(i9) United States
`(12) Patent Application Publication oo) Pub. No.: US 2006/0078602 Al
`Apr. 13, 2006
`Kanios
`(43) Pub. Date:
`
`Illllllllllllllll
`
`US 20060078602A1
`
`(54) DEVICE FOR TRANSDERMAL
`ADMINISTRATION OF DRUGS INCLUDING
`ACRYLIC POLYMERS
`
`(75)
`
`Inventor: David Kanios, Miami, FL (US)
`
`Publication Classiflcation
`
`(51) Int. CI.
`461K 9/70
`(52) U.S. CI
`
`(2006.01)
`
`424/449
`
`Correspondence Address:
`DICKSTEIN SHAPIRO MORIN & OSHINSKY
`LLP
`2101 L Street, NW
`Washington, DC 20037 (US)
`
`(73) Assignee: Noven Pharmaceuticals, Inc.
`
`(21) Appl. No.:
`
`11/245,097
`
`(22) Filed:
`
`Oct. 7, 2005
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/616,860, filed on Oct.
`8, 2004.
`
`(57)
`
`ABSTRACT
`
`A transdermal delivery system is provided where the drug
`delivery rates, onset and profiles of at least one active agent
`are controlled by selectively manipulating the monomeric
`make up of an acrylic-based polymer in the transdermal drug
`delivery system. The drug carrier composition may be
`comprised of (a) one or more acrylic-based polymers having
`one or more different monomers selected from the group
`consisting of hard and soft monomers; (b) one or more
`silicone-based polymers; and (c) one or more active agents
`where the device provides a desired solubility for the active
`agent and controls drug delivery rates, onset and profiles of
`at least one active agent.
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1007
`
`

`

`Patent Application Publication Apr. 13, 2006 Sheet 1 of 2
`
`US 2006/0078602 A1
`
`HORMONE DRUG A (2 % Estrogen)
`
`70* 130%: Soft / Hard AcrjOc Monomers
`50% / 60%: Soft / Hard AcoOc Monomers
`20% / 60%: Soft / Hard AcryOc Monomers
`
`1.00 *
`
`0.75 •
`
`1
`
`I 1 0.50 •
`
`0.25
`
`OJOO |
`0
`
`12
`
`24
`
`• 48
`
`60
`
`Time (hr*)
`
`Figure 1
`
`HORMONE DRUG B (2% Progestin)
`
`70%! 30%: Soft I Hard Acryfic Monomers
`- 60% / 50%: Soft I Hard Acrylic Monomers
`• 20% / 60%: Soft f Hard Acryilc Monomers
`
`OJ
`
`0.0 "
`
`0.4
`
`I
`
`02
`
`-A
`-m
`
`06
`
`0
`
`12
`
`24
`
`M
`
`Ttme (hrs)
`
`Figure 2
`
`49
`
`90
`
`72
`
`

`

`Patent Application Publication Apr. 13, 2006 Sheet 2 of 2
`
`US 2006/0078602 A1
`
`HORMONE DRUG C.( 2% Androgen)
`
`50% / 50%: Soft I Hard Acrylic Monomera
`20% / 80%: Soft / Hard AcfyOc Monomere
`
`s
`
`!
`
`i
`
`<
`
`o *
`0
`
`12
`
`24
`
`36
`Time (hrs>
`
`Figure 3
`
`46
`
`60
`
`72
`
`AMINE DRUG A ( 6% Scopolamine)
`
`70% / 30% : Soft / Hard Acrylic Monomers
`50% / 50%: Soft I Hard Acrylic Monomers
`20% / 80%: Soft / Hard Acrylic Monomers
`
`*
`
`10 -
`
`•c
`
`'B 6 -a
`S
`E
`o
`
`4-
`
`<
`
`0
`' 0
`
`12
`
`T
`24
`Time (hrs)
`
`Figure 4
`
`36
`
`48
`
`

`

`US 2006/0078602 A1
`
`1
`
`Apr. 13, 2006
`
`DEVICE FOR TRANSDERMAL ADMINISTRATION
`OF DRUGS INCLUDING ACRYLIC POLYMERS
`[0001] This application claims the benefit of provisional
`application 60/616,860 filed Oct. 8, 2004, which is hereby
`incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`[0002] This invention relates generally to transdermal
`drug delivery systems, and more particularly to pharmaceu-
`tically acceptable adhesive matrix compositions. The inven­
`tion additionally relates to transdermal drug delivery sys­
`tems where the drug permeation, delivery rates and profiles
`can be selectively modulated within the transdermal drug
`delivery system.
