PHARMACEUTICAL COMPOSITIONS

Abstract: The present invention provides a pharmaceutical composition for the transdermal systemic administration of a pharmacologically active agent characterised in that it contains tizanidine as active agent in a reservoir comprising a hydrophilic polymer.

Description: This invention relates to pharmaceutical compositions, especially for the systemic transdermal administration of pharmacologically active agents. Many pharmaceutical compositions have been proposed for the sustained transdermal administration of pharmacologically active agents into the systemic circulation. These generally comprise essentially a solid reservoir or matrix made of a solid polymer or gel containing the pharmacologically active agent dispersed throughout. On one side of the drug reservoir there is a backing member impermeable to the drug and on the other side a protective peel strip which is taken off before use. The backing member may be larger than the drug reservoir and may carry near its edges an adhesive layer to retain the protective peel strip and, when this is removed, to stick the unit to the skin. Additionally, or alternatively a drug-permeable adhesive layer may be provided on the reservoir to retain the protective peel strip and stick the unit to the skin. In some proposals the drug reservoir has attached to it a drug-permeable control membrane or member, through which the pharmacologically active agent passes, in order to regulate the rate of passage of the active agent, e.g. to prevent dose dumping. In use after the peel strip has been removed, the unit is stuck onto the skin and the pharmacologically active agent passes from the drug reservoir to the skin. More complicated systems have been proposed to improve the penetration rate of the pharmacologically active agent through the skin. However, most systems do not provide a sufficient penetration rate of the pharmacologically active agent or suffer from other disadvantages. Before the priority date of the present application the transdermal pharmaceutical compositions for systemic administration of drugs commercially available on a wide scale were restricted to pharmacologically active agents which exist in liquid form e.g. scopolamine or nitroglycerin, and which in any event easily penetrate the skin. There is thus a need for new approaches to the transdermal application of solid and liquid pharmacologically active agents using controlled release systems. We have now found that the pharmacologically active agent tizanidine may be advantageously administered transdermally from a drug reservoir comprising a hydrophilic polymer having the pharmacologically active agent dispersed throughout. Tizanidine has previously been disclosed for transdermal administration, GB 2098865 A discloses topical microemulsions containing this pharmacologically active agent. The microemulsions are to be applied to the skin as a cream. Tizanidine is a known myotonolytic agent, e.g. for the treatment of local muscle spasms, e.g. rheumatic pains and spastic conditions. Therefore the present invention provides a pharmaceutical composition for the transdermal systemic administration of a pharmacologically active agent characterised in that it contains tizanidine in a reservoir comprising a hydrophilic polymer. The penetration of the active agent through the skin may be observed in standard in vitro or in vivo tests. The hydrophilic polymers take up water and are permeable to water, e.g. moisture from the skin, although the polymers may be insoluble in water. The polymers may swell and provide release of a large amount of pharmacologically active agent leading to a high concentration gradient of pharmacologically active agent between the skin surface and stratum corneum at a pH of from 4 to 7, preferably at skin pH, e.g. 5.5. If desired they may be soluble in organic solvents. Examples of suitable polymers include polyacrylamide and its co-polymers, polyvinylpyrrolidone (PVP), vinyl acetate/vinyl alcohol co-polymers, polyvinyl alcohol (PVA) and derivatives, ethyl cellulose and other cellulose and starch derivatives. The polymer preferably has a mean molecular weight of from about 50,000 to about 300,000 Daltons, such as 100,000 to 200,000 Daltons, and is preferably film forming. Hydrophilic polyacrylates