United States Patent 15
`Heiberet al.
`
`MANTRATAAAUS005227169A
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,227,169
`Jul, 13, 1993
`
`[54]
`
`SORBITAN ESTERS AS SKIN PERMEATION
`ENHANCERS
`
`[56]
`
`[75]
`
`[73]
`
`(21)
`
`Inventors: Sonia Heiber, Salt Lake City; Dinesh
`Patel, Murray; Charles D. Ebert, Salt
`Lake City, all of Utah
`
`Assignee; Theratech, Inc., Salt Lake City, Utah
`
`Appl. No.: 848,110
`
`[22]
`
`Filed:
`
`Mar,9, 1992
`
`[62]
`
`51]
`[52]
`
`[58]
`
`Related U.S. Application Data
`Division of Ser. No. 702,043, May 17, 1991, Pat. No.
`5,122,383.
`
`Ent, CLS ccecccccssessssecssessessesseesssncseeee AG61F 13/00
`
`-» 424/449; 424/443;
`TLS. C1. cesessssecccsssensee
`424/447; 424/448
`Field of Search................ 424/448, 449; 514/946,
`514/947, 443
`
`References Cited
`U.S. PATENT DOCUMENTS
`4,362,737 12/1982 Schifer .cccccscsssssssseseeeeseen 514/399
`cece 424/449
`4,690,683 9/1987 Chien et al.
`
`4,710,191 12/1987 Kwiateket al.
`..
`424/449
`4,746,509 5/1988 Haggiage etal.
`514/947
`
`- 424/449
`4,879,119 11/1989 Konnoetal. .
`4,898,920 2/1990 Lee et al. neeesessssssesenssonee 424/448
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Leon R. Horne
`Attorney, Agent, or Firm—Morrison & Foerster
`{57]
`ABSTRACT
`Skin permeation enhancer compositions are provided
`whichincrease the permeability of skin to transdermally
`administered pharmacologically active agents. The
`compositions contain a sorbitan ester in addition to the
`selected pharmacologically active agent, and may also
`contain a C;-C, aliphatic alcohol. Methods and trans-
`dermal drug delivery systems for using the composi-
`tions are also provided.
`
`27 Claims, 1 Drawing Sheet
`
`I6b
`
`i6a
`
`  
`
`

 
`
`MYLAN- EXHIBIT 1021
`
`

`

`U.S. Patent
`
`July 13, 1993
`
`5,227,169
`
`D9¢OlAvt
`
`|Old.
`
`IPPRISESSSSSSSeeeTNVao_o=<
`
`4
`
`
`
`dl
`
`
`
`

`

`1
`
`3,227,169
`
`SORBITAN ESTERS AS SKIN PERMEATION
`ENHANCERS
`
`This application is a division of application Ser. No.
`07/702,043 filed May 17, 1991, now U.S. Pat. No.
`5,122,383 issued Jun. 16, 1992.
`
`TECHNICAL FIELD
`
`The present invention relates generally to the trans-
`dermal administration of pharmacologically active
`agents, and more particularly relates to methods and
`compositions for enhancing the permeability of the skin
`to such agents.
`
`BACKGROUND
`
`The delivery of drugs through the skin provides
`many advantages; primarily, such a meansof delivery is
`a comfortable, convenient and noninvasive way of ad-
`ministering drugs. The variable rates of absorption and
`metabolism encountered in oral treatment are avoided,
`and other inherent inconveniences—e.g., gastrointesti-
`nal
`irritation and the like ~—are eliminated as well.
`Transdermal drug delivery also makes possible a high
`degree of control over blood concentrations of any
`particular drug.
`Skinis a structurally complex, relatively thick mem-
`brane. Molecules moving from the’ environment into
`and through intact skin must first penetrate the stratum
`corneum and any material on its surface. They must
`then penetrate the viable epidermis, the papillary der-
`mis, and the capillary walls into the blood stream or
`lymph channels. To be so absorbed, molecules must
`overcome a different resistance to penetration in each
`type of tissue. Transport across the skin membraneis
`thus a complex phenomenon. However,it is the cells of
`the stratum corneum which present the primary barrier
`to absorption of topical compositions or transdermally
`administered drugs. The stratum corneum is a thin layer
`of dense, highly keratinized cells approximately 10-15
`microns thick over most of the body.
