United States Patent m
`Heiber et al.
`
`US005227169A
`[i i] Patent Number:
`[45] Date of Patent:
`
`5,227,169
`Jul. 13,1993
`
`[54] SORBITAN ESTERS AS SKIN PERMEATION
`ENHANCERS
`
`[75] Inventors: Sonia Heiber, Salt Lake City; Dinesh
`Patel, Murray; Charles D. Ebert, Salt
`Lake City, all of Utah
`
`[73] Assignee: Theratech, Inc., Salt Lake City, Utah
`
`[21] Appl. No.: 848,110
`
`[22] Filed:
`
`Mar. 9,1992
`
`Related U.S. Application Data
`[62] Division of Ser. No. 702,043, May 17, 1991, Pat. No.
`5,122,383.
`
`[51] Int. C1.5
`[52] U.S. a.
`
`[58] Field of Search
`
`A61F 13/00
`424/449; 424/443;
`424/447; 424/448
`424/448, 449; 514/946,
`514/947, 443
`
`[56]
`
`514/399
`424/449
`424/449
`514/947
`424/449
`424/448
`
`References Cited
`" U.S. PATENT DOCUMENTS
`4,362,737 12/1982 Schafer
`4,690,683 9/1987 Chien et al
`4,710,191 12/1987 Kwiatek et al
`4,746,509 5/1988 Haggiage et al
`4,879,119 11/1989 Konno et al
`4,898,920 2/1990 Lee et al
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Leon R. Home
`Attorney, Agent, or Firm—Morrison & Foerster
`[57]
`ABSTRACT
`Skin permeation enhancer compositions are provided
`which increase the permeability of skin to transdennally
`administered pharmacologically active agents. The
`compositions contain a sorbitan ester in addition to the
`selected pharmacologically active agent, and may also
`contain a C1-C4 aliphatic alcohol. Methods and trans­
`dermal drug delivery systems for using the composi­
`tions are also provided.
`
`27 Claims, 1 Drawing Sheet
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`U.S. Patent
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`July 13, 1993
`
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`5,227,169
`
`1
`SORBITAN ESTERS AS SKIN PERMEATION
`ENHANCERS
`
`2
`CITATION OF ART
`The following references relate to one or more as­
`pects of the present invention.
`This application is a division of application Ser. No. 5
`Skin permeation enhancers, generally: Various com­
`07/702,043 filed May 17, 1991, now U.S. Pat. No.
`pounds for enhancing the permeability of skin are
`5,122,383 issued Jun. 16, 1992.
`known in the art. U.S. Pat. Nos. 4,006,218, 3,551,554
`and 3,472,931, for example, respectively describe the
`TECHNICAL FIELD
`use of dimethylsulfoxide (DMSO), dimethyl formamide
`The present invention relates generally to the trans- 10 (DMF) and N,N-dimethylacetamide (DMA) to en-
`dermal administration of pharmacologically active
`hance the absorption of pharmacologically active
`agents, and more particularly relates to methods and
`agents through the stratum comeum. Other compounds
`compositions for enhancing the permeability of the skin
`which have been used to enhance skin permeability
`to such agents.
`include: decylmethylsulfoxide (CIQMSO); diethylene
`15 glycol monoethyl ether; polyethylene glycol monolau-
`BACKGROUND
`rate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); glyc-
`The delivery of drugs through the skin provides
`ero' monolaurate (U.S. Pat. No. 4,746,515); propylene
`many advantages; primarily, such a means of delivery is
`glycol monolaurate; ethanol (e.g., as in U.S. Pat. No.
`a comfortable, convenient and noninvasive way of ad-
`4,379,454); eucalyptol (U.S. Pat. No. 4,440,777; lecithin
`ministering drugs. The variable rates of absorption and
`(U.S. Pat. No. 4,783,450); the 1-substituted azacy-
`metabolism encountered in oral treatment are avoided,
`cloheptan-2-ones, particularly 1-n-dodecylcyclazacy-
`and other inherent inconveniences—e.g., gastrointesti-
`cloheptan-2-one (available under the trademark Azo-
`nal irritation and the like -are eliminated as well.
