:19]
`United States Patent
`3.797.494
`[11]
`Zaffaroni
`[45FMan 19, 1974
`
`{54]
`
`BANDAGE FOR THE ADMINISTRATION OF
`
`;
`DRUG BY CONTROLLED METERING -_
`THROUGH MICROPOROUS MATERIALS
`
`Inventors Alejandro Zaiiaroni, Atherton. " _
`-
`Calif.
`
`3,598.12:- ' £11971
`Zaffaroni ........................ .... 123!268
`I
`Bierenbaurn.
`1231'263 X
`3.426.754
`211969
`3.053.255
`'9ll962 Meyer ............ ..
`1281068
`3.464,“ 3
`9f1969 Goldfarb et 3]..
`128i268
`_
`3.5!2997
`$1970 ' Cohly et a].
`...... .. [23(296 X
`
`
`
`
`
`Alza Corporation, Palo Alto. Calif.
`
`Primary Examiner—Dalton L. Truluck
`Assistant Examiner—n]. C. McGowan
`
`Assignee:
`Notice:
`
`The portion of the term of this
`patent subsequent to Aug. 10, 1988,
`has been disclaimed.
`'
`
`Filed:
`
`Aug. 9. 1971
`
`Apol. No.:_169.976
`
`Related US. Application Data
`I.
`Continuation-impart of Ser. Nos. 31mm, April
`I969. Pat. No. 3.598.122. and Ser. No. 812.117.
`.April 1.
`i969. .Pat. NO. 3.598.123. and Ser. No.
`150.085. June 4. 191”. Pat. No. 3.731.683.
`
`'
`
`0.5. CI.
`1m.
`Field "at Search..
`.
`
`128mm
`A61! isms
`
`;.. 128260.268. 156.155.
`123:296; 424:19, 20, 23
`
`References Cited
`
`[57] '
`
`ABSTRACT
`
`A bandage for use in the continuous administration of
`drugs to the skin or mucosa, comprising a backing
`member defining one exterior surface, a surface of
`pressure—sensitive adhesive defining a second exteriOr
`surface. and disposed therebetweene reservoir con-
`taining drug formulation confined therein. The reser-
`voir can comprise a distinct layer of the bandage or a
`plurality'of microeapsules distributed throughout the
`adhesive surface. and in either case the drug can be
`confined within an interior chamber of the reservoir
`or distributed throughout a reservoir matrix. The drug
`paSSes'fliroughdrug release ratecontrolling micropo-'
`rous material which continuously metersthe flow of
`drug by viscous 'or diffusive transfer to the skin or run-
`cosa at a controlled and predetermined rate over a pe-
`riod of time.-
`'
`'-
`
`3.598.I22
`
`UNITED-STATES PATENTS
`3:191]
`Zaffaroni .........
`............... .. :23;sz
`
`7 Claims, 5 Drawing Figures
`
`[75]
`
`[73]
`
`i‘]
`
`[22]
`
`[21]
`
`[63]
`
`[52.]
`[51]
`[53]
`
`[55]
`
`I
`
`' Dr. Reddy's — EX1016
`Page 1
`
`
`
`20 .
`
`
`
`..
`
`
`th’ilsw‘yfismg
`A "’9
`
`
`\ r
`‘
`a“. .r
`i n.
`I“ ‘1. s ‘ a
`t
`.
`.1
`4i:
`Q-th‘tfihaflf r’-
`Int
`
`
`' lnzrnnn
`
`
`
`
`
`
`
`
`
`Dr. Reddy's - EX1016
`Page 1
`
`

`

`Phrsmwmw Ian
`
`'
`
`3L797;4é4
`
`
`
`_ 33 '43
`
`mvsmon‘._
`
`Alejandro Zaffaroni
`
`SWI-flmw Arfomey'
`3
`'
`
`'
`
`Page 2
`
`:2!
`
`_-
`
`' I
`
`Page 2
`
`

`

`1
`
`3,797,494
`
`2
`
`BANDAGE FOR THE ADMINISTRATION OF DRUG
`BY'CONTROLLED METERING THROUGH
`MICROPOROUS MATERIALS
`
`RELATED APPLICATIONS
`
`This. application is a continuation-in—part of Ser. No.
`812,116, filed Apr. 1, 1969, and now issued on Aug.