are preferred polymers. The acrylate may be substituted, e.g. a methacrylate. They may be commercially available acrylate/methacrylate co-polymers. Some or all of the acid groups may be esterified, e.g with alkyl groups such as methyl or ethyl groups. Preferably at least 2% of the alkyl groups may contain polar substituents, e.g. a hydroxy group. It has been found that polyacrylates containing cationic functional groups are especially preferred. Transdermal pharmaceutical compositions for the systemic administration of tizanidine through intact skin wherein tizanidine is in a reservoir comprising a polyacrylate containing cationic functional group are novel. Examples of cationic groups include dialkylaminoalkyl groups, e.g. dimethylaminoalkyl groups. Especially preferred cationic groups include quaternary ammonium groups, preferably a tri(alkyl)aminoalkyl group. Examples of such groups are trimethylaminoethyl ester groups. The polyacrylate may contain some carboxylic acid groups in free form or salt anions, e.g. chloride anions in order to balance the cationic groups. The ratio of cationic groups to neutral groups is preferably from 1:10 to 1:50, e.g. from 1:20 to 1:40. Preferably the polymers have an alkali count (defined in analogous manner to acid count) of from about 10 to about 200 mg KOH per gram polymer, e.g. 10 to 30 mg KOH per gram polymer. Examples of commercially available polymers of this type include:- 1) Polymers of acrylate and methacrylate esters containing methyl and ethyl neutral ester groups and trimethylaminoethyl cationic ester groups. Chlorine ions are present. Mean Molecular weight 150,000 Daltons. Viscosity (20°C), maximum 15cP. Refractive index 1.380 - 1.385. Density 0.815 - 0.835 g/cm³. Ratio of cationic ester groups to neutral alkyl groups 1:20 giving an alkali count of 28.1 mg KOH per gram polymer (Eudragit RL 100 Registered Trade Mark available from Röhm, Darmstadt, W.Germany) or 1:40 giving an alkali count of 15.2 mg KOH per gram polymer (Eudragit RS 100 Registered Trade Mark, also available from Röhm). 2) Polymer of methacrylate esters containing trimethylaminoethyl cationic ester groups and other neutral (C₁₋₄)alkyl ester groups. Chloride ions are present. Mean molecular weight 150,000. Viscosity (20°C) 10 cP. Refractive Index 1.38. Density 0.815. Alkali number of 180 mg KOH per gram polymer (Eudragit E 100, Registered Trade Mark, also available from Röhm). The drug reservoir may contain plasticizers and/or softeners preferably skin compatible tensides, e.g. to provide flexibility to the unit, and/or to dissolve partially or totally the pharmacologically active agent in the reservoir. Examples of additives include:- 1) Polyoxyethylene fatty alcohol ethers. The alcohol may e.g. be a C₁₂₋₁₈ alcohol. The HLB value may be e.g. from 10 to 18. A preferred example is polyoxyethylene-(10) oleyl ether. A suitable ether may have a viscosity (25°C) of about 100 cP, a solidification point of about 16°C, an HLB value of 12.4 and an acid count maximum 1.0 (Brij 97 Registered Trade Mark available from Atlas Chemie W. Germany). 2) Polyoxyethylene sorbitan fatty acid esters. The fatty acid may be e.g. a C₁₂₋₁₈ fatty acid. The HLB value may be e.g. from 10 to 18. A preferred example is polyoxyethylene-(20) sorbitan monooleate, e.g. Tween 80, Registered Trade Mark available from Atlas Chemie, W. Germany. 3) Polyoxyethylene-(5-40) stearic acid esters, e.g. Myrj (Registered Trade Mark) available fro Atlas Chemie, W. Germany. 4) Polyoxyethylene glycol fatty alcohol ethers, e.g. polyethylene glycol-(6-25) cetyl ether, glycerin polyethylene ricinoleate, glycerin polyethylene glycol stearate (Cremophor brand, Registered Trade Mark available from BASF, W. Germany). 5) Polyxoxyethylene glycols of Mw from 200 to 600 Daltons, e.g. 300 or 400 Daltons. 6) Esters of poly(2-7)ethylene glycol glycerol ethers having at least one hydroxyl group and an aliphatic (C₆₋₂₂) carboxylic acid, e.g. polyethylene glycol-(7) glyceryl cocoate, e.g. Cetiol HE, Registered Trade Mark, from Henkel, W. Germany. 7) Adipic acid lower alkyl esters, e.g. di-n-butyl adipate and diisopropyl adipate. 8) Glycerin polyethlyene ricinoleate, e.g. Product of 35 moles ethylene oxide and castor oil e.g. Brand Chremophor EL Registered Trade Mark, obtainable from BASF, W. Germany. 