DK175981B1 - Pharmaceutical composition for transdermal systemic administration of a pharmacologically active agent containing tizanidine and method of preparation of the composition - Google Patents

Description

DK 175981 B1

The present invention relates to a pharmaceutical composition as set forth in claim 1f and preferred embodiments of the composition are set forth in claims 2-6. The invention also relates to a process for preparing the composition as claimed in claim 7.

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Many pharmaceutical compositions for prolonged transdermal administration of pharmacologically active agents have been proposed in 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 therein. On one side of the drug reservoir there is a coating which is impermeable to the drug, on the other hand there is a protective tear strip which is removed before use. The coating may be larger than the drug reservoir and may have near its edges an adhesive layer to retain the protective tear strip and, when removed, adhere the device to the skin. Further or alternatively, a drug permeable adhesive layer may be provided on the reservoir to hold the protective tear strip and adhere the device to the skin. In some proposals, the drug reservoir has a drug permeable regulatory membrane or device bound through which the pharmacologically active agent passes to control the rate of penetration of the active agent, e.g., to prevent dose drop ("dose dumping").

When used after the tear strip has been removed, the device adheres to 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 30 systems do not provide a sufficient penetration rate for the pharmacologically active agent or they have other drawbacks. Prior to the priority date of this application, the transdermal pharmaceutical compositions for systemic administration of commercially available drugs were limited to pharmacologically active agents which exist in liquid form, e.g., scopolamine or nitroglycerin, and which in any case readily penetrate the skin.

2 DK 175981 B1

Thus, new ways are needed to address the issue of transdermal application of solid and liquid pharmacologically active agents using controlled release systems.

It has now been found that the pharmacologically active agent tizanidine can be advantageously administered from a drug reservoir containing a hydrophilic polymer with the pharmacologically active agent dispersed therein.

Tizanidine has previously been described for transdermal administration.

10 GB 2098865 A describes topical microemulsions containing this pharmacologically active agent. The microemulsions should be applied to the skin as a cream.

Tizanidine is a known myotonolytic agent, for example for the treatment of local muscle spasms such as rheumatic pain and spastic conditions.

The invention thus relates to a pharmaceutical composition for the transdermal systemic administration of a pharmacologically active agent, and this composition is characterized in that it contains tizanidine in a reservoir containing a hydrophilic polymer.

The penetration of the active agent into the skin can be observed by standard tests in vitro or in vivo.

The hydrophilic polymers absorb water and are permeable to water, for example moisture from the skin, although the polymers may be insoluble in water. The polymers can swell and release a large amount of pharmacologically active agent, leading to a high concentration gradient of pharmacologically active agent between the skin surface and the stratum corneum 30 at a pH of from 4 to 7, preferably at skin pH, e.g. 5th If desired, they may be soluble in organic solvents. Examples of suitable polymers include polyacrylamide and copolymers thereof, polyvinylpyrrolidone (PVP), vinyl acetate-vinyl alcohol copolymers, polyvinyl alcohol (PVA) and derivatives thereof, ethyl cellulose and other cellulose and starch derivatives.

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Preferably, the polymer has an average molecular weight of approx.

50,000 - approx. 300,000 Daltons such as 100,000-200,000 Daltons, and are preferably film-forming.

Hydrophilic polyacrylates are preferred polymers. The acrylate may be substituted, for example, a methacrylate. They may be commercially available acrylate-methacrylate copolymers. Some or all of the acid groups may be esterified, for example with alkyl groups such as methyl or ethyl groups. Preferably, at least 2% of the alkyl groups may contain polymeric substituents, e.g., a hydroxy group.

It has been found that polyacrylates containing cationic functional groups are particularly preferred.

Transdermal pharmaceutical compositions for systemic administration of tizanidine through intact skin, wherein tizanidine is in a reservoir containing a polyacrylate-containing cationic functional group, are novel.

Examples of cationic groups include dialkylaminoalkyl groups, e.g., dimethylaminoalkyl groups.

Particularly preferred cationic groups include quaternary ammonium groups, preferably a tri (alkyl) aminoalkyl group. Examples of 25 such groups are trimethylaminoethyl ester groups.

The polyacrylate may contain some carboxylic acid groups in free form or salt anions, for example chloro anions, in order to balance the cationic groups.

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The ratio of cationic groups to neutral groups is preferably from 1:10 to 1:50, for example from 1:20 to 1:40.

Preferably, the polymers have an alkali number (defined in a manner analogous to the acid number) of from ca. 10 to approx. 200 mg KOH per g polymer, eg 10-30 mg KOH per ml. g polymer.

