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US-12622879-B2 - Transdermal delivery formulation

US12622879B2US 12622879 B2US12622879 B2US 12622879B2US-12622879-B2

Abstract

Compositions and methods for delivering vitamin D to a subject. In one embodiment the invention provides a transdermal patch for the transdermal administration of vitamin D comprising: (a) a backing layer that serves as the outer surface of the patch during use; (b) an adhesive drug reservoir layer for affixing the patch to skin; and (c) a release liner, which upon removal exposes the adhesive drug reservoir layer. The adhesive drug reservoir layer can include vitamin D, a polymeric adhesive, an organic solvent, and a permeation enhancer.

Inventors

  • Ted SCHWARZROCK
  • Gary CLEARY

Assignees

  • TRS II, LLC

Dates

Publication Date
20260512
Application Date
20231127

Claims (17)

  1. 1 . A transdermal patch for the transdermal administration of cholecalciferol comprising: (a) a backing layer that serves as the outer surface of the patch during use; (b) an adhesive drug reservoir layer for affixing the patch to skin; and (c) a release liner, which upon removal exposes the adhesive drug reservoir layer; wherein the adhesive drug reservoir layer consists of about 1 to about 10 wt. % cholecalciferol, a polymeric adhesive, about 3-15 wt. % of” before “an organic solvent an organic solvent, and a permeation enhancer; and the organic solvent comprises isosorbide dimethyl ether or isopropyl laurate.
  2. 2 . The transdermal patch of claim 1 wherein the adhesive is a polyisobutylene adhesive, a silicone adhesive; or an acrylate adhesive.
  3. 3 . The transdermal patch of claim 1 wherein the adhesive drug reservoir layer comprises about 60-90 wt. % polymeric adhesive.
  4. 4 . The transdermal patch of claim 1 wherein the adhesive drug reservoir layer comprises about 1-15 wt. % permeation enhancer.
  5. 5 . The transdermal patch of claim 1 wherein the adhesive is an acrylate or polyisobutylene adhesive and the permeation enhancer is transcutol.
  6. 6 . The transdermal patch of claim 1 wherein the adhesive drug reservoir layer does not contain water.
  7. 7 . The transdermal patch of claim 1 wherein the adhesive drug reservoir layer does not contain an organic base or an inorganic base.
  8. 8 . The transdermal patch of claim 1 wherein the surface area of the adhesive drug reservoir layer of the patch is about 30 cm 2 to about 50 cm 2 .
  9. 9 . The transdermal patch of claim 8 wherein the patch is formulated to deliver greater than 2,000 μg of cholecalciferol through 40 cm 2 of intact unbroken living skin within 5 hours.
  10. 10 . The transdermal patch of claim 8 wherein the patch is formulated to deliver greater than 20,000 μg of cholecalciferol through 40 cm 2 of intact unbroken living skin within 24 hours.
  11. 11 . The transdermal patch of claim 8 wherein the patch is formulated to contain about 4,000-5,000 I.U. of cholecalciferol.
  12. 12 . A transdermal patch for the transdermal administration of vitamin D 3 comprising: (a) a backing layer that serves as the outer surface of the patch during use; (b) an adhesive drug reservoir layer for affixing the patch to skin; and (c) a release liner, which upon removal exposes the adhesive drug reservoir layer; wherein the adhesive drug reservoir layer consists of 1-10 wt. % cholecalciferol, 60-90 wt. % polymeric adhesive, about 3-15 wt. % of” before “an organic solvent an organic solvent, and 1-15 wt. % transcutol; and wherein the organic solvent comprises isosorbide dimethyl ether or isopropyl laurate.
  13. 13 . The transdermal patch of claim 12 wherein the adhesive drug reservoir layer consists of 3 wt. % cholecalciferol, 80-85 wt. % polymeric adhesive, and 5-10 wt. % transcutol.
  14. 14 . A method for the transdermal delivery of cholecalcifero comprising removing the release liner of the transdermal patch of claim 1 and applying the transdermal patch to intact unbroken living skin of a subject, wherein the transdermal patch delivers greater than 0.75 μg/cm 2 of cholecalciferol to the subject within 5 hours.
  15. 15 . The method of claim 14 wherein the transdermal patch is applied to a subject having a 25-hydroxyvitamin D 3 blood serum level of less than 30 ng/mL.
  16. 16 . The method of claim 15 wherein the 25-hydroxyvitamin D 3 blood serum level of the subject increases to greater than 30 ng/ml within 5 hours.
  17. 17 . A method of increasing the 25-hydroxyvitamin D 3 blood serum level of a subject that has a vitamin D malabsorption condition comprising removing the release liner of the transdermal patch of claim 1 and applying the transdermal patch to intact unbroken living skin of the subject, wherein the 25-hydroxyvitamin D 3 blood serum level of the subject increases to greater than 20 ng/ml within 24 hours.

Description

RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 17/174,947 filed Feb. 12, 2021, which is a continuation of U.S. patent application Ser. No. 15/736,651 filed Dec. 14, 2017, which is a National Stage filing under 35 U.S.C. § 371 of International Application No. PCT/US2016/037437 filed Jun. 14, 2016, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62/175,363 filed Jun. 14, 2015, which applications are incorporated herein by reference. BACKGROUND OF THE INVENTION The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences, e.g., gastrointestinal irritation and the like, are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug. Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum, which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low without the use of some means to enhance the permeability of the skin. Numerous chemical agents have been studied as a means of increasing the rate at which a drug penetrates through the skin. As will be appreciated by those in the field, chemical enhancers are compounds that are administered along with the drug (or in some cases the skin may be pretreated with a chemical enhancer) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin. Ideally, such chemical penetration enhancers or “permeation enhancers,” as the compounds are referred to herein, are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum. The permeability of many therapeutic agents with diverse physicochemical characteristics may be enhanced using these chemical enhancement means. However, there are skin irritation and sensitization problems associated with high levels of certain enhancers. Accordingly, although there are many chemical methods of enhancing permeation, there remains an ongoing need for a method that is highly effective in increasing the rate at which a drug permeates the skin, does not result in skin damage, irritation, sensitization, or the like, and can be used to effect transdermal delivery of fat-soluble compounds such as vitamin D. It has now been discovered that the formulation described herein is highly effective and provides all of the aforementioned advantages relative to known permeation enhancers. SUMMARY The invention provides a transdermal patch for the transdermal administration of vitamin D comprising: (a) a backing layer that serves as the outer surface of the patch during use; (b) an adhesive drug reservoir layer for affixing the patch to skin; and (c) a release liner, which upon removal exposes the adhesive drug reservoir layer. The adhesive drug reservoir layer can include, or can consist only of, vitamin D, a polymeric adhesive, an organic solvent, and a permeation enhancer. In one embodiment, the vitamin D is cholecalciferol (vitamin D3), calcifediol (25-hydroxyvitamin D3), ergocalciferol (vitamin D2), calcitriol, or calcipotriene. In one embodiment, the adhesive is a polyisobutylene adhesive, a silicone adhesive; or an acrylate adhesive. In one embodiment, the adhesive drug reservoir layer comprises about 1-10 wt. % of the vitamin D. In one embodiment, the adhesive drug reservoir layer comprises about 60-90 wt. % of the polymeric adhesive. In one embodiment, the adhesive drug reservoir layer comprises about 1-15 wt. % organic solvent. In one embodiment, the adhesive drug reservoir layer comprises about 1-15 wt. % permeation enhancer. In one specific embodiment, the vitamin D is cholecalciferol, the adhesive is an acrylate adhesive, the organic solvent is ethanol, and the permeation enhancer is transcutol. In othe