`In order to increase skin permeability, and in particu-
`lar to increase the permeability of the stratum corneum
`(i.e., so as to achieve enhanced penetration, through the
`skin, of the drug to be administered transdermally), the
`skin may be pretreated with a penetration enhancing
`agent (or “permeation enhancer”, as sometimesreferred
`to herein) prior to application of a drug. Alternatively,
`and preferably, a drug and a permeation enhancer are
`delivered concurrently.
`The presentinvention is directed to a novel composi-
`tion for enhancing the penetration of pharmacologically
`active agents through skin, the composition based on a
`sorbitan ester as will be described herein. The composi-
`tion may or may not contain an aliphatic alcohol as an
`additional component. The sorbitan ester compositions
`of the invention have been found by the inventors.
`herein to be particularly effective in enhancing the pen-
`etration of pharmaceutically active agents through skin.
`While there are a numberof patents and publications
`available whichrelate to the transdermal administration
`of drugs and to skin permeation enhancer compositions,
`applicants are unaware of any art which suggests that
`sorbitan esters are useful as permeation enhancers in the
`absenceofadditional permeation enhancing compounds
`or which describes the sorbitan ester/aliphatic alcohol
`compositions as described and claimed herein.
`
`15
`
`35
`
`55
`
`60
`
`65
`
`2
`
`CITATION OF ART
`
`The following references relate to one or more as-
`pects of the present invention.
`Skin permeation enhancers, generally: Various com-
`pounds for enhancing the permeability of skin are
`knownin the art. U.S. Pat. Nos. 4,006,218, 3,551,554
`and 3,472,931, for example, respectively describe the
`use of dimethyisulfoxide (DMSO), dimethyl formamide
`(DMF) and N,N-dimethylacetamide (DMA) to en-
`hance the absorption of pharmacologically active
`agents through the stratum corneum. Other compounds
`which have been used to enhance skin permeability
`include: decylmethylsulfoxide (CygMSO); diethylene
`glycol moncethyl ether; polyethylene glycol monolau-
`rate (PEGML,;see, e.g., U.S. Pat. No. 4,568,343); glyc-
`erol monolaurate (U.S. Pat. No. 4,746,515); propylene
`glycol monolaurate; ethanol] (e.g., as in U.S. Pat. No.
`4,379,454); eucalyptol (U.S. Pat. No. 4,440,777 ; lecithin
`(U.S. Pat. No. 4,783,450);
`the I-substituted azacy-
`cloheptan-2-ones, particularly 1-n-dodecylcyclazacy-
`cloheptan-2-one (available under the trademark Azo-
`ne ®) from Nelson Research & DevelopmentCo., Irvin,
`Cal.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616
`and 4,557,934); propylene glycol in combination with a
`fatty acid such as linoleic acid (European Patent Publi-
`cation No. 261429); “cell envelope disordering com-
`pounds” such as methyl laurate or oleic acid in combi-
`nation with N-(hydroxyethyl) pyrrolidone (U.S. Pat.
`No. 4,537,776), C3-C4 diols (U.S. Pat. No. 4,552,872,
`European Patent Application Publication No. 043738);
`or a binary system of oleic acid, oleins or oleyl alcohol
`in combination with a lower alcohol (U.S. Pat. No.
`4,863,970).
`Sorbitan analogs as permeation enhancers, specifi-
`cally: T. Ogiso et al., J. Pharmacobio-Dyn., 9:517-525
`(1986), presents studies on percutaneous absorption in
`vivo and the penetration in vitro of indomethacin. Sor-
`bitan monooleate, was tested as a permeation enhancer
`in combination with a dimethyl sulfoxide (DMSO)gel
`and was found to have no enhancingeffect. T. Ogiso et
`al., J. Pharm. Sci., 78(4):319-323 (1989), describes the
`combined use of laurocapram and sorbitan monooleate
`in a permeation enhancer composition also containing a
`DMSOgel, for the transdermal administration of indo-
`methacin. W.-W. Shen et al.
`J. Pharm. Sci,
`65(12):1780-1783 (1986), describes the effect of various
`nonionic surfactants, including sorbitan monopalmitate
`and sorbitan trioleate, on the percutaneous absorption
`of salicylic acid. As with the latter two references, the
`sorbitan esters are used in conjunction with DMSO.
