United States Patent
`
`[19]
`
`[11] Patent Number:
`
`4,624,665
`
`Nuwayser
`[45] Date of Patent:
`Nov. 25, 1986
`
`[54] METHOD OF TRANSDERMAL DRUG
`DELIVERY
`
`Elie S. Nuwayser, Wellesley, Mass.
`Inventor:
`[75]
`[73] Assignee: Biotek, Inc., Woburn, Mass.
`
`[21] App]. No.: 653,362
`
`[22] Filed:
`
`Oct. 1, 1984
`
`[51]
`
`Int. Cl.4 ...................... A61F 13/02; A01N 25/26;
`A6lJ 3/00; A61K 9/70
`[52] US. Cl. ...................................... 604/307; 424/16;
`424/28; 424/78
`[58] Field of Search ............................. 424/16, 28, 78;
`604/307
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,797,494 3/1974 Zaffaroni ............................ 604/897
`4,053,580 10/1977 Chien et a1.
`424/15
`
`4,336,243
`6/1982 Sanvordeker .....
`424/28
`........................... 424/28
`4,466,953
`8/1984 Keith et al.
`
`OTHER PUBLICATIONS
`
`“Topical Nitroglycerin”, by J. F. Dasta et a1., American
`Pharmacy, 22(2), 1982, pp. 29—35.
`Primary Examiner—John E. Kittle
`Assistant Examiner—Mukund J. Shah
`
`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
`
`
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1031
`
`

`

`US. Patent
`
`INov.25, 1986
`
`Sheet 1 of2
`
`4,624,665
`
`
`
`
`
`

`

`US. Patent Nov.25, 1986
`(
`
`Sheet20f2
`
`4,624,665
`
`
`
`
`
`LEVONORGESTRELMICROPARTICLES
`
`
`
`200
`
`|50
`
`'00
`
`DAYS
`
`FIG.30
`
`5O
`
`o
`
`INVITRO
`
`I
`
`,
`2-
`
`200
`
`I50
`
`FIG.3b
`
`DAYS
`
`I00
`
`5O
`
`
`
`
`INRABBITS
`
`(AVG/SW/‘SI'D
`
`2-
`
`'lW/SWVHSONVN
`
`