`ne ® from Nelson Research & Development Co; Irvm,
`j
`' ^ ?S'
`
`'
` '
`
`Transdermal drug delivery also makes possible a high
`degree of control over blood concentrations of any 25 fd 4,557,934); propylene glycol m combination with
`a
`narticiilar drui?
`fatty acid such as Imoleic acid (European Patent Pubh-
`cation No. 261429); "cell envelope disordering com­
`Skin is a structurally complex, relatively thick mem­
`pounds" such as methyl laurate or oleic acid in combi­
`brane. Molecules moving from the environment into
`nation with N-(hydroxyethyl) pyrrolidone (U.S. Pat.
`and through intact skin must first penetrate the stratum
`30 No. 4,537,776); C3-C4 diols (U.S. Pat. No. 4,552,872,
`comeum and any material on its surface. They must
`European Patent Application Publication No. 043738);
`then penetrate the viable epidermis, the papillary der­
`or a binary system of oleic acid, oleins or oleyl alcohol
`mis, and the capillary walls into the blood stream or
`in combination with a lower alcohol (U.S. Pat. No.
`lymph channels. To be so absorbed, molecules must
`4,863,970).
`overcome a different resistance to penetration in each 35
`type of tissue. Transport across the skin membrane is
`ca]1 T 0giso et ^ x pharmaCobio-Dyn., 9:517-525
`thus a complex phenomenon. However, it is the cells of
`(1986)i presents studies on percutaneous absorption in
`the stratum comeum which present the primary barrier
`(he penetration in vitro of indomethacin. Sor-
`vjvo
`to absorption of topical compositions or transdermally
`bitan monooleat^ was tested as a permeation enhancer
`administered drugs. The stratum comeum is a thin layer ^ in combination with a dimethyl sulfoxide (DMSO) gel
`of dense, highly keratinized cells approximately 10-15
`and was found to have no enhancing effect. T. Ogiso et
`microns thick over most of the body.
`al., J. Pharm. ScL, 78(4):319-323 (1989), describes the
`In order to increase skin permeability, and in particu-
`combined use of laurocapram and sorbitan monooleate
`lar to increase the permeability of the stratum comeum
`jj) a permeation enhancer composition also containing a
`(i.e., so as to achieve enhanced penetration, through the 45 DMSO gel, for the transdermal administration of indo-
`skin, of the drug to be administered transdermally), the
`methacin. W.-W. Shen et al., J. Pharm. ScL,
`skin may be pretreated with a penetration enhancing
`65(12):1780-1783 (1986), describes the effect of various
`agent (or "permeation enhancer", as sometimes referred
`nonionic surfactants, including sorbitan monopalmitate
`to herein) prior to application of a drug. Alternatively,
`and sorbitan trioleate, on the percutaneous absorption
`and preferably, a drug and a permeation enhancer are 50 of salicylic acid. As with the latter two references, the
`delivered concurrently.
`sorbitan esters are used in conjunction with DMSO.
