United States Patent m
`Nuwayser
`
`[54] METHOD OF TRANSDERMAL DRUG
`DELIVERY
`[75] Inventor: Elle S. Nuwayser, Wellesley, Mass.
`[73] Assignee: Biotek, Inc., Wobum, Mass.
`[21] Appl. No.: 653,362
`[22] Filed:
`Oct 1,1984
`[51] Int. Q.4
`A61F 13/02; A01N 25/26;
`A61J 3/00; A61K 9/70
`604/307; 424/16;
`424/28; 424/78
`424/16, 28, 78;
`604/307
`
`[58] Field of Search
`
`[52] U.S.C1
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,797,494 3/1974 Zaffaroni
`4,053,580 10/1977 Chienetal
`4,336,243 6/1982 Sanvordeker
`4,466,953 8/1984 Keith etal
`OTHER PUBLICATIONS
`"Topical Nitroglycerin", by J. F. Dasta et al., American
`Pharmacy, 22(2), 1982, pp. 29-35.
`Primary Examiner—John E. Kittle
`Assistant Examiner—Mukund J. Shah
`
`604/897
`. 424/15
`. 424/28
`. 424/28
`
`4,624,665
`[it] Patent Number:
`[45] Date of Patent: Nov. 25,1986
`
`Attorney, Agent, or Firm—Richard P. Crowley
`[57]
`ABSTRACT
`A transdermal drug delivery system useful for the con­
`trolled, for example zero order, release of one or more
`drugs to a selected skin area of a user, which system
`comprises an impervious backing sheet and a face mem­
`brane, the backing sheet and membrane secured to­
`gether to form an intermediate reservoir. The face
`membrane is a macroporous membrane which has pores
`of sufficient size to avoid any rate control of the drug to
`be transdermally delivered to the user. The reservoir
`contains a viscous liquid base material selected to exude
`from the membrane to form a film and to occlude the
`skin of the user to force hydration of the stratum cor-
`neum with water from the lower layers of the epidermis
`of the user and a plurality of solid microparticles gener­
`ally uniformly dispersed and suspended in the liquid
`base material. The microparticles containing an effec­
`tive therapeutic amount of the drug for transdermal
`delivery, such as the contraceptive steroid. In use the
`liquid base material exuded from the macroporous
`membrane face forms a thermodynamically stable thin
`film layer in an intimate contact with the skin, while the
`drug is released from the microparticles into the base
`material and transdermally into the user.
`14 Claims, 3 Drawing Figures
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`
`MYLAN - EXHIBIT 1031
`
`

`

`U.S. Patent Nov. 25,1986
`
`Sheet 1 of2
`
`4,624,665
`
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`IN VITRO
`
`LEVONORGESTREL MICRORARTICLES
`
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`
`

`

`1
`METHOD OF TRANSDERMAL DRUG DELIVERY
`
`4,624,665
`2
`rous membrane. One product depends on a diffusion
`matrix in which nitroglycerin molecules are in equilib­
`rium between lactose crystals and the liquid phase. In
`REFERENCE TO PRIOR APPLICATIONS
`another product, micropockets of nitroglycerin are
`This application discloses to a prior co-pending appli- 5 evenly dispersed throughout a silicone polymer which
`cation U.S. Ser. No. 577,079, filed Feb. 6, 1984, entitled
`controls the drug release rate and prevents dose dump-
`ing.
`COMPOSITE CORE COATED MICROPARTI-
`A description of the different commercial products
`CLES AND PROCESS OF PREPARING SAME.
`which deliver nitroglycerin transdermally is set forth
`The prior application relates to a process for preparing
`coated solid microparticles and to the microparticles so 10
`by Dasta, et al., American Pharmacy, NS22, 2, 29-35,
`prepared and to the use of the microparticles to provide
`February 1982, which article also illustrates the various
`for the sustained release of a drug incorporated in the
`prior art nitroglycerin patches and their construction
`microparticles. The process comprises preparing a sol­
`and operation, and which article is hereby incorporated
`vent solution of an active ingredient such as a drug to be
`by reference.