`10, 1971 as US. Pat. No. 3,598,122 entitled “Bandage
`for Administering Drugs"; Ser. No. 812,1 1?. filed Apr.
`1, 1969, and now also issued on Aug. 10, 1971 es.U.S_.
`Pat. No. 3,598,123 entitled "Bandage"; and Ser.‘ No.
`150,085, filed June 4, 1971. and now issued on May 3,
`1973 as US. Pat. No. 3,731,683 entitled “Bandage for-
`the controlled Metering of Topical Drugs to the Skin";
`all being applicatic‘ms of Alejandro Zait‘aroni.
`
`BRACKGROUND OF THE INVENTION '
`
`This invention relates to a device for the administra-
`tion of drug and, more particularly, to amedical ban-
`dage for the controlled continuous metering of flow of
`systemically Or topically active drug to the skin or mu-
`cosa-over a period of time". "
`'
`-
`-
`'
`-
`“Topically active" drugs, as that term'is used in this
`specification and the ' appended claims, are agents
`which. when applied to the skin or mucosa, primarily
`cause a pharmacological or physiological response at
`or near the site of their application. "Systemically ac-
`tive '-' drugs. as that term is used in this specification and
`the appended claims. areagents which, when applied
`.to the skin or mucosa, are absorbed through the body
`surface to which applied and are transported from their
`site of application by the recipient's circulatory system
`or lymphatic system, to cause a pharmacologic or phys-
`iologic responseat a remote site in the body.
`Systemically active drug: are conventionally adminis-
`tered either orally or by injection. with the primary ob-
`jective of the mode. being to achieve a given desired
`blood level of drug in circulation over a period of time.
`However. these prior art methods possess certain short-
`comings resulting in the failure to obtain these goals.
`For example. the oral route is inadequate for several
`reasons even though the drug is administered at peri-
`odic intervals according to a well defined schedule. The
`rate of absorption of drug'through the gastrointestinal
`tract is affected by both the contents of the train and
`the time of passage of drug through the small intestine.
`' Therefore, such variables as whether the drug is admin-
`isteredbefore or after eating and the type and quantity
`of food eaten (for example, high or lovvr fat content), or
`whether administered before or after a‘ bowel move-
`ment. affect the. rate of absorption of the drug which
`takes place in the small intBSleIe. Additionally, the time
`of passage of drug through the small intestine is af-
`fected by the rate of peristaltic contracting, adding fur-
`ther uncertainty. Also important is the rate of circula-
`tion of bldod to the Small intestine and the fact that
`many drugs administered by this route are rendered in-
`active by gastric acid and digestive enzymes of the gas-
`trointestinal tractor liver where the drug can be metab-
`olized to an inactive product by that organ. These fac-
`tors make it difficult to achieve a desired time course
`of concentration of the drug in the blood. The almost
`inevitable result of oral administration of drugs through
`the gastrointestinal tract is that the level of drug in cir-
`culation surges to a peak level at the. time the drugis
`administered. followed by a decline in concentration in
`
`the blood and body compartments. Thus. a plot of drug
`in circulation after' administration of several tablets a
`day has the-appearance of a series of peaks which may
`surpass the toxic threshold of the drug, and valleys
`which fall below the critical point needed to achieve
`the desired therapeutic effect.
`The administration of drugs by injection can entail
`certain disadvantages. For example, very strict asepsis
`must be maintained to avoid infection of the blood, the
`vascular system or heart. Drug administration by poor
`intravenous injection technique may result in perivas-
`cular injection when it is not intended; and the typical
`result of injection into the blood is a sudden rise in the -
`blood-concentration followed by an uncontrolled de-
`cline. Additionally, administration of drugs by injection
`is inconvenient and painful. Other dosage forms for sys-
`temic.: administration of drug, such as rectal supposito-
`ries and sublingual lozenges, also produce non-uniform
`levels of the therapeutic agent in circulation. These
`dosage forms require great patient cooperation, have
`'low patient acceptability, and are sparingly used
`throughout most of the world.
