throbber
@ ~) Europaisches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`@ Publication number:
`
`0155 229
`A2
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 85810072.0
`
`@ Date of filing: 22.02.85
`
`<®
`
`lnt.CI.4:A61 L 15/03,A61 K 31/40,
`A61 K 47/00, A61 K 9/70
`
`@ Priority: 01.03.84 CH 1008/84
`06.04.84 CH 1753/84
`
`@ Applicant: SANDOZ AG, Lichtstrasse 35, CH-4002 Basel
`(CH)
`Applicant: LTS Lohmann Therapie-Systeme GmbH & Co.
`KG, lrlicherstrasse 55, D-5450 Neuwied 12 (DE)
`
`@ Date of publication of application: 18.09.85
`Bulletin 85/38
`
`® Inventor: Kissel, Thomas, Federerweg 10,
`D-7801 Ehrenkirchen 1 (DE)
`Inventor: Schrank, Henriette,
`Rudolf-Wackernagelstrasse 121, CH-4125 Riehen (CH)
`Inventor: Hoffmann, Hans-Rainer, Burghofstrasse 113,
`D-5450 Neuwied 22 (DE)
`
`@) Designated Contracting States: AT BE CH DE FR GB IT
`LILUNLSE
`
`@ Representative: Norris, Allen Edwin, SANDOZ AG
`Lichtstrasse 35, CH-4002 Basel (CH)
`
`® Pharmaceutical compositions.
`
`f,7) The present invention provides a pharmaceutical com(cid:173)
`position for the transdermal systemic administration of an
`active agent characterised in that the active agent is bopin(cid:173)
`dolol or methysergide. Also the present invention provides a
`pharmaceutical composition for the transdermal systemic
`administration of a pharmacologically active agent charac(cid:173)
`terised in that it contains bopindolol, tizanidine, clemastine,
`ketotifen or methysergide as active agent in a reservoir com(cid:173)
`prising a hydrophilic polymer. Furthermore a pharmaceuti-
`C\.~ cal composition for the transdermal systemic administration
`
`C of pharmacologically active agents characterised in that the
`pharmacologically active agent is in a reservoir comprising
`CJ) a polyacrylate polymer containing cationic ester groups.
`
`"' "' It)
`It) ,..
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`ACTORUM AG
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`PHARMACEUTICAL COMPOSITIONS
`
`This invention relates to pharmaceutical compositions, especially
`for the systemic transdermal administration of pharmacologically
`active agents.
`
`10
`
`15
`
`5 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
`into the skin and the pharmacologically active agent passes from
`the drug reservoir to the skin. More complicated systems have
`
`20
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`25
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`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 systms.
`
`We have now surprisingly found that the pharmacologically active
`15 agent bopindolol, 4-(2-benzoyloxy-3-tert-butylaminopropoxy)-2-
`methylindole, a beta-blocker which is known for oral
`administration e.g. for the treatment of hypertension, and
`methysergide (9,10-didehydro-N-[1-(hydroxymethyl}propyl]-1,6-
`dimethylergoline-8-carboxamide, a known serotonin antagonist
`20 e.g. for the prophylaxis of migraine, have especially interesting
`properties for transdermal administration. These are hereinafter
`referred to as the active agents of the invention.
`
`The penetration of these active agents through the skin may be
`observed in standard in ~itro or in vivo tests.
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`One in vitro test is the well known diffusion test which may be
`effected according to the principles set out in GB 2098865 A and
`by T.J.Franz in J.Invest.Oermatol (1975) 64, 194-195. Solutions
`containing the active agent in unlabelled or radioactively
`labelled form are applied to one· side of isolated pieces of
`intact human skin or hairles-s rat skin about 2 cm2 in area.The
`other side of the skin is in contact with physiological saline.
`The amount of active agent in the saline is measured in
`conventional manner, e.g. by HPLC or spectrophotometric
`techniques, or by determining the radioactivity.
`
`5
`
`10 Typically using rat skin a penetration flux of from 0.1 to 10
`microgram/cm2Jhour over 24 hours is observed for the active
`agents.
`
`In one aspect the present invention provides a method of
`systemically administering the active agent bopindolol or
`15 methysergide which comprises administering the active agent to