`U.S. Pat. No. 4,637,930 to Konno et al. describes a
`transdermal formulation for the administration ofnicar-
`dipine hydrochloride which contains a mixed liquid
`composed of urea and an additional compound which
`may be a sorbitan “middle chain” (6-12 carbon atom)
`fatty acid ester.
`:
`
`SUMMARYOF THE INVENTION
`
`Accordingly,it is a primary object of the invention to
`provide a method for enhancing the rate of penetration
`of a pharmacologically active agent through the skin.
`It is another object of the invention to provide such a
`method which involves applying to a selected area of
`intact skin a therapeutically effective amount of the
`selected pharmacologically active agent in combination
`with a permeation enhancer composition containing a
`sorbitan ester.
`
`

`

`3,227,169
`
`4
`al., the disclosure of which is incorporated by reference
`herein.
`
`3
`It is still another object of the invention to provide
`such a method wherein the permeation enhancer com-
`position consists essentially of: (1) a sorbitan ester; or (2)
`a sorbitan ester in combination with an aliphatic alcohol
`as will be described in detail herein.
`It is a further object of the invention to provide a skin
`permeation enhancer composition comprising the phar-
`macologically active agent and a permeation enhancer
`composition which consists essentially of: (1) a sorbitan
`ester; or (2) a sorbitan ester in combination with an
`aliphatic alcohol.
`It is still a further object of the invention to provide a
`transdermal system in the form of a laminated compos-
`ite designed to adhere to the skin. The composite con-
`tains,
`in addition to the selected pharmacologically
`active agent to be administered, a permeation enhancer
`composition containing a sorbitan ester, and, optionally,
`an aliphatic alcohol.
`Additional objects, advantages and novel features of
`the invention will be set forth in part in the description
`which follows, and in part will become apparent to
`those skilled in the art upon examination ofthe follow-
`ing, or may be learned by practice of the invention.
`In one aspect, the invention is a method for adminis-
`tering a pharmacologically active agent transdermally
`so as to achieve relatively high transdermal fluxes, by
`administering, through a predetermined area ofintact
`skin and for a predetermined period of time, (1) the
`agent, and (2) a permeation enhancer consisting essen-
`tially of a sorbitan ester, or a sorbitan ester in combina-
`tion with a C;~Cy aliphatic alcohol. In a preferred em-
`bodiment, the skin permeation enhancer and the drug
`are administered in a single composition. As the clear-
`ance rate of many drugs from the body is quite high,it
`is generally preferred that administration be substan-
`tially continuous throughout the time period chosen for
`patch application.
`In another aspect of the invention, a composition of
`matter is provided that is useful for the delivery of a
`pharmacologically active agent through the skin, com-
`prising:
`(a) a therapeutically effective amount of the pharma-
`cologically active agent to be administered; and
`(b) an amountof a permeation enhancer composition
`effective to enhance the penetration of the pharmaco-
`logically active agent through the skin, wherein the
`enhancer consists essentially of a sorbitan ester or a
`sorbitan ester combined with a C)-C4aliphatic alcohol.
`In still another aspect of the invention, a therapeutic
`system is provided for administering a drug transder-
`mally, at relatively high fluxes as noted above, in the
`form of a skin patch. Theskin patch is preferably in the
`form of a matrix-type laminated composite containing
`an upper backing layer thatis substantially impermeable
`to the drug, and at least one drug/enhancerreservoir,
`one of which formsthe basal surface of the device and
`is designed to adhere to the skin during use. The reser-
`voir is a matrix which contains both the drug and a
`permeation enhancer as described above. Such a lami-
`nated composite preferably includes a strippable protec-
`tive release liner laminated to the basal surface of the
`drug reservoir. The release liner is a disposable element
`designed to protect the exposed reservoir surface prior
`to use. In an alternative embodiment, a transdermal
`therapeutic system is provided in the form of a liquid
`reservoir-type laminated composite, e.g., as described in
`commonlyassigned U.S. Pat. No. 4,849,224 to Chang et
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG.1 is a schematic sectional view through a lami-
`nated matrix-type transdermal system ofthe invention.