`

`1
`
`4,624,665
`
`METHOD OF TRANSDERMAL DRUG DELIVERY
`
`REFERENCE TO PRIOR APPLICATIONS
`
`This application discloses to a prior co-pending appli-
`cation U.S. Ser. No. 577,079, filed Feb. 6, 1984, entitled
`COMPOSITE CORE COATED MICROPARTI-
`CLES AND PROCESS OF PREPARING SAME.
`The prior application relates to a process for preparing
`coated solid microparticles and to the microparticles so
`' prepared and to the use of the microparticles to provide
`for the sustained release of a drug incorporated in the
`microparticles. The process comprises preparing a sol-
`vent solution of an active ingredient such as a drug to be
`encapsulated, but more particularly a contraceptive
`steroid-type drug and a film-forming polymer and re-
`moving the solvent to provide a dry, composite, uni-
`form admixture of the drug-active ingredient and the
`polymer material. The mixture is then reduced to a
`defined,
`smaller particle size distribution and the
`ground admixture then coated in a fluidized bed with a
`uniform, defined wall thickness of the same or substan-
`tially the same film-forming polymer material used to
`provide the composite core coated microparticles. Typ-
`ically, the dry composite admixture is reduced to a
`particle size of less than 1000 microns, e.g. 200 microns.
`The film forming polymer material employed generally
`is a polymer, like polyvinyl alcohol or a cellulosic mate-
`rial or a biodegradable polymer, such as for example, a
`polylactide, a polyglycolide, and copolymers of lactides
`and glycolides. The drug employed in the microparti-
`cles may vary, but typically may comprise for example,
`a contraceptive steroid-type drug such as levonorges-
`trel or estradiol. For injectable compositions the parti-
`cle size of the microparticles is less than 200 microns
`with a uniform wall coating of about 0.2 to 20 microns.
`The microparticles are useful for the controlled release
`of a drug—active ingredient such as in a zero order re-
`lease pattern and for example, may be employed by
`injecting microparticles suspended in a liquid carrier
`into a patient.
`BACKGROUND OF THE INVENTION
`
`Transdermal delivery of medication is not a new
`concept, as a variety of medications that are readily
`available for delivery through the skin have been avail-
`able in ointment form for over thirty years. With oint-
`ments, however, it is difficult to achieve precise drug
`dosage. In a transdermal patch system, this problem is
`eliminated by controlling the rate of drug release over a
`prescribed period of time. Patches are worn behind the
`car, on the chest, or on the arm and dispense a drug for
`as long as a week at a time. For certain drugs trans-
`dermal delivery has significant advantages over oral
`administration. It eliminates “first pass” inactivation by
`the liver and irregular gastric absorption. Because of
`constant absorption through the skin, it maintains rela-
`tively constant blood levels of the drug.
`‘
`Two drugs, scopolamine and nitroglycerin, have
`recently become commercially available in transdermal
`form. Although there are differences in composition
`and in the mechanism of drug delivery among the avail-
`able transdermal delivery systems, they all appear to be
`functionally similar. Generally the systems have essen-
`tially steady state reservoirs sandwiched between an
`impervious backing and a membrane face. The systems
`usually are attached to the skin by an adhesive gel.
`Some products have a rate-controlling outer micropo-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`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
`another product, micropockets of nitroglycerin are
`evenly dispersed throughout a silicone polymer which
`controls the drug release rate and prevents dose dump-
`mg.
`A description of the different commercial products
`which deliver nitroglycerin transdermally is set forth
`by Dasta, et al., American Pharmacy, N522, 2, 29—35,
`February 1982, which article also illustrates the various
`prior art nitroglycerin patches and their construction
`and operation, and which article is hereby incorporated
`by reference.
`U.S. Pat. No. 4,336,243, issued June 22, 1982 de-
`scribes transdermal nitroglycerin pads wherein the pad
`comprises a silicone polymer matrix being a cross-
`linked silicone rubber having from about 10 to 200 mi~
`crons microseal compartments formed by the in situ
`cross-linking of the silicone rubber after it is admixed
`with a hydrophilic solvent containing the nitroglycerin
`in a hydrophobic solvent which enhances the dispersion
`and transport. U.S. Pat. No. 4,053,580, issued Oct. 11,
`1977 describes an earlier pharmaceutical delivery de-
`vice employing a silicone polymer matrix wherein the
`rate of release of the active ingredient is controlled by
`altering the solubility of the hydrophilic solvent system
`for the polymer matrix.
`Another polymer diffusion matrix transdermal deliv-
`ery system is described in published European patent
`application No. 803000389, of A. Keith entitled Poly-
`meric Diffusion Matrix and Method of Preparation and
`Drug Delivery Device Comprising Said Matrix. This
`application describes a polymeric diffusion matrix com-
`posed of glycerol and polyvinyl alcohol together with a
`water-soluble polymer to provide a polymer matrix
`capable of sustained release of a drug dispersed in the
`matrix. Typically, the water-soluble polymer comprises
`a polyvinylpyrrolidone or a water-soluble cellulosic
`derivative. U.S. Pat. No. 3,797,494, issued Mar. 19, 1974
`describes a transdermal bandage which includes a reser-
`voir with a drug confined within the interior chamber
`of the reservoir and distributed throughout a reservoir
`matrix. In one embodiment the drug is released by a
`controlling microporbus material, which microporous
`material meters the flow of the drug into the skin at a
`controlled rate. In another embodiment an adhesive
`coating is uniformly distributed through microcapsules
`comprising a drug encapsulated with a microporous
`rate controlling material.
`While many transdermal drug delivery systems have
`been described as an economical and effective trans-
`dermal drug delivery system particularly for the deliv-
`ery of contraceptive steroid drugs is still needed, and
`desired, particularly percutaneous delivery of steroid
`contraceptives in a controlled manner for periods of
`time ranging from one to four weeks or more.
`Levonorgestrel is a synthetic steroid which has pow-
`erful progestational activity with minimal side effects at
`very low doses. Estradiol is a natural estrogen which
`has limited oral effectiveness because of “first pass”
`inactivation during circulation. On the other hand the
`synthetic steroid, ethinylestradiol, is active orally, since
`its inactivation by the liver and other tissues is very low.
`These contraceptives and others like Mestranol, Nor-
`ethindrone, etc., are employed in various oral contra-
`ceptives manufactured in this country. Although levo-
`
`

