Resilient transdermal drug delivery device

We claim:

1. A transdermal drug-delivery device in the form of a solid state laminated composite adapted to be adhered to an area of unbroken skin and having mechanical properties that enable it to expand and contract in concert with the normal expansion and contraction of said area of skin comprising:

(a) at least two spaced structural laminas of a resilient elastomeric polymer, one of which forms the upper face surface of the composite, said laminas providing the composite with said mechanical properties;

(b) at least one lamina of a viscoelastic hydrophobic polymer in which (i) a drug and/or (ii) an agent that enhances the solubility of the drug in the viscoelastic hydrophobic polymer and/or is a percutaneous absorption enhancer that increases the permeability of the skin to the drug is dispersed and at least partly dissolved, the viscoelastic hydrophobic polymer lamina being positioned between the structural laminas with the structural lamina(s) underlying the viscoelastic hydrophobic polymer lamina(s) providing no rate-controlling barrier to diffusion of drug and/or agent from the viscoelastic hydrophobic polymer lamina(s) to the skin; and

(c) a lamina of a pharmaceutically acceptable pressure-sensitive adhesive in which (i) said drug and/or (ii) said agent is dispersed and at least partly dissolved, one face of the pressure-sensitive adhesive lamina defining the basal surface of the composite and contacting and adhering to the area of unbroken skin when the device is in use, said pressure-sensitive adhesive lamina providing no rate-controlling barrier to diffusion of the drug and/or agent from the device to the skin, with the proviso that at least one of said viscoelastic hydrophobic polymer lamina(s) and said pressure-sensitive adhesive lamina contains the drug.

2. The device of claim 1 wherein at least one of said lamina(s) of viscoelastic hydrophobic polymer and said lamina of pharmaceutically acceptable pressure-sensitive adhesive contains said agent.

3. The transdermal drug delivery device of claim 2 wherein the device is a sufficient barrier to water vapor transmission that said area of skin becomes hydrated when the device is placed thereon.

4. The device of claim 3 wherein said viscoelastic hydrophobic polymer lamina(s) provide(s) said barrier to water vapor transmission.

5. The device of claim 3 wherein the drug is a steroid.

6. The device of claim 5 wherein the drug is estradiol.

7. The device of claim 3 wherein the drug is fentanyl or a fentanyl analog.

8. The transdermal drug device of claim 1 wherein the device is not occlusive.

9. The transdermal drug delivery device of claim 8 wherein the water vapor transmission rate of the device is 11-18 g/m.sup.2 -hr.

10. The device of claim 2 wherein the drug is contained in the lamina of pharmaceutically acceptable pressure-sensitive adhesive and said agent is contained in the lamina of pharmaceutically acceptable pressure-sensitive adhesive and at least one of the lamina(s) of viscoelastic hydrophobic polymer.

11. The device of claim 3 wherein the drug is contained in the lamina of pharmaceutically acceptable pressure-sensitive adhesive and said agent is contained in the lamina of pharmaceutically acceptable pressure-sensitive adhesive and at least one of the lamina(s) of viscoelastic hydrophobic polymer.

12. The transdermal drug-delivery device of claim 3 wherein the agent is a fatty acid ester or fatty alcohol ether of a C.sub.2 to C.sub.4 alkanediol where each fatty acid or fatty alcohol portion of the ester or ether is of 8 to 22 carbon atoms.

13. The transdermal drug-delivery device of claim 3 wherein the drug is estradiol, fentanyl or a fentanyl analog and the agent is a fatty acid monoester of propylene glycol in which the fatty acid portion is of 8 to 22 carbon atoms or a mixture of said monoester and a fatty acid dieste- of propylene glycol wherein each fatty acid portion is of 8 to 22 carbon atoms.

14. The transdermal drug-delivery device of claim 13 wherein the fatty acid monoester of propylene glycol is propylene glycol monolaurate and the fatty acid diester of propylene glycol is propylene glycol dilaurate.

15. The transdermal drug-delivery device of claim 12 wherein the resilient elastomer is a polyether block amide copolymer, a polyethylene methyl methacrylate block copolymer, a polyurethane, a silicone elastomer, or a polyester block copolymer composed of hard and soft segments.

