(12) United States Patent
`Asmussen et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US006335031Bl
`US 6,335,031 Bl
`Jan.1,2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) TTS CONTAINING AN ANTIOXIDANT
`
`(75)
`
`Inventors: Bodo Asmussen, Bendorf-Sayn;
`Michael Horstmann, Neuwied, both of
`(DE); Kai Kopke, Triengen (CH);
`Henricus L. G. M. Tiemessen,
`Weil-Haltingen (DE); Steven Minh
`Dinh, Briarcliff Manor; Paul M.
`Gargiulo, New York, both of NY (US)
`
`(73) Assignees: Novartis AG, Basel (CH); LTS
`Lohmann Therapie-Systeme GmbH
`Co. KG, Neuwied (DE)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/291,498
`
`(22) Filed:
`
`Apr. 14, 1999
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. PCT/EP99/00078,
`filed on Jan. 8, 1999.
`Foreign Application Priority Data
`
`(30)
`
`Jan. 12, 1998
`
`(DE) ................................................... 9800526
`
`(52) U.S. Cl. ............................ 424/449; 424/448; 602/57;
`602/60; 604/290; 604/305; 604/307
`(58) Field of Search ..................................... 424/449, 448;
`602/57, 60; 604/290, 305, 307
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,602,176 A * 2/1997 Enz ............................... 514/490
`
`FOREIGN PATENT DOCUMENTS
`
`FR
`2 611 707
`wo
`98/30243
`wo
`98/31356
`* cited by examiner
`
`9/1988
`7/1998
`7/1998
`
`Primary Examiner-S. Mark Clardy
`Assistant Examiner-Michael A Williamson
`(74) Attorney, Agent, or Firm-Stephen G. Kalinchak; John
`D. Thallemer
`
`(57)
`
`ABSTRACT
`
`Pharmaceutical composition comprising (S)-N-ethyl-3-[1-
`dimethylamino )ethyl]-N -methyl-phenyl-carbamate in free
`base or acid addition salt form and an anti-oxidant. Said
`pharmaceutical compositions may be delivered to a patient
`using a transdermal delivery device.
`
`(51)
`
`Int. CI? ...................................................... A61F 13/00
`
`20 Claims, No Drawings
`
`Page 1 of 8
`
` Ex. 1001
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`Mylan Ex. 1001
`IPR Petition - USP 6,335,031
`
`

`
`1
`TTS CONTAINING AN ANTIOXIDANT
`
`US 6,335,031 Bl
`
`10
`
`This a continuation-in-part of application PCT/EP99/
`00078, filed Jan. 8, 1999. The entire contents of the PCT/
`EP99/00078 disclosure are incorporated herein by reference.
`This invention relates to a pharmaceutical composition
`for systemic administration of a phenyl carbamate, e.g. by
`transdermal administration. In particular this invention
`relates to a pharmaceutical composition of the phenyl
`carbamate-(S)-N -ethyl-3-[1-dimethylamino )ethyl ]-N-
`methyl-phenyl-carbamate---(hereinafter referred to as com(cid:173)
`pound A) in free base or acid addition salt form as disclosed
`in published UK patent application GB 2 203 040, the
`contents of which are incorporated herein by reference.
`Compound A is useful in inhibiting acetylcholinesterase
`in the central nervous system, e.g. for the treatment of 15
`Alzheimer's disease.
`A transdermal composition in the form of a patch is
`described in Example 2 of GB 2,203,040 according to which
`compound A is mixed with two polymers and a plasticiser to
`form a viscous mass. This mass is applied to a foil which is
`cut into patches.
`It has now been found after exhaustive testing that
`compound A is susceptible to degradation, particularly in the
`presence of oxygen. The transdermal composition described
`in GB 2203040 has been found to degrade, possibly by 25
`oxidative degradation, despite the formation of an occlusive
`polymer matrix around compound A and its storage in
`air-tight packaging.
