WO1991018572A1

WO1991018572A1 - Device for transdermal administration of drugs

Info

Publication number: WO1991018572A1
Application number: PCT/US1991/003698
Authority: WO
Inventors: Alfred Moo-Young; Ana Zepeda-Ortega; Horacio Bruno Croxatto
Original assignee: Robertson, Dale, N.
Priority date: 1990-06-01
Filing date: 1991-05-24
Publication date: 1991-12-12

Abstract

Applicants' invention relates to a device for transdermally administering a drug, which comprise a drug-polymer matrix (2) containing a therapeutically effective amount of the drug, a drug impermeable layer (1) adhered to the drug-polymer matrix (2) and substantially impervious to the drug, and attachment means (4) attached to the drug impermeable layer (1), said attachment means (4) being capable of attachment to a carrier for holding the device, wherein the drug-polymer matrix (2) releases the drug so that the drug may be absorbed by the skin.

Description

Device For Transdermal Administration of Drugs

Background of the Invention

With most drugs transdermal administration is preferable to oral administration. When administered orally, many drugs, particularly hormones, must be given in relatively large doses because they are metabolized during absorption and further metabolized by the liver in the so-called "hepatic first-pass." Transdermal administration bypasses the digestive system and the liver, and smaller doses of drugs may be used to attain effective serum concentration levels. Transdermal administration also advantageously provides a steady level of drug to the patient, as opposed to an initial high rate and decreasing levels of drug delivery after oral administration. Side effects are thus minimized with transdermal administration, since lower dosages are required and are administered more slowly and continuously.

Devices for transdermal administration are widely used for a number of drugs such as dramamine, nitroglycerin and estrogen. Conventional devices for this purpose are known as "patches," and are thin, membranous films that adhere to the skin to release drugs through the skin. These devices are easily applied and allow for rapid termination of drug infusion when necessary. One such patch for use as a contraceptive device is described in U.S. Patent No. 4,818,540 issued April 4, 1989 to Chien et al. Chien et al. disclose a patch that administers estrogen and progestin, comprising a backing layer substantially impervious to estrogen and progestin, a polymer matrix disk layer in which the hormones are dispersed, and attachment means for securing the patch to the patient's skin. —- Patches that adhere to the skin are useful for only several days, after which they must be changed. 5 For example, the Chien et al. patch must be changed about every seven days. Use of such patches for more than a few days in one location results in skin irritation and may cause dermatitis due to the occlusion of the skin and reactions to the adhesives 0 and enhancers contained in the patches. Patient compliance is decreased by these side effects, caused by direct adherence of the patches to the skin. Moreover, because of the adhesive, patches cannot be easily removed from the skin. 5 It has now been found that transdermal devices for administration of drugs need not adhere to the skin in order to deliver a therapeutically effective amount of drug to the subject.

Summary of the Invention 0 Accordingly, applicants' invention relates to a device for transdermally administering a drug, said device having a drug releasing surface and an attachment surface and comprising in sequence a drug-polymer matrix containing a therapeutically 5 effective amount of the drug, a drug impermeable layer adhered to the drug-polymer matrix and substantially impervious to the drug, and attachment means adhered to the drug impermeable layer and located on the attachment surface, said attachment means being capable 0 of attachment to a carrier for holding the device, wherein the drug-polymer matrix releases the drug through the drug releasing surface to the skin. Brief Description όf^~the Drawings

Figure 1 shows a cross-sectional view of a device for transdermally administering drugs according to the invention. Figure 2 is a graph depicting the in vitro release rates of the hormone ST1435 from the device shown in Figure 1 before use, and after 2 cycles, 3 cycles and 4 cycles of use.

Figures 3(a) , 3(b) , 3(c) and 3(d) are graphs depicting endocrine profiles before and after administration of the hormone ST1435 via the device shown in Figure 1.

Figures 4(a) and 4(b) show cross-sectional views of two devices for transdermally administering drugs according to the invention.

Figures 5(a) and 5(b) are graphs depicting in vitro release rates of the hormone ST1435 from the devices shown in Figures 4(a) and 4(b), respectively. Figure 6 shows a further device for transdermally administering drugs according to the invention.