16. The transdermal drug-delivery device of claim 12 wherein the hydrophobic polymer is a polysiloxane, a polyacrylate, a polyurethane, a rubbery polymer, a plasticized ethylene-vinyl acetate copolymer, or a low molecular weight polyether block amide copolymer.

17. The transdermal drug-delivery device of claim 14 wherein the resilient elastomer is a polyether block amide copolymer or a polyurethane, the hydrophobic polymer is polyisobutene, the pressure-sensitive adhesive is polydimethylsiloxane, the thickness of each of the structural laminas is 10 to 75 microns, the thickness of the viscoelastic hydrophobic polymer laminas is 50 to 100 microns, and the thickness of the pressure-sensitive adhesive lamina is 50 to 100 microns.

18. The transdermal drug-delivery device of claim 17 wherein the loading of estradiol, fentanyl, or fentanyl analog in the pressure-sensitive adhesive lamina is 1% to 20% by weight based on the mixture, the loading of propylene glycol monolaurate in the pressure-sensitive adhesive lamina is 2% to 20% by weight based on the mixture, and the loading of propylene glycol monolaurate or mixture of monolaurate and dilaurate in each viscoelastic hydrophobic polymer layer is 5% to 15% based on the mixture.

19. A transdermal drug delivery drive in the form of a solid laminated composite adapted to be adhered to an area of unbroken skin and having mechanical properties that enable it to expand and contract in concert with the normal expansion and contraction of said area of skin, comprising in the following order

(a) a first structural lamina of a resilient elastomer, one side of which forms the upper face surface of the device;

(b) a first viscoelastic hydrophobic polymer lamina containing 5% to 15% by weight of propylene glycol monolaurate or a mixture of propylene glycol monolaurate and propylene glycol dilaurate;

(c) a second structural lamina of a resilient elastomer which provides no rate-controlling barrier to diffusion of propylene glycol monolaurate or propylene glycol dilaurate from (b);

(d) a second viscoelastic hydrophobic polymer lamina containing 5% to 15% propylene glycol monolaurate;

(e) a third structural lamina of a resilient elastomer which in combination with the first and second structural laminas provides the device with said mechanical properties, said third structural lamina providing no rate-controlling barrier to diffusion of propylene glycol monolaurate or propylene glycol dilaurate from (d);

(f) a lamina of a pharmaceutically acceptable pressure-sensitive adhesive, one face of which defines the basal surface of the composite and adheres to the area of unbroken skin when the device is in use, said lamina or pharmaceutically acceptable pressure-sensitive adhesive containing 1% to 20% by weight estradiol, fentanyl, or fentanyl analog and 2% to 20% by weight of propylene glycol monolaurate or a mixture of propylene glycol monolaurate and propylene glycol dilaurate or propylene glycol dilaurate and providing no rate-controlling barrier to diffusion of estradiol or propylene glycol monolaurate, to the skin.

20. The transdermal drug delivery devices of claim 19 wherein the resilient elastomer is a polyurethane; the viscoelastic hydrophobic polymer is polyisbutene; and the pressure-sensitive adhesive is polydimethylsiloxane.

21. The transdermal drug delivery device of claim 3 wherein the thickness of each structural lamina is 10 to 75 microns, the thickness of each viscoelastic hydrophobic polymer lamina is 50 to 100 microns, and the thickness of the pressure-sensitive adhesive lamina is 50 to 100 microns.

Description Submit all comments and votes

TECHNICAL FIELD

This invention is in the field of transdermal drug-delivery. More particularly it relates to a transdermal drug-delivery device in the form of a solid state laminated composite that is adapted to be adhered to the skin and that includes a multiplicity of spaced resilient structural lamines that provide the device with mechanical properties that enable the device to stretch in concert with the area of skin to which it is adhered and which facilitate its handling prior to application. One embodiment of the invention is particularly adapted for administering estradiol transdermally. Another is particularly adapted for administering fentanyl or fentanyl derivatives transdermally.

