Method and device for transdermal delivery of parathyroid hormone using a microprojection array

Abstract

A method and a drug delivery system for transdermally administering parathyroid hormone (PTH) in a pulsatile fashion are provided, where the drug delivery system comprises an array of microprojections each comprising PTH.

It is claimed: 
     
         1 . A method of transdermally administering a dose of PTH to a mammalian subject, comprising:
 applying to a skin site of a subject a microprotusion array comprising a plurality of microprotrusions extending from an approximately planar base, each microprotrusion comprising an end portion distal to the base and an upper portion proximal to the base, the end portion comprising a tip of the microprotrusion, at least the end portion comprising parathyroid hormone (PTH) in a water-soluble polymer matrix,   inserting all or a portion of the plurality of microprotrusions into the skin, and   maintaining the array on the skin site for about 15 minutes or less;   whereby the method achieves an average time to maximum PTH plasma concentration (T max ) of about ten minutes or less.   
     
     
         2 . The method of  claim 1 , wherein the PTH is human parathyroid hormone (1-34). 
     
     
         3 . The method of  claim 1 , wherein after the microprotrusions are inserted into the skin, at least a portion of the end portions including the tip of the plurality of microprotrusions detach from the microprotrusion array. 
     
     
         4 . The method of  claim 1 , wherein the water-soluble polymer matrix comprises at least one water-soluble polymer and at least one of a sugar or a sugar alcohol. 
     
     
         5 . The method of  claim 4 , wherein the sugar or sugar alcohol is selected from sucrose and sorbitol. 
     
     
         6 . The method of  claim 4 , wherein the polymer matrix comprises about 10-35% dry weight of the at least one sugar or sugar alcohol. 
     
     
         7 . The method of  claim 4 , wherein the polymer is at least one dextran polymer. 
     
     
         8 . The method of  claim 7 , wherein the at least one dextran polymer is selected from Dextran 1, Dextran 10, Dextran 20, Dextran 40, Dextran 70, and Dextran 75. 
     
     
         9 . The method of  claim 7 , wherein the polymer matrix comprises about 20-70% dry weight of at the least one dextran polymer. 
     
     
         10 . The method of  claim 1 , wherein the water-soluble matrix further comprises a buffer selected from the group consisting of histidine and histidine hydrochloride. 
     
     
         11 . The method of  claim 1 , wherein the base is comprised of a water-insoluble polymer. 
     
     
         12 . The method of  claim 11 , wherein the upper portion of each microprotrusion is comprised of the water-insoluble polymer. 
     
     
         13 . The method of  claim 11 , wherein the water-insoluble polymer comprises a poly(lactic acid-co-glycolic acid). 
     
     
         14 . The method of  claim 1 , whereby the method is effective to achieve an elimination half-life that is less than about 45 minutes. 
     
     
         15 . The method of  claim 1 , whereby the method is effective to achieve an elimination half-life that is at least about 20% faster than the elimination half-life achieved with the same, or lower dose, of PTH delivered via subcutaneous injection. 
     
     
         16 . A microprotrusion array for transdermal administration of a dose of parathyroid hormone (PTH) to a mammalian subject, said array comprising a plurality of microprotrusions extending from an approximately planar base, each microprotrusion comprising an end portion distal to the base and an upper portion proximal to the base, at least the end portion comprising parathyroid hormone (PTH) in a water-soluble polymer matrix,
 the water-soluble polymer matrix comprised of:   (i) about 7.5-12.8% dry weight PTH;   (ii) about 20-70% dry weight of at least one dextran polymer; and   (iii) about 10-35% dry weight of at least one sugar or sugar alcohol;   wherein the upper portion is comprised of at least one water-insoluble polymer;   wherein said use comprises the transdermal administration of a dose of PTH to a mammalian subject by:   applying the microprotrusion array to a skin site of the subject;   inserting all or a portion of the plurality of microprotrusions into the skin, and   maintaining the array on the skin site for about 15 minutes or less;   whereby the use achieves an average time to maximum PTH plasma concentration (T max ) of about ten minutes or less.   
     
     
         17 . The microprotrusion array of  claim 16 , wherein the PTH is human parathyroid hormone (1-34). 
     
     
         18 . The microprotrusion array of  claim 16 , wherein the at least one dextran polymer is selected from Dextran 1, Dextran 10, Dextran 20, Dextran 40, Dextran 70, and Dextran 75. 
     
     
         19 . The microprotrusion array of  claim 16 , wherein the water-soluble polymer matrix comprises about 35-70% dry weight of the at least one dextran polymer. 
     
     
         20 . The microprotrusion array of  claim 16 , wherein the at least one sugar or sugar alcohol is selected from sucrose and sorbitol. 
     
     
         21 . The microprotrusion array of  claim 16 , wherein the base is comprised of a water-insoluble polymer. 
     
     
         22 . The microprotrusion array of  claim 16 , wherein the array comprises a total dose of about 10-100 μg PTH. 
     
     
         23 . The microprotrusion array of  claim 16 , wherein the array comprises a total dose of about 32 μg PTH. 
     
     
         24 . The microprotrusion array of  claim 16 , wherein the array comprises a total dose of about 64 μg PTH. 
     
     
         25 . A kit, comprising:
 a microprotrusion array comprised of a plurality of microprotrusions extending from an approximately planar base, each microprotrusion comprising an end portion distal to the base and an upper portion proximal to the base, the end portion of each microprotrusion comprising parathyroid hormone (PTH) in a water-soluble polymer matrix comprising about 7.5-12.8% dry weight PTH, about 20-70% dry weight of at least one dextran polymer, and about 10-35% dry weight of at least one sugar or sugar alcohol, and the upper portion being comprised of at least one water-insoluble polymer, said array comprising a therapeutically effective amount of PTH in the water-soluble polymer matrix, and   an applicator-assembly to which the microprotrusion array is insertable or affixable;   wherein at least the end portion of each microprotrusion is fabricated to achieve an average time to maximum PTH plasma concentration (T max ) of about ten minutes or less when applied to a subject.