`encapsulated, but more particularly a contraceptive 15 U.S. Pat. No. 4,336,243, issued June 22, 1982 de-
`steroid-type drug and a film-forming polymer and re-
`"
`scribes transdermal nitroglycerin pads wherein the pad
`moving the solvent to provide a dry, composite, uni­
`comprises a silicone polymer matrix being a cross-
`form admixture of the drug-active ingredient and the
`linked silicone rubber having from about 10 to 200 mi­
`polymer material. The mixture is then reduced to a
`crons microseal compartments formed by the in situ
`defined, smaller particle size distribution and the 20
`cross-linking of the silicone rubber after it is admixed
`ground admixture then coated in a fluidized bed with a
`with a hydrophilic solvent containing the nitroglycerin
`uniform, defined wall thickness of the same or substan­
`in a hydrophobic solvent which enhances the dispersion
`tially the same film-forming polymer material used to
`and transport. U.S. Pat. No. 4,053,580, issued Oct. 11,
`provide the composite core coated microparticles. Typ­
`1977 describes an earlier pharmaceutical delivery de­
`ically, the dry composite admixture is reduced to a 25
`vice employing a silicone polymer matrix wherein the
`particle size of less than 1000 microns, e.g. 200 microns.
`rate of release of the active ingredient is controlled by
`The film forming polymer material employed generally
`altering the solubility of the hydrophilic solvent system
`is a polymer, like polyvinyl alcohol or a cellulosic mate­
`for the polymer matrix.
`rial or a biodegradable polymer, such as for example, a
`Another polymer diffusion matrix transdermal deliv­
`polylactide, a polyglycolide, and copolymers of lactides 30
`ery system is described in published European patent
`and glycolides. The drug employed in the microparti­
`application No. 80300038.9, of A. Keith entitled Poly­
`cles may vary, but typically may comprise for example,
`meric Diffusion Matrix and Method of Preparation and
`a contraceptive steroid-type drug such as levonorges-
`Drug Delivery Device Comprising Said Matrix. This
`trel or estradiol. For injectable compositions the parti­
`application describes a polymeric diffusion matrix com­
`cle size of the microparticles is less than 200 microns 35
`posed of glycerol and polyvinyl alcohol together with a
`with a uniform wall coating of about 0.2 to 20 microns.
`water-soluble polymer to provide a polymer matrix
`The microparticles are useful for the controlled release
`capable of sustained release of a drug dispersed in the
`of a drug-active ingredient such as in a zero order re­
`matrix. Typically, the water-soluble polymer comprises
`lease pattern and for example, may be employed by
`.
`.
`.
`injecting microparticles suspended in a liquid carrier 40 a polyvinylpyrrolidone or a water-soluble cellulosic
`into a patient.
`derivative. U.S. Pat. No. 3,797,494, issued Mar. 19,1974
`describes a transdermal bandage which includes a reser­
`BACKGROUND OF THE INVENTION
`voir with a drug confined within the interior chamber
`of the reservoir and distributed throughout a reservoir
`Transdermal delivery of medication is not a new
`concept, as a variety of medications that are readily 45 matrix. In one embodiment the drug is released by a
`available for delivery through the skin have been avail-
`controlling microporous material, which microporous
`able in ointment form for over thirty years. With oint-
`material meters the flow of the drug into the skin at a
`ments, however, it is difficult to achieve precise drug
`controlled rate. In another embodiment an adhesive
`dosage. In a transdermal patch system, this problem is
`coating is uniformly distributed through microcapsules
`eliminated by controlling the rate of drug release over a 50 comprising a drug encapsulated with a microporous
`prescribed period of time. Patches are worn behind the
`rate controlling material.
`ear, on the chest, or on the arm and dispense a drug for
`While many transdermal drug delivery systems have
`as long as a week at a time. For certain drugs trans-
`been described as an economical and effective trans­
`dermal delivery has significant advantages over oral
`dermal drug delivery system particularly for the deliv-
`administration. It eliminates "first pass" inactivation by 55 ery of contraceptive steroid drugs is still needed, and
`the liver and irregular gastric absorption. Because of
`desired, particularly percutaneous delivery of steroid
`constant absorption through the skin, it maintains rela-
`contraceptives in a controlled manner for periods of
`lively constant blood levels of the drug.
`time ranging from one to four weeks or more.
`Two drugs, scopolamine and nitroglycerin, have
`Levonorgestrel is a synthetic steroid which has pow-
`recently become commercially available in transdermal 60 erful progestational activity with minimal side effects at
`form. Although there are differences in composition
`very low doses. Estradiol is a natural estrogen which
`and in the mechanism of drug delivery among the avail-
`has limited oral effectiveness because of "first pass"
`able transdermal delivery systems, they all appear to be
`inactivation during circulation. On the other hand the
`functionally similar. Generally the systems have essen-
`synthetic steroid, ethinylestradiol, is active orally, since
`tially steady state reservoirs sandwiched between an 65 its inactivation by the liver and other tissues is very low.
