Dispersions of drugs and other substances in non-aqueous, typically polymeric, matrices are commonly used as reservoirs for various delivery devices. Representative devices are described in U.S. Pat. No. 3,598,122 (corresponding to Belgium 769155 and South Africa 7104095) and 3,598123 (corresponding to Belgium 769155) to Zaffaroni et at; U.S. Pat. Nos. 4,031,894 and 4,262,003 to Urquhart et at; and U.S. Pat. No. 4,201,211 (corresponding to GB 1577259, CH 646876, DE 2755661, and FR 239190) to Chandrasekaran et at; all of which are incorporated herein by reference. Transdermal devices for the administration of scopolamine of the type disclosed by Urquhart et al have been used extensively for the prevention of motion sickness. In U.S. Pat. No. 4,832,953 (corresponding to EP 304227), also incorporated herein by reference, Campbell et al report that transdermal scopolamine systems manufactured in accordance with the Urquhart reference above began to develop scopolamine hydrate crystals after 5 years of manufacturing systems without hydrate crystals appearing. The hydrate crystal problem worsened over the next two years to the point of significantly adversely affecting the release rate of scopolamine from the transdermal device.
These products were manufactured, according to Campbell et at, by solvent casting of chloroform solutions of scopolamine base in polyisobutene (PIB) and mineral oil (MO) onto impermeable webs to form drug reservoir and adhesive fills. Upon evaporation of the chloroform, a dispersion of liquid scopolamine base in the PIB/MO matrix forms. The drag reservoir and adhesive films there were then laminated to opposite sides of a release rate controlling membrane (the membrane formed from a mineral oil impregnated film). The resulting completed system had a removable release liner lamina, an adhesive lamina, a rate controlling membrane lamina, a drug reservoir lamina, and an impermeable backing lamina. Once the lamina were assembled, the systems were die cut and packaged in individual heat sealed foil pouches.
After another two years, the problem reported by Campbell et al became so severe that commercial production had to be halted until a solution was found. In an attempt to solve that problem, Campbell et al heat treated each of the reservoir laminate, the adhesive laminate and the multilaminate overnight with no visible effect. The casting solutions there were also heat treated and allowed to stand for extended periods with no effect. Since the problem found by Campbell et al was the formation of hydrate crystals, various attempts to remove water were tried, but again to no avail.
Against this background, Campbell et al found that if the assembled and cut (and preferably packaged) systems are heated to above the melting point of the scopolamine hydrate crystals, upon cooling to ambient temperature, the hydrate crystals did not reappear. Cambell et al reports heating the finished systems to a temperature of 60.degree. C. (the scopolamine hydrate crystals melt at 59.degree. C.) and holding the systems there for a period of 24 hours.
It has now been observed that systems which have been manufactured according to Campbell et al, have begun to develop an additional crystal which is not eliminated by the Campbell et al heating step. The crystals have been identified as being a higher melting (67.degree.-70.degree. C.) polymorph of hydrated scopolamine base. Attempts to solve this problem by merely raising the temperature at which the finished systems are heated in the Campbell process have been unsuccessful. While the crystals which form are melted, the result is a system wherein the distribution of active is vastly different from that in the original systems, thereby resulting in systems having vastly different release properties.