`FIG, 2 is a schematic sectional view through a lami-
`nated liquid reservoir-type transdermal system of the
`invention.
`‘
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Before describing the present compositions, systems
`and methodsofthe invention in detail, it is to be under-
`stood that this invention is not limited to the particular
`drugs, sorbitan esters, aliphatic alcohols, or laminate
`materials described herein as such may, ofcourse, vary.
`It is also to be understood that the terminology used
`herein is for the purpose of describing particular em-
`bodiments only, and is not intended to be limiting.
`It must be noted that, as used in this specification and
`the appended claims, the singular forms “a,” “an” and
`“the” include plural referents unless the content clearly
`dictates otherwise. Thus, for example, reference to a
`laminated structure containing “a drug” includes a mix-
`ture of two or more drugs, reference to “an adhesive”
`includes reference to one or more of such adhesives,
`and reference to “a sorbitan ester” includes reference to
`a mixture of two or moresorbitan esters.
`In describing and claiming the present invention, the
`following terminology will be used in accordance with
`the definitions set out below.
`“Penetration enhancement”or “permeation enhance-
`ment” as used herein relates to an increase in the perme-
`ability of skin to a pharmacologically active agent,i.e.,
`SO as to increase the rate at which the agent permeates
`into and through the skin. A “permeation enhancer”is
`a material which achieves such permeation enhance-
`ment, and a “penetration enhancing amount”of an en-
`hancer as used herein means an amount effective to
`enhanceskin penetration of a selected agentto a desired
`degree.
`By “transdermal” drug delivery, applicant is using
`the term in its conventional sense, i.e., to indicate deliv-
`ery of a drug by passage through the skin and into the
`blood stream. By “transmucosal” drug delivery, appli-
`cant intends delivery of a drug by passage of a drug
`through the mucosal tissue into the blood stream. “Top-
`ical” drug delivery is used to mean local administration
`of a topical drug as in, for example, the treatment of
`various skin disorders. These terms will sometimes be
`used interchangeably herein, i.e., aspects of the inven-
`tion which are described in the context of “trans-
`dermal” drug delivery, unless otherwise specified, can
`apply to transmucosal or topical delivery as well. That
`is, the compositions, systems, and methods of the inven-
`tion, unless explicitly stated otherwise, should be pre-
`sumed to be equally applicable with any one of these
`three modes of drug delivery.
`The term “drug” or “pharmacologically active
`agent” as used herein is intended to mean a compound
`or composition of matter which, when administered to
`an organism (human or animal) induces a desired phar-
`macologic and/or physiologic effect by local and/or
`systemic action. In general, the terms include the thera-
`peutic or prophylactic agents in all major therapeutic/-
`prophylactic areas of medicine. Examples of drugs use-
`ful in conjunction with the present invention include:
`
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`

`

`3,227,169
`
`5
`anti-infectives such as antibiotics and antiviral agents;
`analgesics and analgesic combinations; anorexics; an-
`tihelminthics; antiarthritics; antiasthmatic agents; anti-
`cholinergic agents; anticonvulsants; antidepressants;
`antidiabetic agents; antidiarrheals; antihistamines; anti-
`inflammatory agents, antimigraine preparations; anti-
`motion sickness drugs; antinauseants; antineoplastics;
`antiparkinsonism drugs; antipruritics, antipsychotics;
`antipyretics; antispasmodics; anticholinergics; sympa-
`thomimetics; xanthine derivatives; cardiovascular prep-
`arations including calcium channel blockers and beta-
`blockers such as pindolol and antiarrhythmics; antihy-
`pertensives; diuretics; vasodilators including general
`coronary, peripheral and cerebral; central nervous sys-
`tem stimulants; cough andcold preparations, including
`decongestants;
`steroids; hypnotics;
`immunosuppres-
`sives; muscle relaxants; parasympatholytics; psychos-
`timulants; sedatives; and tranquilizers. For purposes of
`the aforementioned definition, “drugs” as used herein
`also include locally administered topical medicaments
`such as antibacterial agents, antifungals, antimicrobials,
`cutaneous growth enhancers, antipsoriatics, anti-acne
`medicaments, and thelike.