9) Triacetin-(1,2,3). The amount and type of additive required will depend on a number of factors, e.g. the HLB value of the tenside and the flexibility of the unit required. Surprisingly the amount of additive does not significantly influence the capability of the polyacrylate to form films. Generally the weight ratio of tenside to the hydrophilic polymer is from about 1:10 to 5:1, e.g. 1:10 to 1:3. The drug reservoir may contain skin penetration promoters, e.g. 1-dodecylazacycloheptan-2-one (Azone) and N,N-diethyl-m-toluamide (DEET). The amount of type of skin penetration promoter, and/or additive present will depend on a number of factors. Generally the weight ratio of skin penetration promoting agent to hydrophilic polymer will be from about 1:1 to 1:10. Preferably the amount of tenside and/or skin penetration promoter is from about 3 to about 50%, preferably 20 to 40% by weight of the pharmaceutical composition. If desired the drug reservoir may contain a hydrophobic elastomer, e.g. a synthetic resin. Such resins are conventional in the plaster art. Suitable resins include non-swellable acrylate resins. These may if desired be adhesive. The weight ratio of hydrophilic polymer to resin may for example be from 1:0.5 to 1:10. The resin may contain modifiers, extenders, e.g. of softening point about 50 to 100°C. Such extenders may have adhesive or softening properties. Examples of such extenders include resin acids, glyceryl and phthalate esters of resin acids, hydrogenated abietyl alcohol and its phthalate esters. The extenders fo example be present in an amount of from 5 to 40% of the weight of the resin. The active agent for use in the pharmaceutical compositions may be in free form, e.g. free base form or in pharmaceutically acceptable salt form, e.g. pharmaceutically acceptable acid addition salt form. Such acid addition salt forms include the hydrogen malonate, hydrogen maleate, hydrogen fumarate, hydrochloride, tartrate, etc. Preferably a solid active agent has an average particle diameter of from about 30 to about 50 microns. The active agent may be partly suspended and/or partly dissolved in the reservoir. It may be dispersed so finely that to the eye a smooth homogenous film results. The pharmaceutical compositions of the invention are useful for the systemic administration of tizanidine through intact skin, as indicated in standard in vitro and in vivo tests. The release of active agent from the pharmaceutical compositions may be followed for example by determining e.g. by ultraviolet spectroscopy, the amount of active agent released on shaking the pharmaceutical composition in 0.9% NaCl solution at 37°C at a paddle speed of about 120 rpm. The penetration of the active agent through isolated rat and human skin may be followed in the well known diffusion test effected according to the principles, e.g. set out in GB 2098865 A and in T.J. Franz, J. Invest. Dermatol (1975), 64 , 191-195. The pharmaceutical compositions of the invention are applied to the external side of isolated rat or human skin pieces about 2 cm² in area. The rat skin is hairless. The other side is continuously washed with physiological saline. The amount of active agent in the saline is determined in convention manner, e.g. HPLC. The penetration flux over 24 hours may then be ascertained, and if desired the steady state flux. The penetration flux rate is in the order of 1 to 10 microgram/cm²/hour. Alternatively the penetration of the active agent may be followed in vivo by applying the pharmaceutical composition to intact skin, e.g. on the chest, back, arm or behind the ear, of a subject and measuring the amount of active agent in the blood. The pharmaceutical compositions of the invention may be used for the same indications as known for oral or intravenous administration. The amount of the pharmaceutically active agent to be adminstered will individually depend on the the drug release characteristics of the pharmaceutical compositions, the drug penetration rate observed in in vitro and in vivo tests, the potency of the active agent, the size of the skin contact area, the part of the body to which the unit is stuck, and the duration of action required. The amount of the active agent and area of the pharmaceutical composition etc may be determined by routine bioavailability