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Examples of commercially available polymers of this type include: 1) Polymers of acrylate and methacrylate esters containing neutral methyl and ethyl ester groups and cationic trimethylaminoethyl ester groups. Chloride ions are present. Average molecular weight 150,000 Daltons. Viscosity (20 ° C) maximum 15 cP. Refractive index 1,380-1,385. Density 0.815-0.835 g / cm *. Ratio of cationic ester groups to neutral alkyl groups 1:20, giving an alkali 10 of 28.1 mg KOH per liter. g of polymer (Eudragit® RL 100 available from Rohm, Darmstadt, West Germany) or 1:40, giving an alkali content of 15.2 mg KOH per day. g of polymer (Eudragit® RS 100, also available from Rohm).

2) Polymer of methacrylic ester containing cationic trimethylaminoethyl ester groups and other neutral C 1-6 alkyl ester groups. Chloride ions are present. Average molecular weight 150,000. Viscosity (20 ° C) 10 cP. Refractive index 1.38. Density 0.815. Alkalit of 180 mg KOH per g polymer (Eudragit® E 100, also available from 20 Rohm).

The drug reservoir may contain plasticizing and / or plasticizing agents, preferably skin compatible surfactants, for example to provide the unit with flexibility, and / or to partially or completely dissolve the pharmacologically active agent in the reservoir.

Examples of additives include: 1) Polyoxyethylene fatty alcohol ethers. The alcohol may be, for example, a 30 Cg / l alcohol. The HLB value may be, for example, 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 approx.

16 ° C, an HLB value of 12.4 and an acid number of maximum 1.0 (Brij® 97 available from Atlas Chemie, West Germany).

2) Polyoxyethylene sorbitan fatty acid esters. The fatty acid may be, for example, a Cij.iB fatty acid. For example, the HLB value may be from 10 to 18. A preferred example is polyoxyethylene (20) sorbitan monooleate, for example, Tween® 80 available from Atlas Chemie, West Germany.

3) Polyoxyethylene (5-40) stearic acid esters, eg Myrj® available from Atlas Chemie, West Germany.

4) Polyoxyethylene glycol fatty alcohol ethers, e.g., polyethylene glycol (6-25) -10 cetyl ether, glycerol polyethylene ricinoleate, glycerol polyethylene glycol stearate (labeled Cremophor® available from BASF, West Germany).

5) Polyoxyethylene glycols having a molecular weight of 200 to 600 Daltons, e.g., 300 or 400 Daltons.

6) Esters of poly (2-7) ethylene glycol glycerol ether having at least one hydroxy group and an aqueous (C6-22) carboxylic acid, e.g., polyethylene glycol (7) glyceryl cocoate, e.g., Cetiol® HE, from Henkel, West Germany.

7) Adipic acid lower alkyl esters, e.g., di-n-butyladipate and diisopropyladipate.

8) Glycerol polyethylene glycol ricinoleate, eg the product of 35 moles of ethylene oxide and castor oil, eg labeled Chremophor® EL available from 25 BASF, West Germany.

9) Triacetin- (1,2,3). The amount and nature of the additive required will depend on a number of 30 factors, such as the surfactant HLB value and the required flexibility of the device. Surprisingly, the amount of additive does not significantly affect the ability of the polyacrylate to form films. In general, the weight ratio of surfactant to hydrophilic polymer is from ca. 1:10 to 5: 1, e.g., 1:10 to 1: 3.

The drug reservoir may contain skin-penetrating agents, e.g., 1-dodecylazacycloheptan-2-one (azone) and N, N-diethyl-m-toluamide (DEET).

35 6 The amount and nature of skin penetrating agents and / or additives present will depend on a number of factors. Generally, the weight ratio of skin permeation promoting agent to hydrophilic polymer will be from approx. 1: 1 to 1:10. The amount of surfactant 5 and / or skin permeation agent is preferably from ca. * 3 to approx. 50% by weight, preferably 20-40% by weight of the pharmaceutical composition.

If desired, the drug reservoir may contain a hydrophobic elastomer, e.g., a synthetic resin. Such resins are common in the plastics technique. Suitable resins include non-swellable acrylate resins. These, if desired, can be sticky. For example, the weight ratio of hydrophilic polymer to resin may be from 1: 0.5 to 1:10. The resin may contain modifiers, extenders, for example with a softening point of approx. 50-100 ° 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. For example, the extender may be present in an amount of from 5 to 40% by 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 additon salt forms include the hydrogen malonate, hydrogen malinate, hydrogen fumarate, hydrochloride, tartrate, etc. A solid active agent preferably has an average particle diameter of from 30 to 50 µm.