`“Carriers” or “vehicles” as used herein refer to car-
`rier materials without pharmacological activity which
`are suitable for administration in conjunction with the
`presently disclosed and claimed compositions, and in-
`clude any such carrier or vehicle materials known in the
`art, e.g., any liquid, gel, solvent, liquid diluent, solubi-
`lizer, or the like. The carriers and vehicles suitable
`herein are “pharmaceutically acceptable” in that they
`are nontoxic, do not interfere with drug delivery, and
`are not for any other reasons biologically or otherwise
`undesirable. Examples of specific suitable carriers and
`vehicles for use herein include water, mineraloil, sili-
`cone, inorganic gels, aqueous emulsions, liquid sugars,
`waxes, petroleum jelly, and a variety of other oils and
`polymeric materials.
`By a “therapeutically effective” amount ofa drug or
`pharmacologically active agent is meant a nontoxic but
`sufficient amount of the drug or agent to provide the
`desired therapeutic effect.
`:
`The invention is thus in one embodiment a method
`for enhancingthe rate of penetration ofa pharmacologi-
`cally active agent through the skin, wherein the method
`involves co-administration of the agent through a pre-
`determined area of intact skin, and for a predetermined
`period of time, the selected agent and a permeation
`enhancer consisting essentially of a sorbitan ester or a
`sorbitan ester in combination with a C;-Cy aliphatic
`alcohol. The sorbitan esters which are useful in. con-
`junction with the present invention have the structure
`
`20
`
`25
`
`40
`
`45
`
`6
`.
`—-O(CO)R’as defined above. Rj, Ra and R3, maybe, for
`example, lauryl, myristyl, palmity], stearyl, palmitoleyl,
`oleyl, linoleyl, linolenyl, or ricinoleylesters, or the like.
`Exemplary sorbitan esters are long-chain sorbitan
`monoesters, wherein R1 is as defined above, R’is hydro-
`carbon of 11 to 21 carbon atoms, and R2 and R3 are both
`hydroxyl. Particularly preferred compounds within the
`class of sorbitan monoesters are sorbitan monooleate
`and sorbitan monolaurate.
`In addition to a sorbitan ester, the permeation en-
`hancer composition of the invention mayalso include a
`C;-C4 aliphatic alcohol component. Examples ofsuit-
`able alcohols within this class include ethanol, D-
`propanol, isopropanol, t-butanol, and mixtures thereof.
`- The method of delivery of the present compositions
`May vary, but necessarily involves application of drug
`and enhancerto a selected intact surface of the skin or
`othertissue for a period of time sufficient to provide the
`desired blood level of drug. The method preferably
`involves administration of drug and enhancersimulta-
`neously, in a single composition,i.e., as an ointment, gel,
`cream,or the like, or may involve use of a drug delivery
`device as taught,
`for example,
`in U.S. Pat. Nos.
`4,849,224, 4,983,395, 4,568,343, 3,797,494 or 3,742,951.
`Whenthe drug to be administered and the permeation
`enhancer as described above are applied in the form of
`an ointment, gel, cream orthe like, the amount of drug
`contained within the composition will depend on a
`variety of factors, including the desired rate of delivery,
`the desired dosage, the disease to be treated, the nature
`and activity of the drug, the desired effect, possible
`adverse reactions, the ability and speed of the drug
`selected to reach its intended target, and otherfactors
`within the particular knowledge of the patient and the
`physician. The amount of enhancerwill typically be in
`the range of 0.1 wt. % to 40 wt. % relative to the total
`composition, more preferably on the order of about 2.5
`wt. % to 15 wt. %. The composition may,in addition to
`drug and enhancer, include one or moreselected carri-
`ers or excipients, and/or various agents and ingredients
`commonly employed in dermatological ointments and
`lotions. For example, fragrances, opacifiers, preserva-
`tives, antioxidants, gelling agents, perfumes, thickening
`agents,
`stabilizers,
`surfactants, emollients, coloring
`agents, and the like may be present so long as they are
`pharmaceutically acceptable and compatible with the
`drug and enhancer.
`A transdermal delivery system for the administration
`of a drug can be constructed with the drug/enhancer
`composition described hereinabove. Preferred trans-
`dermal drug delivery systems for use herein are lami-
`nated composites which contain one or more drug/per-
`meation enhancer reservoirs, a backing layer and, op-
`tionally, one or more additional layers (e.g., additional
`drug and/or enhancer reservoirs) as those skilled in the
`art of transdermal drug delivery will readily appreciate.