`The present applicant has found that stable pharmaceu(cid:173)
`tical compositions comprising compound A can now be 30
`obtained, which show insignificant degradation of com(cid:173)
`pound A over a prolonged time period, e.g. 2 years, as
`indicated by standard tests, e.g. stress tests.
`In one aspect, the invention provides a pharmaceutical
`composition comprising Compound A in free base or acid 35
`addition salt form and an anti-oxidant.
`The pharmaceutical compositions of the present inven(cid:173)
`tion show a reduction in degradation by-products in stress
`stability tests.
`The pharmaceutical compositions of the invention may 40
`contain high amounts of compound A, e.g. from 1 to 40% by
`weight, e.g. 10-35%, more particularly 20-35%, e.g. 30%.
`The compound A may be in any of a wide variety of
`pharmaceutical diluents and carriers known in the art. The
`diluent or carrier may contain trace amounts of free radicals 45
`without affecting the stability of the pharmaceutical com(cid:173)
`position of the invention.
`The diluent or carrier is preferably one or more polymers,
`more preferably a hydrophilic polymer or polymers. In a
`preferred embodiment the diluent of carrier is selected from 50
`at least one polymer selected from acrylate polymers, and
`polymethacrylate polymers. The polymers preferably have a
`mean molecular weight of from about 50,000 to about
`300,000 Daltons, e.g. 100,000 to 200,000 Daltons. The
`polymers preferably are capable of forming a film, thus to be
`compatible to the skin.
`As a polymer one can mention in particular an acrylate
`co-polymer, e.g. co-polymers of butyl acrylate, ethyl hexyl
`acrylate and vinyl acetate. Preferably the polymer is cross(cid:173)
`linked. A preferred acrylate polymer is one of the Durotak 60
`brand available from National Starch and Chemical
`Company, Zutphen, Holland, e.g. Durotak 87-2353
`(hereinafter polymer A), 387-2051 or 387-2052 (hereinafter
`polymer D).
`The diluent or carrier is preferably present in an amount
`of up to 90%, more preferably 70% by weight base on the
`total weight of the pharmaceutical composition.
`
`2
`The polymer, when a hydrophilic polymer, may conve(cid:173)
`niently take up water and is permeable to water, e.g. mois(cid:173)
`ture from the skin, although the polymer may be insoluble
`in water. The polymer 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. around 5.5. If
`desired such polymers 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 (PYA)
`and derivatives, ethyl cellulose and other cellulose and
`starch derivatives.
`Hydrophilic polyacrylates are preferred polymers. The
`polyacrylate 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 (C1 _10) groups, more particularly
`20 alkyl groups having 1 to 4 carbon atoms such as methyl or
`ethyl groups.
`Examples of commercially available polymers of this
`type include:
`1) Polymers of methacrylate containing alkyl (C1 _4 ) ester
`groups. Preferably the polymer matrix is a mixture of an
`acrylate polymer and a methacrylate polymer e.g. in a
`weight ratio of from 5:1 to 1:1, e.g. 4:1 to 2:1 e.g. 3:1, e.g.
`butylmethylacrylate and methylmethylacrylate. MW
`20000, e.g. Plastoid B from Rohm, Darmstadt, Germany
`(hereinafter polymer B).
`2) Polymers of acrylate and methacrylate esters containing
`methyl and ethyl neutral ester groups and trimethylami(cid:173)
`noethyl cationic ester groups. Chloride ions may be
`present. Mean Molecular weight 150000 Daltons. Viscos(cid:173)
`ity (20° C.), maximum 15 cP. Refractive index
`1.380-1.385. Density 0.815--0.835 g/cm3
`. Ratio of cat-
`ionic 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 Rohm) 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).
`3) Polymers of methacrylate esters containing trimethylami(cid:173)
`noethyl cationic ester groups and other neutral (C1 _4)alkyl
`ester groups. Chloride ions may be present. Mean molecu(cid:173)
`lar 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 Rohm and hereinafter referred
`to a polymer C).
