Spaced drug delivery system

Abstract

The present invention provides to a method of administration of two or more therapeutically active agents comprising orally administering to a patient a spaced drug delivery system, wherein the time of release of the two or more therapeutically active agents is designed to provide desired control on the disease condition. The present invention also provides a method of administration of two or more therapeutically active agents comprising orally administering to a patient a spaced drug delivery system at a specified time prior to food intake by the patient. The present invention further provides a spaced drug delivery system that releases two or more antidiabetic agents at different times after oral administration, for the treatment of diabetes mellitus or conditions associated with diabetes mellitus. More particularly, the present invention provides a spaced drug delivery system that immediately releases one or more antidiabetic agents after oral administration of the system, and releases as a pulse one or more antidiabetic agents in a reliable manner at about a predetermined time after oral administration of the system.

1 . A method of administration of two or more therapeutically active agents comprising orally administering to a patient a spaced drug delivery system, wherein at least one first therapeutically active agent is released immediately upon oral administration of the spaced drug delivery system, and at least one second therapeutically active agent is released as a pulse at a predetermined time after oral administration, wherein the two or more therapeutic agents act on the disease condition by similar or dissimilar, but complementary mechanisms, to control the symptoms of the disease, or a measurable indicator of the disease condition, and further wherein the time of release of the two or more therapeutically active agents is designed to provide desired control on the disease condition. 
     
     
         2 . A method of administration of two or more therapeutically active agents comprising orally administering to a patient a spaced drug delivery system at a specified time prior to food intake by the patient, wherein at least one therapeutically active agent is released immediately upon oral administration of the spaced drug delivery system and at least one therapeutically active agent is released as a pulse after a delay at about the time when food is taken. 
     
     
         3 . A method of administration of two or more therapeutically active agents as claimed in  claim 1 , wherein the two or more therapeutically active agents are therapeutically active antidiabetic agents. 
     
     
         4 . A spaced drug delivery system designed to provide desired control on the disease condition, comprising
 a. a first composition comprising one or more first therapeutically active agent(s), and   b. a second composition comprising one or more second therapeutically active agent(s), wherein at least one first therapeutically active agent is released immediately upon oral administration of the spaced drug delivery system, and at least one second therapeutically active agent is released as a pulse at a predetermined time after oral administration, wherein the two or more therapeutic agents act on the disease condition by similar or dissimilar, but complementary mechanisms, to control the symptoms of the disease, or a measurable indicator of the disease condition, and further wherein the time of release of the two or more therapeutically active agents is designed to provide desired control on the disease condition.   
     
     
         5 . A spaced drug delivery system for the treatment of diabetes mellitus or conditions associated with diabetes mellitus, comprising—
 a. a first composition comprising one or more therapeutically active antidiabetic agent(s), which is/are released as a pulse after a delay, and 
 b. a second composition comprising one or more therapeutically active antidiabetic agent(s), which is/are released immediately upon oral administration of the spaced drug delivery system. 
 
     
     
         6 . A spaced drug delivery system as claimed in  claim 5 , wherein the first composition is a timed pulse release composition that releases as a pulse an antidiabetic agent after a predetermined time spacing or interval after oral administration of the spaced drug delivery system. 
     
     
         7 . A spaced drug delivery system as claimed in  claim 5 , wherein the antidiabetic agent in the first composition is a biguanide antidiabetic agent, and the antidiabetic agent in the second composition is a sulfonyl urea. 
     
     
         8 . A spaced drug delivery system as claimed in  claim 5 , wherein the antidiabetic agents in the first composition are selected from the group consisting of an alpha glucosidase inhibitor, a thiazolidinedione, and an insulin secretagogue; and the antidiabetic agent in the second composition is an insulin secretagogue; further wherein the insulin secretagogues, if present in both first and second compositions, are not the same. 
     
     
         9 . A spaced drug delivery system as claimed in  claim 5 , wherein the antidiabetic agent in the first composition is a biguanide antidiabetic agent, and the antidiabetic agent in the second composition is selected from the group consisting of insulin secretagogue and a thiazolidinedione, optionally in combination with an alpha glucosidase inhibitor. 
     
     
         10 . A spaced drug delivery system as claimed in  claim 5 , wherein the antidiabetic agent in the first composition is a biguanide antidiabetic agent, and the antidiabetic agent in the second composition is an alpha glucosidase inhibitor. 
     
     
         11 . A spaced drug delivery system as claimed in  claim 7  comprising metformin hydrochloride and glipizide in a weight ratio ranging from 250:1 to 50:1. 
     
     
         12 . A spaced drug delivery system as claimed in  claim 11  comprising metformin hydrochloride in an amount ranging from about 200 mg to about 1.5 gm, and glipizide in an amount ranging from about 2 mg to about 15 mg. 
     