`A large number'of locally 'acting drugs are available
`to treat skin disorders or other conditions which mani-
`fest themselves in a manner such that they are suscepti-
`ble to treatment via the skin. These drugs are conven-
`tionally topically administered to the- skin with the ac-
`tive agent carried in the form of ointments, creams,
`salves, liniments, powders. dressings, and the like. The
`popularity of these types of formulations resides in the
`fact that it is quite easy to topically apply the agent to
`the skin in this manner. In most cases, however, it is not
`possible to determine how much of the preparation has
`been taken up or..efl‘ectively administered to the siting
`since only non-uniform levels of the agent are avail-
`able. nor. is there-any assurance that. sufficient medica-
`tion'urill be available for the duration of periods that it
`is required. A further undesirable feature is the unsight—
`liness of these formulations which often discourages
`- patients from using them during their waking hours of
`the day when they are most likely to be seen by others.
`Further, the preparations are subject to rub off onto
`clothing, thus causing much inconvenience and annoy-
`ance-to-the user.
`"
`-
`
`.
`
`SUMMARY OF THE INVENTION
`
`Accordingly, an object of this invention isto provide
`a bandage for the improved continuous administration
`of a predetermined controlled quantity of topically or
`systemically active drug-to or through the skin .or body
`mucosa over a period of time, which overcomes the dis- -
`advantages inherent in the aforesaid prior art modes of
`administration.
`-
`'
`'
`_
`Another object of this invention is to provide a ban-'
`dage- which can beadapted'to deliver controlled quan-
`tities of drug having a wide variety of chemical and
`physical properties and over a wide range of drug deliv-
`ery rates.-
`-
`'
`'
`'
`'
`-
`'-
`'
`in accomplishing these objects. one feature of the in-
`vention resides in'abandage for the continuous admin—
`istration of controlled quantities of drug to the skin or
`mucosa, comprised of a laminate .of: (l) a backing
`member; bearing (2) a discrete middle reservoir layer
`containing a drug confined within. a body, the body
`being formed from drug release rate controlling micro-
`porous material permeable to the passage of the drug,
`to continuously meter the flow of a therapeutically ef-
`
`_
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 3
`
`Page 3
`
`

`

`3,797,494
`
`3
`fective amount of the drug to the skin or mucosa from
`the reservoir at a controlled and predetermined rate
`over a period of time; and (3) a pressure-sensitive ad-
`hesive surface adapted for contact with the skin or mu-
`cosa and positioned on one surface of the reservoir re-
`mote from the backing member.
`Another aspect of this invention resides in a bandage
`comprised of a laminate of: (l) a backing member:
`bearing (2) a discrete middle reservoir containing a
`drug confined therein, the reservoir being formed of
`material permeable to passage of the drug; and (3) a
`pressure-sensitive adhesive surface adapted for contact
`with the skin or mucosa and positioned on one surface
`of the reservoir remote from the backing member and
`Wherein one or more drug release rate controlling mi-
`croporous membranes are interposed between the sur-
`face of the reservoir and pressure-sensitive adhesive so
`as to continuously meter the flow of a therapeutically
`effective amount of the drug from the reservoir at a
`controlled and predetermined rate over a period of
`time. The reservoir can be a container having the agent
`. confined therein or a solid or microporous matrix hav-
`ing agent dispersed therein.
`Still another embodiment of this invention resides in
`an adhesive bandage comprising a laminate of: (1} a
`backing member; bearing (2) a pressure-sensitive ad-
`hesive on one surface thereof adapted for contact with
`the skin or mucosa, said pressure-sensitive adhesive
`having distributed therethrough, (3) a plurality of dis-
`crete microcapsules. each of which microcapsules
`comprises a drug confined within a body of drug re-
`lease rate controlling porous material to continuously
`meter the flow of a therapeutically effective amount of
`the drug to the skin or mucosa of the patient from the
`microcapsules at a controlled and predetermined rate
`over a period of time.
`Other objects. features and advantages of the inven-
`tion will become more apparent from the following de-
`scription when taken in conjunction with the accompa-
`nying drawings.
`I
`-
`The term “reservoir”, as used herein to define the
`drug containing portion of the subject bandage, is in-
`tended to connote a broad class of structures capable
`of fulfilling-the intended function. and includes both
`discrete porous microcapsules. as well as distinct reser-
`voir compartments cir layers. Likewise. as will be here-
`inafter more completely developed. the foregoing term
`encompasses containers having one or more interior
`drug containing chambers. as well as solid matrices and
`microporous matrices having a systemically or topically
`active drug distributed therethrough.