`If desired the pharmaceutical composition may contain
`other additives, such as plasticizers and/or softeners prefer(cid:173)
`ably skin compatible tensides, e.g. to provide flexibility to
`the pharmaceutical composition, and/or to dissolve partially
`55 or totally compound A
`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,
`Germany).
`65 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-
`
`Page 2 of 8
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` Ex. 1001
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`

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`US 6,335,031 Bl
`
`10
`
`45
`
`3
`(20) sorbitan monooleate, e.g. Tween 80, Registered
`Trade Mark available from Atlas Chemie, Germany.
`3) Polyoxyethylene-(5-40) stearic acid esters, e.g. Myrj
`(Registered Trade Mark) available from Atlas Chemie,
`Germany.
`4) Polyoxyethylene glycol fatty alcohol ethers, e.g. polyeth(cid:173)
`ylene glycol-(6-25) cetyl ether, glycerin polyethylene
`ricinoleate, glycerin polyethylene glycol stearate
`(Cremophor brand, Registered Trade Mark available from
`BASF Germany).
`5) Polyoxyethylene glycols of MW from 200 to 600 Daltons,
`e.g. 300 or 400 Daltons.
`6) Esters of poly(2-7)ethylene glycol glycerol ether having
`at least one hydroxyl group and an aliphatic (C 6 _22)
`carboxylic acid, e.g. Polyethylene glycol-(7) glyceryl
`cocoate, e.g. Cetiol HE, Registered Trade Mark, from
`Henkel, Germany.
`7) Adipic acid lower alkyl esters, e.g. di-n-butyl adipate and
`diisopropyl adipate.
`8) Glycerin polyethylene glycol ricinoleate, e.g. Product of
`35 moles ethylene oxide and castor oil, e.g. Brand Cre- 20
`mophor EL Registered Trade Mark, obtainable from
`BASF, Germany.
`9) Tracetin-(1,2,3).
`10) Fatty acid, e.g. a C12_18 fatty acid.
`11) Fatty alcohol, e.g. a C12_18 fatty alcohol.
`The amount and type of additive required may depend on
`a number of factors, e.g. the HLB value of the tenside and
`the flexibility of the pharmaceutical required. The amount of
`additive does not significantly influence the capability of the
`polyacrylate to form films. Generally the weight ratio of
`tenside to the polymer may be from about 1:10 to 5:1, e.g.
`1:10 to 1:3.
`Preferably, however, no such additive is present or is only
`present in an amount less than 1% by weight based on the
`total weight of the pharmaceutical composition.
`The pharmaceutical composition may contain skin pen(cid:173)
`etration promoters, e.g. 1-dodecylazacycloheptan-2-one
`(azone) and N,N-diethyl-m-toluamide (DEET).
`The amount and type of skin penetration promoter, and/or
`additives present may depend on a number of factors. 40
`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 may be from about 3 to about 50%, preferably 20
`to 40% by weight of the pharmaceutical composition.
`Preferably however no such additive is present or is only
`present in an amount less than 1% by weight of the phar(cid:173)
`maceutical composition.
`If desired the pharmaceutical composition may contain a
`hydrophobic elastomer, e.g. a synthetic resin. Such resins are
`conventional in the plaster art. Suitable resins may include
`non-swellable acrylate resins. These may if desired be
`adhesive. The weight ratio of polymer, e.g. 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 may
`include resin acids, glyceryl and phthalate esters of resin
`acids.
`A preferred pharmaceutical composition according to the
`invention comprises
`a) (S)-N -ethyl-3-[1-dimethylamino )ethyl]-N -methyl(cid:173)
`phenyl-carbamate as compound A in free base form in
`an amount of 20 to 40 weight-%,
`b) polymethacrylate in an amount of 10 to 30% by weight
`c) acrylate copolymer in an amount of 40 to 60% by
`weight, and
`
`4
`d) a-tocopherol in an amount of between 0.05 and 0.3%
`by weight
`wherein the total weight of the pharmaceutical composition
`is 100%.