`
`BACKGROUND OF THE INVENTION
`[0003] The use of transdermal drug delivery systems to
`topically administer an active agent is well known. These
`systems incorporate the active agent into a carrier compo­
`sition, such as a polymeric and/or pressure-sensitive adhe­
`sive composition, from which the active agent is delivered
`through the skin or mucosa of the user.
`transdermal drug
`[0004] Active-ingredient-containing
`delivery systems ("patches") are essentially divided into two
`major technical systems: reservoir systems and matrix sys­
`tems. The present invention relates to matrix systems where
`the active ingredient(s) are embedded in a semi-solid matrix
`made up of a single polymer or a blend of polymers.
`[0005] Both types of devices employ a backing layer that
`forms the protective outer surface of the finished
`transder­
`mal system and which is exposed to the environment during
`use. A release liner or protective layer that forms the inner
`surface covers the polymeric adhesive which is employed
`for affixing the system to the skin or mucosa of a user. The
`release liner or protective layer is removed prior to appli­
`cation, exposing the adhesive, typically a pressure-sensitive
`adhesive.
`[0006] In the "classic" reservoir-type device, the active
`agent is typically dissolved or dispersed in a carrier to yield
`a non-finite carrier form, such as, for example, a fluid or gel.
`In the reservoir-type device, the active agent is generally
`kept separate from the adhesive. The device has a pocket or
`"reservoir" which physically serves to hold the active agent
`and carrier, and which is formed in or by a backing layer. A
`peripheral adhesive layer is then used to affix the device to
`the user.
`[0007] The reservoir-type devices have a number of dis­
`advantages including a non-uniform drug release profile
`where a high dose of drug is initially released upon appli­
`cation to the user, often described as a "burst effect." This
`burst or high initial release of drug then drops off after a
`period of time to a rate that necessary to achieve a thera­
`peutically effective amount. Drug delivery according to this
`profile is generally described as first order release.
`[0008] While classic reservoir-type devices are still in use
`today, the term reservoir is being used interchangeably
`herein with matrix-type devices which still rely upon a
`separate adhesive means used to affix the device to the user.
`[0009]
`In a matrix-type device, the active agent is dis­
`solved or dispersed in a carrier that typically is in a finite
`
`carrier form. The carrier form can be self-adhesive or
`non-adhesive. Non-adhesive matrix-type devices, that is,
`those which still rely on a separate adhesive means to affix
`the device to the user, employ a drug permeable adhesive
`layer (often referred to as an "in-line adhesive" since the
`drug must pass through this layer) applied over the drug
`matrix carrier layer. To better control the release rate of the
`drug, the non-adhesive matrix-type devices often employ
`one or more additional drug permeable layers such as, for
`example, rate controlling membranes. The non-adhesive
`matrix-type devices often contain excipients, such as drug
`delivery enhancers, to help control the release rate. These
`devices are often referred to as multilayer or multilaminate.
`[0010] In a "monolithic" or "monolayer" matrix-type
`device, the active agent is typically solubilized or homog-
`enously blended in an adhesive carrier composition, typi­
`cally a pressure-sensitive adhesive or bioadhesive, which
`functions as both the drug carrier and the means of affixing
`the system to the skin or mucosa. Such devices, commonly
`referred to as drug-in-adhesive devices, are described, for
`example, in U.S. Pat. Nos. 4,994,267; 5,446,070; 5,474,783
`and 5,656,286, all of which are assigned to Noven Pharma­
`ceuticals, Inc., Miami, Fla. and herein incorporated by
`reference.