BACKGROUND OF THE INVENTION

A variety of devices have been proposed or used for administering drugs transdermally. These devices are generally laminated composites that include a reservoir layer that contains the drug, a pressure-sensitive adhesive layer by which the device is attached to the skin, and a backing layer that forms the outer "skin" of the device. Depending upon the inherent permeability of the skin to a particular drug, the device may also include means for coadministering a percutaneous absorption enhancer or an element, such as a membrane interposed between the reservoir and the skin, that regulates the rate at which the drug and/or the enhancer is administered to the skin.

U.S. Pat. No. 4,379,454 and 4,460,372 described a device for coadministering a drug and a percutaneous absorption enhancer transdermally. The drug is presented to the skin at a rate in excess of that which the skin is inherently capable of absorbing and the enhancer is presented to the skin at a substantially constant rate that is sufficient to permit the skin to pass therapeutic levels of drug to circulation. The device includes a membrane interposed between a drug- and enhancer-containing reservoir layer and a pressure-sensitive adhesive layer that regulates the rate at which the enhancer is presented to the skin. In the commercial estradiol embodiment of this device (marketed under the mark ESTRADERM) the enhancer is ethanol and the estradiol-ethanol mixture is contained in the reservoir in a fluid form. Using such a form complicates the procedures for manufacturing the device and detracts from the ability to optimize certain physical characteristics of the device such as thickness, resiliency, and adhesiveness, that are associated with wearability.

Other patent publications relating to devices for administering estradiol transdermally are German Patent Publications 3,315,245 and 3,315,272, European Patent Publications 0013606 and 0040861 and U.S. Pat. No. 4,438,139.

Patent publications relating to transdermal delivery of opioids in general and fentanyl or fentanyl derivatives or analogs (sufentanil, carfentanil, lofentanil, and alfentanil) are EPA 0171742 and U.S. Pat. Nos. 4,588,580 and 4,626,539.

U.S. Pat. No. 4,435,180 described a transdermal drug-delivery device comprising a body of a mixture of elastomer and drug, the body being in a form such as an arm or wrist band which inherently creates a compressive force when worn to keep the body firmly in contact with the skin.

The focus of much of the prior art relating to transdermal drug delivery has been on the release kinetics of the drug or enhancer from the device. Because of this the design of most prior devices has centered about the achievement of desired drug release kinetics, and, for the most part has ignored or given only secondary consideration to mechanical properties than enhance its wearability and cosmetic acceptability. In this regard, the present invention provides a transdermal drug-delivery device that provides acceptable drug release kinetics as well as resiliency, thinness and, when permitted, breathability.

DISCLOSURE OF THE INVENTION

The invention is a transdermal drug-delivery device in the form of a solid state laminated composite adapted to be adhered to a predetermined area of unbroken skin and having mechanical properties that enable it to expand and contract in concert with the normal expansion and contraction of said area of skin comprising:

(a) at least two spaced structural laminas of a resilient polymer, said laminas providing the composite with said mechanical properties;

(b) at least one lamina of a viscoelastic hydrophobic polymer optionally in which (i) a drug and/or (ii) an agent that enhances the solubility of the drug in the viscoelastic hydrophobic polymer and/or is a percutaneous absorption enhancer that increases the permeability of the skin to the drug is dispersed and at least partly dissolved, the viscoelastic hydrophobic polymer lamina being positioned between the structural laminas with the structural lamina(s) underlying the viscoelastic hydrophobic polymer lamina(s) providing no rate-controlling barrier to diffusion of drug and/or agent from the viscoelastic hydrophobic polymer lamina(s) to the skin; and

(c) a lamina of a pharmaceutically acceptable pressure-sensitive adhesive optionally in which (i) said drug and/or (ii) said agent is dispersed and at least partly dissolved, one face of the pressure-sensitive adhesive lamina defining the basal surface of the composite and contacting and adhering to the are of unbroken skin when the device is in use, said pressure-sensitive adhesive lamina providing no rate-controlling barrier to diffusion of the drug and/or agent from the device to the skin, with the proviso that at least one of said viscoelastic hydrophobic polymer lamina(s) and said pressure-sensitive adhesive lamina contains the drug.