`impervious backing and a membrane face. The systems
`These contraceptives and others like Mestranol, Nor-
`usually are attached to the skin by an adhesive gel.
`ethindrone, etc., are employed in various oral contra-
`Some products have a rate-controlling outer micropo-
`ceptives manufactured in this country. Although levo-
`
`

`

`dMt
`dt
`
`= AirDKA
`
`rpTj
`ro - n
`
`4,624,665
`4
`3
`the stratum comeum to swell and hydrate by forcing
`norgestrel pills contain 150 micrograms of the drug,
`the diffusion of water from the lower layers of the epi­
`studies with implantable drug delivery systems indicate
`dermis and thus to accelerate the drug delivery. The
`that only 30 micrograms per day are sufficient to pre­
`first phase in transdermal delivery is dependent on the
`vent fertility.
`Thus, it is desirable to provide an effective trans- 5 rate of diffusion of the drug within the vehicle and its
`rate of release from the vehicle. The drug concentration
`dermal drug delivery system for the transdermal deliv­
`in the vehicle determines the thermodynamic activity
`ery of drugs, particularly contraceptive steroids.
`and influences the diffusion of the drug out of the vehi-
`SUMMARY OF THE INVENTION
`cle.
`The present drug delivery system suspends drug/­
`The invention concerns a transdermal drug delivery 10
`polymer microparticles, in a delivery vehicle which
`system and a method of manufacture and use of such
`microparticles control the rate of release of the drug to
`system. In particular the invention relates to a trans­
`the vehicle. Drug delivery from microcapsules is zero
`dermal drug delivery system particularly useful for the
`order provided solid particles are present inside the
`controlled release of a contraceptive steroid drug or a
`15 microcapsule in equilibrium with a saturated solution of
`combination of such drugs.
`The invention relates to a transdermal drug delivery
`the drug. It is dependent on the diffusion coefficient of
`system which may be employed with a drug which is
`the drug in the polymer, the thickness of the capsule
`desired to be delivered transdermally at a controlled or
`wall, and the microcapsule dimensions in accordance
`sustained rate, typically a zero order rate or other deliv­
`with this equation:
`ery release patterns as desired. The transdermal drug 20
`delivery system of the invention prevents dose dumping
`of the drug caused by accidental rupture of the retaining
`member and ensures effective and prolonged delivery
`of the drug.
`Where M is the mass of the drug released, dM/dt is
`The invention relates to a method of and system for 25
`the steady state release rate at time t, DK is the mem­
`accelerating the transdermal delivery of drugs into a
`brane permeability, D is the diffusion coefficient of the
`patient by sealing the skin of the patient with a thin
`drug in the membrane in cm2/sec., K is the distribution
`layer of a viscous material to occlude the skin and trans­
`coefficient, C is the difference in drug concentration
`porting a desired dosage of a drug across the thin layer
`between the internal and external surface of the mem­
`typically from a rate-controlling system in contact with 30
`brane, and r0r; are the outer and inner radii of the cap­
`the thin layer. The rate-controlling system may be a thin
`sule wall, respectively.
`rate-controlling membrane interposed between the drug
`Drug release from monolithic microparticles such as
`and the thin layer. Preferably the rate-controlling sys­
`microspheres is first order and is additionally dependent
`tem comprises microparticles of the drug or a combina­
`on drug concentration in the particle. Thus, the pres­
`tion of drugs to be delivered suspended in the same or 35
`ence of the microparticles in the base vehicle helps to
`similar viscous material and contained within a con­
`maintain a constant thermodynamic activity of the drug
`tainer system. The container system generally com­
`in the vehicle by insuring that the concentration of the
`prises a macroporous non-rate-controlling face mem­
`drug is close to saturation.