`the skin. In a further aspect the present invention provides the
`use of bopindolol or methysergide as active agent in the
`manufacture of a medicament suitable for systemic transdermal
`administration. In a further aspect the present invention
`20 provides a pharmaceutical composition for the transdermal
`systemic administration of an active agent characterised in that
`the active agent is bopindolol or methysergide.
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`In general for application e.g. behind the ear an amount of
`bopindolol or methysergide from about 1 to 6 mg is indicated,
`e.g. 5 mg for a dose for 1 to 3 days.
`
`5
`
`The active agents of the invention may be administered in any
`conventional liquid or solid transderma1 pharmaceutical
`composition, e.g. as described in Remington's Pharmaceutical
`Sciences 16th Edition Mack; Sucker, Fuchs and Spieser,
`Pharmaceutische Technologie 1st Edition,Springer and in GB
`2098865 A or DOS 3212053 the contents of which are incorporated
`10 herein by reference. Conveniently the composition is in the form
`of a viscous liquid, ointment or solid matrix. The active agent
`may be incorporated in a plaster.
`
`We have now found that the above active agents, bopindolol and
`methysergide, as well ~the following pharmacologically active
`15 agents tizanidine, ketotifen and clemastine may be advantageously
`administered transdermally from a drug reservoir comprising a
`hydrophilic polymer having the pharmacologically active agent
`dispersed throughout.
`
`Tizanidine, ketotifen and clemastine have previously been
`20 disclosed for transdermal administration. GB 2098865 A discloses
`topical microemulsions containing these pharmacologically active
`agents The microemulsions are· to be applied to the skin as a
`cream.
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`Tizanidine is a known myotonolytic agent e.g. for the treatment
`of local muscle spasms e.g. rheumatic pains and spastic
`conditions. Ketotifen and clemastine are anti-histamines e.g. for
`the treatment of allergic conditions. Ketotifen also is an
`anti-anaphylatic agent, e.g. for·the prophylaxis of asthma.
`
`5
`
`In a further aspect the present invention provides a
`pharmaceutical composition for the transdermal systemic
`administration of pharmacologically active agents characterised
`in that it contains bopindolol, tizanidine, clemastine, ketotifen
`10 or methysergide in a reservoir comprising a hydrophilic polymer.
`In yet a further aspect the present invention provides the use of
`these active agents in a hydrophilic polymer for the manufacture
`of a transdermal medicament suitable for systemic administration
`of the active agent through intact skin.
`
`15 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
`20 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.
`
`25
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`The polymer preferably has a mean molecular weight of from about
`50,000 to about 300,000 Oaltons, such as 100,000 to 200,000
`Oaltons, and is preferably film forming.
`
`Hydrophilic polyacrylates are preferred polymers. The acrylate
`5 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.
`
`10
`
`It has been found that polyacrylates containing cationic
`functional groups are especially preferred.
`
`Transdermal pharmaceutical compositions for the systemic
`administration of pharmacologically active agents through intact
`skin wherein the active agent is in a reservoir comprising a
`15 polyacrylate containing catonic functional groups are novel and
`form part of the present invention.
`
`The present invention also provides the use of a
`pharmacologically active agent in a polyacrylate containing
`cationic groups for the manufacture of a medicament suitable for
`transdermal systemic administration of the pharmacologically
`active agent through intact skin of a subject. In another aspect
`the present invention prdvides a method of systemically
`
`20
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`administering a pharmacologically active agent to a subject which
`comprises contacting a reservoir of the pharmacologically active