`The present invention is directed to a novel composi-
`U.S. Pat. No. 4,637,930 to Konno et al. describes a
`tion for enhancing the penetration of pharmacologically
`transdermal formulation for the administration of nicar-
`active agents through skin, the composition based on a
`dipine hydrochloride which contains a mixed liquid
`sorbitan ester as will be described herein. The composi- 55 composed of urea and an additional compound which
`tion may or may not contain an aliphatic alcohol as an
`may be a sorbitan "middle chain" (6-12 carbon atom)
`additional component. The sorbitan ester compositions
`fatty acid ester,
`of the invention have been found by the inventors
`SUMMARY OF THE INVENTION
`herein to be particularly effective in enhancing the pen­
`etration of pharmaceutically active agents through skin. 60 Accordingly, it is a primary object of the invention to
`While there are a number of patents and publications
`provide a method for enhancing the rate of penetration
`available which relate to the transdermal administration
`of a pharmacologically active agent through the skin,
`of drugs and to skin permeation enhancer compositions,
`It is another object of the invention to provide such a
`applicants are unaware of any art which suggests that
`method which involves applying to a selected area of
`sorbitan esters are useful as permeation enhancers in the 65 intact skin a therapeutically effective amount of the
`absence of additional permeation enhancing compounds
`selected pharmacologically active agent in combination
`or which describes the sorbitan ester/aliphatic alcohol
`with a permeation enhancer composition containing a
`compositions as described and claimed herein.
`sorbitan ester.
`
`Sorbitan ^ ^
`
`enhancerS) spedfi.
`
`

`

`5
`
`
`
`5,227,169
`3
`4
`It is still another object of the invention to provide
`al., the disclosure of which is incorporated by reference
`such a method wherein the permeation enhancer com­
`herein.
`position consists essentially of: (1) a sorbitan ester; or (2)
`BRIEF DESCRIPTION OF THE DRAWING
`a sorbitan ester in combination with an aliphatic alcohol
`as will be described in detail herein.
`FIG. 1 is a schematic sectional view through a lami­
`nated matrix-type transdermal system of the invention.
`It is a further object of the invention to provide a skin
`FIG. 2 is a schematic sectional view through a lami­
`permeation enhancer composition comprising the phar­
`nated liquid reservoir-type transdermal system of the
`macologically active agent and a permeation enhancer
`invention.
`'
`composition which consists essentially of: (1) a sorbitan
`ester; or (2) a sorbitan ester in combination with an 1(3
`DETAILED DESCRIPTION OF THE
`aliphatic alcohol.
`INVENTION
`It is still a further object of the invention to provide a
`Before describing the present compositions, systems
`transdermal system in the form of a laminated compos­
`and methods of the invention in detail, it is to be under­
`i
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`tains, in addition to the selected pharmacologically
`stood that this invention is not limited to the particular
`drugs, sorbitan esters, aliphatic alcohols, or laminate
`active agent to be administered, a permeation enhancer
`materials described herein as such may, of course, vary.
`composition containing a sorbitan ester, and, optionally,
`It is also to be understood that the terminology used
`an aliphatic alcohol.
`herein is for the purpose of describing particular em-
`Additional objects, advantages and novel features of
`20 bodiments only, and is not intended to be limiting.
`the invention will be set forth in part in the description
`It must be noted that, as used in this specification and
`which follows, and in part will become apparent to
`the appended claims, the singular forms "a," "an" and
`those skilled in the art upon examination of the follow­
`"the" include plural referents unless the content clearly
`ing, or may be learned by practice of the invention.
`dictates otherwise. Thus, for example, reference to a
`In one aspect, the invention is a method for adminis­
`25 laminated structure containing "a drug" includes a mix­
`tering a pharmacologically active agent transdermally
`ture of two or more drugs, reference to "an adhesive"
`so as to achieve relatively high transdermal fluxes, by
`includes reference to one or more of such adhesives,
`administering, through a predetermined area of intact
`and reference to "a sorbitan ester" includes reference to
`skin and for a predetermined period of time, (1) the
`a mixture of two or more sorbitan esters.
`agent, and (2) a permeation enhancer consisting essen­
`In describing and claiming the present invention, the
`tially of a sorbitan ester, or a sorbitan ester in combina­
`following terminology will be used in accordance with
`tion with a C1-C4 aliphatic alcohol. In a preferred em­
`the definitions set out below.