Figure 7 shows a further device for transdermally administering drugs according to the invention.

Figure 8 shows a further device for transdermally administering drugs according to the invention. Figure 9 is a graph depicting the .in vitro release rates of the hormone ST1435 from the device shown in Figure 8.

Detailed Description of the Invention

Devices for transdermally administering drugs are presented which do not require adhesion to the skin in order to deliver a therapeutically effective amount of a drug to a subject. These devices avoid occlusion of the skin and do not expose the subject to adhesives or enhancers. By use of these devices, dermatitis is thus prevented and patient convenience and compliance is increased compared with use of transdermal patches. The devices of the present invention do not contain adhesive on the drug delivery layer next to the skin. Instead, adhesive is located on the surface of the device remote from the skin. The device is then affixed by attachment means to an item of clothing or ornamentation such as a watch or bracelet, which when worn will hold the device next to the skin of the patient without the need for direct attachment to the skin. Figures 1, 4, 6, 7 and 8 show various devices for transdermally administering drugs according to the invention. In each figure reference number 5 represents the drug releasing surface, while reference number 6 represents the attachment surface. The devices shown in Figures 1, 4, 6, 7 and 8 each comprise a drug impermeable layer 1 that is substan¬ tially impervious to the drug to be administered, thereby preventing diffusion of the drug toward the attachment surface 6. The drug impermeable layer 1 may be made of a polymer such as polyethylene, polyester, polypropylene, polyamide, polycarbonate, polyacrylate, ethylene-vinylacetate (EVA) copolymers, or Teflon®. The drug impermeable layer 1 preferably comprises a metallized polymer. Particularly suitable materials are metallized polyethylene and metallized polyester. The thickness of the drug impermeable layer 1 should range from 0.002 to 0.005 inches, preferably 0.002 to 0.004 inches.

Attached to the drug impermeable layer 1 is a drug-polymer matrix 2. The drug-polymer matrix 2 functions to release the drug across the drug releasing surface 5 so that it may be absorbed by the skin. The drug-polymer matrix 2 must be made of a material that is compatible with the drug to be administered and, in addition, is biologically acceptable. Suitable polymer materials for use as the drug-polymer matrix 2 are Silastic® MDF4-4210 (medical grade polydimethylsiloxane available from Dow Corning Corp.), EVA copolymers, and othe medical grade polymers. Preferably, the drug-polymer matrix 2 is made from Silastic® MDF4-4210. The thickness of the drug-polymer matrix 2 can be varied depending on how long the device is intended to be used and mechanical convenience of construction.

The drug-polymer matrix 2 is prepared by mixing the desired quantity of the drug with the desired monomer starting material before polymerization. The drug should be evenly dispersed in the monomer starting material. The monomer starting material containing the drug is then polymerized, cured and hardened to form the drug-polymer matrix 2.

The drug-polymer matrix 2 initially may comprise 20 to 70% by weight of the drug to be administered.

Preferably, the drug-polymer matrix 2 releases the drug at a controlled, substantially constant rate. The drug-polymer matrix 2 may contain a greater amount of the drug than is necessary to saturate the drug-polymer matrix 2. In this manner, as the drug diffuses out of the drug-polymer matrix 2, more of the drug may be absorbed by the drug-polymer matrix from the "reservoir" of unabsorbed drug in the device.

The device according to the invention also comprises attachment means 4. The attachment means 4 are adhered to the drug impermeable layer 1 and serve to affix the device to a carrier, such as an article of clothing or jewelry, or any other item that contacts the skin when worn. For example, particularly useful carriers are bracelets and watches. Suitable carriers need not be in tight, complete contact with the skin; however they must be capable of simple apposition to the skin.

Suitable materials for use as the attachment means 4 include any type of adhesive material capable of adhering the device to a carrier. For example, the attachment means 4 may comprise an adhesive chemical compound or a mechanical adhesive_such as a velcro or snap fastener.