`

`4,624,665
`
`3
`norgestrel pills contain 150 micrograms of the drug,
`studies with implantable drug delivery systems indicate
`that only 30 micrograms per day are sufficient to pre-
`vent fertility.
`Thus, it is desirable to provide an effective trans-
`dermal drug delivery system for the transdermal deliv-
`ery of drugs, particularly contraceptive steroids.
`SUMMARY OF THE INVENTION
`
`The invention concerns a transdermal drug delivery
`system and a method of manufacture and use of such
`system. In particular the invention relates to a trans-
`dermal drug delivery system particularly useful for the
`controlled release of a contraceptive steroid drug or a
`combination of such drugs.
`The invention relates to a transdermal drug delivery
`system which may be employed with a drug which is
`desired to be delivered transdermally at a controlled or
`sustained rate, typically a zero order rate or other deliv-
`ery release patterns as desired. The transdermal drug
`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.
`The invention relates to a method of and system for
`accelerating the transdermal delivery of drugs into a
`patient by sealing the skin of the patient with a thin
`layer of a viscous material to occlude the skin and trans-
`porting a desired dosage of a drug across the thin layer
`typically from a rate-controlling system in contact with
`the thin layer. The rate-controlling system may be a thin
`rate-controlling membrane interposed between the drug
`and the thin layer. Preferably the rate-controlling sys-
`tem comprises microparticles of the drug or a combina-
`tion of drugs to be delivered suspended in the same or
`similar viscous material and contained Within a con-
`tainer system. The container system generally com-
`prises a macroporous non-rate-controlling face mem-
`brane with an impervious backing to form a pool or
`patch-like system of desired face membrane area with
`the face of the membrane placed over and in contact
`with the thin occluding viscous layer on the skin. The
`thin viscous layer may be coated or placed on the skin
`repeatedly and the patch system placed on top of the
`thin viscous layer or the viscous layer formed in situ by
`exudation through the membrane face when the patch
`or pool system is placed in position on the skin. The
`patch or pool container system generally is retained in a
`transdermal position by the use of a peripheral adhesive
`layer about the patch or pool. Typically the face or
`transport area of the membrane is covered prior to use
`by a removable cover such as a peelable strip of imper-
`vious sheet material.
`In another embodiment microcapsules containing a
`drug for delivery may be suspended in a viscous mate-
`rial and the composition then spread as a layer over the
`skin of the user with or without a covering material.
`The present drug delivery system for the transdermal
`delivery of medicaments is based on the use of solid
`microparticles. The system releases the drug from rate=
`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
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`the stratum corneum to swell and hydrate by forcing
`the diffusion of water from the lower layers of the epi-
`dermis and thus to accelerate the drug delivery. The
`first phase in transdermal delivery is dependent on the
`rate of diffusion of the drug within the vehicle and its
`rate of release from the vehicle. The drug concentration
`in the vehicle determines the thermodynamic activity
`and influences the diffusion of the drug out of the vehi-
`cle.
`
`The present drug delivery system suspends drug/-
`polymer microparticles, in a delivery vehicle which
`microparticles control the ‘rate of release of the drug to
`the vehicle. Drug delivery from microcapsules is zero
`order provided solid particles are present inside the
`microcapsule in equilibrium with a saturated solution of
`the drug. It is dependent on the diffusion coefficient of
`the drug in the polymer, the thickness of the capsule
`wall, and the microcapsule dimensions in accordance
`with this equation:
`
`t
`--—‘1dM' = 411pr
`
`.
`,
`
`r0 — r,-
`0”
`
`Where M is the mass of the drug released, dM/dt is
`the steady state release rate at time t, DK is the mem-
`brane permeability, D is the diffusion coefficient of the
`drug in the membrane in chsec., K is the distribution
`coefficient, C is the difference in drug concentration
`between the internal and external surface of the mem-
`brane, and ror; are the outer and inner radii of the cap-
`sule wall, respectively.
`Drug release from monolithic microparticles such as
`microspheres is first order and is additionally dependent
`on drug concentration in the particle. Thus, the pres-
`ence of the microparticles in the base vehicle helps to
`maintain a constant thermodynamic activity of the drug
`in the vehicle by insuring that the concentration of the
`drug is close to saturation.
`The delivery of the vehicle to the skin is regulated by
`a macroporous membrane (for example ranging from
`about 1 to 1000 microns) whose properties and poree
`size are selected to match those of the base vehicle. A
`hydrophobic membrane, for example, is best used with
`a hydrophobic delivery base vehicle and hydrophilic
`membrane with a hydrophilic vehicle while smaller
`micron pores e.g. 50 to 200 deliver a smaller quantity of
`the vehicle than larger micron pores e.g. 300 to 600.
`The principal barrier to permeation of small mole-
`cules through the skin is provided by the stratum cor-
`neum or “horny layer” of cells which is about 10 to 15
`microns thick. This layer is composed of a dispersion of
`hydrophilic proteins in a continuous lipid matrix. The
`lipid component of the layer which comprise only
`20—30% of the weight of the tissue are directly responsi-
`ble for its unique low permeability (Scheuplein, 1971).
`The stratum corneum may be regarded as a passive
`diffusion membrane, albeit not entirely inert, which
`follows Fick’s Law in which the steady state flux Js is:
`
`=KmDCs
`S
`
`J:
`
`_ Cm
`solute sorbed per cc of tissue
`__
`where Km _ solute in solution per cc solvent _ CS
`
`Cs=concentration difference of solute across mem-
`brane
`
`