`The term “drug or agent", when not further quali-
`fied. includes both topically active and systemically ac-
`tive drugs. as hereinbefore defined.
`-
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`In the drawings:
`_
`FIG. 1 is a cross-sectional view of an embodiment of
`the medical bandage of the invention, wherein the drug
`is uniformly distributed throughout a matrix of micro-
`porous material permeable to the passage of the drug
`by flow through the pores of the material and the mate-
`rial is laminated to a backing member. The matrix ma-
`terial which acts as a reservoir for the drug bears a
`coating of the pressure-sensitive adhesive thereon;
`FIG. 2 is a cross-sectional view of still another em-
`bodiment of the invention. wherein the adhesive ban-
`
`ll]
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`
`dage of the invention is comprised of a backing mem-
`ber having a reservoir on one surface thereof of drug
`uniformly distributed throughout a matrix material per-
`meable to passage of the drug. and on the surface of the
`reservoir remote from the backing member bearing a
`pressure-sensitive adhesive coating. A microporous
`membrane'is interposed between the reservoir layer
`and the pressure-sensitive adhesive coating;
`FIG. 3 is a cross-sectional view of another embodi-
`ment of the bandage of the invention. wherein the res-
`ervoir laminated to the backing member is a hollow
`container permeable to passage of drug by flow
`through the pores of one surface thereof. and having
`the drug confined within the interior chamber thereof.
`The reservoir bears a coating of pressure-sensitive ad-
`hesive thereon;
`FIG. 4 is a perspective view of the medical adhesive _
`bandage of the invention, wherein the drug is microch-
`capsulated with a porous material permeable to the
`passage of the drug, and the microcapsules are uni-
`formly distributed throughout
`the pressure-sensitive
`coating;
`FIG. 5 is a cross~sectional view of the bandage of the
`invention shown in FIG. 4.
`'
`
`DETAILED DESCRIPTION OF THE INVENTION
`In accordance with this invention there is provided a
`bandage suitable. by virtue of the microporous materi-
`als employed therein. for the predetermined controlled
`administration of drug to the skin or mucosa of the
`body over a period of time. To use the bandage of the
`invention it is applied tothe patient‘s skin or mucosa
`and should be in firm contact therewith 'so as to form
`a tight seal. Flow of drug from the reservoir is metered
`through the pores of the rate release controlling mate-
`rial in accordancewith the laws of hydrodynamics or
`diffusion, as hereinafter discussed. at a predetermined
`rate. In Operation. drug molecules are continuously re-
`movedfrom the reservoir and migrate to the skin or
`mucosa of the patient. In the case of systemic drugs, the
`drugs are absorbed by the skin or mucosa and enter cir-
`culation through the 'capillaryinetwork.
`'
`'
`.
`The reservoir containing the drug is formed of mate-
`rial permeable to the drug to permit passage of the
`drug. Depending upon the particular embodiment as
`described above, the drug reservoir can be of micropo-
`rous material or otherwise. However, as is apparent in
`the latter case. the drug must first pass through a micro-
`porons membrane material prior to reaching the skin or
`mucosa. It is therefore critical to the practice of this in-
`vention for all embodiments that. at some point after or
`concurrent with the release of drug from the reservoir
`and prior to reaching the skin or mucosa, the drug pass
`through the drug release rate controlling microporous
`membrane or matrix material to meter the flow thereof.
`The rate of passage or permeation of drug through the
`microporous material
`is determined by the transfer
`mechanism which can be either by:
`I_. diffusive flux of drug molecules as is the case, as
`hereinafter described. where the micropores of the
`rate controlling microporous membrane or matrix
`material are impregnated with a diffusive medium
`for the drug in which the drug molecules can dis-
`solve in and flow through to a direction of lower
`Chemical potential; or
`
`Page 4
`
`Page 4
`
`

`

`5
`
`3,797,494
`
`6
`
`structures are commercially available and can be made '
`by a; multitude of different methods. e.‘g.,- etched. nu-
`clear track, and materials employed, e.g.. polyelec-
`trolyte, ion exchange polymers, as described in R. E.
`Resting, Synthetic Polymer Membranes, McGraw Hill.