tests comparing the blood levels of the active agent after administration of the active agent in a pharmaceutical composition according to the invention to intact skin and blood levels of active agent observed after oral or intravenous administration of a therapeutically effective dose of the pharmacologically active agent. Given the daily dose of a drug for oral administration, the choice of a suitable quantity of drug to be incorporated in a transdermal composition according to the invention will depend upon the pharmacokinetic properties of the active agent, including the first pass effect; the amount of drug which can be absorbed through the skin from the matrix in question for a given area of application and in a given time; and the time for which the composition is to be applied. Thus, a drug with a high first pass effect may require a relatively low quantity in the transdermal composition when compared with the oral daily dose, since the first pass effect will be avoided. On the other hand, generally a maximum of only approx. 50% of the drug in the matrix is released through the skin in a 3 day period. The pharmaceutical compositions of the invention in general have for example an effective contact area of drug reservoir on the skin of from about 1 to about 50 square centimetres, preferably about 2 to 20 square centimetres, and are intended to be applied for from 1-7 days, preferably 1-3 days. An Example of a representative dose is for tizanidine a dose of 20 mg in a patch of ca. 10 cm² to be administered once every 3 days for the systemic treatment of rheumatic pains and muscle spasms. The pharmaceuitical compositions of the invention may be produced in conventional manner by dispersing or dissolving the pharmacologically active agent through a hydrophilic drug reservoir. The weight ratio of the pharmacologically active agent to hydrophilic polymer may vary between wide limits. The weight ratio may be for example sufficient to produce a supersaturation of the pharmacologically active agent in the drug reservoir. In general the weight ratio is from about 1:10 to about 1:1. For example in the case of tizanidine the amount may be for example from 10 to 40 percent, e.g. 15 to 30 or 20 to 25 percent, by weight. If the drug reservoir is not itself adhesive a pressure sensitive adhesive may be used to stick the drug reservoir to intact skin. Any conventional adhesive may be used, e.g. a polyacrylate. The layer may be applied to the drug reservoir and have a thickness of from about 1 to about 200 microns preferably 10 to 100 microns, If the adhesive layer is thin enough then the pharmacological agent will pass through it. Alternatively the adhesive layer may be applied to the edges of an outer cover for the drug reservoir and the outer cover stuck to the intact skin holding the drug reservoir in close contact with the intact skin. The drug reservoir may be produced in conventional manner, e.g. in an adhesive plaster or patch. If it is a polymer matrix it may be produced by dispersing or dissolving the pharmacologically active agent in a solution of the polymer and other additives in a volatile organic solvent, e.g. ethanol, methylene chloride, or acetone. A film is formed by spreading the dispersion or solution over the outer protective cover. The wet film may have a thickness of about 0.05 to 0.5 millimetres, e.g. 0.1 to about 0.3 millimetres. The film is allowed to dry, e.g. at room temperature or a slightly elevated temperature below 50°C. The drug reservoir may be built up in a series of layers and then any adhesive layer provided in the last layer. The pharmaceutical compositions of the invention may be produced in conventional manner for skin penetration pharmaceutical compositions. Figure 1 of the accompanying drawings gives a schematic cross-section through the layers of a representative pharmaceutical composition according to the invention. Figure 2 of the accompanying drawings gives a schematic cross-section of an another embodiment, e.g. in the form of a bandage or plaster. In figures 1 and 2 there are several layers a - d and in the case of Figure 2, additionally layer e. Layer a is a medical cover made out of e.g. polyester/aluminium laminate foil. Layer b is an occlusive foil, e.g. of aluminium foil. If desired this may be