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The active agent may be partially suspended and / or partially dissolved

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in the reservoir. It may be dispersed so finely that, for the mere j in the eye, it results in an evenly homogeneous film. | The pharmaceutical compositions of the invention are useful for the systemic administration of tizanidine through intact skin, as indicated by standard tests in vitro and in vivo. , i________ 7 DK 175981 B1

The release of active agent from the pharmaceutical compositions may be followed, for example, by the amount of active agent released by shaking the pharmaceutical composition in 0.9% NaCl solution at 37 ° C at a stirring rate of approx. 120 rpm for example, 5 is determined by ultraviolet spectroscopy.

The penetration of the active agent through isolated rat and human skin can be followed by the well-known diffusion test performed in accordance with the principles described, for example, in GB 10 2098865 A and in T.J. Franz, J.Invest.Dermatol. 64, 1975, pp. 191-195.

The pharmaceutical compositions according to the invention are applied to the outer side of isolated pieces of rat or human skin having an area of approx. 2 cm *. The rat skin is hairless. The other side is washed continuously with physiological saline solution. The amount of active agent in the salt water is determined in a conventional manner, e.g., HPLC. Then, the permeation flux can be determined over 24 hours and, if desired, the flux at the stationary state. The penetration flux rate is of the order of 1-10 µg / cmVtime. Alternatively, the active agent penetration can be followed in vivo by applying the pharmaceutical composition to intact skin, for example on the chest, back, arm, or behind the ear, on a subject and measuring the amount of active agent in the blood.

The pharmaceutical compositions of the invention can be used for the same indications known for oral or intravenous administration. The amount of pharmaceutically active agent to be administered will depend individually on the drug release properties 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 device adheres. , 'and the desired duration of action. The amount of active agent and the area of the pharmaceutical composition etc. can be determined by usual bioavailability tests comparing the blood levels of the active agent after administration of the active agent in a pharmaceutical composition according to the invention on intact skin and blood levels of 8 active agent observed. following oral or intravenous administration of a therapeutically effective dose of the pharmacologically active agent.

If the daily dose of a drug for oral administration is given, the choice of a suitable amount of drug to be incorporated into a transdermal composition of the invention will depend on 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 relevant matrix for a given application range and within 10 for a given period of time; and the time during which the preparation is to be applied.

Thus, a drug with a high first-pass effect may require one; relatively low amount in the transdermal preparation compared to the oral daily dose since the first-pass effect will be avoided. On the other hand, in general, a maximum of only approx.

15 50% of a drug in the matrix through the skin within a 3-day $ period.

The pharmaceutical compositions of the invention generally have, for example, an effective contact area of the drug reservoir on the skin of from about.

20 to approx. 50 cm 2, preferably approx. 2-20 cm 2 and is intended to be applied for 1-7 days, preferably 1-3 days.

An example of a representative dose is for tizanidine a dose of 20 mg in a surface of approx. 10 cm2 to be administered once every 25 days for systemic treatment of rheumatic pain and muscle cramps.

The pharmaceutical compositions of the invention may be prepared by conventional means by dispersing or dissolving the pharmacologically active agent in a hydrophilic drug reservoir.

The weight ratio of the pharmacologically active agent to hydrophilic polymer may vary within wide limits. For example, the weight ratio may be sufficient to provide a supersaturation of the pharmacologically active agent in the drug reservoir. In general, the weight ratio is from approx. 1:10 to approx. 1: 1.

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For example, in the case of tizanidine, the amount may be, for example, from 10 to 40% by weight, such as 15-30 or 20-25% by weight.

If the drug reservoir is not itself adhesive, a pressure sensitive adhesive may be used to adhere the drug reservoir to intact skin. Any conventional adhesive may be used, for example a polyacrylate. The layer may be applied to the drug reservoir virus and may have a thickness of from ca. 1 to approx. 200 µm, preferably 10-100 µm. If the adhesive layer is thin enough, the pharmacological agent will pass through it. Alternatively, the adhesive layer may be applied to the edges of an outer cover of the drug reservoir, and the outer cover may be adhered to the intact skin, thereby keeping the drug reservoir in close contact with the intact skin.

The drug delivery reservoir may be prepared in a conventional manner, for example, in an adhesive patch or patch. If it is a polymer matrix, it can be prepared 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.