`Chapters 4 and 5.. 1971; J. D. Ferry, Ultrafiltration
`Membranes, Chemical Review, Vol. 18,.'l'-'age 373,
`1934'. 'Materials'possessing from 5 percent to 95 per-
`cent voids and having an effective pore size 'of from
`about 10 angstroms to about 10.0 microns can be suit-
`ably employed
`the practice of this invention. Materi-
`als with pore sizes significantly below SO-angstroms can
`be considered to be mulecular diffusion type menu
`branes and matrices. In order to obtain the most advan-
`tageous results, the materials should be formed. into
`structures with the-desired morphology in accordance-
`with methods knownto those skilled in the art to
`
`IO
`
`15
`
`-
`20
`
`25
`
`30
`
`35
`
`2. pressure induced viscous type flow of drug mole-.
`cules through the pores in the microporous mem-
`brane or matrix rate controlling material.
`'
`Thus, the microporous material has a structure that en-
`ables the drug to pass through the pro-existing pores or
`capillaries, either by diffusive permeability or micropo-
`rous hydrodynamic flow, depending upon the mode of
`use as describd hereinafter. Since the microporous rate
`controlling material is preferably selected so thatute -
`drug is substantially insoluble therein, as hereinafter
`described, flow of drug through the structure of the ma-
`terial can be neglected.
`. For drug transfer mechanism ( 1) set forth above, i.e., _
`wherein the drug diffuses through a diffusive medium
`for the drug, the release rate. can be controlled in ac-
`cordance with Fick’s First Law. depending on the par—
`ticular design by selection of dependent variables such
`as the diffusivity and solubility of. the drug in the dim:-
`sive medium and the thickness and porosity of the ma-
`terial properly modified by a tortuosity factor. For drug
`transfer mechanism.(2), i.e., flow of drug through-the
`pores of the microporous rate controlling material, the
`pressure differential, the thickness of the membrane,
`the viscosity of the permeant drug. the sizeof the per-
`meant molecule relative to the pore size, the absolute
`value of the pore Size, and the number-of pores or per-
`cent voids in the material are the controlling factors
`governing permeability; For the simplest type' of 'flow
`mechanism of this type, e.g., viscous flow. 'the-ambunt
`of drug passing through the porous structure is given by
`Poiseuille‘s equation for viscous__flow.
`'
`.
`j
`'
`_'
`'
`Therefore, .the selection of_ appropriate materials for
`fabricating the microporous rate Controlling membrane
`or matrix material will be dependent on the particular
`drug to be used in the bandage. Both organic and inor-
`ganic polymeric materialscan be shaped into a wide va—
`riety of forms with tailored morphology and a wide _'
`range of chemical and physical properties to advanta—
`geously control release of-a wide variety of drugs, in-
`cluding those with large molecular structures such as
`insulin, and over a large dosage range rate appropriate
`pore size selection. Additionally, by impregnating the
`interconnected pores ofthe microporous structure with
`a diffusive medium for the drug ._to be administered, a
`given microp'orous membrane or matrix material can
`be adapted to control the release of drugs having a wide __
`range of chemical properties by diffusive permeability.
`Thus. by varying the composition, pore size, and effec-'
`-tive thickness of the microporous rate controlling ma-
`terial, the viscosity of the drug to 'be'adr'ninistered by
`appropriate formulation or by impregnating the'ma'te-
`rial with suitable solvent, the'dosag'e rate per area: of
`bandage can be controlled since the material functions
`to meter the flow of drug from the device. Therefore,
`bandages of thesame surface area can provide differ--
`e'nt dosages of a drug by varying the above discussed
`parameters. _
`The microporous-rate controlling materials ofthis in- _
`ve'nticn are known in the art and can be visualized as
`a plurality of spongedik'e fused polymer particles which
`provide a supporting structure having'therethrough a
`dispersion of microscopic sized interconnecting voids
`or pores. The rate coon-oiling structures formed from
`the materials can be isotropic. wherein the structure is
`homogeneous throughout the-cross-section of the ma-
`trix or membrane material, or anisotropic wherein the
`structure is nonghomo'genous. These rate controlling
`
`achieve the. desired release rate of drug. Additionally, _
`the material must have the appropriate chemical resis-
`tance tothe drug used and be non-toxic when used as
`an element of the bandage of the invention.
