Sustained release drug delivery system

Abstract

Disclosed is a controlled release dosage form comprising a therapeutically effective amount of a pharmaceutically active agent, which may be Acyclovir, that releases in about 12 hours 80-100% of the active agent in a simulated gastric juice in a first order rate of release in a USP type 2 dissolution test, and not containing a solubilizer or a swelling enhancer or both, containing (a) a tablet made from polymer matrix of at least two biocompatible polymers, which may be Carbopol 974P and polyethylene oxide, the pharmaceutically active agent and pharmaceutically permitted excipients; the tablet capable of rapid swelling without disintegration in the simulated gastric juice to a size that results in its gastric retention in the stomach and start controlled release of the active agent by starting controlled erosion as well as diffusion immediately after coming into contact with the gastric juice.

What is claimed is: 
     
         1 . A controlled release dosage form containing no solubilizer, comprising a therapeutically effective amount of a pharmaceutically active agent, comprising:
 a. a tablet made from a polymer matrix of at least two biocompatible polymers, at least one of which is mucoadhesive, the pharmaceutically active agent and pharmaceutically permitted excipients; the tablet capable of rapid swelling without disintegration in a simulated gastric juice to a size that results in its gastric retention in a stomach and start a controlled release of the active agent by starting a controlled erosion immediately after coming into contact with the gastric juice, or   b. microspheres of ungrafted chitosan or a chitosan derivative incorporating the active agent, wherein the pharmaceutically active agent is not a polymeric molecule and after administration in the stomach, the microspheres adhere to the gastric mucosa for a long time releasing the active agent in a controlled way,   wherein:
 the controlled release dosage form containing no solubilizer releases in about 12 hours of between 80-100% of the active agent in a first order rate of release in a USP-2 type dissolution test. 
   
     
     
         2 . The controlled release dosage form of  claim 1 , wherein the controlled release dosage form is the tablet, and the USP-2 type dissolution test is done in the simulated gastric juice and the polymers are mucoadhesive, swellable polymers comprising one or more selected from the group consisting of high molecular weight non-linear polyacrylic acid polymer cross-linked with polyalkenyl polyether, polyethylene oxide, hypermellose, sodium alginate, sodium carboxymethyl cellulose, poly(meth)acrylates based co-polymers, xanthan gum. 
     
     
         3 . The controlled release dosage form of  claim 1 , wherein the controlled release dosage form is the tablet, and the active agent is Acyclovir or Acyclovir derivatives. 
     
     
         4 . The controlled released dosage form of  claim 1 , wherein said permitted pharmaceutical excipients comprise one or more selected from the group consisting of a binder, a diluent, a pH modifier, a glidant, a lubricant, a film former, an anti-adherent, a coating agent, and a colorant. 
     
     
         5 . A controlled release dosage form comprising a tablet made from therapeutically effective amount of Acyclovir and containing no solubilizer that releases in about 12 hours of between 80-100% of the active agent in a first order rate of release in a USP-2 type dissolution test, wherein the USP-2 type dissolution test is done in a simulated gastric juice, and the tablet comprises a polymer matrix of high molecular weight non-linear polyacrylic acid polymer cross-linked with polyalkenyl polyether, polyethylene oxide, microcrystalline cellulose and polyvinylpyrrolidone having a viscosity of 44000-54000 cps, magnesium stearate, and colloidal silicon oxide as excipient. 
     
     
         6 . The controlled release dosage form of  claim 5  comprising, for every 1000 mg of the dosage form;
 i. Acyclovir in an amount of 763.37 mg, a high molecular weight polymer of acrylic acid crosslinked with allyl ethers of pentaerythritol in an amount of 100 mg, microcrystalline cellulose in amount 93.83 mg, polyvinylpyrrolidone having a viscosity of 44000-54000 cps in an amount of 30 mg, magnesium stearate in an amount of 7.5 mg, and colloidal silicon dioxide 5.0 mg, or 
 ii. Acyclovir in an amount of 763.37 mg, a high molecular weight polymer of acrylic acid crosslinked with allyl ethers of pentaerythritol in an amount of 150 mg, microcrystalline cellulose in an amount 93.83 mg, polyvinylpyrrolidone having a viscosity of 44000-54000 cps in an amount of 30 mg, magnesium stearate in an amount of 7.5 mg, and colloidal silicon dioxide 5.0 mg, or 
 iii. Acyclovir in an amount of 763.37 mg, a high molecular weight polymer of acrylic acid crosslinked with allyl ethers of pentaerythritol in an amount of 50 mg, polyethylene oxide in an amount of 50 mg, microcrystalline cellulose in an amount of 93.83 mg, polyvinylpyrrolidone having a viscosity of 44000-54000 cps in an amount of 30 mg, magnesium stearate in an amount of 7.5 mg, and colloidal silicon dioxide 5.0 mg. 
 
     
     
         7 . The controlled release dosage form of  claim 1 , wherein the controlled release dosage form is the microspheres, and the chitosan derivative is Trimethyl chitosan or Thiolated chitosan and wherein the USP-2 type dissolution test is done in HCL buffer having pH 1.2 as a dissolution medium in first hour and a phosphate buffered saline having pH 6.8 is used in next 11 hours. 
     
     
         8 . The controlled release dosage form of  claim 1 , wherein the controlled release dosage form is the microspheres, and the microspheres are packed in a sachet or are used as an ingredient to make a solid unit dosage form comprising a tablet and a capsule. 
     