omitted. Layer c may be made out of 1 to 10 layers of a drug reservoir. The drug reservoir is a homogenous dispersion of active agent particles or a solution of active agent in a polymer matrix. Layer d may be an adhesive layer. In one embodiment (not shown) the layer d may extend to between the outer edges of layer a and layer e. Alternatively the layer e may be omitted completely. Layer a may extend around layers b to d in Figure 2. Layer e is a protective peel off layer which is stuck to the adhesive layer as well as to the edges of the cover layer a. On use any protective layer e is peeled off and the unit stuck to intact skin. The present invention also provides a process for the production of a pharmaceutical composition for transdermal administration which comprises dispersing a) tizanidine in a polyacrylate polymer containing cationic functional groups, to form a drug reservoir, or b) tizanidine through a hydrophilic polymer and optionally applying an adhesive layer. In the following examples all temperatures are in degrees Centigrade and are uncorrected. All amounts are in parts by weight unless otherwise stated. Details of components are given in Lexikon for Pharmazie, Kosmetik and angrenzende Gebiete by H.P. Fiedler, 2 Edition, Cantor Aulendorf, W.Germany or from the relevant manufacturers. In the following examples, the indicated terms have the meaning shown below:- PAM Amine polymer RL: Polyacrylate/methacrylate cationic polymer as defined above under the term EUDRAGIT RL 100. PAM Amine polymer RS: Polyacrylate/methacrylate cationic polymer as defined above under the term EUDRAGIT RS 100. PAM Amine polymer E: Polymethacrylate cationic polymer as defined above under the term EUDRAGIT E 100. Polyoxyethylene(10) oleyl ether: BRIJ 97 as defined above. Glycerin polyethylene glycol(35) ricinoleate = Cremophor EL as defined above. Polyoxyethylene(20) sorbitan monooleate = Tween 80 as defined above. Acrylate synthetic resin is self cross-linking acrylate Brand Durotack 280-2416 available from Delft National Chemie Zutphen Netherlands available as a light yellow solution containing as solvent 57% ethyl acetate, 32% ethanol, 9% hexane, 2% methanol: solids content 41%, Viscosity (Brookfield) = 2100-6000 mPas, Plasticity (Williams) ± 3 mm, Density 0.94 Flashpoint 0.94. EXAMPLE A: Preparation of pharamceutical composition containing a hydrophilic polymer Composition Pharmacologically active agent 20% Hydrophilic polymer 40% Tenside 40% 1.2 g of hydrophilic polymer are dissolved in 3 g acetone or ethanol or other appropriate volatile organic solvent with stirring in 1 to 2 hours. 0.6 g pharmacologically active agent and 1.2 g of tenside softener are added. The mixture is vigorously stirred for about 5 to 20 minutes with a high speed stirrer to give a viscous mass. The mass is spread as a film on top of an aluminised polyester foil (thickness 23 microns) using a conventional apparatus, e.g. an Erichsen film apparatus Model 411/150. The mass is spread across the foil at a speed of 18 mm/sec to produce a film of thickness 0.2 mm when wet. The film is allowed to dry at room temperature over 4 to 6 hours. The resultant hydrophilic polymer drug matrix weighs 8.5 mg per square centimetre and contains 1.7 mg active agent per square centimetre. A further film of an acrylate adhesive (Rohm Pharma 7708/47) is then applied onto the drug polymer matrix as a thin layer (0.1 mm thickness) in analogous manner. The aluminium foil is then cut up into patches about 10 sq cm in area. Unless otherwise stated the drug matrix is built up from one film layer. It may if desired be built up as more than one layer. The release of active agent is measured in vitro in standard skin diffusion tests through freshly isolated hairless rat skin. The rat skin piece is located in a Franz diffusion chamber - see T.J.Franz, J.Invest.Dermatol 1975 (64) 191-195. The receptor phase is pumped continuously and every hour samples are taken and measured for active agent content using HPLC. The trial lasts 24 hours and the penetration flux over 24 hours (hereinafter referred to as "flux") and if desired a steady state flux after a lag time of 3 to 10 hours is measured. EXAMPLE 1: Tizanidine composition Prepared as disclosed in Example A with a composition of Tizanidine hydrochloride 20% PAM Amine