`[0011] While matrix-type devices, especially drug-in-ad­
`hesive devices, achieve more uniform and controlled drug
`deliver rates over longer periods of time, most transdermal
`systems remain subject to a higher initial drug release than
`is required to achieve therapeutic efficacy. For many drugs
`and/or therapeutic situations, it would be advantageous to
`eliminate or suppress this higher initial release and achieve
`a "steady state" (zero order) release profile which uniformly
`delivers a therapeutically effective amount of drug over the
`extended duration of device's desired use, preferably up to
`7 days or more.
`[0012] The high initial blood level concentration of certain
`drugs may cause adverse or undesired effects, or create
`toxicity concerns, thereby limiting the use of transdermal
`administration. In other instances, the higher initial blood
`level concentration may reduce the amount of drug required
`for treatment to the point of risking under dosing, or the
`higher initial blood level concentration may make it imprac­
`tical to increase the duration of the device's application
`while retaining therapeutic effectiveness. Reducing the fre­
`quency of replacing the transdermal drug delivery system
`would increase user compliance, reduce any lag or drop off
`in efficacious blood levels, and reduce the amount of drug
`required for treatment (also provided by reducing the higher
`initial blood level associated with the higher release rate).
`[0013] Drug concentration in transdermal delivery sys­
`tems can vary widely depending on the drug and polymers
`used. Low drug concentrations in the adhesive can result in
`difficulties in achieving an acceptable delivery rate of the
`medicament, preferably one approximating zero order kinet­
`ics. High drug concentrations, on the other hand, frequently
`affect the adhesion properties of the adhesives, and tend to
`promote unwanted crystallization.
`[0014] Simple diffusion models for permeation of drugs
`through the skin suggest that permeation rates are concen­
`tration dependent, that is, dependent on both the amount and
`the degree of drug within the pressure-sensitive adhesive
`composition. Some adhesives, such as, for example, poly-
`
`

`

`US 2006/0078602 A1
`
`2
`
`Apr. 13, 2006
`
`acrylate adhesives have a high affinity for many drugs and
`thus tend to solubilize higher concentrations of drug than do,
`for example, rubber adhesives. However, the use of poly-
`acrylates alone as the adhesive is not without its drawbacks
`as polyacrylate adhesives, for example, may tend to cause
`skin irritation, especially when the transdermal device is
`used for extended periods of time.
`[0015] Therefore, despite the existence of many different
`types of transdermal delivery systems in the art, there
`remains a continuing need for improving the selective
`modulation of drug permeation, delivery rates and drug
`profiles in transdermal delivery systems.
`
`SUMMARY OF THE INVENTION
`
`[0016] Based upon the foregoing, it is an object of the
`present invention to overcome the limitations of the prior
`transdermal systems, and to provide a transdermal drug
`delivery system which allows selective modulation of drug
`permeation and delivery rates and profiles.
`[0017] Another object is to provide a transdermal system,
`which is simple and inexpensive to manufacture. The
`present invention provides a transdermal drug delivery sys­
`tem for the topical application of one or more active agents
`contained in one or more polymeric and/or adhesive carrier
`layers which is manufactured to optimize drug loading while
`providing desirable adhesion to skin or mucosa as well as
`providing modulation of the drug delivery and profile.
`[0018] The invention is also directed to compositions and
`methods of controlling drug delivery rates, onset and pro­
`files of at least one active agent in a transdermal delivery
`system by selectively manipulating the monomeric make up
`of an acrylic-based polymer in the transdermal drug delivery
`system. The drug carrier composition may be comprised of
`(a) one or more acrylic-based polymers having one or more
`different monomers selected from the group consisting of
`hard and soft monomers; (b) one or more silicone-based
`polymers having one or more silanol contents (capping)
`and/or resin to polymer ratios and or a rubber; and (c) one
`or more active agents where the device provides a desired
`solubility for the active agent and controls drug delivery
`rates, onset and profiles of at least one active agent. Further
`manipulation of drug delivery, onset and profiles can be
`achieved by varying the concentrations of the drug in the
`drug-loaded carrier.
`[0019] Further embodiments of the invention include
`those described in the detailed description.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0020] FIG. 1 is a graphic representation of the effects on
`drug delivery, onset and profile of 17(3-estradiol with dif­
`ferent proportions of hard and soft acrylic-based monomers
`in the pressure sensitive adhesives.