Prior to use the device also includes a release liner lamina that covers the basal surface of the pressure-sensitive adhesive lamina and is adapted to be removed from the device to expose the basal surface of the pressure-sensitive adhesive lamina.

In embodiments which involve a steroidal drug, such as estradiol, or certain opioids such as fentanyl and fentanyl analogs, it may be necessary that the device be a sufficient barrier to water vapor transmission to cause the area of skin to become hydrated and thus more permeable to the drug. In other embodiments involving drugs that do not require that the skin be hydrated, the components of the device may be made from water vapor permeable materials so as to make the device breathable.

Another aspect of this invention is a pharmaceutical composition for transdermal or transmucosal administration comprising a drug and a permeation enhancing amount of a fatty acid ester or fatty alcohol of a C.sub.2 to C.sub.4 alkanediol where each fatty acid or fatty alcohol portion of the ester or ether is of about 8 to 22 carbon atoms.

Still another aspect of the invention is a method of enhancing the permeation of a body surface to a drug administered to the surface comprising coadministering to the surface a permeation enhancing amount of a fatty acid ester or a fatty alcohol ether of a C.sub.2 to C.sub.4 alkanediol where each fatty acid or fatty alcohol portion of the ester of ether is of about 8 to 22 carbon atoms.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an enlarged sectional view of one embodiment of the transdermal drug-delivery device of the invention.

FIGS. 2 and 3 are graphs of fentanyl flux from the device described in Examples 16 and 19, respectively, versus time.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 shows a device, generally designated 11, which is an embodiment of the invention and is designed for administering a drug, such as estradiol or fentanyl, transdermally at therapeutically effective rates. Device 11 is in the form of a seven-layer laminated composite that is adapted to be adhered to a predetermined area of unbroken skin. The seven layers of the device are: a first structural layer 12 that forms the upper face surface of the device; a hydrophobic viscoelastic polymer layer 13; a second structural layer 14; a second hydrophobic viscoelastic polymer layer 15; a third structural layer 16; a pressure-sensitive adhesive layer 17 which contains the drug; and a release liner layer 18.

Structural layers 12, 14, and 16 are the components of the composite that provide the composite with resiliency and firmness. In this regard, the term "resiliency" denotes the ability of the composite to recover its size and form following deformation. This ability is a function of the thicknesses of the layers, their yield strengths, and their elastic moduli. The term "firmness" is related to the degree of flexibility of the body and is intended to mean that despite its thinness, the composite does not readily and rapidly fold upon itself during normal handling prior to application to the skin. Resiliency permits the composite to be worn comfortably on areas of the skin, such as joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the composite disengaging from the skin due to differences in the flexibility or resiliency of the skin and the composite. The firmness of the composite lessens the likelihood that the composite will fold upon itself while being handled prior to application to the skin such that portions of its adhesive surface will contact each other and stick together.

One or more of the structural layers may contain drug/enhancer, provided same does not impair the structural integrity of the layer(s) or their mechanical properties.

One or more of the structural layers (12, 14, 16), or hydrophobic viscoelastic polymer layers, or combinations thereof may also be used to impart the device with a desirable or necessary degree of occlusivity which in turn causes the area of skin on which the device is placed to become hydrated. In such a role, layers are selected that have levels of water vapor transmissibility that make the device occlusive to the degree required to cause the area of skin to be hydrated. In such instances it is preferably that the device provide at least about 90% hydration, more preferably at least about 95% hydration of the skin, as measured by a dielectric hydration probe available from Dr. Howard Maibach, U.C.S.F., San Francisco, Calif. Such occlusivity is desirable when drugs such as estradiol or other steroids are being administered. If the drug being administered is such that skin hydration is not necessary or desirable, it is preferably to use layers that provide a composite that is "breathable", i.e., transmits water vapor from the skin to the atmosphere. Such breathability contributes to the nonocclusive nature of the composite and lessens the likelihood that the area of skin on which the composite is worn will become irritated. In the case of device 11, the hydrophobic viscoelastic polymer layers 13 and 15 are the principal layers that make the device occlusive. Thus, in devices that need not be occlusive, these layers may be eliminated if not needed as reservoir layers, thus providing a five-layer composite, or replaced with water vapor permeable layers. In nonocclusive embodiments of the device the water vapor transmission rate (WVTR) of the laminated composite is typically in the range of 11-18 g/m.sup.2 -hr (as measured using an Evaporimeter at normal room temperature and humidity, i.e., 20.degree. C., 60% relative humidity).