`agent in a polyacrylate containing cationic ester groups to
`i nt act skin •
`
`5 Examples of cationic groups jnclude 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.
`
`10 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.
`
`15 Preferably the polymers have an alkali count (defined in
`analogou~ 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:-
`
`20 1) Polymers of acrylate and methacrylate esters containing methyl
`and ethyl neutral ester groups and trimethylaminoethyl cationic
`ester groups. Chloride ions are present. Mean Molecular weight
`150000 Oaltons. Viscosity (2o•c), maximum 15cP. Refractive index
`1.380 - 1.385. Density 0.815 - 0.835 g/cm3. Ratio of cationic
`25 ester groups to neutral alkyl groups 1:20 giving an alkali count
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`of 28.1 mg KOH per gram polymer (Eudragit RL 100 Registered Trade
`Mark available from Rohm, 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 Rohm).
`
`2) Polymer of methacrylate esters containing trimethylaminoethyl
`cationic ester groups and other neutral (Cl-4)alkyl ester
`groups. Chloride ions are present. Mean molecular weight
`150,000. Viscosity (20°C) 10 cP. Refractive Index 1.38. Density
`10 0.815. Alkali number of 180 mg KOH per gram polymer (Eudragit E
`100, Registered Trade Mark, also available from Rohm).
`
`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
`15 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.
`20 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).
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`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
`5 Atlas Chemie, W.Germany.
`
`3) Polyoxyethylene-(5-40) stearic acid esters, e.g. Myrj
`(Registered Trade Mark) available from Atlas Chemie, W.Germany.
`
`4) Polyoxyethylene glycol fatty alcohol ethers, e.g. polyethylene
`glycol-(6-25) cetyl ether, glycerin polyethylene ricinoleate,
`10 glycerin polyethylene glycol stearate (Cremophor brand,
`Registered Trade Mark available from BASF W.Germany).
`
`5) Polyoxyethylene glycols of MW from 200 to 600 Daltons, e.g.
`300 or 400 Daltons.
`
`15
`
`6) Esters of poly(2-7)ethylene glycol glycerol ether having at
`least one hydroxyl group and an aliphatic (Cfi-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.
`
`20 8) Glycerin polyethylene glycol 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).
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`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.
`
`5
`
`The drug reservoir may contain skin penetration promoters, e.g.
`1-dodecylazacycloheptan-2-one(azone) and N,N-diethyl-m-toluamide
`(DEET).
`
`10 The amount and type of skin penetration promoter, and/or
`additives 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
`15 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
`20 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 SO to 1oo·c. Such extenders may have
`adhesive or softening properties. Examples of such extenders
`include resin acids, glyceryl and phthalate esters of resin
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`acids, hydrogenated abietyl alcohol and its phthalate esters. The
`extenders for example be present in an amount of from 5 to 40% of
`the weight of the resin.
`
`5
`
`Any pharmacologically active agent capable of penetration of the
`skin may be dispersed throughout the hydrophilic polymer. The
`indication for which the active agent is used is not critical. It
`is preferred that the daily transdermal dose for such agents is
`less than 20 mg per day, e.g. less than 10 mg per day.
`
`The active agent for use in any of the pharmaceutical
`10 compositions mentioned above 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.
`15 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.
`
`20 The pharmaceutical compositions of the invention are useful for
`the systemic administration of pharmacologically active agents
`through intact skin, as indicated in standard in vitro and in
`vivo tests.
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`The release of active agent from the pharmaceutical compositions
`may b~ fa;1lowed 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.