`[0021] FIG. 2 is a graphic representation of the effects on
`drug delivery, onset and profile of norethindrone acetate
`with different proportions of hard and soft acrylic-based
`monomers in the pressure sensitive adhesives.
`[0022] FIG. 3 is a graphic representation of the effects on
`drug delivery, onset and profile of testosterone with different
`proportions of hard and soft acrylic-based monomers in the
`pressure sensitive adhesives.
`
`[0023] FIG. 4 is a graphic representation of the effects on
`drug delivery, onset and profile of scopolamine with differ­
`ent proportions of hard and soft acrylic-based monomers in
`the pressure sensitive adhesives.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`[0024] The foregoing and other objects are achieved by
`this invention which provides a transdermal drug delivery
`system to provide an adhesive matrix composition which
`effectively delivers drugs to a user over an extended period
`of time.
`[0025] Unless defined otherwise, all technical and scien­
`tific terms used herein have the same meaning as commonly
`understood by one of ordinary skill in the art to which the
`invention pertains.
`[0026] The invention relates to a pressure-sensitive adhe­
`sive composition comprising a single polymer or a blend of
`at least two polymers together with a drug. The blend of at
`least two polymers is preferred and is herein referred to as
`a multiple polymer adhesive system. The term "blend" is
`used herein to mean that there is no, or substantially no,
`chemical reaction or cross-linking (other than simple
`H-bonding) between the different polymers in the multiple
`polymer adhesive system.
`[0027] As used herein, the term "pressure-sensitive adhe­
`sive" refers to a viscoelastic material which adheres almost
`instantaneously to most substrates with the application of
`very slight pressure and remains permanently tacky. A
`polymer is a pressure-sensitive adhesive within the meaning
`of the term as used herein if it has the properties of a
`pressure-sensitive adhesive per se or functions as a pressure-
`sensitive adhesive by admixture with tackifiers, plasticizers
`or other additives. The term pressure-sensitive adhesive also
`includes mixtures of different polymers and mixtures of
`polymers, such as polyisobutylenes (PIB) of different
`molecular weights, the resultant mixtures being a pressure-
`sensitive adhesive. In the last case, the polymers of lower
`molecular weight in the mixture are not considered to be
`"tackifiers," the term "tackifier" being reserved for additives
`which differ other than in molecular weight from the poly­
`mers to which they are added.
`[0028] The term "topical" or "topically" is used herein in
`its conventional meaning as referring to direct contact with
`an anatomical site or surface area on a mammal including
`skin, teeth, nails and mucosa.
`[0029] The term "mucosa" as used herein means any moist
`anatomical membrane or surface on a mammal such as oral,
`buccal, vaginal, rectal, nasal or ophthalmic surfaces.
`[0030] The term "transdermal" as used herein means pas­
`sage into and/or through skin or mucosa for localized or
`systemic delivery of an active agent.
`[0031] The term "solubilized" is intended to mean that in
`the carrier composition there is an intimate dispersion or
`dissolution of the active agent at the crystalline, molecular
`or ionic level. As such, the solubilized active agent is
`considered herein to be in "non-crystallized" form when in
`the compositions of the present invention.
`[0032] The phrase "pharmaceutically acceptable flexible,
`finite" is intended to mean a solid form capable of conform-
`
`

`

`US 2006/0078602 A1
`
`3
`
`Apr. 13, 2006
`
`ing to a surface to which it is applied, and which is capable
`of maintaining the contact in such solid form so as to
`facilitate topical application without adverse physiological
`response, and without being appreciably decomposed by
`aqueous contact during use by a subject.
`[0033] The term "user" or "subject" is intended to include
`all warm-blooded mammals, preferably humans.
`[0034] The phrase "substantially zero-order" as used
`herein means transdermal delivery of an active agent at a
`release rate which is approximately constant once steady
`state is attained, typically within 12 to 24 hours after topical
`application. While variability in blood levels of active agent
`are contemplated within the scope of this meaning once
`steady state release is attained, the depletion rate of active
`agent over the duration of use should typically not exceed
`about 20% to about 25%.