Polymer RL 40% Polyoxyethylene-(10)-oleyl ether 40% Active agent penetration rate in rat skin: Penetration Flux ± = 0.0145 mg/cm²/hr Total penetration ± = 0.290 mg/cm² ca 21.46% Remainder detected in plaster ca 47% EXAMPLE 2: Tizanidine composition Prepared in analogous manner to that described in Example A with a composition of Tizanidine hydrochloride 1.144 g PAM Amine polymer RL 1.928 g Polyoxyethylene-(10)-oleyl ether 1.928 g The active agent is dissolved in 5 g ethanol as solvent. Spreading speed 6 mm/sec. Thickness of wet film 0.25 mm. Concentration of active agent in film 2.6 mg/cm². No adhesive acrylate film is present. Active agent penetration rate through rat skin: Penetration Flux = 8.5 microgram/cm²/hr Steady state flux = 16.2 microgram/cm²/hr In a clinical trial a 2 cm² patch of the composition is applied to the left underarm and after 12, 24 and 36 hours the remaining tizanidine content in the patch determined. Flux rate = 5.1 microgram/cm²/hr EXAMPLE 3: Prepared as described in Example 2 using as solvent methylene chloride instead of ethanol. Composition: Tizanidine hydrochloride 1.144 g PAM Amine polymer RL 1.928 g Polyoxyethylene-(10)-oleyl ether 1.628 g Triacetin (1,2,3) 0.250 g Penetration rate through rat skin: Penetration flux 10.4 microgram/cm²/hr In a clinical trial a 2 cm² patch was applied as in Example 2. Penetration flux 4.9 microgram/c m2 /hr EXAMPLE 4: Tizanidine pharmaceutical composition Prepared in analogous manner to that disclosed in Example 2. Spreading speed = 18 mm/sec. Thickness of wet film: 0.2 mm Concentration of active agent: 1.7 mg/cm² An acrylate film adhesive layer is applied as in Example A. Penetration rate through rat skin. Penetration flux = 14.5. microgram/cm²(hr Steady state flux = 30.8 microgram/cm²)hr EXAMPLE 5: Tizanidine pharmaceutical compositions The tenside in Example 2 is replaced by an equivalent amount of i) Polyethylene glycol 300 ii) Glycerin polyethylene glycol-(35) ricinoleate iii) Polyoxyethylene-(20) sorbitan monooleate iv) azone and/or PAM Amine polymer RL is replaced by PAM Amine polymer RS or PM Amine polymer E. EXAMPLE B: In analogous manner to that described in Example A a pharmaceutical composition is made without an acrylate adhesive layer. The drug matrix is based on an elastomer. B1 B2 Weight g/m² 80 79 Tizanidine hydrochloride mg/10 cm² 15.00 14.81 Tizanidine free base 17.16 16.95 Acrylate synthetic resin parts by weight 50 50 PAM Amine polymer RL parts by weight 50 - PM Amine polymer E parts by weight - 50 Polyethylene glycol 400 2% 2% In vitro data active agent release mg/10 cm² 2 hours 14.36 19.48 4 hours 15.78 22.22 8 hours 17.33 24.03 24 hours 22.57 28.98

Claims: A pharmaceutical composition for the transdermal systemic administration of a pharmacologically active agent characterised in that it contains tizanidine as an active agent in a reservoir comprising a hydrophilic polymer. A composition according to claim 1 wherein the polymer is a polyacrylate polymer. A composition according to claim 1 wherein the polymer is a polyacrylate polymer containing cationic functional groups. A composition according to any one of claims 1 - 3 wherein the polymer is an acrylate/methacrylate polymer. A composition according to any one of claims 1 - 4 wherein the polymer contains trimethylaminoethyl ester groups. A composition according to any one of claims 1 - 5 in the form of an adhesive plaster or patch comprising a) a cover layer, c) a drug reservoir comprising 1 to 10 layers of homogeneous dispersion of active agent particles or a solution of active agent in a polymer matrix, and d) an adhesive layer, reservoir c) being located between layers a) and d). A process for the production of a pharmaceutical composition for transdermal administration which comprises dispersing a) tizanidine in a polyacrylate polymer containing cationic functional groups, to form a drug reservoir, or b) tizanidine through a hydrophilic polymer and optionally applying an adhesive layer.

Inventors: HOFFMANN, HANS-RAINER, KISSEL, THOMAS, SCHRANK, HENRIETTE
Applicants: LTS LOHMANN THERAPIE-SYSTEME GMBH & CO. KG, SANDOZ AG
Application year: 1985
Main classification: A61L15
IPC codes: A61P37, A61P11, C07D409, A61K31, C07D457, A61P17, A61K9, A61P9, C07D209, C07D417, A61K47, A61L15, A61P25, C07D207, A61P29, A61P43