`bodiment, the skin permeation enhancer and the drug
`"Penetration enhancement" or "permeation enhance-
`are administered m a smgle composition. As the clear-
`ment,. ^ used herein relates t0 an increase in the perme­
`ance rate of many drugs from the body is quite high, it 35 ability 0f skin to a pharmacologically active agent, i.e.,
`is generally preferred that administration be substan­
`so as to increase the rate at which the agent permeates
`tially continuous throughout the time period chosen for
`into and through the skin. A "permeation enhancer" is
`patch application.
`a material which achieves such permeation enhance­
`In another aspect of the invention, a composition of
`.
`.
`.
`,
`ment, and a "penetration enhancing amount" of an en-
`matter is provided that is useful for the delivery of a 4Q hancer as used herein means an amount effective to
`pharmacologically active agent through the skin, com-
`enhance skin penetration of a selected agent to a desired
`prising:
`degree.
`(a) a therapeutically effective amount of the pharma-
`By "transdermal" drug delivery, applicant is using
`cologically active agent to be admimstered; and
`the term in its conventional sense, i.e., to indicate deliv-
`(b) an amount of a permeation enhancer composition 45 ery of a drug by passage through the skin and into the
`effective to enhance the penetration of the pharmaco­
`blood stream. By "transmucosal" drug delivery, appli­
`logically active agent through the skin, wherein the
`cant intends delivery of a drug by passage of a drug
`enhancer consists essentially of a sorbitan ester or a
`through the mucosal tissue into the blood stream. "Top­
`sorbitan ester combined with a C1-C4 aliphatic alcohol.
`ical" drug delivery is used to mean local administration
`In still another aspect of the invention, a therapeutic 50 of a topical drug as in, for example, the treatment of
`system is provided for administering a drug transder­
`various skin disorders. These terms will sometimes be
`mally, at relatively high fluxes as noted above, in the
`used interchangeably herein, i.e., aspects of the inven­
`form of a skin patch. The skin patch is preferably in the
`tion which are described in the context of "trans­
`form of a matrix-type laminated composite containing
`dermal" drug delivery, unless otherwise specified, can
`an upper backing layer that is substantially impermeable 55 apply to transmucosal or topical delivery as well. That
`to the drug, and at least one drug/enhancer reservoir,
`is, the compositions, systems, and methods of the inven-
`one of which forms the basal surface of the device and
`tion, unless explicitly stated otherwise, should be pre­
`is designed to adhere to the skin during use. The reser­
`sumed to be equally applicable with any one of these
`voir is a matrix which contains both the drug and a
`three modes of drug delivery.
`permeation enhancer as described above. Such a lami- 60
`The term "drug" or "pharmacologically active
`nated composite preferably includes a strippable protec­
`agent" as used herein is intended to mean a compound
`tive release liner laminated to the basal surface of the
`or composition of matter which, when administered to
`drug reservoir. The release liner is a disposable element
`an organism (human or animal) induces a desired phar­
`designed to protect the exposed reservoir surface prior
`macologic and/or physiologic effect by local and/or
`to use. In an alternative embodiment, a transdermal 65 systemic action. In general, the terms include the thera-
`therapeutic system is provided in the form of a liquid
`peutic or prophylactic agents in all major therapeutic/­
`reservoir-type laminated composite, e.g., as described in
`prophylactic areas of medicine. Examples of drugs use­
`commonly assigned U.S. Pat. No. 4,849,224 to Chang et
`ful in conjunction with the present invention include:
`
`30
`
`

`

`25
`
`30
`
`5,227,169
`5
`6
`anti-infectives such as antibiotics and antiviral agents; —0(C0)R' as defined above. Ri, Raand R3, may be, for
`analgesics and analgesic combinations; anorexics; an-
`example, lauryl, myristyl, palmityl, stearyl, palmitoleyl,
`tihelminthics; antiarthritics; antiasthmatic agents; anti-
`oleyl, linoleyl, linolenyl, or ricinoleyl esters, or the like,
`cholinergic agents; anticonvulsants; antidepressants;
`Exemplary sorbitan esters are long-chain sorbitan
`antidiabetic agents; antidiarrheals; antihistamines; anti- 5 monoesters, wherein R] is as defined above, R' is hydro-
`inflammatory agents, antimigraine preparations; anti-
`carbon of 11 to 21 carbon atoms, and Raand R3 are both
`motion sickness drugs; antinauseants; antineoplastics;
`hydroxyl. Particularly preferred compounds within the
`antiparkinsonism drugs; antipruritics; antipsychotics;
`class of sorbitan monoesters are sorbitan monooleate
`antipyretics; antispasmodics; anticholinergics; sympa­
`and sorbitan monolaurate.