`[0035] The term "active agent" (and its equivalents
`"agent,""drug,""medicament" and "pharmaceutical") is
`intended to have the broadest meaning and includes at least
`one of any therapeutic, prophylactic, pharmacological or
`physiological active substance, cosmetic and personal care
`preparations, and mixtures thereof, which is delivered to a
`mammal to produce a desired, usually beneficial, effect.
`More specifically, any active agent that is capable of pro­
`ducing a pharmacological response, localized or systemic,
`irrespective of whether therapeutic, diagnostic, cosmetic or
`prophylactic in nature, is within the contemplation of the
`invention. Also within the invention are such bioactive
`agents as pesticides, insect repellents, sun screens, cosmetic
`agents, etc. It should be noted that the drugs and/or bioactive
`agents may be used singularly or as a mixture of two or more
`such agents, and in amounts sufficient to prevent, cure,
`diagnose or treat a disease or other condition, as the case
`may be. In the case of drugs, the drug can be in its free base
`or acid form, or in the form of salts, esters, amides, prodrugs,
`enantiomers or mixtures thereof, or any other pharmaco­
`logically acceptable derivatives, or as components of
`molecular complexes
`[0036] The drug is used in a "pharmacologically effective
`amount." This term means that the concentration of the drug
`is such that in the composition it results in a therapeutic level
`of drug delivered over the term that the transdermal dosage
`form is to be used, preferably with zero order kinetics. Such
`delivery is dependent on a great number of variables includ­
`ing the drug, the time period for which the individual dosage
`unit is to be used, the flux rate of the drug from the system
`and a number of other variables. The amount of drug needed
`can be experimentally determined based on the flux rate of
`the drug through the system and through the skin when used
`with and without enhancers. Having determined the flux rate
`needed, the transdermal delivery system is designed so that
`the release rate over the period of time of therapeutic use
`will be at least equal to the flux rate. Of course, the surface
`area of the transdermal delivery system also affects the
`delivery of the drug from the system.
`[0037] Drugs in general can be used in this invention.
`These drugs include those categories and species of drugs
`set forth on page ther-5 to ther-29 of the Merck Index, 11th
`Edition Merck & Co. Rahway, N.J. (1989).
`[0038] Exemplary of drugs that can be administered by the
`novel dermal drug delivery system include, but are not
`limited to:
`
`1. Central nervous system stimulants and agents
`[0039]
`such as Dextroamphetamine, Amphetamine, Methamphet-
`amine, D-Amphetamine, L-Amphetamine, D,L-Amphet-
`amine, Phentermine, Methylphenidate and Nicotine.
`[0040] 2. Analgesics and/or Anti-Migraine such as
`Acetaminophen, Acetylsalicylic Acid, Buprenorphine,
`Codeine, Fentanyl, Lisuride, Salicylic Acid derivatives and
`Sumatriptan.
`[0041] 3. Androgen agents such as Fluoxymesterone,
`Methyl Testosterone, Oxymesterone, Oxymetholone, Test­
`osterone and Testosterone derivatives.
`[0042] 4. Anesthetic agents such as Benzocaine, Bupivic-
`aine, Cocaine, Dibucaine, Dyclonine, Etidocaine, Lidocaine,
`Mepivacaine, Prilocaine, Procaine and Tetracaine.
`[0043] 5. Anoretic agents such as Fenfluramine, Mazindol
`and Phentermine.
`[0044] 6. Anti-Bacterial (antibiotic) agents including Ami­
`noglycosides, fS-Lactams, Cephamycins, Macrolides, Peni­
`cillins, Polypeptides and Tetracyclines.
`[0045] 7. Anti-Cancer agents such as Aminolevulinic Acid
`and Tamoxifen.
`[0046] 8. Anti-Cholinergic agents such as Atropine, Euca-
`tropine and Scopolamine.
`[0047] 9. Anti-Diabetic agents such as Glipizide, Gly-
`buride, Glypinamide and Insulins.
`[0048] 10. Anti-Fungal agents such as Clortrimazole,
`Ketoconazole, Miconazole, Nystatin and Triacetin.