20 A film is formed by spreading the dispersion or solution over the outer protective covering. The wet film can have a thickness of approx. 0.05-0.5 mm, for example from 0.1 to approx. 0.3 mm. The film is allowed to dry, for example at room temperature or slightly elevated temperature below 50 ° C. The drug reservoir may be built up in series of layers, providing an optional adhesive layer in the last layer.

The pharmaceutical compositions of the invention can be prepared in a conventional manner for skin permeating pharmaceutical compositions. FIG. 1 of the drawing schematically shows a cross-section through the layers 30 of a representative pharmaceutical composition according to the invention. FIG. 2 of the drawing schematically shows a cross-section through another embodiment, for example in the form of a bandage or a patch. In Figures 1 and 2 there are several layers a-d, and in the case of Figs. 2 there is a further layer e.

The layer a is a medical cover made of, for example, polyester / aluminum laminate foil. Layer b is a barrier film, for example aluminum foil. If desired, this can be omitted. Layer c may be made from 1-10 layers of a drug reservoir. The drug reservoir is a homogeneous dispersion of active agent particles or active agent solution in a polymer matrix. Layer d can be an adhesive layer. In one embodiment (not shown), layer d may extend between the outer edges of layer a and layer e. Alternatively, layer e may be omitted completely. Layers a 5 may extend around layers b-d of FIG. 2. Layer e is a protective tear layer adhered to the adhesive layer as well as to the edges of the cover layer a.

When used, any protective layer is torn off and the unit 10 is adhered to intact skin.

In the following examples, all temperatures are uncorrected. All quantities are in parts by weight unless otherwise stated.

15 Details of the components are given in "Lexicon flir Pharmazie, Kosmetik und angrenzende Gebiete" by H.P. Fiedler, 2nd ed. Cantor Aulendorf, West Germany or from the relevant manufacturers.

In the following examples, the names given herein have the meaning given below: PAM Amine Polymer RL: Cationic polyacrylate / methacrylate polymer as defined above under the designation EUDRAGIT® RL 100.

25 PAM Amine polymer RS: Cationic polyacrylate / methacrylate polymer as defined above under the designation EUDRAGIT® RS 100.

30 PAM Amine polymer E: Cationic polymethacrylate polymer as defined above under the designation EUDRAGIT® E 100.

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Polyoxyethylene (10) oil ether: BRIJ® 97 as defined above. Glycerol polyethylene glycol (35) -ricinoleate = Cremophor® EL as defined above.

Polyoxyethylene (20) sorbitan monooleate = Tween® 80 as defined above.

Synthetic acrylate resin is a self-crosslinking acrylate of the brand Durotack 280-2416 available from Delft National Chemie, Zutphen, The Netherlands and available as a light yellow solution containing as solvent a 57% ethyl acetate, 32% ethanol, 9% hexane, 2% methanol: solid content 41%, viscosity (Brookfield) s 2100-6000 mPas, plasticity (Williams) ± 3 mm, density 0.94, flash point 0.94.

EXAMPLE A

Preparation of Pharmaceutical Preparation Containing a Hydrophilic Polymer 20 Composition

Pharmacologically active agent 20%

Hydrophilic polymer 40%

Tenside 40% 1.2 g of hydrophilic polymer are dissolved in 3 g of acetone or ethanol or another suitable volatile organic solvent with stirring for 1-2 hours. 0.6 g of pharmacologically active agent and 1.2 g of surfactant plasticizer are added. The mixture is stirred vigorously for 5-20 minutes using a high speed stirrer to give a viscous mass.

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The pulp is spread as a film on top of an aluminized polyester film (thickness 23 µm) using conventional apparatus, e.g., an Erichsen film apparatus model 411/150. The mass is spread over the film at a rate of 18 mm / second to form a film having a thickness of 0.2 mm in wet state.

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The film is allowed to dry at room temperature over 4-6 hours. The resulting hydrophilic polymer drug matrix weighs 8.5 mg / ml. and contains 1.7 mg of active agent per ml. cm 2.

An additional film of an acrylate adhesive (Rohm Pharma 7708/47) is then applied on top of the drug polymer matrix in the form of a thin layer (thickness 0.1 mm) in an analogous manner. .j i

The aluminum foil is then cut into pieces with an area of 10 cm2.

10; Unless otherwise stated, the drug matrix is constructed from one film layer. It can, if desired, be built up as more than one layer.

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Active agent release is measured in vitro by standard skin diffusion.