`FIG. 1 depicts an exemplary system, generally desig-
`nated 10, that when applied to skin administers a se-
`lected pharmacologically active agent as outlined
`above. System 10 is a laminated composite in which the
`top layer 12 is a backing layer, its face forming the top
`surface of the composite. The drug reservoir, contain-
`ing drug, enhancer as described herein, and optional
`carriers or vehicles, is shown at 14, immediately below
`and adjacent to the backing layer. Prior to use, the
`laminate also includes a strippable protective release
`liner. In a preferred embodiment, as described in co-
`
`Gere
`HO~CH oO
`R2
`
`H
`
`H
`
`HR;
`
`wherein the substituent R; has the structure —O¢-
`CO)R’, where R’is selected from the group consisting
`of saturated, mono-unsaturated, di-unsaturated andtri-
`unsaturated aliphatic hydrocarbon substituents of 7 to
`21 carbon atoms, preferably 11 to 21 carbon atoms, and
`maybe substituted with 1 to 3 hydroxyl groups. The
`substituents R2 and R3 may be the sameor different and
`are selected from the group consisting of hydroxyl and
`
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`

`

`7
`pending commonly assigned Ser. No. 07/625,906, filed
`Dec. 10, 1990, and entitled “Method and Systems for
`Administering Nitroglycerin Transdermally at En-
`hanced Transdermal Fluxes,” the release liner is in the
`form of two sheets 16a and 16b,the first sheet 16a par-
`tially overlapping the second sheet 166. Additional
`structural layers and/or additional drug/enhancerres-
`ervoirs may also be present.
`The drug reservoir is preferably comprised of a
`contact adhesive which is a pressure-sensitive adhesive
`suitable for long-term skin contact. It must also be phys-
`ically and chemically compatible with the drug and
`enhancer employed, and with any carriers or vehicles
`incorporated into the drug/enhancer composition. Fur-
`ther, the adhesive selected for use as the reservoir layer
`must be such that the drug and enhancerare at least
`somewhatsoluble in the adhesive. The drug reservoir
`will generally be in the range of about 2 to 4 mils in
`thickness. Suitable adhesives for use as the drug reser-
`voir
`include polysiloxanes, polyacrylates, polyure-
`thanes, tacky rubbers such as polyisobutylene, and the
`like. Particularly preferred contact adhesives for use as
`the drug reservoir herein are cross-linked acrylates
`(e.g.,
`the Durotake (®) adhesives, available from Na-
`tional Starch & Chemical Co., New York, N.Y., or the
`Gelvae ® adhesives, available from Monsanto Co., St.
`Louis, Mo.).
`The backing layer, whichis, as shown, adhered to the
`drug reservoir and serves as the upper layer of the de-
`vice during use, functions as the primary structural
`element of the device. The backing layer is made of a
`sheetor film of a preferably flexible elastomeric mate-
`rial that is substantially impermeable to the drug/en-
`hancer composition. The layer will typically be on the
`order of 1.0 to about 4.0 mils in thickness, and is prefera-
`bly of a material that permits the device to follow the
`contoursof the skin, such that it may be worn comfort-
`ably on any skin area,e.g., at joints or other points of
`flexure. In this way, in response to normal mechanical
`strain, thereis little or no likelihood of the device disen-
`gaging from the skin dueto differences in theflexibility
`or resiliency of the skin and the device. Examples of
`polymers useful for the backing layer herein are poly-
`ethylene, polypropylene, polyesters, polyurethanes,
`polyethylene vinyl acetate, polyvinylidene chloride,
`block copolymers such as PEBAX,and the like. The
`backing layer may also comprise laminates of one or
`more of the foregoing polymers.
`Therelease liner is a disposable element which serves
`only to protect the device prior to application. Typi-
`cally, the release liner is formed from a material imper-
`meable to the drug, vehicle, and adhesive, and whichis
`easily stripped from the contact adhesive that serves as
`the drug reservoir layer. Preferred release liners for use
`herein are those which are generally suitable for use in
`conjunction with pressure-sensitive adhesives. Silanized -
`polyester films are presently preferred.