`brane with an impervious backing to form a pool or
`The delivery of the vehicle to the skin is regulated by
`patch-like system of desired face membrane area with 40
`a macroporous membrane (for example ranging from
`the face of the membrane placed over and in contact
`about 1 to 1000 microns) whose properties and poree
`with the thin occluding viscous layer on the skin. The
`size are selected to match those of the base vehicle. A
`thin viscous layer may be coated or placed on the skin
`hydrophobic membrane, for example, is best used with
`,
`,
`, ,
`,. ,
`,
`repeatedly and the patch system placed on top of the
`thin viscous layer or the viscous layer formed in situ by 45 a hydrophobic delivery base vehicle and hydropMic
`membrane with a hydrophihc vehicle while smaller
`exudation through the membrane face when the patch
`mlcro" Pore!> e-S- 50 to 200 deliver a smaller quantity of
`or pool system is placed in position on the skin. The
`the vehicle than larger micron pores e.g. 300 to 600
`patch or pool container system generally is retained in a
`The principal barrier to permeation of small mole-
`transdermal position by the use of a peripheral adhesive
`layer about the patch or pool. Typically the face or 50 cules thro?gh ^e skin is provided by the stratum cor-
`neum or * horny ^ of cells which ^ about 10 to 15
`transport area of the membrane is covered prior to use
`microns thick. This layer is composed of a dispersionof
`by a removable cover such as a peelable strip of imper-
`hydrophihc proteins m a continuous lipid matrix. The
`vious sheet material
`lipid component of the layer which comprise only
`In another embodiment microcapsules containing a
`drug for delivery may be suspended in a viscous mate- 55 20-3°%.of the weiSht of the tlfu.e ^ directly responsi-
`ble for lts unlclue low permeability (Scheuplem, 1971).
`rial and the composition then spread as a layer over the
`T1Le stratum comeum may be regarded as a passive
`skin of the user with or without a covering material.
`diffusion membrane, albeit not entirely inert, which
`The present drug delivery system for the transdermal
`follows Flck s Law ,n whlch the steady state ^ Js ls:
`delivery of medicaments is based on the use of solid
`microparticles. The system releases the drug from rate- 60
`controlling microparticles which are suspended in a
`dermatologically acceptable viscous liquid base. Drug
`release from microcapsules is controlled by microcap­
`sule size and wall thickness. The system is also charac­
`terized by a macroporous membrane which delivers a 65
`thin liquid film of the base vehicle to the skin and whose
`function is to deliver the drug to the skin. The function
`of the viscous liquid film is to occlude the skin causing
`
`Cm
`_
`solute sorbed per cc of tissue
`solute in solution per cc solvent — Cs
`Cs=concentration difference of solute across mem­
`brane
`
`js — Km D Cs
`
`where Km —
`
`

`

`6
`TABLE 1-continued
`FLUX RATES OF STEROIDS
`FLUX (MOLES/CM2 HR).
`(Feldman 1969)
`(SCHAEFER 1979)
`7.5 X 10-12
`
`STEROID
`Corticosterone
`
`.
`
`,
`
`,
`
`«
`
`«
`
`•
`
`.
`
`4,624,665
`5
`D=average membrane diffusion coefficient for sol-
`ute
`S=membrane thickness
`Swelling of the comeum can be produced by hygro­
`scopic or other substances if they penetrate the hydro- 5
`philic zone or if lipophilic substances penetrate the
`hydrophobic zones. Increasing the state of hydration
`increases the porosity and thickness of the layer and
`Table 1 shows that the flux gates of estradiol and
`favorably influences the transport of the drug by two to
`progesterone are fairly high in comparison to the cor-
`three fold. The simplest method for increasing hydra- 10 ticosterones. These flux rates depend on the concentra­
`tion is to occlude the skin which forces the diffusion of
`tion of the applied substance in the vehicle. At low
`water from the lower layers of the epidermis. Estimated
`concentrations the rates are proportional to the concen­
`diffusion constant for low molecular weight nonelectro-
`tration in the vehicle. This proportionality is not 1 to 1
`lyte is 10-9 sq./sec. for stratum comeum and lO-6 cm.
`since a doubling of the concentration increases the flux
`sq./sec. for the dermis.
`by about 30-50%.
`The degree of hydration of the stratum comeum is
`This general pattern of regional variation was found
`provided by the macroporous membrane which deliv­
`to hold for other chemical moieties (steroids, pesticides,
`ers a thin liquid film of the vehicle to its outer surface to
`and antimicrobials). Although the stratum comeum is
`occlude the skin. The liquid film is simultaneously in
`generally accepted to be the major barrier to percutane­
`contact with the skin and the liquid or viscous vehicle 20
`ous penetration, this appears to hold only if the skin is
`of the reservoir through the macroporous channels of
`intact. Damage to the stratum comeum makes the other
`the membrane. Occlusion of the skin which follows may
`layers function as barriers. For example, the penetration
`be influenced by the properties of the vehicle and the
`of hydrocortisone through modified skin results in a
`membrane.