`thomimetics; xanthine derivatives; cardiovascular prep- 10
`In addition to a sorbitan ester, the permeation en­
`arations including calcium channel blockers and beta-
`hancer composition of the invention may also include a
`blockers such as pindolol and antiarrhythmics; antihy­
`C1-C4 aliphatic alcohol component. Examples of suit­
`pertensives; diuretics; vasodilators including general
`able alcohols within this class include ethanol, D-
`coronary, peripheral and cerebral; central nervous sys­
`propanol, isopropanol, t-butanol, and mixtures thereof.
`tem stimulants; cough and cold preparations, including J J
`The method of delivery of the present compositions
`decongestants; steroids; hypnotics; immunosuppres­
`may vary, but necessarily involves application of drug
`sives; muscle relaxants; parasympatholytics; psychos­
`and enhancer to a selected intact surface of the skin or
`timulants; sedatives; and tranquilizers. For purposes of
`other tissue for a period of time sufficient to provide the
`the aforementioned definition, "drugs" as used herein
`also include locally administered topical medicaments JQ desired blood level of drug. The method preferably
`involves administration of drug and enhancer simulta­
`such as antibacterial agents, antifungals, antimicrobials,
`neously, in a single composition, i.e., as an ointment, gel,
`cutaneous growth enhancers, antipsoriatics, anti-acne
`medicaments, and the like.
`cream, or the like, or may involve use of a drug delivery
`"Carriers" or "vehicles" as used herein refer to car­
`device as taught, for example, in U.S. Pat. Nos.
`rier materials without pharmacological activity which
`4,849,224, 4,983,395, 4,568,343, 3,797,494 or 3,742,951.
`are suitable for administration in conjunction with the
`When the drug to be administered and the permeation
`presently disclosed and claimed compositions, and in­
`enhancer as described above are applied in the form of
`clude any such carrier or vehicle materials known in the
`an ointment, gel, cream or the like, the amount of drug
`art, e.g., any liquid, gel, solvent, liquid diluent, solubi-
`contained within the composition will depend on a
`lizer, or the like. The carriers and vehicles suitable
`variety of factors, including the desired rate of delivery,
`herein are "pharmaceutically acceptable" in that they
`the desired dosage, the disease to be treated, the nature
`are nontoxic, do not interfere with drug delivery, and
`and activity of the drug, the desired effect, possible
`are not for any other reasons biologically or otherwise
`adverse reactions, the ability and speed of the drug
`undesirable. Examples of specific suitable carriers and
`selected to reach its intended target, and other factors
`vehicles for use herein include water, mineral oil, sili­
`3S within the particular knowledge of the patient and the
`cone, inorganic gels, aqueous emulsions, liquid sugars,
`physician. The amount of enhancer will typically be in
`waxes, petroleum jelly, and a variety of other oils and
`the range of 0.1 wt. % to 40 wt. % relative to the total
`polymeric materials.
`composition, more preferably on the order of about 2.5
`By a "therapeutically effective" amount of a drug or
`wt. % to 15 wt. %. The composition may, in addition to
`pharmacologically active agent is meant a nontoxic but
`40 drug and enhancer, include one or more selected carri­
`sufficient amount of the drug or agent to provide the
`ers or excipients, and/or various agents and ingredients
`desired therapeutic effect.