`

`5
`D=average membrane diffusion coefficient for sol-
`ute
`.
`S=membrane thickness
`
`4,624,665
`
`5
`
`Swelling of the comeum can be produced by hygro-
`scopic or other substances if they penetrate the hydro-
`philic zone or if lipophilic substances penetrate the
`hydrophobic zones. Increasing the state of hydration
`increases the porosity and thickness of the layer and
`favorably influences the transport of the drug by two to
`three fold. The simplest method for increasing hydra- 10
`tion is to occlude the skin which forces the diffusion of
`water from the lower layers of the epidermis. Estimated
`diffusion constant for low molecular weight nonelectro-
`lyte is 10‘9 sq./sec. for stratum corneum and 10"6 cm.
`sq./sec. for the dermis.
`The degree of hydration of the stratum comeum is
`provided by the macroporous membrane which deliv-
`ers a thin liquid film of the vehicle to its outer surface to
`occlude the skin. The liquid film is simultaneously in
`contact with the skin and the liquid or viscous vehicle 20
`of the reservoir through the macroporous channels of
`the membrane. Occlusion of the skin which follows may
`be influenced by the properties of the vehicle and the
`membrane.
`
`15
`
`Following topical administration of many drugs in— 25
`eluding steroids like estrogen and norgesterone, a reser-
`voir can form in the skin. The existence of this reservoir
`and its localization in the stratum corneum was first
`proven by Vickers (1963). Much of the work in this area
`has dealt with local action of drugs (e.g. hexachloro- 30
`phene, sunscreens, cortisol). However, prolonged toxic
`response following topical administration of vasocon-
`strictors demonstrates that a cutaneous reservoir can
`provide sustained release into the systemic circulation.
`Accumulation of both estrogen and progesterone in
`subcutaneous tissue and underlying muscle has been
`observed and is more pronounced with percutaneous
`than with subcutaneous administration. The duration of
`the local reservoir appears to be dependent on the nor-
`mal 14 day cycle of epidermal turnover. Irritation with 40
`a detergent or methotrexate increases turnover and can
`reduce the duration of the reservoir by nearly 50%.
`Inhibition of turnover with fluorinated steroids can
`double the duration to 28 days. In addition a compound
`which very rapidly penetrates and diffuses is maintained
`in the reservoir for a short period of time (e.g. nicotine,
`3—4 days). Since occlusion of the area of application
`appears necessary to promote sustained absorption from
`the reservoir, continued absorption following removal
`of the delivery system should be minimal unless the
`concentration is very high.
`Pronounced and prolonged effects of estrogens and
`gestagens can be expected by the transdermal route
`since it is the total amount of hormone absorbed by the
`body that is decisive, and not the peak height of the
`hormone level. The flux rate of steroids through human
`skin has been studied by others and are shown below in
`Table l.
`TABLE 1 60
`
`FLUX RATES OF STEROIDS
`
`35
`
`45
`
`50
`
`55
`
`FLUX {MOLES/CMZ HR).
`STEROID
`
`(Feldman 1969)
`(SCHAEFER 1979)
`17/3 estradiol
`8.2 x 10-11
`5.8 x 10-10
`17/3 estradiol
`4.6 x 10-10
`Testosterone
`1 x 10-9
`Estriol
`7.8 x 10-1‘
`Progesterone
`Hydrocortisone
`
`3.4 x 10-11
`2.5 x 10-11
`
`5 x 10-11
`
`65
`
`6
`
`TABLE l—continued
`FLUX RATES OF STEROIDS
`
`FLUX gMOLES/CM2 HR).
`STEROID
`(Feldman 1969)
`(SCHAEFER 1979)
`Corticosterone
`7.5 X [0‘12
`
`Table 1 shows that the flux gates of estradiol and
`progesterone are fairly high in comparison to the cor-
`ticosterones. These flux rates depend on the concentra-
`tion of the applied substance in the vehicle. At low
`concentrations the rates are proportional to the concen—
`tration in the vehicle. This proportionality is not 1 to 1
`since a doubling of the concentration increases the flux
`by about 30—50%.
`This general pattern of regional variation was found
`to hold for other chemical moieties (steroids, pesticides,
`and antimicrobials). Although the stratum corneum is
`generally accepted to be the major barrier to percutane-
`ous penetration, this appears to hold only if the skin is
`intact. Damage to the stratum comeum makes the other
`layers function as barriers. For example, the penetration
`of hydrocortisone through modified skin results in a
`tenfold increase in the penetration of hydrocortisone
`from 1% to 10% when the skin is occluded. The thin
`liquid film which is exuded by the macroporous mem-
`brane occludes the skin to increase drug penetration.
`The drug delivery system of the invention is based on
`the use of drug polymer solid microparticles or rate—
`controlling microcapsules which are suspended in a
`dermatologically acceptable viscous liquid base mate-
`rial or vehicle. The base is separated from the skin by a
`non drug non rate-controlling macroporous membrane.
`The outer rim or perimeter of the membrane is covered
`by a nonsensitizing hypoallergenic adhesive layer or
`other means to secure the system to the skin which
`holds the microporous membrane in contact or adjacent
`to the skin and prevents loss of the drug to the sur-
`rounding area. The microcapsules release the drug to
`the base in a controlled release pattern and maintains it
`in a thermodynamically stable condition. Release is
`controlled by the selected microcapsule size and thick-
`ness of the microcapsule wall. Thus, controlled release
`is obtained and the presence of the microcapsules pre-
`vents dose dumping caused by accidental rupture of the
`retaining membrane and ensures a prolonged delivery
`of the drug.
`An important feature of the drug delivery system in
`this embodiment is the macroporous retaining mem=
`brane which separates the liquid base from skin. This
`membrane delivers a thin film controlled amount of the
`base material to its outer face surface to contact the ‘
`skin. The liquid film occludes the skin and forces hydra-
`tion of the stratum comeum with water from the lower
`layers of the epidermis. This in turn accelerates delivery
`of the drug, e.g. steroids across the stratum cornehm.
`Intimate contact between the skin and the thermody-
`namically stable viscous liquid base also ensures uni-
`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.
`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
`
`