`
`~
`
`5
`
`The penetration of the active agent through i so 1 a ted, 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
`10 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 conventional manner, e.g. HPLC. The
`15 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 micrograms/cm2f 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.
`
`20
`
`The pharmaceutical compositions of the invention may be used for
`the same indications as known for oral or intravenous
`25 administration. The amount of pharmaceutically active agent to be
`administered will individually depend on the drug release
`characteristics of the pharmac-eutical compositions, the drug
`penetration rate observed )n in vitro and in vivo tests, the
`potency of active agent, the size of the skin contact area, the
`part of the body to which the unit is stuck, and the duration of
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`action required. The amount of active agent and area of the
`pharmaceutical composition etc may be determined by routine
`bioavailability tests comparing the blood levels of active agents
`after administration of the active agent in a pharmaceutical
`composition according to the invention to intact skin and blood
`levels of active agent obseryed after oral or intravenous
`administration of a therapeutically effective dose of the
`pharmacologically active agent.
`
`5
`
`Given the daily dose of a drug for oral administration, the
`10 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
`15 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,
`20 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
`25 about 2 to 20 square centimetres, and are intended to be applied
`for from 1-7 days, preferably 1-3 days.
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`Examples of representative doses are:-
`
`1} 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.
`
`5
`
`2) Bopindolol A dose of 1 to 10 mg in a patch of 10 cm2 to be
`administered once over 3 consecutive days in each
`week for treatment of hypertension.
`
`3) Clemastine A dose of about 1 to 20 mg in a patch of ca 10cm2
`to be administered once every 3 days for
`treatment of allergiest eg. hay fever.
`
`10
`
`4) Ketotifen
`
`A dose of about 1 to 20 mg in a patch of ca 10cm2
`to be administered once every 3 days for
`prophylaxis of asthma.
`
`15
`
`5) Methysergide A dose of about 1 to 10 mg in a patch of ca 10
`cm2 to be administered once every 3 days for
`prophylaxis of migraine and migraine interval
`treatment.
`
`The pharmaceutical compositions of the invention may be produced
`in conventional manner by dispersing or dissolving an appropriate
`20 pharmacologically active agent through a hydrophilic drug
`reservoir.
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`The.weight rat~o of 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.
`
`5
`
`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
`10 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
`15 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.
`
`20
`
`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
`25 over the outer protective cover. The wet film may have a
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`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 50aC. The drug reservoir
`may be built up in a series of layers and then any adhesive layer
`provided in the last layer.
`
`5
`
`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
`10 pharmaceutical composition according to the invention. Figure 2
`of the accompanying drawings gives a schematic cross-section of a
`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
`15 out of e.g. polyester/aluminium laminate foil. Layer b is an
`occulsive 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 poly-
`20 mer 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 1 ayer as we 11 as to the edges of the cover 1 ayer a.
`
`On use any protective layer e is peeled off and the unit stuck to
`intact ski n.
`
`In the following examples all temperatures are in degrees
`Centigrade and are uncorrected. All amounts are in parts by
`30 weight unless otherwise stated.
`
`Page 17 of 32
`
`Noven Ex. 1007
`
`