`In another aspect the present invention provides the use of
`an anti -oxidant to stabilize a pharmaceutical composition
`containing Compound A
`Before the finding by the present applicant that an anti(cid:173)
`oxidant is necessary in compositions of this invention, it was
`hitherto thought unnecessary.
`The applicant has found that an effective stabilising effect
`is surprisingly achieved when the antioxidant is selected
`from tocopherol, esters thereof, e.g. tocopherol acetate,
`ascorbyl palmitate, ascorbic acid, butylhydroxytoluene,
`butylhydroxyanisole or propyl gallate, preferably
`15 a-tocopherol or ascorbyl palmitate. The antioxidant may be
`conveniently present in an amount of from about 0.01 to
`about 0.5%, e.g. 0.05 to 0.20, e.g. 0.15%, more particularly
`0.1% by weight based on the total weight of the pharma-
`ceutical composition.
`Pharmaceutical compositions of the invention produced
`in analogous manner to example 1 described hereinafter
`containing 0.1% tocopherol show for Example only 1.3%
`degradation products compared to 4.46% degradation prod(cid:173)
`ucts in equivalent compositions not containing tocopherol in
`25 2 month stress tests at 60° C. Pharmaceutical compositions
`of the invention in analogous manner to example 1 described
`hereinafter containing 0.15% tocopherol show for example
`only 0.25% degradation products compared to 1.09% deg(cid:173)
`radation products in compositions not containing tocopherol
`30 in 3 month stress tests at 40° C. at 75% room humidity.
`The pharmaceutical composition of the invention is pref(cid:173)
`erably used for transdermal application.
`In another aspect of the invention there is provided a
`transdermal device for administering a Compound A which
`35 comprises a pharmaceutical composition containing Com(cid:173)
`pound A, a backing layer providing support for the phar(cid:173)
`maceutical composition, an adhesive for fixing the pharma(cid:173)
`ceutical composition to the backing layer and a release-liner
`releasably contacting said adhesive.
`The pharmaceutical composition may be conveniently
`contained in a discrete thin layer, the upper and lower
`surfaces of which may be coated in a layer of adhesive the
`surface of which in turn provide backing layer and release(cid:173)
`liner contacting surfaces.
`The pharmaceutical composition contained in the discrete
`layer may comprise the Compound A and other excipients in
`a polymer matrix, the polymer matrix therefor being pro(cid:173)
`vided by the diluent or carrier aforementioned. If desired
`Compound A may be dispersed throughout, or dissolved in,
`50 said polymer matrix.
`The transdermal device may alternatively be of a more
`simple construction wherein the polymer matrix containing
`the pharmaceutical composition additionally comprises an
`adhesive. In such a simple construction there is no need for
`55 the layers of the aforementioned adhesive in order to fix and
`releasably fix respectively the backing layer and release(cid:173)
`liner as the polymer matrix containing the Compound A is
`self adhesive.
`The thickness of the pharmaceutical composition layer in
`60 a transdermal device may be in the order of from 20 to 100
`,urn, more preferably 60 to 100.
`The backing layer is preferably made of poly(ethylene
`terephthalate) PET foil. The backing layer should be thick
`enough to resist wrinkling which may arise upon prolonged
`65 periods in storage and through the movement of a subject's
`skin. Typically, the backing layer is, e.g. from approximately
`10 ,urn to 15 ,urn, in thickness.
`
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`
`US 6,335,031 Bl
`
`10
`
`40
`
`5
`In a preferred embodiment, the backing layer is a double
`layer which consists of a PET layer as aforementioned and
`an EVA layer, e.g. Scotch Pack 1012.
`The release-liner may be a disposable element which
`serves to protect the pharmaceutical composition prior to its
`application. Typically the release-liner is produced from a
`material impermeable to compound A, and adhesive. This
`release-liner may be easily stripped away from the adhesive.