`[0049] 11. Anti-Inflammatory and/or Corticoid agents
`such as Beclomethasone, Betamethasone, Betamethasone
`Diproprionate, Betamethasone Valerate, Corticosterone,
`Cortisone, Deoxycortocosterone and Deoxycortocosterone,
`Acetate, Diclofenac, Fenoprofen, Flucinolone, Fludrocorti­
`sone, Fluocinonide, Fluradrenolide, Flurbiprofen, Halcino-
`nide, Hydrocortisone, Ibuprofen, Ibuproxam, Indoprofen,
`Ketoprofen, Ketorolac, Naproxen, Oxametacine, Oxyphen-
`butazone, Piroxicam, Prednisolone, Prednisone, Suprofen
`and Triamcinolone Acetonide.
`[0050] 12. Anti-Malarial agents such as Pyrimethamine.
`[0051] 13. Anti-Parkinson's and/or Anti-Alzhiemer's
`agents
`such
`as Bromocriptine, 1-Hydroxy-Tacrine,
`Levodopa, Lisaride Pergolide, Pramipexole, Ropinirole,
`Physostigimine, Tacrine Hydrochloride and Teruride.
`[0052] 14. Anti-Psychotic and/or Anti-Anxiety agents
`such as Acetophenazine, Azapirones, Bromperidol, Chlor-
`proethazine, Chlorpromazine, Fluoxetine, Fluphenazine,
`Haloperidol,
`Loxapine, Mesoridazine, Molindone,
`Ondansetron, Perphenazine, Piperacetazine, Thiopropazate,
`Thioridazine, Thiothixene, Trifluoperazine and Triflupro-
`mazine.
`[0053] 15. Anti-Ulcerative agents such as Enprostil and
`Misoprostol.
`[0054] 16. Anti-Viral agents such as Acyclovir, Rimanta­
`dine and Vidarabine.
`[0055] 17. Anxiolytic agents such as Buspirone, Benzo­
`diazepines such as Alprazolam, Chlordiazepoxide, Clon-
`
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`US 2006/0078602 A1
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`4
`
`Apr. 13, 2006
`
`azepam, Clorazepate, Diazepam, Flurazepam, Halazepam,
`Lorazepam, Oxazepam, Oxazolam, Prazepam and Triaz­
`olam.
`[0056] 18. fS-Adrenergic agonist agents such as Albuterol,
`Carbuterol, Fenoterol, Metaproterenol, Rimiterol, Quinter-
`enol, Salmefamol, Soterenol, Tratoquinol, Terbutaline and
`Terbuterol.
`[0057] 19. Bronchodilators such as Ephedrine derivatives
`including Epiniphrine and Isoproterenol, and Theophylline.
`[0058] 20. Cardioactive agents such as Atenolol, Benzy-
`droflumethiazide, Bendroflumethiazide, Calcitonin, Capto-
`pril, Chlorothiazide, Clonidine, Dobutamine, Dopamine,
`Diltiazem, Enalapril, Enalaprilat, Gallopamil, Indometha-
`cin, Isosorbide Dinitrate and Mononitate, Nicardipine, Nife­
`dipine, Nitroglycerin, Papaverine, Prazosin, Procainamide,
`Propranolol, Prostaglandin E^ Quinidine Sulfate, Timolol,
`and Verapamil.
`[0059] 21. a-Adrenergic agonist agents such as Phenyl­
`propanolamine.
`[0060] 22. Cholineigic agents such as Acetylcholine,
`Arecoline, Bethanechol, Carbachol, Choline, Methacoline,
`Muscarine and Pilocarpine.
`[0061] 23. Estrogens such as Conjugated Estrogenic Hor­
`mones, Equilenin, Equilin, Esterified Estrogens, Estradiol,
`IVfS-Estradiol, Estradiol Benzoate, IVfS-Estradiol Valerate,
`Estradiol IVfS-Cypionate, Estriol, Estrone, Estropipate, 17(3-
`Ethinyl Estradiol and Mestranol.
`[0062] 24. Muscle relaxants such as Baclofen.
`[0063] 25. Narcotic antagonist agents such Nalmfene and
`Naloxone.