     
         13 . A spaced drug delivery system as claimed in  claim 7 , comprising metformin hydrochloride and glibenclamide in a weight ratio ranging from 250:1 to 50:1. 
     
     
         14 . A spaced drug delivery system as claimed in  claim 13 , comprising metformin hydrochloride and glibenclamide in a weight ratio of 100:1. 
     
     
         15 . A spaced drug delivery system as claimed in  claim 7 , comprising metformin hydrochloride in an amount ranging from about 200 mg to about 1.5 gm, and glibenclamide in an amount ranging from about 1 mg to about 10 mg. 
     
     
         16 . A spaced drug delivery system as claimed in  claim 4  comprising a timed pulse release composition comprising a core composition comprising one or more therapeutically active antidiabetic agents, a swelling agent, and optionally water soluble compound(s) for inducing osmosis, and a coat composition comprising one or more film forming polymers, wherein upon swelling of the core the coat ruptures and releases the therapeutically active agent in a reliable manner at about a predetermined time after oral administration of the composition. 
     
     
         17 . A spaced drug delivery system as claimed in  claim 16  wherein the timed pulse release composition is optimized as follows:
 a. the core composition is capable of swelling at a desired rate to a sufficient extent, 
 b. the coat composition has the desirable film strength, plasticity, and water permeability, and 
 c. the amount of coat composition applied is adjusted, 
 
       such that upon swelling of the core the coat ruptures and releases as a pulse the therapeutically active agent in a reliable manner at about the predetermined time after oral administration of the composition wherein the reliable manner of rupture comprises rupturing of 36 tablets out of a total of 36 tablets at about the predetermined time, when tested by subjecting the tablets to USP dissolution test using an aqueous media at 37±0.5° C., in a USP Type I or Type II apparatus at an rpm selected from the range of about 50 rpm to about 100 rpm. 
     
     
         18 . A spaced drug delivery system as claimed in  claim 17  wherein the predetermined time is in the range from about 1 hr to about 4 hr, and the 36 out of the 36 tablets rupture within ±50% of the predetermined time. 
     
     
         19 . A spaced drug delivery system as claimed in  claim 18  wherein the predetermined time is about 70 min. 
     
     
         20 . A spaced drug delivery system as claimed in  claim 19 , wherein the “release of therapeutically active agent as a pulse” comprises release of not more than 10% of the active ingredient at 45 min and at least 70% of the active ingredient at 2 hrs when tested by subjecting the tablets to USP dissolution test using pH 6.8 buffer at 37±0.5° C., in a USP Type II apparatus at an rpm of 75. 
     
     
         21 . A spaced drug delivery system as claimed in  claim 16 , wherein the swelling agent is selected from the group consisting of croscarmellose sodium, crosslinked polyvinylpyrrolidone and sodium starch glycolate. 
     
     
         22 . A spaced drug delivery system as claimed in  claim 21 , wherein the core further comprises a wicking agent. 
     
     
         23 . A spaced drug delivery system as claimed in  claim 22 , wherein the wicking agent is selected from microcrystalline cellulose and colloidal silicon dioxide. 
     
     
         24 . A spaced drug delivery system as claimed in  claim 23 , wherein the core further comprises starch. 
     
     
         25 . A spaced drug delivery system as claimed in  claim 16 , wherein the film forming polymers in the coat comprise a mixture of a water insoluble polymer and a water soluble polymer. 
     
     
         26 . A spaced drug delivery system as claimed in  claim 25 , wherein the water insoluble polymer is ethyl cellulose and the water soluble polymer is hydroxypropyl methylcellulose (HPMC). 
     
     
         27 . A spaced drug delivery system as claimed in  claim 26 , wherein the predetermined time of release is about 70 min and the weight ratio of ethyl cellulose to hydroxypropyl methylcellulose is in a range from about 6:3 to about 9:3. 
     
     
         28 . A spaced drug delivery system as claimed in  claim 26 , wherein the core is coated to a weight gain of about 5% to about 10%. 
     
     
         29 . A spaced drug delivery system as claimed in  claim 27 , wherein the core is coated to a weight gain of about 9% to about 10%. 
     
     
         30 . A spaced drug delivery system as claimed in  claim 17  wherein the predetermined time is in the range of about >4 hr to about 12 hr, the 36 out of the 36 tablets rupture within ±25% of the predetermined time. 
     
     
         31 . A method for treating diabetes mellitus or conditions associated with diabetes mellitus in a human, which method comprises administering a spaced drug delivery system claimed in  claim 5 . 
     
     
         32 . A method of administration of two or more therapeutically active agents as claimed in  claim 2 , wherein the two or more therapeutically active agents are therapeutically active antidiabetic agents. 
     
     
         33 . A method for treating diabetes mellitus or conditions associated with diabetes mellitus in a human, which method comprises administering a spaced drug delivery system claimed in  claim 6 .