rous membrane. One product depends on a diffusion
METHOD OF TRANSDERMAL DRUG DELIVERY matrix in which nitroglycerin molecules are in equilibrium 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
COMPOSITE CORE COATED MICROPARTI- ing.
CLES AND PROCESS OF PREPARING SAME. A description of the different commercial products
The prior application relates to a process for preparing which deliver nitroglycerin transdermally is set forth
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 desteroid-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 crossform admixture of the drug-active ingredient and the linked silicone rubber having from about 10 to 200 mipolymer material. The mixture is then reduced to a cr0ns 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 wjth a hydrophilic solvent containing the nitroglycerin uniform, defined wall thickness of the same or substan- m a hydrophobic solvent which enhances the dispersion tially the same film-forming polymer material used to ^ transport. U.S. Pat. No. 4,053,580, issued Oct. 11, provide the composite core coated microparticles. Typ- 1977 describes an earlier pharmaceutical delivery deically the dry compositeadmixture is reduced to a 25 ^ loyin a silicone lymer matrix wherein the particle size of less than 1000 microns, e g. 200 microns. rate of re,ease of tfae active mgredient is controlled by The film forming polymer material employed generally ^ the solubilit of the hydrophmc soivent system is a polymer like polyvinyl alcohol or a cellulosic mate- foj. ^ j matrfx
ml or a biodegradable polymer such as for example a ... matrfx transdemal ddiv.
polylactide, a polyglycohde, and copolymers of lactides 30 K J . * „
j i i'j Ttt J Li J • *u ery system is described in published European patent
and glycohdes. The drug employed in the microparti- ^' * 80300038.9, of A. Keith entitled Poly
cles may vary, but typically may comprise for example, vv. ~~ ■ . J "~ * '" ~r'
a contraceptive steroid-type drug such as levonorges- TMenc ^fusi0n Matnx ^d Method °cf Pf\Pfatl0ni?d
trel or estradiol. For injectable compositions the parti- Dru? Dehvfy DTMce Compnsmg Said Matrix. This
cle size of the microparticles is less than 200 microns 35 application describes a polymeric diffusion matrix com
with a uniform wall coating of about 0.2 to 20 microns. Posed °f glycerol and polyvinyl alcohol together with a
The microparticles are useful for the controlled release water-soluble polymer to provide a polymer matrix
of a drug-active ingredient such as in a zero order re- caPable of stained release of a drug dispersed in the
lease pattern and for example, may be employed by matrix- Typically, the water-soluble polymer comprises
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
Transdermal delivery of medication is not a new of the reservoir and distributed throughout a reservoir
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 transdermal delivery has significant advantages over oral dermal drug delivery system particularly for the delivadministration. 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 tively 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 powrecently 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, Norusually are attached to the skin by an adhesive gel. ethindrone, etc., are employed in various oral contraSome products have a rate-controlling outer micropo- ceptives manufactured in this country. Although levo