`[0064] 26. Progestational agents such as Chlormadinone
`and Chlormadinone Acetate, Demegestone, Desogestrel,
`Dimethisterone, Dydrogesterone, Ethinylestrenol, Ethister-
`one, Ethynodiol and Ethynodiol Diacetate, Gestodene, 17a-
`Hydroxyprogesterone,
`Flydroxygesterone
`Caproate,
`Medroxyprogesterone and Medroxyprogesterone Acetate,
`Megestrol Acetate, Melengestrol, Norethindrone and Nore-
`thidrone Acetate, Norethynodrel, Norgesterone, Norgestrel,
`19-Norprogesterone, Progesterone, Promegestone and esters
`thereof. Free base forms of drugs which have a greater
`aflinity for the acid (carboxyl) functional group in a carboxyl
`functional acrylic-based polymer are preferred in some
`applications.
`[0065] The drugs and mixtures thereof can be present in
`the composition in different forms, depending on which
`form yields the optimum delivery characteristics. Thus, in
`the case of drugs, the drug can be in its free base or acid
`form, or in the form of salts, esters, prodrugs, specific
`enantiomers or racemates, or any other pharmacologically
`acceptable derivatives, or as components of molecular com­
`plexes.
`[0066] Preferred drugs include crystalline drugs, such as,
`for example, estradiol, norethindrone acetate, testosterone,
`scopolamine
`[0067] As used herein, "therapeutically effective" means
`an amount of an active agent that is sufScient to achieve the
`desired local or systemic effect or result, such as to prevent,
`cure, diagnose, mitigate or treat a disease or condition, when
`
`applied topically over the duration of intended use. The
`amounts necessary are known in the literature or may be
`determined by methods known in the art, but typically range
`from about 0.1 mg to about 20,000 mg, and preferably from
`about 0.1 mg to about 1,000 mg, and most preferably from
`about 0.1 to about 500 mg per human adult or mammal of
`about 75 kg body weight per 24 hours.
`[0068] The amount of drug to be incorporated in the
`composition varies depending on the particular drug, the
`desired therapeutic effect, and the time span for which the
`device is to provide therapy. For most drugs, the passage of
`the drugs through the skin will be the rate-limiting step in
`delivery. Thus, the amount of drug and the rate of release is
`typically selected so as to provide transdermal delivery
`characterized by a zero order time dependency for a pro­
`longed period of time. The minimum amount of drug in the
`system is selected based on the amount of drug which passes
`through the skin in the time span for which the device is to
`provide therapy. Normally, the amount of drug in the system
`can vary from about 0.1% to about 50%. Flowever, the
`composition of this invention is particularly useful for drugs
`which are used in relatively low concentrations, especially
`0.3% to 30% of the total composition, more preferably from
`about 0.5% to about 15% of the total composition, most
`preferably from about 1% to about 10% of the total com­
`position.
`[0069] As used herein, the term "supersaturated" used in
`reference to the drug means that the amount of drug present
`is in excess of its solubility or dispersability in a multiple
`polymer adhesive system.
`[0070] As used herein "flux" is defined as the percutane­
`ous absorption of drugs through the skin, and is described by
`Pick's first law of diffusion:
`
`J=-D(dCJdx),
`[0071] where J is the flux in g/cm2/sec, D is the diffusion
`coefScient of the drug through the skin in cm2/sec and
`dCm/dx is the concentration gradient of the active agent
`across the skin or mucosa.
`[0072] The invention resulted from the discovery that the
`transdermal permeation rate of a drug from the pressure-
`sensitive adhesive system can be selectively modulated by
`adjusting the monomeric make up of the acrylic based
`polymer in the system. As used herein, the term "transder­
`mal permeation rate" means the rate of passage of the drug
`through the skin; which, as known in the art, may or may not
`be affected by the rate of release of the drug from the carrier.
`
`[0073] Solubility parameter, also referred to herein as
`"SP," has been defined as the sum of all the intermolecular
`attractive forces, which are empirically related to the extent
`of mutual solubility of many chemical species. A general
`discussion of solubility parameters is found in an article by
`Vaughan, "Using Solubility Parameters in Cosmetics For­
`mulation,"/. Soc. Cosmet. Chem., Vol. 36, pages 319-333
`(1985).