`. Materials. useful in forming the microporcus rate
`controlling materials used in this invention include,-_but _
`are not limited to the following.-
`Polycarbonates, i.e.. linear polyesters of carbonic '
`acids in which carbonate groups recur in the polymer
`chain, by phosgeuation of a dihydrmty aromatic such as -
`bisphenol A; Such materials are sold under the trade
`designation Lexan'by the General Electric Company. _
`. Polyvinylchl'orides; one such material 'is' sold under
`the 'tradedesignation Geon 121_ by 3.6. Goodrich -
`Chemical'Company...
`'. .
`-
`..
`--
`,
`.
`._
`_
`.
`3_Polyamides such'as polyhexamethylene adipamide
`and other such polyamides'popularly'knotvn .as “113;.
`lon“.'—One particularly advantageous materialis that
`sold under. the trade name “NOMEX” by E. I. DuPont
`de Nemours & Co; '
`'
`'
`'
`Modacrylic copolymers. such as that sold under the .
`trade designation DYNEL and formed of polyvinyl-
`chloride (60 percent) and acrylonitrile (40 percent).
`styrene—acrylic acid cepolymers. and the like.
`"
`. Polysulfones such as those of the typecharacterized
`by diphenylene sulfone. groups in the linear; chain-
`thereof are useful.-Such materials'are available from
`Union .Carbide._Corporation under the trade designa-
`tion.P-.-l700.'--
`"
`'
`"
`'
`-
`Halogenated polymers such as polyvinylidene fluo-
`ride sold under.t-he trade designation Kynar by Pennsalt
`Chemical Corporation, polyvinylfluoride sold under
`the trade name Tedlar by E. I. DuPont de Nemours d:
`(30., and the .polyfluo‘rohalocarbon sold under the trade
`' name Aclar-by Allied Chemical Corporation.
`--Polychlomethers .such as that sold under the trade. .
`' name Penton by Hercules Incorporated, and other such
`thermoplastic polyether's.
`-
`-
`.
`-
`_
`_
`Acetal polymers such as the'polyformaldehyde sold
`under the trade nambe Deli-in by E. 'I. DuPont-dc Ne-
`mours-& Co..andthe like.
`-
`.
`-.
`'
`Acrylic resins such as polyacrylonitrile-polymethyl'
`methacrylate, poly nabutyl methacrylate and the like.
`Other polymers such as polyurethanes. poly_imides,.
`polybenzinudazolea'polyvinyl acetate, aromatic and
`aliphatic, polyethers,icellulose esters. 3.3;, cellulose tri-_
`acetate;'cellulose; collodion (cellulose nitrate with 11%
`nitrogen ): epoxy resins; olefins. 'e.g.,.poly'ethylene-po_ly4 -'
`propylene; porous'rubber; cross-linked.me (ethylene
`oxide); crossFIinlted-ipolyyinylpyrrolidone: crossslinlted
`
`45
`
`50
`
`55
`
`60
`
`'65
`
`.
`.
`
`'
`
`Page 5
`
`Page 5
`
`

`

`7
`
`3,797,494
`
`8
`
`poly (vinyl alcohol); polyelectrolyte structures formed
`of two ionically asaociated polymers of the type as set
`forth in U.S. Pat. Nos. 3,549,016 and 3,546,l42; deriv-
`atives of polystyrene such as poly (sodium styrenesul-
`fonate)
`and
`polyvinyIbenzyltrimethyl-ammonium
`chloride);
`poly(hydroxyethyl
`methacrylate)‘,
`poly(isobutyl vinyl ether}, and the like, may also be uti-
`lized. A large number of copolyrners which can be
`formed by reacting various proportions of monomers
`from the aforesaid list or polymers arr-also useful for
`preparing rate controlling structures useful in the in-
`vention.
`.