`tenfold increase in the penetration of hydrocortisone
`Following topical administration of many drags in- 25
`from 1% to 10% when the skin is occluded. The thin
`eluding steroids like estrogen and norgesterone, a reser-
`id fllm which is exuded b the macroporous men,,
`li
`voir can form m the skm The existence of this reservoir
`brane occludes ^ skin t0 increase d
`penetration,
`and its locdization m the stratum comeum was first
`m of the inventi^n is hased on
`The d
`deli
`proven by Vickers (1963). Much of the work in this area
`j
`solid micro articles or rate_
`the use of d
`has dealt with local action of drugs (e.g. hexacWoro- 30 controllin micr£
`ules which are SUSpended in a
`phene, sunscreens, Cortisol). However prolonged toxic
`dermatolo icall acceptable viscous liquid base mate-
`response following topical administration of vasocon- ^ or vehicle The base ^ g
`ed ^ ^ skin b a
`stnetors demonstrates that a cutaneous reservoir can
`non rate.controlli P macr0p0rous membrane,
`non
`provide sustained release into the systemic circulation.
`The ^ ^ or
`rinleter 0bfthe membrane is covered
`Accumulation of both estrogen and progesterone in ^ u
`•. • .
`,
`„
`.
`„
`.
`,
` i •
`by a nonsensitizing hypoallergenic adhesive layer or
`,
` A
`,
` j
`1 1 . 1 .
`
`subcutaneous tissue and underlying muscle has been
`^
`*.
`,
`, .
`«
`other means to secure the system to the skin which
`4. ^ 1 • v x.
`u
`observed and is more pronounced with percutaneous
`^
`•
`**
`j-
`*
`~
`holds the microporous membrane m contact or adjacent
`than with subcutaneous administration. The duration of
`, • m*:
`,
`Ai_
`. ^ ,.
`.u ,
`,
`.
`, ,
`j
`,
`
`, .
`* 1
`c
`to the skin and prevents loss of the drug to the sur-
`J
`.
`the local reservoir appears to be dependent on the nor-
`Ji
`.
`
`,
` 1 ^ J
`mal 14 day cycle of epidermal turnover. Irritation with 40 rounding area. Tlie microcapsules release the drug to
`a detergent or methotrexate increases turnover and can
`the ^ m a f trolled release pattern and maintains it
`reduce the duration of the reservoir by nearly 50%. m * thermodynanncal y stable condition. Release is
`Inhibition of turnover with fluorinated steroids can
`controlled by the selected microcapsule size and thick-
`double the duration to 28 days. In addition a compound
`nessuof th® microcapsule wal1-
`controlled release
`which very rapidly penetrates and diffuses is maintained 45 « obtamed and the presence of the microcapsules pre-
`in the reservoir for a short period of time (e.g. nicotine,
`vents dose dumPlnS caufd ^ accidental rupture of the
`3-4 days). Since occlusion of the area of application
`membrane and ensures a prolonged delivery
`appears necessary to promote sustained absorption from
`ot tne drug.
`„ ,
`.
`t
`the reservoir, continued absorption following removal
`^An important feature of the drag delivery system m
`of the delivery system should be minimal unless the 50 this embodiment is the macroporous retaining mem-
`concentration is very high.
`bran® whlch separatesi the liquid base from skm. This
`Pronounced and prolonged effects of estrogens and
`membrane delivers a thm film controlled amount of the
`gestagens can be expected by the transdermal route
`base matenal t0 ,lts out,er face ^ce to contact the
`since it is the total amount of hormone absorbed by the
`skln- The liquid film occludes the skm and forces hydra-
`body that is decisive, and not the peak height of the 55 tion of the stratum comeum with water from the lower
`hormone level. The flux rate of steroids through human
`layers of the epidermis. This in turn accelerates delivery
`skin has been studied by others and are shown below in
`of the druS> e-g- steroids across the stratum comeum.
`Intimate contact between the skin and the thermody-
`Table 1.
`namically stable viscous liquid base also ensures uni-
`60 form delivery of the drug throughout the treatment
`period. Unlike microporous membranes, the macropo­
`rous membrane does not control the rate of drug deliv­
`ery to the skin, but solely the amount and thickness of
`the film of liquid material in contact with the skin.