`commonly employed in dermatological ointments and
`The invention is thus in one embodiment a method
`lotions. For example, fragrances, opacifiers, preserva­
`for enhancing the rate of penetration of a pharmacologi­
`tives, antioxidants, gelling agents, perfumes, thickening
`cally active agent through the skin, wherein the method
`45 agents, stabilizers, surfactants, emollients, coloring
`involves co-administration of the agent through a pre­
`agents, and the like may be present so long as they are
`determined area of intact skin, and for a predetermined
`pharmaceutically acceptable and compatible with the
`period of time, the selected agent and a permeation
`drug and enhancer.
`enhancer consisting essentially of a sorbitan ester or a
`A transdermal delivery system for the administration
`sorbitan ester in combination with a C1-C4 aliphatic
`50 of a drug can be constructed with the drug/enhancer
`alcohol. The sorbitan esters which are useful in con­
`composition described hereinabove. Preferred trans­
`junction with the present invention have the structure
`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-
`55 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-
`60 lected pharmacologically active agent as outlined
`above. System 10 is a laminated composite in which the
`wherein the substituent Ri has the structure —0(-
`top layer 12 is a backing layer, its face forming the top
`CO)R', where R' is selected from the group consisting
`of saturated, mono-unsaturated, di-unsaturated and tri-
`surface of the composite. The drug reservoir, contain­
`unsaturated aliphatic hydrocarbon substituents of 7 to
`ing drug, enhancer as described herein, and optional
`21 carbon atoms, preferably 11 to 21 carbon atoms, and 65 carriers or vehicles, is shown at 14, immediately below
`may be substituted with 1 to 3 hydroxyl groups. The
`and adjacent to the backing layer. Prior to use, the
`substituents R2 and R3 may be the same or different and
`laminate also includes a strippable protective release
`are selected from the group consisting of hydroxyl and
`liner. In a preferred embodiment, as described in co-
`
`HO— ?Ho JfrV
`
`CH2—Ri
`I
`
`H R3
`
`

`

`5,227,169
`7
`8
`pending commonly assigned Ser. No. 07/625,906, filed
`above, with the quantity of the drug therein, and with
`Dec. 10, 1990, and entitled "Method and Systems for
`the remainder of the drug reservoir comprised of adhe­
`Administering Nitroglycerin Transdennally at En­
`sive and optional carriers, vehicles or the like. If the
`hanced Transdermal Fluxes," the release liner is in the
`drug is a hydrophobic material such as a steroid, it is
`form of two sheets 16c and 16b, the first sheet 16a par- 5 preferred that the quantity of drug contained within the
`tially overlapping the second sheet 16b. Additional
`reservoir is at "subsaturation" as described in detail in
`structural layers and/or additional drug/enhancer res­
`applicants' copending, commonly assigned U.S. appli­
`ervoirs may also be present.
`cation Ser. No. 07 626,685, filed Dec. 11, 1990, the
`The drug reservoir is preferably comprised of a
`disclosure of which is hereby incorporated by reference
`contact adhesive which is a pressure-sensitive adhesive 10 in its entirety. To use these laminated composites, one is
`suitable for long-term skin contact. It must also be phys­
`applied directly to the skin of a patient, to release the
`ically and chemically compatible with the drug and
`drug/enhancer composition to the skin, allowing the
`enhancer employed, and with any carriers or vehicles
`drug to permeate into the circulation. The adhesive
`incorporated into the drug/enhancer composition. Fur­
`layer which serves as the drug reservoir should be in
`ther, the adhesive selected for use as the reservoir layer 15 firm contact with the skin,
`must be such that the drug and enhancer are at least
`In general, such devices are fabricated using methods
`somewhat soluble in the adhesive. The drug reservoir
`standard in the art, e.g., solvent-evaporation film cast­
`will generally be in the range of about 2 to 4 mils in
`ing in which all components of the drug/enhancer com­
`thickness. Suitable adhesives for use as the drug reser­
`position are admixed with the adhesive which will serve
`voir include polysiloxanes, polyacrylates, polyure- 20 as the drug reservoir, and cast onto a substrate which is
`thanes, tacky rubbers such as polyisobutylene, and the
`either the backing layer or release liner. Other layers are
`like. Particularly preferred contact adhesives for use as
`then laminated to this initial structure.