`A preferred release-liner is made of poly( ethylene
`terephthalate) PET foil. A release-liner, e.g. of about 50 to
`250 ,urn, e.g. 100 ,urn thickness PET film, may be applied
`over the pharmaceutical composition.
`The release liner may be silicone-coated. Said coating is
`preferably formed of any fiuorosilicone compound which is
`conventionally used in the art, e.g a polyfiuoroalkylsiloxane. 15
`It is particularly preferred to employ such a fiuorosilicone
`coating when the adhesive used to affix the pharmaceutical
`composition to the release liner is not itself a silicone
`adhesive.
`The adhesive may be chosen from any adhesive suitable
`for skin contact and is preferably an adhesive in which
`Compound A dissolves at least partly. Preferably the adhe(cid:173)
`sive is a contact adhesive which is pressure sensitive.
`Preferred adhesive are chosen from amine-resistant silicone
`pressure sensitive adhesives known in the art, for example
`the BIO-PSA adhesives produced by Dow Coming
`Corporation, in particular BIO-PSA Q7-4302.
`In a very simple construction of the transdermal device,
`the adhesive may in fact be the polymer of the polymer
`matrix.
`In a further embodiment, the invention provides a trans(cid:173)
`dermal device comprising a backing layer, a layer compris(cid:173)
`ing compound A in a polymer matrix, a release-liner and,
`disposed between the layer comprising compound A in a
`polymer matrix and the release liner, a discrete layer of
`adhesive material for releasably fixing said transdermal
`device to patients skin.
`Preferably, the adhesive material is a silicone adhesive
`chosen from amine-resistant silicone pressure sensitive
`adhesives as hereinabove described.
`Typically, a transdermal device of said further embodi-
`ment comprises:
`a) a polymethacrylate backing layer
`b) Compound A in free base form in an acrylate copoly-
`mer
`c) a BIO-PSA Q7-4302 silicone adhesive layer
`d) a release-liner.
`Preferably, said further embodiment also comprises sili(cid:173)
`cone oil, e.g. silicone oil Q7-9120 from Dow Coming
`Corporation, in an amount of 0.1 to 5% by weight, e.g. 1%.
`The backing layer thickness is preferably from 10 to 50 ,urn,
`e.g. 23 ,urn, and has preferably a round shape.
`In general transdermal devices of the invention may be
`produced in a simple manner. A solvent-evaporation process
`may be used for said compositions. Thus all the ingredients
`of the pharmaceutical composition may be mixed in a
`solvent, e.g. acetone, ethylacetate or hexane, and cast onto
`a substrate which may act as the backing layer or the
`release-liner.
`The transdermal device aforementioned may be conve(cid:173)
`niently formed in continuous sheets and may be cut into
`patches of any desirable size or configuration before use.
`However, the patches so-formed may expose the pharma(cid:173)
`ceutical composition-containing layer of the laminate to the
`atmosphere at the outer edges of the patch.
`In an alternative embodiment, however, a transdermal
`device is provided wherein in the patches formed therefrom,
`
`6
`the pharmaceutical composition is not exposed to the atmo(cid:173)
`sphere during storage or during application. Such patches
`further reduce the likelihood of the Compound A being
`exposed to oxidative influences. The transdermal device
`may comprise, e.g. a continuous backing layer, a continuous
`release-liner and located there-between, in discrete portions,
`a pharmaceutical composition portion, the backing layer
`being configured such that it may be releasably fixed with an
`adhesive to the release-liner so to seal said pharmaceutical
`composition in a pocket defined by the inner surface of the
`backing layer and inner surface of the release-liner. This
`embodiment may be conveniently referred to as a cover
`patch.
`The pocket described hereinabove is preferably filled with
`an adhesive so as to encapsulate completely the discrete
`portion of pharmaceutical composition. Preferably the adhe(cid:173)
`sive is a silicone pressure sensitive adhesive as described
`hereinabove.