`65 The macroporous membrane ensures the presence of
`a continuous drug-filled liquid base pathway between
`the viscous base reservoir and the skin. The dimensions
`of the macropores and the degree of hydrophobicity of
`
`TABLE 1
`FLUX RATES OF STEROIDS
`FLUX (MOLES/CM2 HR).
`(Feldman 1969)
`(SCHAEFER 1979)
`5.8 X 10-'°
`8.2 X 10-11
`4.6 X 10-10
`1 X lO"9
`7.8 X lO"11
`
`STEROID
`17^ estradiol
`17^ estradiol
`Testosterone
`Estriol
`Progesterone
`Hydrocortisone
`
`5 X 10-11
`
`3.4 X 10—"
`2.5 X lO-15
`
`

`

`4,624,665
`8
`7
`thin film. The active drug ingredient is released at a
`the membrane are selected to match the properties of
`selected zero order rate from the plurality of micropar-
`the liquid base (i.e. viscosity, hydrophobicity). The
`tides suspended in the liquid material; and therefore,
`function of the macroporous membrane is to permit
`transported directly through the viscous liquid base
`only a small, but sufficient quantity of the base material
`to pass through the pores to the skin surface without 5 material into the skin of the user. The drug delivery
`system of the invention contributes significantly to the
`being messy or leaky.
`accelerated permeation of the drug through the skin,
`Microparticles are suspended in the liquid base mate-
`since the skin is continuously in contact with the drug in
`rial to provide a thermodynamically stable base with a
`solution. Further, since the skin is occluded to permit
`constant driving force of the drug in the liquid base.
`The microparticles or microspheres suspended in the 10 hydration of water from the lower layers, the perme­
`ation of the drug from the liquid base material into the
`liquid base material comprise solid mixtures of the drug
`hydrated stratum comeum is much faster than when a
`in a polymer and one embodiment may comprise the
`dry dehydrated comeum is presented. In addition, the
`microparticles as described in the assignee's co-pending
`skin is continuously in contact with the viscous liquid
`application Ser. No. 577,079 (hereby incorporated by
`15 base material which is generally selected to have emol­
`reference).
`lient properties. This emollient contributes to the accel­
`The transdermal drug delivery system of the inven­
`erated delivery by maintaining the outer skin softness
`tion usually includes an impervious backing sheet with
`and pliability to assure continuous contact between the
`a macroporous face membrane, the backing sheet and
`skin, the liquid base material and the membrane surface
`the macroporous membrane typically secured together
`generally along its edges to form an intermediate layer- 20 which is in quite a contrast to contact with a dry solid
`matrix of the prior art.
`like reservoir therebetween. The macroporous mem­
`The drug polymer microparticles produce a thermo­
`brane has pores of sufficient size to avoid rate control of
`dynamically stable liquid base as a source of the active
`the active drug ingredient to be transdermally deliv­
`drug and practically eliminates the problem of drug
`ered, but of a the size sufficient to permit the liquid base
`material to be exuded therefrom so as to form a thin film 25 dose dumping if the membrane is accidentally ruptured
`as with prior art transdermal drug delivery systems.
`of the base material for intimate contact with the skin of
`The rate of drug delivery may be modified and tailored
`the user adjacent the face of the macroporous mem­
`by several variables, such as the microparticle size,
`brane.
`composition, polymer composition, wall thickness, and
`The reservoir comprises a dermatologically-accepta-
`ble, generally viscous liquid base material, the viscosity 30 the macroporous membrane properties and porosity
`and the selection of the viscous liquid base composition
`should be sufficiently high to suspend the microparti-
`and properties as to the degree of hydrophilicity or
`cles therein and to prevent leakage or excessive flow
`hydrophobicity. The various additives may be com-
`through the membrane pores, but low enough to permit
`pounded and added into the liquid base material, which
`the function of the thin film on the skin. A plurality of
`solid microparticles or microspheres are generally uni- 35 compounds may be employed to impart special proper-
`ties to the liquid base material; for example, to enhance
`formly dispersed and suspended in the liquid base mate­
`diffusion, control steroid reservoir formation, improve
`rial within the reservoir. The microparticles include an
`antiseptic properties, reduce infection, control viscos­
`effective therapeutic amount of an active drug ingredi­
`ity, or to add emollient or lubricant properties where
`ent or a combination thereof, such as a contraceptive
`steroid, like levonorgestrel or estradiol or a combina- 40 prolonged usage of the transdermal drug delivery sys-
`tem is desired.