`

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

`

`9
`through the wall of the microparticle and so the drug
`may move effectively through the liquid base material
`in the reservoir and onto the thin film adjacent the user
`directly into the skin of the user. For example, the liquid
`base material may comprise a hydrophobic material
`such as a long chain, e.g. C3—C2; hydrocarbon-type
`material particularly for use with water-insoluble or
`very low water soluble drugs, such as for example, a
`grease-like hydrocarbon such as a petroleum based jelly
`e.g. Vaseline, a semisolid mixture of hydrocarbons hav-
`ing a mp of 38°-60° C. The liquid base material may
`comprise also a hydrophilic-type material such as a
`polyethylene glycol, glycerol, or a water solution
`placed in a gel-like form through the use of viscosity
`modifying additives or gel-like material such as polyvi-
`nylpyrrolidone, agar, proteins, thickeners and the like.
`In addition, it should be noted that the liquid base mate-
`rial in the reservoir may contain other modifying addi-
`tives to impart other desirable properties, such as the
`use of emollients such as glycols like glycerine, viscos-
`ity controlling agents, preservatives, thickening agents,
`antibacterial agents, such as a quaternary ammonium
`compound,
`stabilizers, depletion indicating devices
`such as dyes, waxes and other material typically em-
`ployed in pharmaceutical and cosmetic applications and
`which are dermatologically and pharmaceutically ac-
`ceptable.
`The macroporous membrane material comprises a
`sheet material having pores to permit the passage of the
`viscous liquid base material. The function of the mem-
`brane is merely to contain the viscous liquid within the
`reservoir and to permit a thin film to be formed on the
`face side of the membrane. The macroporous membrane
`may be formed of a variety of materials either synthetic
`or natural polymeric material, but typically a membrane
`material as used in the prior art, such as for example, of
`a cellulosic material, an ethylenevinyl acetate copoly-
`mer material, cellulose acetate material, vinyl halides,
`polyvinyl chloride, nylon, porous polyolefms such as
`polyethylene, polypropylene and fluorocarbons and
`other materials which are adapted to be formed with or
`have pores of controlled size.
`The microparticles employed in the drug delivery
`system generally comprise solid microparticles wherein
`the core of the particle contains an admixture of a poly-
`mer together with one or more of the drugs which are
`to be delivered by the microparticles, the active ingredi-
`ent in the core may comprise a varying amount and
`range for example from 5 to 95 percent by weight, such
`as 20 to 80 percent by weight with the remainder made
`up a core polymer material. The amount of microparti-
`cles in the base material may vary and range f