`It is an optional feature of all the transdermal devices
`20 described hereinabove that they comprise a layer of adhesive
`between the pharmaceutical composition and the release
`liner. This, has the primary function of fixing the release
`liner in contact with the remainder of the device thus
`protecting the pharmaceutical composition before use.
`25 However, if the adhesive is a silicone adhesive, then the
`layer may additionally act as a membrane through which the
`Compound A may pass at a controlled rate into the patient
`through the skin. Without wishing to be limited to a par(cid:173)
`ticular theory, it is suggested that the Compound A, dis-
`3D persed throughout the polymer matrix exhibits little ten(cid:173)
`dency to migrate into the silicone adhesive layer during
`storage. Accordingly, there is relatively low concentration of
`Compound A in the silicone layer. In use, the subjects skin,
`however, may display a much higher affinity for Compound
`35 A than the silicone layer and the initial low concentration of
`Compound A in the silicone layer passes into the subject's
`body. The silicone layer surprisingly prevents the subject
`from receiving a sudden high dose of Compound A upon
`application of the device and instead promotes a gradual
`increase of concentration in the subject.
`The cover patch transdermal device may conveniently be
`formed as a continuous sheet or webbing and may be cut, or
`tom along a frangible area dividing each device, into patches
`before use although such devices may be provided as
`45 discrete patches.
`The transdermal devices of the invention in general have,
`for example an effective contact area of pharmaceutical
`composition on the skin of from about 1 to about 80 square
`centimeters, preferably about 10 square centimeters, and are
`50 intended to be applied at intervals of about once every 1 to
`7 days, preferably 1-3 days. Compound A is well tolerated
`at a dose of 36 mg in free base form in up to 80 cm2 of
`patches according to the invention containing 36 mg com(cid:173)
`pound A from which 12 mg was absorbed. Compound A
`55 may, for example be administered at a dose of 8 mg in a
`patch of ca. 10 cm 2
`, once every day. The patch may be
`applied, for example on the abdomen, thigh, behind an ear,
`or on a shoulder or upper arm.
`The pharmaceutical composition, optionally formed as a
`60 transdermal device, of the present invention are useful for
`the same indications as for known compositions containing
`compound A. The exact amounts of compound A to be
`administered may depend on a number of factors, e.g. the
`drug release characteristics of the compositions, the drug
`65 penetration rate observed in vitro and in vivo tests, the
`duration of action required, the form of compound A, and for
`transdermal compositions the size of the skin contact area,
`
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`
`7
`and the part of the body to which the unit is fixed. The
`amount of and, e.g. area of the composition etc. may be
`determined by routine bioavailability tests comparing the
`blood levels of active agents after administration of com(cid:173)
`poundAin a composition according to the invention to intact
`skin and blood levels of Compound A observed after oral
`administration of a therapeutically effective dose of the
`compound.
`Orally, the Compound A is well tolerated at an initial dose
`of 1.5 mg twice a day orally and the dose may be stepped up 10
`to 3 mg twice daily in week 2. Higher dosages are possible,
`for example 4.5 mg twice daily and even 6 mg twice daily.
`Tolerability is seen to be even better for the transdermal
`device, wherein 24 mg were absorbed in 24 hours.
`The following example illustrates the invention.
`
`15
`
`EXAMPLE 1
`
`A composition is prepared consisting of the following
`components (by weight)
`
`Compound A
`Polymer
`Methacrylate
`a-tocopherol
`
`(I)
`
`(II)
`
`30%
`20% (A)
`49.85% (B)
`0.15%
`
`30%
`20% (D)
`49.85% (C)
`0.15%
`
`The components are added to ethyl acetate and mixed to
`give a viscous mass. The mass is spread onto a 100 ,urn
`transparent PET foil to produce a film 60 ,urn thick. A 15 ,urn
`thick PET foil release-liner is applied onto the dried mass.
`The patch is cut up into patches 10, 20, 30 or 40 cm2 in area.