15 tests through freshly isolated hairless rat skin. Place the rat skin piece I

given in a Franz diffusion chamber, cf. T.J. Franz, J. invest. Dermatol 64, (1975), pp. 191-195. The receptor phase is continuously pumped and samples taken every hour are measured for active agent content using HPLC. The test lasts 24 hours and 20 the penetration flux is measured over 24 hours (hereafter referred to as "flux") and, if desired, a flux at equilibrium state;

after a decay time of 3-10 hours. IN

EXAMPLE 1 25

Tizanidinpræparat

Prepared as described in Example A with a composition of 30 Tizanidine hydrochloride 20% in PAM Amine polymer RL 40%

Polyoxyethylene-10-oleyl ether 40%

Active agent penetration rate in rat skin:

Penetration flux ± - 0.0145 mg / cm2 / hour Total permeation ± - 0.290 mg / cm1 approx. 21.46%

Residue measured in plastics approx. 47% 35 GB 175981 B1 13 EXAMPLE 2 Tizanidine Preparation 5 Prepared by analogy to that described in Example A with a composition of

Tizanidine hydrochloride 1.144 g PAM Amine polymer RL 1.928 g 10 Polyoxyethylene-10-oleyl ether 1.928 g I The active agent is dissolved in 5 g ethanol as the solvent.

Spreading rate 6 mm / second 15 Thickness of wet film 0.25 mm

Active agent concentration in film 2.6 mg / cm 2 No adhesive acrylate film is present.

Active agent penetration rate through rat skin: 20

Penetration flux = 8.5 µg / cmVtime Flux at equilibrium state = 16.2 µg / cmVtime.

In a clinical trial, a 2 cm 2 piece of preparation 25 was applied to the left forearm and after 12, 24 and 36 hours the residual tizanidine content in the piece was determined.

Flux rate = 5.1 vg / cm2 / hour. IN

i in 30! EXAMPLE 3 14

Prepared as described in Example 2 using methylene chloride as solvent instead of ethanol. Composition: 5 liters of 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 10

Penetration rate through rat skin:

Penetration flux = 10.4 pg / cmVtime.

In a clinical trial, a 2 cm * piece was applied as in Example 2.

Penetration flux = 4.9 µg / cm / hr.

EXAMPLE 4

Pharmaceutical tizanidine preparation 25 Prepared analogously to that described in Example 2. !

Spread rate = 18 mm / second Thick film thickness: 0.2 mm Active agent concentration: 1.7 mg / cm * 3q Apply an adhesive acrylate film layer as in Example A.

Penetration rate through rat skin.

Penetration flux = 14.5 vg / cmV hour 35 Flux at equilibrium state ~ 30.8 ug / cm * / hour.

EXAMPLE 5

Pharmaceutical tizanidium preparations 5 The surfactant of Example 2 is replaced by an equivalent amount of pi) Polyethylene glycol 300 ii) Glycerol polyethylene glycol (3,5} -rin cinoleate iii) Polyoxyethylene (20) - $ orbitan monooleate 10 rv) Azone and / or PAM amine polymer RL is replaced by PAM amine polymer RS or PM amine polymer E.

EXAMPLE B

In a manner analogous to that described in Example A, a pharmaceutical composition is prepared without an adhesive acrylate layer. The drug matrix is based on an elastomer.

20 B1 B2 in Weight (g / ma) 80 79

Tizanidine Hydrochloride (mg / 10 cm *) 15.00 14.81

Tizanidine Free Base 17.16 16.95 25 Synthetic Acrylate 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% 30 In vitro data, release of active agent in mg / 10 cm * 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 (7)

A pharmaceutical composition for transdermal systemic administration of a pharmacologically active agent, characterized in that it contains tizanidine as an active agent in a reservoir comprising a hydrophilic polymer. Composition according to claim 1, characterized in that the polymer is a polyacrylic polymer. 10 Composition according to claim 1, characterized in that the polymer is a polyacrylate polymer containing cationic functional groups. Composition according to any one of claims 1-3, characterized in that the polymer is an acrylate / methacrylate polymer. Composition according to any one of claims 1-4, characterized in that the polymer contains trimethylaminoethyl ester groups. Composition according to any one of claims 1-5, characterized in that it is in the form of an adhesive patch or patch comprising a) a cover layer, c) a drug reservoir comprising 1-10 layers of a homogeneous dispersion of particles of active agent or solution of active agent in a polymer matrix, and d) an adhesive layer, the reservoir c) 25 being disposed between layers a) and d). Process for the preparation of a pharmaceutical composition for transdermal administration, characterized in that a) tizanidine is dispersed. in a polyacrylate polymer containing cationic functional groups or b) dispersing tizanidine in a hydrophilic polymer and optionally applying an adhesive layer.