`the drug reservoir herein are cross-linked acrylates
`In an alternative embodiment, laminated composites
`(e.g., the Durotake ® adhesives, available from Na­
`containing drug in a liquid reservoir, as described in
`tional Starch & Chemical Co., New York, N.Y., or the 25 U.S. Pat. No. 4,849,224, may be used. As described in
`Gelvae (g) adhesives, available from Monsanto Co., St.
`that patent, the disclosure of which is incorporated by
`Louis, Mo.).
`reference herein, such devices shown generally at 18 in
`The backing layer, which is, as shown, adhered to the
`FIG. 2 are comprised of an uppermost layer of a heat-
`drug reservoir and serves as the upper layer of the de­
`sealable backing film 20 having an inverted, cup-shaped
`vice during use, functions as the primary structural 30 recess that serves the reservoir 22 for the drug-enhancer
`element of the device. The backing layer is made of a
`formulation. The underside of the outer edge of the
`sheet or film of a preferably flexible elastomeric mate­
`backing film carries a ring-shaped layer 24 of a pressure-
`rial that is substantially impermeable to the drug/en­
`sensitive adhesive peripheral to the reservoir. Underly­
`hancer composition. The layer will typically be on the
`ing the reservoir, just inward of the peripheral ring of
`order of 1.0 to about 4.0 mils in thickness, and is prefera- 35 adhesive, is a membrane layer 26 that is permeable to
`bly of a material that permits the device to follow the
`the drug-enhancer formulation. A peel scalable inner
`contours of the skin, such that it may be worn comfort­
`liner 28 underlies membrane 26 and portions of backing
`ably on any skin area, e.g., at joints or other points of
`film 20. A peel-sealable release liner 30 covers the entire
`flexure. In this way, in response to normal mechanical
`underside of the assembly and forms the basal surface of
`strain, there is little or no likelihood of the device disen- 40 the device. Device 18 has a heat seal 32 between the
`gaging from the skin due to differences in the flexibility
`membrane and backing film and a peelable (imperma­
`or resiliency of the skin and the device. Examples of
`nent) heat seal 34 between the backing film and the
`polymers useful for the backing layer herein are poly­
`inner liner 28. An alternative liquid reservoir-type de­
`ethylene, polypropylene, polyesters, polyurethanes,
`vice which may be used in conjunction with the present
`polyethylene vinyl acetate, polyvinylidene chloride, 45 compositions is described in U.S. Pat. No. 4,983,395,
`block copolymers such as PEBAX, and the like. The
`also incorporated by reference herein.
`backing layer may also comprise laminates of one or
`Preferred daily dosages obtained with the present
`more of the foregoing polymers.
`methods and systems will, similarly, vary with the drug
`The release liner is a disposable element which serves
`administered. The targeted daily dosage will depend on
`only to protect the device prior to application. Typi- 50 the individual being treated, the indication addressed,
`cally, the release liner is formed from a material imper­
`the length of time the individual has been on the drug,
`meable to the drug, vehicle, and adhesive, and which is
`and the like.
`easily stripped from the contact adhesive that serves as
`EXPERIMENTAL
`the drug reservoir layer. Preferred release liners for use
`herein are those which are generally suitable for use in 55
`The following examples are put forth so as to provide
`conjunction with pressure-sensitive adhesives. Silanized
`those with ordinary skill in the art with a complete
`polyester films are presently preferred.