`The liner is removed before application to the skin.
`The compositions and devices of this invention provide
`storage stable systems. Insignificant degradation is detected
`after storage of up to 6 months at room temperature.
`
`EXAMPLE 2
`
`A composition is prepared according to Example 1 with
`Ascorbyl-palmitate instead of a-tocopherol. Insignificant
`amounts of degradation products are detected after storage
`of at least four months at room temperature.
`
`EXAMPLE 3
`
`20
`
`25
`
`40
`
`45
`
`A composition is prepared according to Example 1 with a
`mixture of Ascorbyl-palmitate and a-tocopherol instead of
`a-tocopherol alone. Insignificant amounts of degradation 50
`products are detected after storage of at least four months at
`room temperature.
`
`EXAMPLE 4
`
`A two-parts composition is prepared consisting of the
`following components
`
`Compound A
`Polymer
`Methacrylate
`a-tocopherol
`Total 1st part
`(area weight 60 mg/10 cm2
`
`)
`
`Composition per unit (10 cm2
`
`)
`
`18 mg
`29.94 mg
`12 mg
`0.06
`70 mg
`
`30%
`49.85%
`20%
`0.1%
`100%
`
`55
`
`65
`
`US 6,335,031 Bl
`
`8
`
`-continued
`
`Composition per unit (10 cm2
`
`)
`
`and
`Bio-PSA Q7-4302
`Silicone oil Q7-9120
`a-tocopherol
`Total 2nd part
`(area weight 30 mg/1 0 cm2
`
`)
`
`29.67 mg
`0.3 mg
`0.03 mg
`30 mg
`
`98.9%
`1.0%
`0.1%
`100%
`
`The two parts are then put together in the form of a patch.
`What is claimed is:
`1. A pharmaceutical composition comprising:
`(a) a therapeutically effective amount of (S)-N-ethyl-3-{
`(1-dimethylamino )ethyl} -N -methyl-phenyl-carbamate
`in free base or acid addition salt form (Compound A);
`(b) about 0.01 to about 0.5 percent by weight of an
`antioxidant, based on the weight of the composition,
`and
`(c) a diluent or carrier.
`2. A pharmaceutical composition according to claim 1
`containing 1 to 40% by weight of Compound A in free base
`or acid addition salt form.
`3. A pharmaceutical composition according to claim 1
`wherein the anti-oxidant is tocopherol, esters thereof, ascor(cid:173)
`bic acid, butylhydroxytoluene, butylhydroxyanisole or pro(cid:173)
`pyl gallate.
`4. A pharmaceutical composition according to claim 1
`30 wherein the anti-oxidant is a-tocopherol or ascorbyl palmi(cid:173)
`tate.
`5. A pharmaceutical composition according to claim 1
`wherein the anti -oxidant is tocopherol and is present in an
`amount of 0.1% by weight based on the weight of the
`35 pharmaceutical composition.
`6. A pharmaceutical composition according to claim 1
`comprising
`(a) Compound A in free base form in an amount of 20 to
`40% by weight,
`(b) polymethacrylate in an amount of 10 to 30% by
`weight,
`(c) acrylate copolymer in an amount of 40 to 60% by
`weight, and
`(d) a-tocopherol in an amount of between 0.05 and 0.3%
`by weight
`wherein the total weight of the pharmaceutical composition
`is 100%.
`7. A transdermal device comprising a pharmaceutical
`composition as defined in claim 1, wherein the pharmaceu(cid:173)
`tical composition is supported by a substrate.
`8. A transdermal device according to claim 7, wherein the
`pharmaceutical composition is located between an adhesive
`layer and the substrate.
`9. A transdermal device according to claim 8, wherein a
`release liner releasably contacts the adhesive layer.
`10. The pharmaceutical composition of claim 1, further
`comprising silicone oil.