The device for transdermal administration of drugs may also comprise one or more rate limiting membranes 3 to help control the rate at which the drug is released from the drug-polymer matrix 2 to the skin. The rate limiting membrane 3 is preferably made from a porous or perforated material, such as cellulose, dialysis membrane, and EVA copolymers. The thickness of the rate limiting membrane 3 should range from about 0.002 to 0.005 inches, and is preferably 0.002 inches. In the device shown in Figure 4(b) , a rate limiting membrane 3 is attached to the side of the drug-polymer matrix 2 opposite the drug impermeable layer 1, thereby located on the drug releasing surface 5. As shown in Figure 1, the drug-polymer matrix 2 may be divided into two layers, and a rate limiting membrane 3 inserted between the layers of the drug-polymer matrix 2. In this manner, two or more layers of drug-polymer matrix 2 with equivalent or different thicknesses may be used with rate limiting membranes 3 sandwiched between the layers of drug-polymer matrix 2 in order to slow drug diffusion toward the drug releasing surface 5. The various layers of the device may be held together by bonding material 7, as shown in Figures 6, 7 and 8. Suitable bonding materials include Silastic® Adhesive A (available from Dow Corning Corp.), and other medical grade adhesives. The same material as is used in the drug-polymer matrix 2 may be used for the bonding material 7, thereby ensuring that the drug can readily diffuse through the bonding material 7 to the skin. Alternatively, the various layers of the device may be held together by an outer coating 8, as shown in Figures 6, 7 and 8. The outer coating 8 may be made from polydimethylsiloxane, other medical grade silicone polymers or any medical grade polymer that will allow diffusion of the drug through it to the skin at a therapeutically effective rate. Either bonding material 7 or an outer coating 8 may be used separately, or they may be used together in the same device. However, the drug must be able to diffuse through both the bonding material 7 and the outer coating 8. The outer coating 8 also functions to protect the skin from direct contact with drug-polymer matrix 2 and therefore is preferably included at least on the drug releasing surface 5.

Individual devices may be prepared by molding, or large sheets of the materials that make up the various layers may be laminated and cut into individual devices. If laminated, neither the bonding material nor the outer coating 8 are necessary to hold the device together, although, as stated above, the outer coating 8 may be included for protective purposes. Any drug capable of penetrating the skin and diffusing through the drug-polymer matrix 2, and if included, the rate limiting membrane 3, the bonding material 7 and the outer coating 8, can be administered by the device. Drugs unable to penetrate the skin in therapeutically effective amounts are unsuited for the present invention. With initial drug loads of about 25% by weight, the device may be used for up to about 180 days before it should be replaced with a new one. The device may be used continuously in the same location, or can be moved from one location to another, for example from the left arm to the right arm. The initial drug load, preferably in the range of 20-70% by weight of the drug-polymer matrix 2 determines the useful life of the device.

The following non-limiting examples demonstrate use of the device for administering the progestin analog ST1435 (16-methylene-17-α-acetoxy-19-nor- 4-pregnene-3,20 dione) . This hormone inhibits ovulation. The following examples show that ST1435 may be safely administered using applicants' device, without the problems encountered with administration via a "patch" adhered to the skin, such as dermatitis. The transdermal application of ST1435 is described in Applicants' copending U.S. patent application Serial No. 07/532,215, the disclosure of which is incorporated herein by reference. Example 1

A device as shown in Figure 1 was made which comprised a drug impermeable layer 1 and a rate limiting membrane 3 sandwiched between two layers of drug-polymer matrix 2 of different thicknesses. Attachment means 4 were located on the attachment surface 6 of the device. It contained no enhancers or alcohol and no adhesive on the drug releasing surface 5. The device was tested for administration of the hormone ST1435 to inhibit ovulation. The device was made as follows. 1402.5 mg of