`As illustrated in FIG. 1, the bandage 20 of the inven-
`tion is comprised of drug 24 uniformly distributed in
`the interstices of the microporous matrix material
`forming reservoir 22. The matrix material is laminated
`to backing member 21 and bears a pressure-sensitive
`adhesive coating 23 thereon. The microporous matrix
`material 22 functions to control the release rate of the
`drug impregnated therein. The reservoir can be pre—
`pared by employing any of the known impregnating
`techniques. Thus, the drug can be added to the rate
`controlling material in liquid form and uniformly dis
`tributed therethrough by mixing, and subsequently
`converted to a microporous structure by the various
`methods known to the an. One such method calls for
`dissolving a natural or synthetic polymer in a suitable
`solvent in which it has sufficient solubility to permit the
`preparation of a solution that is sufficiently viscous for
`cbnventional film casting. The preferred method is to
`cast a film of a polymer solution having the drug
`therein, and, shortly after casting, to immerse it in a
`non—solvent or "diluent." a medium which is compati-
`ble with the solvent, but not a solvent for the polymer.
`The original solution then forms two phases, 'One
`polymer-rich and one polymer-poor. Under the proper
`conditions, both of these phases are physically continu-_
`ous. so that theresulting polymer membrane is me-
`chanically reasonably strong. but it is completely inter-
`laced with continuous pores. The size and uniformity of
`the pores depend on the conditions of preparation. Al-
`ternatively, preformed microporous materials can be
`impregnated with drug by immersion in a bath of the
`drug to diffuse the drug into the material. While the
`matrix material can be of any convenient thickness,
`typically a thickness of from 20 to 200 microns is em-
`ployed.‘
`FIG. 2 illustratesa further modified form of the in-
`vention wherein the adhesive bandage 30 of the inven-
`tion is Comprised of a backing member 21 having a res-
`ervoir 32 on one surface thereof. A microporo‘us rate
`controlling membrane 35 is interposed between the
`reservoir 32- and a-pressure-sensitive adhesive coating
`23. Drug 24 is confined in polymeric matrix material 32
`which acts as the reservoir for the drug. Matrix material
`32 can be solid material as illustrated, or microporous
`as illustrated for reservoir 12 in FIG. 1. If desired, addi-
`tional membranes can be juxtaposed next to membrane
`35 in order to achieve optimum rate release properties.
`The matrix material 32 when solid or microporous
`should have a release rate to drug which is higher than
`that of the rate controlling microporousmembrene 35,
`such that passage through the latter is the rate control-
`ling step. Materials used to form the matrix reservoir 32
`of FIG. 2, when solid, can be those heretofore exempli-
`fied for preparing the microporous rate controlling ma-
`terial and. in addltion, include hydrophobic polymers
`
`l0
`
`IS
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`50
`
`55
`
`60
`
`65
`
`such as plasticized or unplasticized polyvinylchloride,
`plasticized nylon, plasticized soft nylon, plasticized
`polyethyleneterephthalate. natural
`rubber,
`(Cg—C,
`olefins-l e.g., polyethylene. polyisoprene. polyisobutyl-
`ene, polybutadiene; silicone rubbers. especially the
`medical grade polydimethylsiloxanes, as described in
`U.S. Pat. No. 3,2?9,996, hydrophilic polymers such as
`the hydrophilichydrogels of esters of acrylic and meth-
`acrylic acid (as described in U.S. Pat. Nos. 2,967,57 6
`and 3,220,960, and Belgian Patent No. 701,813). mod-
`ified collagen. cross-linked polyvinylalcohol. and cross-
`linked partially hydrolyzed polyvinylacetate. Of course,
`these materials used to form the matrix must be perme-
`able to passage of the drug, as by diffusion. Accord-
`ingly. selection of appropriate materials will, in each
`instance, be dependent on the particular drug to be ad-
`ministered.
`'
`FIG. 3 illustrates a further form of the invention
`wherein bandage 40 includes a backing member 21 and
`a reservoir 42 in the form of a hollow container having
`an interior chamber 43 containing drug 34. Wall or sur-
`face 45 of reservoir 42, remote from backing member
`21, is of a microporous membrane structure permeable
`to passage of drug 34, to meter the flow of drug to pres-
`sure-sensitive adhesive layer 23 on the outer surface
`thereof. The sides of the reservoir 42, other than rate
`controlling microporous membrane 45, preferably are
`impermeable to passage of the drug, and can be made
`of the same materials used to make the backing mem-
`ber as hereinafter described. As discussad, one face
`surface of the drug reservoir bears a backing member
`21. The purpose of the backing is to prevent passage of
`the drug through the surface 'of the reservoir distant
`from the adhesive layer. An ancillary purpose of the
`backing is to provide support for the bandage where
`needed. When the outer surface of the reservoir 33 is
`impermeable to the drug and strong enough, the back-
`ing becomes unnecessary. The other surface of the res-
`ervoir bears a coating of a pressure-sensitive adhesive.