`tion thereof for transdermal delivery for a particular
`The liquid base material may comprise a variety of
`therapeutic purpose such as contraception. The drug is
`materials, but typically should be a viscous-type liquid
`present in an effective therapeutic amount within the
`material capable of suspending the plurality of solid
`microparticles suspended in the reservoir with the mi­
`croparticles generally designed to provide for a zero 45 microparticles therein and also to be exuded through
`the selected pores of the macroporous membrane so as
`order release of the active drug material. Preferably, the
`to form a thin stable thermodynamic film on the skin of
`microparticles are composed of an admixture of a poly­
`the user. The liquid base material should be dermatolog-
`mer with the active drug ingredient in the microparti­
`ically acceptable to the user. The viscosity of the liquid
`cles varying as desired, but generally from about 0.1 to
`30 percent by weight, for example, 1 to 20 percent and 50 base material should be high enough so that the liquid
`base material will not run from the macropores of the
`wherein the microparticle has a thin polymer wall coat­
`macroporous membranes and deplete the reservoir or
`ing thereon such as a wall coating imparted in a fluid
`become messy to the user, and yet not high enough to
`bed coating system or by other means. Typically an
`prevent the liquid base material from entering the pores
`adhesive layer is placed about the periphery of the drug
`delivery system and usually an impermeable material 55 and forming the thin film on the skin of the user after a
`protective face layer has been peeled away from the
`such as a protective peel strip is secured to the open face
`outer face of the macroporous membrane. Typically,
`of the macroporous membrane, which peel strip is to be
`the liquid base material should have a gel or grease-like
`removed just prior to use.
`viscosity and properties.
`In use and on removing of the peel strip, the drug
`The liquid base material should be selected to be
`delivery system in the form of a patch is applied to the 60
`compatible with and to permit the transport of the drug
`skin of the user at a desirable location and the patch
`within the microparticles. Typically, if the drug is a low
`adhered by an adhesive exposed after removal of the
`water soluble-type drug then the liquid base material
`peel strip. The macroporous nature of the membrane
`would be a low water soluble base material generally
`permits the viscous liquid base material in the reservoir
`to exude through the macropores to form a thin film on 65 matching the hydrophobicity of the drug and vice versa
`where the drug is water soluble, the liquid base material
`the face of the macroporous membrane and places the
`may be selected to be also water soluble so that there is
`macroporous membrane in intimate contact with the
`transport and compatibility from the drug release
`skin of the user thus forming a thin dynamically stable
`
`

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`4,624,665
`9
`10
`through the wall of the microparticle and so the drug
`typically less than about 200 microns. The microparti-
`may move effectively through the liquid base material
`cles may comprise microspheres and the microparticles
`in the reservoir and onto the thin film adjacent the user
`designed to deliver a constant and sustained dose of the
`directly into the skin of the user. For example, the liquid
`active ingredient for periods ranging from several hours
`base material may comprise a hydrophobic material 5 to several years; for example, one day to one month. In
`such as a long chain, e.g. C8-C22 hydrocarbon-type
`one embodiment the control release rate may be a zero
`material particularly for use with water-insoluble or
`order release rate. The microparticles may be formed of
`very low water soluble drugs, such as for example, a
`natural or synthetic polymeric materials both of the
`grease-like hydrocarbon such as a petroleum based jelly
`core material and the coating material and particularly
`e.g. Vaseline, a semisolid mixture of hydrocarbons hav- 10 with biodegradable polymers such as the lactides,
`ing a mp of 38o-60° C. The liquid base material may
`glycolides, or copolymers of lactide and glycolide as
`comprise also a hydrophilic-type material such as a
`biodegradable polymers. For example, in one embodi-
`polyethylene glycol, glycerol, or a water solution
`ment microparticles may be prepared from employing
`placed in a gel-like form through the use of viscosity
`an active drug steroid such as levonorgestrel or estra-
`modifying additives or gel-like material such as polyvi- 15 diol and combinations in admixture with a biodegrad-
`nylpyrrolidone, agar, proteins, thickeners and the like.
`able (polylactide) polymer and then coated with a bio-
`In addition, it should be noted that the liquid base mate-
`degradable (polyactide) polymer to prepare the mi-
`rial in the reservoir may contain other modifying