Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-02-03
2001-01-16
Clardy, S. Mark (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S449000, C514S691000, C514S947000, C602S041000, C604S289000, C604S304000, C604S305000, C604S307000, C604S892100
Reexamination Certificate
active
06174545
ABSTRACT:
FIELD OF INVENTION
This invention relates to an improved process for the manufacture of drug delivery devices and to drug delivery devices produced thereby. The improvement comprises a heat equilibration process which controls the migration of a drug from the drug reservoir through the adjoining layers of the device. Preferably, this process enables improved control over the concentration of the drug in the body contacting layer, such as the contact adhesive layer of a transdermal device, resulting in greater control of the initial loading dose of drug delivered by such devices. The process has particular application in the manufacture of transdermal drug delivery devices comprising a drug reservoir containing a drug at or above saturation.
BACKGROUND OF THE INVENTION
Transdermal delivery devices for the delivery of a wide variety of drugs have been known for some time. Typical devices range from simple monolithic devices such as disclosed in U.S. Pat. No. 4,758,434, to devices including in-line adhesives and release rate controlling membranes as disclosed in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,742,951, 4,031,894, 4,060,084, 4,144,317, 4,201,211, and 4,379,454, all of which are incorporated herein by reference. Such rate-controlled devices generally comprise a backing layer which is impermeable to the drug, a drug reservoir which can contain a permeation enhancer or permeation enhancer mixture in addition to the drug, a contact adhesive layer, and a rate controlling membrane positioned between the drug reservoir and contact adhesive. The layers are typically laminated or heat sealed together to produce a transdermal device.
It is known in the transdermal art to provide the drug reservoir with an initial amount of drug at a concentration at or above its saturation concentration in the reservoir in order to maintain a unit activity source of the drug so that the delivery of drug from the device will remain substantially constant over the intended delivery period. Subsaturated systems, such as disclosed in U.S. Pat. Nos. 4,379,454, 4,908,027, 5,004,610, and 5,344,656, hereby incorporated in their entirety by reference, are also known in the art.
In addition to providing the drug in the drug reservoir, it is also known to preload the contact adhesive with an amount of the drug. For example, U.S. Pat. Nos. 4,201,211, 4,588,580, and 4,832,953, hereby incorporated in their entirety by reference, disclose transdermal drug delivery devices wherein the contact adhesive layer is prepared by solvent casting a mixture of the drug and adhesive. Typically, the preloaded amount corresponds to the amount necessary to provide an initial loading dose which creates a concentration gradient across skin and saturates the skin binding sites underlying the device with the drug to be delivered. Additionally, U.S. Pat. No. 4,832,953 discloses heating a laminate system comprising a dispersion of a liquid in a non-aqueous matrix in order to prevent formation of a crystalline hydrate.
In addition, Cleary “Transdermal Delivery Systems: A Medical Rationale”,
Topical Drug Bioavailability, Bioequivalence, and Penetration
, Plenum Press 1993, pp 17-68, provides additional background information regarding commercially available transdermal drug delivery systems. A reasonably complete summary of the factors involved in percutaneous absorption of drugs may be found in Govil, “Transdermal Drug Delivery Devices”,
Drug Delivery Devices
, Marcel Dekker, Inc. 1988, pp 385-419; Chien “Transdermal Systemic Drug Delivery Recent Development and Future Prospects”, S.T.P. Pharma Sciences, Vol. 1, No. 1, pp 5-23, 1991; and Cleary “Transdermal Drug Delivery”,
Skin Permeation Fundamentals and Application
, pp 207-237, 1993, all of which are incorporated herein by reference.
The transdermal route of parenteral delivery of drugs provides many advantages, and transdermal systems for delivering a wide variety of drugs or other beneficial agents have been described. Steroids including testosterone, for example, have been studied for their suitability for transdermal delivery and transdermal drug delivery systems for delivering testosterone are disclosed in the prior art. Current transdermal testosterone systems can be generally classified as either scrotal or non-scrotal systems. Each has its own advantages and disadvantages.
Scrotal systems such as described in U.S. Pat. Nos. 4,704,282, 4,725,439, and 4,867,982, are more limited as to the available surface area for drug delivery while, on the other hand, they do not require the use of permeation enhancers. Non-scrotal systems such as described in U.S. Pat. Nos. 5,152,997 and 5,164,990, while not as limited in area of application, require the use of multiple permeation enhancers and are thus susceptible to the problems attendant therewith, particularly irritation. Irritation occurs as the skin reacts to topically applied substances, particularly those maintained under occlusion, by blistering or reddening accompanied by unpleasant burning, itching, and stinging sensations. It is desirable to keep the number of possibly irritating substances in a transdermal delivery device to a minimum.
More specifically, U.S. Pat. Nos. 4,704,282, 4,725,439, and 4,867,982, which are hereby incorporated by reference in their entirety, disclose the transdermal administration of testosterone through intact scrotal skin. These patents teach that scrotal skin provides a five fold increase in permeability to testosterone over non-scrotal skin. Testosterone is provided in an ethylene vinyl acetate copolymer matrix and is delivered through scrotal skin without the use of permeation enhancers.
U.S. Pat. Nos. 5,152,997 and 5,164,990, hereby incorporated in their entirety by reference, disclose the transdermal administration of testosterone through areas of intact, non-scrotal skin. The U.S. Pat. No. 5,164,990 patent requires an ethanol carrier and additionally includes a permeation enhancer or permeation enhancer mixture such as glycerol monooleate and methyl laurate in order to deliver therapeutically effective amounts of testosterone through non-scrotal skin.
Additionally, U.S. Pat. No. 5,223,262 discloses a system for transdermally delivering a hydrophobic alkanol soluble active agent to the skin at a constant rate utilizing a lower alkanol penetration enhancer. The system comprises an overlying solvent reservoir containing a lower alkanol solvent and a drug reservoir containing an active agent in aqueous alkanol. The two reservoirs are separated by a one way membrane permeable to the alkanol solvent and substantially impermeable to the active agent and water.
WO 96/35427, hereby incorporated in its entirety by reference, discloses a transdermal therapeutic system for the delivery of testosterone which comprises an alcoholic carrier saturated with testosterone and is free of any permeation enhancers. The release rate of the active agent is regulated by the adhesive layer.
WO 97/10812, hereby incorporated in its entirety by reference, discloses methods for manufacturing transdermal drug delivery systems containing supersaturated drug reservoirs which obtain higher drug fluxes. The method involves heating the drug reservoir components to a predetermined temperature and subsequently cooling the drug reservoir components in order to provide a supersaturated reservoir such that it contains only a single phase of drug and reservoir material.
As noted above, it is often desirable to preload the adhesive with an amount of drug in excess of the saturation concentration and this has been done by premixing the drug into the adhesive. However, the process of premixing a drug into the adhesive layer, though enabling an amount of drug in excess of saturation to be initially added to the adhesive, presents considerable practical problems. The drug must be sent to the adhesive supplier to be mixed with the adhesive and subsequently sent back to the manufacturing site where the device is ultimately manufactured. This requires undesirable shipping, time, and perhaps most significantly, this process requires particul
Campbell Patricia S.
Enscore David J.
Frame Richard D.
Nedberge Diane
ALZA Corporation
Bates Owen J.
Clardy S. Mark
Date Vandana
Williamson Michael A.
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