The use of a multiplicity of spaced structural laminas has been found to provide better mechanical properties than use of a single structural lamina having a thickness equal to the combined thicknesses of the spaced laminas. Because of this, suitable mechanical properties may be achieve with a thinner composite employing less elastomer.

Examples of resilient elastomers that may be used to form laminas 12, 14, and 16 are polyether block amide copolymers (e.g., PEBAX copolymers), polyethylene methyl methacrylate block copolymers (EMA) such as NUKRELL polymers, polyurethanes such as PELLATHANE or ESTANE polymers, silicone elastomers and polyester block copolymers that are composed of hard and soft segments (e.g., HYTREL polymers). The laminas 12, 14, and 16 may be made of the same elastomer or different elastomers. Preferably, they are made of the same resilient elastomer. The structural laminas may be dense (i.e., nonporous) or microporous. The individual thickness of each of these layers will normally be in the range of about 10 to 75 microns. Laminas 14 and 16 do not constitute rate controlling barriers to diffusion of either drug or, when present, enhancer to the skin (i.e., the rate of drug/enhancer administration does not depend on the rate of diffusion of drug/enhancer through these laminas). Depending upon the particular elastomer, these laminas have varying degrees of water barrier properties.

Layers 13 and 15 serve: (1) optionally as reservoirs for enhancer and/or drug; (2) as barriers to water vapor transmission; (3) to resist liquid uptake due to the low solubility of water therein; and (4) to provide additional resiliency and elasticity. In preferred embodiments of an estradiol device, these layers contain enhancer and are composed of a pressure-sensitive adhesive material which is permeable to the enhancer and in which the enhancer is less soluble than in the pressure-sensitive adhesive layer. The incorporation of enhancer into these layers prevents back migration of enhancer from the pressure-sensitive adhesive lamina 17. In such embodiments, layers 13 and 15 will normally contain between about 5% and about 15% by weight enhancer based on the total weight of the layer. The thickness of each of layers 13 and 15 will normally be in the range of 50 to 100 microns

Layers 13 and 15 may be made from the hydrophobic pressure-sensitive adhesive polymers used to make layer 17 (listed below) or other suitable hydrophobic polymers such as styrene-butadiene copolymers. In embodiments in which one or both of these layers serve as drug/enhancer reservoirs, the polymer should be permeable to drug/enhancer. In such instances the polymer will have a diffusion coefficients and exhibit drug/enhancer solubility comparable to those described below with respect to lamina 17.

Lamina 17 is composed of a pressure-sensitive adhesive optionally containing drug and/or enhancer. When a pressure-sensitive adhesive is used in layers 13 and 15, the same or different material may be used in lamina 17. When lamina 17 functions as a drug/enhancer reservoir, the diffusion coefficient of the adhesive material used in lamina 17 to the drug/enhancer and the solubility of the drug/enhancer in the material are such that the polymer is permeable to the drug/enhancer. Polymers having diffusion coefficients (D) greater than about 10.sup.-14 cm.sup.2 /sec, usually in the range of 10.sup.-8 to 10.sup.-12 cm.sup.2 /sec (determined from desorption curves described by Baker, R. W. and Lonsdale, H. K., Controlled Release; Mechanism and Rates in Advances in Experimental Medicine and Biology, vol. 47, Tanquary, A. C. and Lacey, R. E. Eds. Plenum Press, N.Y., 1974), relative to the drug, the enhancer, or the combination thereof, and in which the solubility of the drug/enhancer is greater than about 1 mg/ml, usually in the range of 1 to 50 mg/ml are suitable. Examples of polymer types that have the required drug/enhancer permeability and desirable adhesiveness are polysiloxanes (silicone polymers such as polydimethylsiloxane and polymethylphenylsiloxane), hydrophobic polyacrylates, plasticized ethyle