`
`[0074] The present invention relates to a drug-in-adhesive
`system that is preferably formulated so that it is a pressure-
`sensitive adhesive at room temperature and has other desir­
`able characteristics for adhesives used in the transdermal
`drug delivery art. Such characteristics include good adher­
`ence to skin, ability to be peeled or otherwise removed
`
`

`

`US 2006/0078602 A1
`
`5
`
`Apr. 13, 2006
`
`without substantial trauma to the skin, retention of tack with
`aging, etc. In general, the multiple polymer adhesive system
`should have a glass transition temperature (Tg), measured
`using a differential scanning calorimeter, of between about
`-70° C. and 70° C.
`[0075] The drug-in-adhesive system preferably includes at
`least one acrylic-based polymer, one polysiloxane or rubber
`and an active agent, where the monomeric make-up of the
`acrylic-based polymer modulates the drug delivery charac­
`teristics. In addition to selecting the monomeric makeup of
`the acrylic-based polymer, forming a blend of multiple
`polymers results in an adhesive system having a character­
`istic "net solubility parameter," the selection of which
`advantageously permits a selectable modulation of the deliv­
`ery rate of the drug by adjusting the solubility of the drug in
`the multiple polymer adhesive system.
`[0076] The term "acrylic-based" polymer is defined as any
`polyacrylate, polyacrylic, acrylate and acrylic polymer. The
`acrylic-based polymers can be any of the copolymers, ter-
`polymers, and the like of various acrylic acids or esters. The
`acrylic-based polymers useful in practicing the invention are
`polymers of one or more monomers of acrylic acids and
`other copolymerizable monomers. The acrylic-based poly­
`mers also can include copolymers of alkyl acrylates and/or
`methacrylates and/or copolymerizable secondary mono­
`mers. The acrylic-based polymer may be functional or non
`functional.
`[0077] As used herein, "functionality" is broadly defined
`as a measure of the type and quantity of functional groups
`that a particular acrylic-based polymer has.
`[0078] As used herein, "functional monomers or groups,"
`are monomer units in acrylic-based polymers which have
`reactive chemical groups which modify the acrylic-based
`polymers directly or provide sites for further reactions.
`Examples of functional groups include carboxyl, epoxy and
`hydroxy groups.
`[0079] As used herein "non-functional acrylic-based poly­
`mer" is defined as an acrylic-based polymer that has no or
`substantially no functional reactive moieties present in the
`acrylic. These are generally acrylic esters which can be
`copolymerized with other monomers which do not have
`functional groups, such as vinyl acetate.
`[0080] The term "carrier" as used herein refers to any
`non-aqueous material known in the art as suitable for
`transdermal drug delivery administration, and includes any
`polymeric material into which an active agent may be
`solubilized in combination or admixture with the other
`ingredients of the composition. The polymeric materials
`preferably comprise adhesives and, in particular, pressure-
`sensitive adhesives. The carrier material is typically used in
`an amount of about 40% to about 95%, and preferably from
`about 50% to about 80%, by weight based on the dry weight
`of the total carrier composition.
`[0081] The term "carrier composition" may also refer to
`enhancers, solvents, co-solvents and other types of addic-
`tives useful for facilitating transdermal drug delivery.
`[0082] The acrylic-based polymer according to the present
`invention is preferably polymerized from at least two mono­
`mers. The first monomer includes at least one soft acrylic
`monomer and the second monomer includes at least one
`hard acrylic monomer.
`
`As used herein, the term "soft acrylic monomer" is
`[0083]
`intended to refer to a monomer which is present in the
`transdermal drug delivery system as one monomer in the
`acrylic pressure-sensitive adhesive that has a glass transition
`temperature (Tg) from about -70° C. to about -10° C., more
`preferably from about -60° C. to about -20° C., and most
`preferably from about -60° C. to about -24° C. Some
`examples of soft acrylic monomers include: 2-ethyl hexyl
`acrylate, isobutyl acrylate, ethyl acrylate, butyl acrylate,
`dodecyl methacrylate, 2-ethylhexyl methacrylate, 2-ethoxy-
`ethyl acrylate, isopropyl acrylate, and 2-methoxyethyl acry­
`late.
`[0084] As used herein, the term "hard acrylic monomer" is
`intended to refer to a monomer which is present in the
`transdermal drug delivery system as a one monomer in the
`acrylic pressure sensitive adhesive that has a glass transition
`temperatur