`disclosure and description of how to formulate compo­
`In a preferred embodiment, as noted above, a two-
`sitions and systems of the invention, and are not in­
`part release liner is used, wherein a first strippable pro­
`tended to limit the scope of what the inventors regard as
`tective sheet (shown as 16<z in FIG. 1) partially overlaps 60 their invention. Efforts have been made to ensure accu-
`a second strippable protective sheet 166, such that the
`racy with respect to numbers used (e.g., amounts, tem­
`area of overlap gives rise to a tab which extends from
`peratures, etc.), but some experimental errors and devia­
`the basal surface of the laminate, enabling ready re­
`tions should be allowed for. Unless indicated otherwise,
`moval of the strippable sheets from the reservoir layer.
`parts are parts by weight, temperatures are in degrees
`The preferred laminated composites of the invention 65 Centigrade, and pressure is at or near atmospheric,
`are as shown in FIG. 1, having a backing layer, a drug
`Estradiol, norethindrone acetate, progesterone and
`reservoir, and a two-piece release liner; the drug reser­
`pindolol were obtained from Sigma Chemical Co., St.
`voir contains a drug/enhancer composition as described
`Louis, Mo. Polyacrylate adhesive solutions were ob-
`
`

`

`10
`
`15
`
`10
`TABLE II
`Effect of Sorbitan Esters on Estradiol Flux
`From Three Different Acrylic Adhesive Matrices
`Formulation
`Flux (fig/cm2/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
`0.41 ± 0.07
`1070
`1070/15% SMO
`0.68 ± 0.13
`0.99 ± 0.31
`1070/15% SMO
`
`5,227,169
`9
`tained from National Starch & Chemical Co., New
`Jersey (Durotake ® 80-1194, 80-1054, 80-1070) and
`from Monsanto Corporation (Gelvae (R) 737). Sorbitan
`monooleate, sorbitan monolaurate and sorbitan trioleate
`Were all obtained from ICI Americas. Ethanol (USP 5
`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
`EXAMPLE 3
`sive coating. A 0.0075 inch thick low density polyethyl­
`ene film (Schoeller Technical Paper Co., New York)
`The procedure above was followed to prepare addi­
`was then laminated onto the dried adhesive surface to
`tional acrylic adhesive matrices containing estradiol
`(both with and without a sorbitan ester), so as to evalu-
`produce a three-layer transdermal matrix system con­
`struction.
`2o ate the effect of drug loading on estradiol flux. The
`acrylic adhesive used was Durotak (§) 80-1070 ("1070"),
`The in vitro skin flux of the particular drugs tested
`and the sorbitan ester used was sorbitan monooleate
`was evaluated across human cadaver skin as described
`by Merrit and Cooper (/. Controlled Release (1984)
`(present at subsaturation in all systems tested). Results
`1:161) using a high-performance liquid chromatography
`416 set forth in Table III. Sorbitan Monooleate was
`(HPLC) assay. For these studies the release liner was 25 found to increase estradiol flux in both of the systems
`tested.
`removed from a previously cut section of the above
`transdermal matrix construction. The adhesive matrix
`was then positioned onto the stratum comeum surface
`of heat separated human epidermis and the skin, with
`the adhering transdermal system, was then immediately 30
`mounted onto the diffusion cell. The steady state flux
`(ftg/cmVhr) of drug was determined by linear regres­
`sion analysis of the cumulative amount of drug permeat­
`ing (fig/cm2) across the skin as a function of the time
`(hr).
`
`TABLE III
`Effect of Drug Loading on Estradiol
`Flux from an Acrylic Adhesive Matrix
`With and Without Sorbitan Monooleate
`Skin 1
`(fig/cm2/hr)
`0.22 ± 0.08
`0.56 ± 0.08
`0.43 ± 0.18
`1.00 ± 0.16
`
`Formulation
`1 wt. % estradiol, no enhancer
`2 wt. % estradiol, no enhancer
`1 wt. % estradiol, 5 wt. % SMO
`2 wt. % estradiol, 5 wt. % SMO
`
`35