30An alkyl ester. Particularly preferably from acrylic acid and acrylic acid-C10-C30Copolymers of mixtures of alkyl esters. In a particularly preferred embodiment, the acrylate/C10-30 alkyl acrylate is a crosslinked polymer.
The relative ratio by weight of the acrylic polymer and the cellulose derivative in the pharmaceutical composition (antiperspirant composition) is preferably 0.1 to 10.0, more preferably 0.2 to 5.0, even more preferably 0.5 to 2.0, and particularly 0.75 to 1.75.
The total proportion of the acrylic polymer and the cellulose derivative in the pharmaceutical composition (antiperspirant composition) is preferably 0.01 to 20.0% by weight, more preferably 0.1 to 10.0% by weight, even more preferably 0.3 to 5.0% by weight, and particularly 1.0 to 2.0% by weight.
In a preferred embodiment, the pharmaceutical composition (antiperspirant composition) comprises 0.5 to 1.0% by weight of the acrylate/C10-30 alkyl acrylate crosspolymer and 0.2 to 0.8% by weight of hydroxypropyl cellulose.
The pharmaceutical composition (antiperspirant composition) of the present invention is preferably a hydrogel. The water content in the hydrogel is preferably 5.0 to 90.0% by weight, more preferably 10.0 to 70.0% by weight, even more preferably 20.0 to 50.0% by weight, and particularly 25.0 to 40.0% by weight.
The pharmaceutical composition (antiperspirant composition) of the present invention preferably comprises C2-C4Alkyl alcohols, with ethanol being particularly preferred. In this case, the pharmaceutical composition (antiperspirant composition) preferably comprises 29.0 to 73.0% by weight of ethanol and 5.0 to 50.0% by weight of water, more preferably 34.0 to 68.0% by weight of ethanol and 10.0 to 45.0% by weight of water, even more preferably 39.0 to 63.0% by weight of ethanol and 15.0 to 40.0% by weight of water, particularly preferably 44.0 to 58.0% by weight of ethanol and 20.0 to 35.0% by weight of water, and especially 54.8 to 57.5% by weight of ethanol and 27.2 to 30.8% by weight of water.
In addition to the acrylic polymer and the cellulose derivative, the pharmaceutical composition (antiperspirant composition) optionally comprises at least one active ingredient and additional ingredients such as skin care products, adjuvants, solvents, penetration enhancers, and the like. In the composition, the active ingredients, optional additional ingredients and their preferred percentages are for example as defined above.
The pharmaceutical composition in the form of a hydrogel (antiperspirant composition) thus preferably comprises an active ingredient as defined above and/or a carboxylic diester and/or C2-C4Alkyl alcohol and/or polymer matrix. The following ingredients each represent preferred weight percentages of the composition and their relative weight ratios to each other as well as preferred active ingredients, preferred carboxylic acid diesters and preferred C2-C4The alkyl alcohols are all as defined aboveAnd (5) defining.
Instead of or in addition to the carboxylic acid diester, the pharmaceutical composition (antiperspirant composition) may comprise a penetration enhancer selected from the group consisting of:
(i) containing 10 to 30 carbon atoms and optionally substituted by 1 to 2 hydroxyl groups, carboxyl groups or C1-C4Aliphatic fatty acid esters substituted with an acyloxy group;
(ii) containing 10 to 30 carbon atoms and optionally substituted by 1 to 2 hydroxyl groups, carboxyl groups or C1-C4An acyloxy group-substituted aliphatic fatty acid alcohol; or
(iii) A compound of the general formula (VII):
HO-(CH2CH2-O)n-R18 (VII)
wherein R is18Is C1-C12Alkyl radical, C1-C12Alkenyl radical, C1-C12Alkanoyl or C1-C12Alkenoyl and the index n is a number from 1 to 10.
The pharmaceutical composition (antiperspirant composition) preferably comprises R18Is C1-C4A compound of the general formula (VII) wherein the alkyl group and the index n are numbers from 1 to 3.
Particularly preferred compounds of the formula (VII) are: HO-CH2CH2O-CH3、HO-CH2CH2O-CH2CH3、HO-CH2CH2O-CH2CH2CH3、HO-CH2CH2O-CH2CH2CH2CH3、HO-(CH2CH2O)2-CH3、HO-(CH2CH2O)2-CH2CH3、HO-(CH2CH2O)2-CH2CH2CH3、HO-(CH2CH2O)2-CH2CH2CH2CH3、HO-(CH2CH2O)3-CH3、HO-(CH2CH2O)3-CH2CH3、HO-(CH2CH2O)3-CH2CH2CH3、HO-(CH2CH2O)3-CH2CH2CH2CH3、HO-(CH2CH2O)4-CH3、HO-(CH2CH2O)4-CH2CH3、HO-(CH2CH2O)4-CH2CH2CH3And HO- (CH)2CH2O)4-CH2CH2CH2CH3。
For the pharmaceutical composition (antiperspirant composition), it is particularly preferred to comprise a compound wherein R18An embodiment of the compound of formula (VII) which is ethyl and is labelled n ═ 2, i.e. diethylene glycol monoethyl ether.