`11. A transdermal device comprising a backing layer, a
`60 layer comprising a therapeutically effective amount of (S)(cid:173)
`N -ethyl-3-{ (1-dimethylamino )ethyl} -N -methyl-phenyl(cid:173)
`carbamate (Compound A) and an amount of antioxidant
`effective to stabilize Compound A from degradation in a
`polymer matrix, a release-liner and, disposed between the
`layer comprising Compound A in a polymer matrix and the
`release-liner, a discrete layer of adhesive material for releas(cid:173)
`ably fixing said transdermal device to a patient's skin.
`
`Page 5 of 8
`
` Ex. 1001
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`

`
`US 6,335,031 Bl
`
`9
`12. The transdermal device of claim 1, wherein the
`discrete layer of adhesive material also comprises silicone
`oil.
`13. The transdermal device of claim 1, wherein the
`antioxidant is tocopherol, esters thereof, ascorbic acid,
`butylhydroxytoluene, butylhydroxyanisole, or propyl gal(cid:173)
`late.
`14. The transdermal device of claim 1, wherein the
`antioxidant is a-tocopherol or ascorbyl palmitate.
`15. A method of stabilizing (S)-N-ethyl-3-{(1-
`dimethylamino)ethyl}-N-methyl-phenyl-carbamate in free
`base or acid addition salt form (Compound A), wherein the
`method comprises forming a composition by combining
`Compound A with an amount of anti-oxidant effective to
`stabilize Compound A from degradation.
`
`10
`16. A method according to claim 15, wherein the anti(cid:173)
`oxidant is tocopherol, esters thereof, ascorbic acid,
`butylhydroxytoluene, butylhydroxyanisole or propyl gallate.
`17. The method of claim 15, wherein the anti-oxidant is
`a-tocopherol or ascorbyl palmitate.
`18. The method of claim 15, wherein the anti-oxidant is
`present in an amount of from about 0.01 to about 0.5% by
`weight based on the weight of the composition.
`19. The method of claim 15, wherein a-tocopherol is
`10 present as the antioxidant in an amount of 0.1% by weight
`of the composition.
`20. The method of claim 15, wherein the composition also
`comprises silicone oil.
`
`* * * * *
`
`Page 6 of 8
`
` Ex. 1001
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`INVENTOR(S)
`
`: 6,335,031 B1
`: January 1, 2002
`: Asmussen et al.
`
`Page 1 of 2
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`Title page,
`Item [30], should read:
`--Jan. 12, 1998 (GB) .............. 9800526 --.
`
`Item [56], References Cited, U.S. PATENT REFERENCES, should read:
`-- 4,948,807
`8/1990
`Rosin et al. ........................ 514/484
`5,344,656
`9/1994
`Enscore et al. ...................... 424/448
`5,462,745
`10/1995
`Enscore et al. ...................... 424/448 --
`
`Item [56], References Cited, FOREIGN PATENT REFERENCES, should read:
`-- EP
`427 741 B1
`5/1991
`wo
`89/12470
`12/1989 --
`
`Column 9,
`Lines 1-3, should read:
`
`-- The transdermal device of claim 11, wherein the discrete layer of adhesive material
`also comprises silicone oil. --.
`Lines 4-7, should read:
`
`-- The transdermal device of claim 11, wherein the antioxidant is tocopherol, esters
`thereof, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, or propyl gallate. --.
`
`Page 7 of 8
`
` Ex. 1001
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`INVENTOR(S)
`
`: 6,335,031 B1
`: January 1, 2002
`: Asmussen et al.
`
`Page 2 of 2
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`Column 9, cont'd.
`Lines 8-9, should read:
`
`-- The transdermal device of claim 11, wherein the antioxidant is a-tocopherol or
`ascorbyl palmitate. --.
`
`Signed and Sealed this
`
`First Day of October, 2002
`
`Attest:
`
`Attesting Officer
`
`JAMES E. ROGAN
`Director of the United States Patent and Trademark Office
`
`Page 8 of 8
`
` Ex. 1001