`If desired, additional microporous rate controlling
`membranes can be juxtaposed on top of membrane 45
`to further tailor the rate of flow of drug. Of course. in
`each instance, the membrane will have different cha-
`racteristics than the reservoir membrane 45 of the par-
`ticular. device. This use of a pair of multiplicity ofmel'n-
`branes. that is, the reservoir wall and the further mem-
`brat-1el 'allows'for precise metering of drug out of the
`reservoir; for the thickness. porosity and composition
`of both membranes can be varied to provide for wide
`range of dosage. levels for a given area of bandage. It
`will be appreciated that this type of membrane can be
`used With either the matrix (FIGS. 1 or 2) or container
`type (FIG. 3)'of reservoir. To provide additional me-
`chanical strength, if necessary, the rate controlling mi-
`croporous membrane 45 can be supported byan appro-
`priate mesh or screen having a greater release rate to
`drug than does membrane 45.
`-
`_
`The reservoir of the embodiment in FIG. 3 can be
`
`formed by molding into the form of a hollow container
`with the drug trapped therein. While the non-rate con-
`trolling walls of the reservoir can be of any convenient
`thickness. usually they have a thickness of from 0.01 to
`7 millimeters. The rate controlling membranes 35 and
`45, in FIGS. 2 and 3, respectively, can have varying
`thickness depending upon the nature of the membrane,
`its porosity and the number of membranes used in com
`
`-
`
`Page 6
`
`Page 6
`
`

`

`.
`
`9
`
`'
`
`-
`
`3,797,494:
`
`_'
`
`__
`
`_.
`
`.
`
`--
`
`_
`
`as
`
`5
`
`15
`
`.
`
`'
`
`_
`
`.
`
`-_I
`
`
`
`average particle size of 'form itch-1000 micro'a am
`
`'
`
`-
`
`25
`
`30
`
`35
`
`.
`
`'
`
`50
`
`55
`
`60
`
`as
`
`10
`reins-'coatingrofthe encapsulating material to form mi- --
`bination. Typically. a thickness'of from 20 to 200ml-
`crons isemployed.
`_
`-
`'
`crocapsules having an interior. chamber containing the -'
`It will,_of course, be appreciated that the pressure-
`drugilf. desired, particles of a-matrix, such as starch.
`sensitive adhesive surface need not form a continuous
`gum _ acacia, gum tragacanth, and -. mlyvinychDride,
`layer on the subject bandage. Particularly in the case of
`cube-impregnatedwith the drug and encapsulated
`a bandage having a distinct reservoir layer, equally ad-
`with other motorials such as the nucroporous rate con—
`vantageous results are obtained by providing an an_nu-_'
`trolling m'aterial's previously described. which function
`lar surface of adhesive around the periphery of the ban- -
`to meter the flow of drug to the adhesives; use of a mi- _
`dage face. In this manner a liquid tight adhesive seal be-
`croporous matrix and a different rate controlling mem-
`tween the bandage and the patient‘s‘ skin or mucosa is 10 brane coating to slow the passage of the drug from the
`maintained. and at the same time, drug maybe directly
`microcapsules, Which is desirable-arid: drugsthat are
`absorbed by .the skin from the exposed surface of the
`released too-rapidly from available encapsulating mate-
`drug reservoir layer without first migrating through an
`rials, .istherefore also contemplated herein._
`adhesive layer. As a further alternative. in the embodi-
`Any of the encapsulation or impregnation techniques
`ment of the invention employing adistinct reservoir
`known in the art can be used to prepare the mierocap-
`layer, to prevent passage of the drug into the adhesive
`sales to be. incorporated-him the pressure-sensitive atl-
`layer prior to use, the adhesivecan besupplied sepa-
`' hesiv'e in accord with the embodiment of FIGS. 4 and
`5.' The porous microca'psules can be made by téch-
`rately from the reservoir and backing, with the device
`assembled at the point of use. For example, the adhe~
`niques' as set forth in US. Ser. No. T5135], corre-
`sive in sheet form can have both su