Medical Grade 382 Silastic® from the Dow Corning Corp. was mixed with 467.5 mg of the hormone ST1435. Although 382 Silastic® is no longer commercially available, Silastic® MDF4-4210, a heat curable platinum catalyzed system, is a suitable substitute. Four drops of catalyst (stannous octoate. Catalyst M® from Dow Corning Corp.) were added according to the manufacturer's instructions. Two separate layers of drug polymer matrix 2 of different thicknesses were formed by polymerization carried out in a 2 cm x 7.5 cm x 0.1 cm mold. A thin Teflon® lining was layered on the outer surface of the device as the drug impermeable layer 1 to prevent hormone diffusion in that direction. A perforated dialysis membrane was inserted as the rate limiting membrane 3 between the inner (thicker) layer of drug-polymer matrix 2 and the outer (thinner) layer of drug-polymer matrix 2 to slow hormone diffusion toward the drug releasing surface 5. Attachment means were used only on the backs of the drug impermeable layers 1 so that the devices could be attached to the back of suitable carriers. Thus, the elements of conventional transdermal devices responsible for skin irritation, namely enhancers, alcohols and adhesives were either missing or placed so as to be removed from contact with the skin.

Before use the device was incubated for 7 days in 600 ml of water at 37°C with permanent agitation to obtain an estimation of the ST1435 in vitro release rate.

The device was tested sequentially on a bracelet for one cycle each on four healthy, normally menstruating women protected by sexual abstinence or by IUD (cases 13-02, 03-04, 31-01 and 40-01). The in vitro release rate of ST1435 from the device was determined before use and after 2, 3 and 4 cycles of use. Before use, the device released approximately 2-2.5 mg ST1435 per day, after an initial burst. After 2 cycles of use, the release rate was between 1.5 and 2.5 mg ST1435 per day; after 3 cycles of use, it was approximately 2.2 mg ST1435 per day and after 4 cycles of use_it was 1.5 mg ST1435 per day. Figure 2 shows the in vitro release rates of ST1435 from the device, before use, after 2 cycles, 3 cycles and 4 cycles of use.

All four volunteers completed the study with the device. Endocrine profiles obtained from the volunteers are shown in Figures 3(a)-3(d). The endocrine profiles suggest that all subjects displayed ovulatory patterns during the control, pretreatment cycle. During the treatment cycle, urinary estrone glucuronide levels were elevated; however, pregnanediol glucuronide levels remained low. In three cases

(13-02, Fig. 3(a); 03.-04, Fig. 3(b); and 31-01, Fig. 3(c) ) , there were no LH peaks during the treatment cycle, whereas, in one case (40-01, Fig. 3(d)) an LH peak was observed at day 8; however, the peak was smaller than that observed in the pretreatment period. Progesterone levels were indicative of anovulatory cycles in 3 of the 4 cases. In case 13-02, one sample showed an elevated plasma level but this was not accompanied by an elevated pregnanediol glucuronide peak.

Figure 3(a) shows a late progesterone peak during the treatment cycle that was not accompanied by elevated pregnanediol glucuronide or LH peaks. Figure 3(b) shows that plasma levels of ST1435 were elevated. Progesterone levels during the pretreatment cycle were indicative of an ovulatory cycle whereas progesterone levels were markedly suppressed during treatment cycle. The post-treatment cycle was anovulatory. Figure 3(c) shows pretreatment and post treatment profiles indicative of ovulatory cycles. Ovulation was suppressed during treatment cycle. Post treatment cycle in case 03-04 was anovulatory; in case 31-01 it was longer than normal with a disturbed LH pattern; in case 40-01 it was shorter than normal. The bleeding patterns in 3 of the treated cycles were undisturbed, whereas in case 31-01 there were breakthrough bleedings on days 14 and 19 respectively.

These data demonstrate that the device can be used to successfully administer hormones through the skin to attain therapeutically effective serum levels. Example 2

Two devices as shown in Figures 4(a) and 4(b) were used for transdermal delivery of the hormone ST1435. The first was a disk having the structure shown in Figure 4(a), about 3 cm in diameter with a 25% drug load, and the second was a band having the structure shown in Figure 4(b), also containing a 25% drug load. Each contained a drug impermeable layer 1 made of metallized polyethlene, and a drug-polymer matrix 2 made of Silastic® MDF4-4210. The band also contained a rate limiting membrane made of Silastic® MDF4-4210. These devices contained no enhancers or alcohol. The drug-polymer matrices 2 were prepared by mixing ST1435 and Silastic® MDF4-4210, and then polymerizing in a mold, as described in Example 1. The various layers were bonded together with very thin layers of Medical Grade Silastic® Adhesive A (Dow Corning Corp.). Attachment means were used only on the backs of the drug impermeable layers 1 so that the devices could be attached to the back of suitable carriers. Again, the elements of conventional transdermal devices responsible for skin irritation, namely enhancers, alcohols and adhesives were either missing or placed so as to be removed from contact with the skin.