`In a preferred embodiment, as noted above, a two-
`part release liner is used, wherein a first strippable pro-
`tective sheet (shown as 16a in FIG.1) partially overlaps
`a secondstrippable protective sheet 165, such that the
`area of overlap gives rise to a tab which extends from
`the basal surface of the laminate, enabling ready re-
`moval ofthe strippable sheets from the reservoir layer.
`The preferred laminated composites of the invention
`are as shown in FIG.1, having a backing layer, a drug
`reservoir, and a two-piece release liner; the drug reser-
`voir contains a drug/enhancer composition as described
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`65
`
`3,227,169
`
`8
`above, with the quantity of the drug therein, and with
`the remainder of the drug reservoir comprised of adhe-
`sive and optional carriers, vehicles or the like. If the
`drug is a hydrophobic material such as a steroid,it is
`preferred that the quantity of drug contained within the
`Teservoir is at “subsaturation” as described in detail in
`applicants’ copending, commonly assigned U.S. appli-
`cation Ser. No. 07 626,685, filed Dec. 11, 1990, the
`disclosure of whichis hereby incorporated by reference
`in its entirety. To use these laminated composites, oneis
`applied directly to the skin of a patient, to release the
`drug/enhancer composition to the skin, allowing the
`drug to permeate into the circulation. The adhesive
`layer which serves as the drug reservoir should be in
`firm contact with the skin.
`In general, such devices are fabricated using methods
`standard in the art, e.g., solvent-evaporation film cast-
`ing in which all components of the drug/enhancer com-
`position are admixed with the adhesive which will serve
`as the drug reservoir, and cast onto a substrate whichis
`either the backing layer or release liner. Other layers are
`then laminatedto this initial structure.
`In an alternative embodiment, laminated composites
`containing drug in a liquid reservoir, as described in
`U.S. Pat. No. 4,849,224, may be used. As described in
`that patent, the disclosure of which is incorporated by
`reference herein, such devices shown generally at 18 in
`FIG, 2 are comprised of an uppermost layer of a heat-
`sealable backingfilm 20 having an inverted, cup-shaped
`recess that serves the reservoir 22 for the drug-enhancer
`formulation. The underside of the outer edge of the
`backing film carries a ring-shaped layer 24 of a pressure-
`sensitive adhesive peripheral to the reservoir. Underly-
`ing the reservoir, just inward of the peripheral ring of
`adhesive, is a membrane layer 26 that is permeable to
`the drug-enhancer formulation. A peel sealable inner
`liner 28 underlies membrane 26 and portions of backing
`film 20. A peel-sealable release liner 30 covers the entire
`underside of the assembly and formsthe basal surface of
`the device. Device 18 has a heat seal 32 between the
`membrane and backing film and a peelable (imperma-
`nent) heat seal 34 between the backing film and the
`inner liner 28. An alternative liquid reservoir-type de-
`vice which maybe used in conjunction with the present
`compositions is described in U.S. Pat. No. 4,983,395,
`also incorporated by reference herein.
`Preferred daily dosages obtained with the present
`methodsand systemswill, similarly, vary with the drug
`administered. The targeted daily dosage will depend on
`the individual being treated, the indication addressed,
`the length of time the individual has been on the drug,
`and the like.
`
`EXPERIMENTAL
`
`Thefollowing examples are put forth so as to provide
`those with ordinary skill in the art with a complete
`disclosure and description of how to formulate compo-
`‘sitions and systems of the invention, and are not in-
`tended to limit the scope of whatthe inventors regardas
`their invention. Efforts have been made to ensure accu-
`racy with respect to numbers used (e.g., amounts, tem-
`peratures, etc.), but some experimental errors and devia-
`tions should be allowed for. Unless indicated otherwise,
`parts are parts by weight, temperatures are in degrees
`Centigrade, and pressure is at or near atmospheric.
`Estradiol, norethindrone acetate, progesterone and
`pindolol were obtained from Sigma Chemical Co., St.