`
`-17-
`
`0155229
`100-6560
`
`Details of components are given in Lexicon for Pharmazie,
`Kosmetic 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.
`
`10
`
`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.
`
`15 Polyoxyethylene(lO) oleyl ether: BRIJ 97 as defived above.
`Glycerin Polyethylene glycol(35) ricinoleate = Cremophor EL as
`defined above.
`Polyoxyethylene(20) sorbitan monooleate = Tween 80 as defined
`above.
`20 Polyethylene(?) glycol glyceryl cocoate = Cetiol HE as defined
`above.
`
`Page 18 of 32
`
`Noven Ex. 1007
`
`

`
`-18-
`
`0155229
`WCY-&560
`
`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) t 3 mm, Density 0.94 Flashpoint 0.94.
`
`5
`
`Page 19 of 32
`
`Noven Ex. 1007
`
`

`
`-19-
`
`100-6560
`
`EXAMPLE A: Preparation of pharmaceutical composition containing
`a hydrophilic polymer
`
`Composition
`Pharmacologically active agent
`5 Hydrophilic polymer
`Tens ide
`
`20%
`40%
`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
`10 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.
`
`15
`
`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
`20 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.
`
`Page 20 of 32
`
`Noven Ex. 1007
`
`

`
`-20-
`
`0155229
`100-6560
`
`The aluminium foil is then cut up into patches about 10 sq em 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.
`
`5 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
`10 measured for active agent content using HPLC. The trial lasts 24
`hours and the penetration flux over 24 hours (hereinafter
`referred to as 11flux 11
`) and if desired a steady state flux after a
`lag time of 3 to 10 hours is measured.
`
`Page 21 of 32
`
`Noven Ex. 1007
`
`

`
`-21-
`
`0155229
`100-6560
`
`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%
`
`5
`
`Active agent penetration rate in rat skin:
`
`Penetration Flux t = 0.0145 mg/cm2/hr
`Total penetration ± = 0.290 mg/cm2 ca 21.46%
`Remainder detected in plaster ca 47%
`
`10 EXAMPLE 2: Tizanidine composition
`
`Prepared in analogous manner to that described in Example A with
`a composition of
`
`1.144 g
`Tizanidine hydrochloride
`1.928 g
`PAM Amine polymer RL
`Polyoxyethylene-10 oleyl ether 1.928 g
`
`15
`
`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
`20 No adhesive acrylate film is present.
`
`Page 22 of 32
`
`Noven Ex. 1007
`
`

`
`-22-
`
`0155229
`100-6560
`
`Active agent penetration rate through rat skin:
`Penetration Flux = 8.5 microgram/cm2/hr
`Steady state flux = 16.2 microgram/cm2fhr
`
`5
`
`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/cm2fhr
`
`EXAMPLE 3:
`
`Prepared as described in Example 2 using as solvent methylene
`10 chloride instead of ethanol. Composition:
`
`1.144 g
`Tizanidine hydrochloride
`PAM Amine polymer RL
`1.928 g
`Polyoxyethylene-10 oleyl ether 1.628 g
`Triacetin (1,2,3)
`0.250 g
`
`15 Penetration rate through rat skin:
`Penetration Flux 10.4 microgram/cm2fhr
`
`In a clinical trial a 2 cm2 patch was applied as in Example 2.
`Penetration Flux 4.9 microgram/cm2fhr
`
`Page 23 of 32
`
`Noven Ex. 1007
`
`

`
`-23- -
`
`0155229
`100-6560
`
`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
`5 Concentration of active agent: 1.7 mg/cm2
`An acrylate film adhesive layer is applied as in Example A.
`
`Penetration rate through rat skin.
`= 14.5 microgram/cm2/hr
`Penetration Flux
`Steady state Flux = 30.8 microgram/cm2/hr
`
`10 EXAMPLE 5: Tizanidine pharmaceutical compositions
`
`The tenside in Example 2 is replaced by an equivalent amount of
`
`15
`
`Polyethylene glycol 300
`i)
`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.
`
`Page 24 of 32
`
`Noven Ex. 1007
`
`

`
`-24-
`
`0155229
`100-6560
`
`EXAMPLES 6-8: Clemastine pharmaceutical compositions
`
`The following compositions are made in analogous manner to
`example 2.
`
`Example
`
`Clemastine hydrogen fumarate
`PAM Amine polymer RL
`PM Amine polymer E
`Polyoxyethylene (10) oleyl ether
`Polyethylene glycol 300
`
`6
`
`7
`
`1 g
`2 g
`- g
`2 g
`
`1.34 g
`
`2.41 g
`1.25 g
`
`8
`
`1
`
`g
`
`2.66 g
`
`1.34 g
`
`Solvent
`Solvent amount (g/g dry film)
`Thickness of wet film (mm)
`Spreading speed (mm/sec)
`Acrylate adhesive film
`(Wet film thickness)
`Active Agent Penetration through
`isolated rat skin.
`Penetration Flux (microgram/
`cm2/hr)
`Steady state flux
`(microgram/cm2fhr)

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