In vitro release rate studies using these devices indicated that after an initial burst, the disk released approximately 0.8 mg ST1435 per day for about 40 days, and somewhat less at 85 days. When tested in vitro the band of Figure 4(b) gave an initial release rate of about 1 mg ST1435 per day, which slowly decreased to about 0.8 mg per day at 90 days. These results are shown in Figure 5.

The band of Figure 4(b) was tested for one cycle in two volunteers. Ovulation inhibition was not accomplished, as plasma progesterone levels were not suppressed to anovulatory levels. Therefore it appears that the in vitro release rate should be greater than about 0.8 mg ST1435 per day in order to achieve anovulatory ST1435 serum levels. Example 3

A device as shown in^"Figure 8 was prepared and tested for .in vitro release rates of the hormone

ST1435. The device comprised a drug-polymer matrix 2 made of Silastic® MDF4-4210, which had an initial drug load of 25% by weight ST1435 and was prepared as described in Example 1. A layer of metallized polyethylene was applied to the drug-polymer matrix 2 as the drug impermeable layer 1. Silastic® adhesive was used as bonding material 7 to hold the layers together and an outer coating 8 of clear Silastic® (containing no drug) was applied around the outside of the device.

Figure 9 shows the in vitro release rate of the hormone ST1435 obtained with this device. After 4 days, the release rate remained stable at about 2 mg of ST1435 per day. At this dose level, ST1435 can readily be used to inhibit ovulation.

Claims

1. A device for transdermally administering a drug, said device having a drug releasing surface and an attachment surface and comprising in sequence a drug-polymer matrix containing a therapeutically effective amount of the drug, a drug impermeable layer adhered to the drug-polymer matrix and substantially impervious to the drug, and attachment means adhered to the drug impermeable layer and located on the attachment surface, said attachment means being capable of attachment to a carrier for holding the device, wherein the drug-polymer matrix releases the drug through the drug releasing surface to the skin.

2. The device according to claim 1, further comprising a rate limiting membrane located between the drug-polymer matrix and the drug releasing surface.

3. The device according to claim 1, wherein the drug-polymer matrix is split into two layers, and a rate limiting membrane is located between the two layers of the drug-polymer matrix.

4. The device according to claim 1, wherein the drug-polymer matrix and the drug impermeable layer are attached by a bonding material comprising a medical grade adhesive.

5. The device according to claims 2 or 3, wherein the drug-polymer matrix, the drug impermeable layer and the rate limiting membrane are attached by a bonding material comprising a medical grade adhesive.

6. The device according to claim 1, further comprising an outer coating of a material comprising a medical grade silicone polymer.

7. The device according to claim 1, wherein the drug-polymer matrix comprises a polymer selected from the group consisting of medical grade polydimethylsiloxane and EVA copolymers.

8. The device according to claim 1, wherein the drug-polymer matrix initially contains 20 to 70% by weight of the drug.

9. The device according to claim 1, wherein the drug is 16-methylene-17-α-acetoxy-19-nor-4-pregnene- 3,20 dione.

10. The device according to claim 1, wherein the drug impermeable layer is made of a polymer selected from the group consisting of polyethylene, polyester, polypropylene, polyamide, polycarbonate, polyacrylate, and EVA copolymers.

11. The device according to claim 10, wherein the polymer is a metallized polymer.

12. The device according to claims 2 or 3, wherein the rate limiting membrane is made of a material selected from the group consisting of cellulose, dialysis membrane and EVA copolymer.