`Louis, Mo. Polyacrylate adhesive solutions were ob-
`
`

`

`5,227,169
`
`10
`TABLEII
`
`Effect of Sorbitan Esters on Estradiol Flux
`From Three Different Acrylic Adhesive Matrices
`Formulation
`Flux (ug/cm?/hr)
`1194
`0.38 + 0.36
`1194/15% SMO
`1.69 + 0.58
`1194/15% SML
`0.96 + 0.47
`1054
`0.55 + 0.12
`1054/15% SMO
`0.95'+ 0.40
`1054/15% SML
`1.07 + 0.07
`1070
`0.41 + 0.07
`1070/15% SMO
`0.68 + 0.13
`1070/15% SMO
`0.99 + 0.31
`
`EXAMPLE3
`
`The procedure above was followed to prepare addi-
`tional acrylic adhesive matrices containing estradiol
`(both with and withouta sorbitan ester), so as to evalu-
`ate the effect of drug loading on estradiol flux. The
`acrylic adhesive used was Durotak (R) 80-1070 (“1070”),
`and the sorbitan ester used was sorbitan monooleate
`(present at subsaturation in all systems tested). Results
`are set forth in Table III. Sorbitan Monooleate was
`found to increase estradiol flux in both of the systems
`tested.
`
`9
`tained from National Starch & Chemical Co., New
`Jersey (Durotake ® 80-1194, 80-1054, 80-1070) and
`from Monsanto Corporation (Gelvae ® 737). Sorbitan
`monooleate, sorbitan monolaurate andsorbitantrioleate
`Were all obtained from ICI Americas. Ethanol (USP
`95%) was obtained from Fisher Scientific.
`Adhesive laminates were formulated by mixing the
`selected polyacrylate solutions with drug and/or en-
`hancer, followed by evaporation of solvent. The con-
`centrated solution was cast onto the silanized surface of
`a polyester release liner (Release Technologies, 2-EST-
`A-S242M), using a 10 mil gap Gardner knife. The cast
`adhesive was then dried at 80° C. for 15 minutes in a
`convection oven to yield a final 0.050 inch thick adhe-
`sive coating. A 0.0075 inch thick low density polyethy]-
`ene film (Schoeller Technical Paper Co., New York)
`was then laminated onto the dried adhesive surface to
`produce a three-layer transdermal matrix system con-
`struction.
`The in vitro skin flux of the particular drugs tested
`was evaluated across human cadaver skin as described
`by Merrit and Cooper (J Controlled Release (1984)
`1:161) using a high-performanceliquid chromatography
`(HPLC)assay. For these studies the release liner was
`removed from a previously cut section of the above
`transdermal matrix construction. The adhesive matrix
`TABLEIII.
`was then positioned onto the stratum corneum surface
`Effect of Drug Loading on Estradiol
`of heat separated human epidermis and the skin, with
`Flux from an Acrylic Adhesive Matrix
`With and Without Sorbitan Monooleate
`the adhering transdermal system, was then immediately
`Skin 2
`Skin 1
`mounted onto the diffusion cell. The steady state flux
`Formulation (ug/em?/hr)—(ug/cm2/hr)
`
`(ug/cm2/hr) of drug was determined by linear regres-
`1 wt. % estradiol, no enhancer
`0.22 + 0.08
`0.34 + 0.03
`sion analysis of the cumulative amountof drug permeat-
`2 wt. % estradiol, no enhancer
`0.56 + 0.08
`0.72 + 0.09
`ing (ug/cm2) across the skin as a function of the time
`1 wt. % estradiol, 5 wt. % SMO
`0.43 + 0.18
`0.55 + 0.07
`2 wt. % estradiol, 5 wt. % SMO
`1.00 + 0.16
`0.98 + 0.08
`
`10
`
`20
`
`25
`
`30
`
`35
`
`EXAMPLE1
`
`The aforementioned procedure was used to evaluate
`the effect of increasing sorbitan ester levels on estradiol
`flux from acrylic adhesives. The sorbitan ester used was
`sorbitan monolaurate (“SML”);
`the acrylic adhesive
`used was Durotake ®) 80-1194 (“1194”).
`Results are set forth in Table I. As may be seen, the
`flux obtained was found to increase with increasing
`quantities of sorbitan monolaurate.
`TABLE I
`
`
`40
`
`45
`
`Effect of Increasing Sorbitan Monolaurate
`Levels on Estradiol Flux from an Acrylic Adhesive
`Estradiol Conc.
`Flux
`
`Enhancer System
`(mg/ml)
`(ug/cm?/hr)
`No