     
         9 . A method of administering a therapeutically effective amount of a pharmaceutically active agent from a controlled release dosage form containing no solubilizer to a patient, wherein the administration is done through an oral route comprising:
 i. a tablet made from a polymer matrix of at least two biocompatible polymers, at least one of which is mucoadhesive, the pharmaceutically active agent and pharmaceutically permitted excipients; the tablet capable of rapid swelling without disintegration in a simulated gastric juice to a size that results in its gastric retention in a stomach and start a controlled release of the active agent by starting a controlled erosion immediately after coming into contact with the gastric juice, or   ii. microspheres of ungrafted chitosan or a chitosan derivative incorporating as the active agent, wherein the pharmaceutically active agent is not a polymeric molecule and after administration in the stomach, the microspheres adhere to the gastric mucosa for a long time releasing the active agent in a controlled way,   wherein:
 the controlled release dosage form containing no solubilizer releases in about 12 hours of between 80-100% of the active agent in a first order rate of release in a USP-2 type dissolution test. 
   
     
     
         10 . The method of  claim 9 , wherein the controlled release dosage form is the tablet, and the USP-2 type dissolution test is done in the simulated gastric juice and the polymers and pharmaceutically permitted excipients comprise high molecular weight non-linear polyacrylic acid polymer cross-linked with polyakenyl polyether and polyethylene oxide, microcrystalline cellulose, polyvinylpyrrolidone having a viscosity of 44000-54000, magnesium stearate, and colloidal silicon oxide. 
     
     
         11 . The method of  claim 9 , wherein the controlled release dosage form is the tablet, and the active agent is Acyclovir or Acyclovir derivatives. 
     
     
         12 . The method of  claim 9 , wherein the controlled release dosage form is the tablet, and said permitted pharmaceutical excipients comprise one or more selected from the group consisting of a binder, a diluent, a pH modifier, a glidant, a lubricant, a film former, an anti-adherent, a coating agent, and a colorant. 
     
     
         13 . The method of  claim 9 , wherein the controlled release dosage form is the tablet, and the controlled release dosage form comprises Acyclovir, high molecular weight non-linear polyacrylic acid polymer cross-linked with polyakenyl polyether, polyethylene oxide, microcrystalline cellulose, polyvinylpyrrolidone having viscosity of 44000-54000, magnesium stearate, colloidal silicon oxide. 
     
     
         14 . The method of  claim 9 , wherein for every 1000 mg of the dosage form the controlled release dosage form being the tablet comprises Acyclovir 763.37 mg, high molecular weight non-linear polyacrylic acid polymer cross-linked with polyakenyl polyether 974P 75 mg, polyethylene oxide 25 mg, microcrystalline cellulose 93.83 mg, polyvinylpyrrolidone having viscosity of 44000-54000 30 mg, magnesium stearate 7.5 mg, colloidal silicon oxide 5.0 mg. 
     
     
         15 . The method of  claim 9 , wherein the controlled release dosage form is the microspheres, and the chitosan derivative is Trimethyl chitosan or Thiolated chitosan and wherein the USP-2 type dissolution test is done in HCL buffer having pH 1.2 as a dissolution medium in first hour and a phosphate buffered saline having pH 6.8 is used in next 11 hours. 
     
     
         16 . The method of  claim 9 , wherein the controlled release dosage form is the microspheres, and the microspheres are packed in a sachet or are used as an ingredient with optional addition of other pharmaceutically permitted ingredients and excipients to make a solid unit dosage form comprising a tablet and a capsule. 
     
     
         17 . A process of making an oral dosage form containing no solubilizer, comprising a therapeutically effective amount of a pharmaceutically active agent, the process comprising:
 i. making a wet granulation of a mixture comprising the pharmaceutically active ingredient, a matrix of at least two biocompatible polymers wherein at least one of which is mucoadhesive, and excipients, adding a glidant and pressing into a tablet, or   ii. preparing a solution of chitosan or a chitosan derivative in acetic acid, adding an aqueous solution of the pharmaceutically active agent, adding this mixture to continuous phase consisting of light liquid paraffin and heavy liquid paraffin (1:1) containing a surfactant under constant stirring to form a water-in-oil emulsion, adding gluteraldehyde drop wise over a period of time, continuing stirring for a period of time, separating the microspheres formed by centrifugation, washing with petroleum ether to remove liquid paraffin, suspending in a sodium bisulfite solution and stirring for a period of time to remove residual gluteraldehyde, washing finally with distilled water, drying the microspheres   wherein:
 the controlled release dosage form containing no solubilizer releases in about 12 hours of between 80-100% of the active agent in a first order rate of release in a USP-2 type dissolution test. 
   
     
     
         18 . The process of  claim 17 , wherein the pharmaceutically active agent is Acyclovir, and
 i. under the process of (i), the polymers are high molecular weight non-linear polyacrylic acid polymer cross-linked with polyakenyl polyether, polyethylene oxide, microcrystalline cellulose, polyvinylpyrrolidone having viscosity of 44000-54000, and   ii. under the process of (ii), the chitosan derivatives are selected from the group consisting of Trimethyl chitosan and Thiolated chitosan, and   wherein
 the USP-2 type dissolution test is done in HCL buffer having pH 1.2 as dissolution medium in first hour and phosphate buffered saline having pH 6.8 is used in next 11 hours. 
   
     
     
         19 . The process of  claim 18 , wherein, under the process of (ii), the microspheres are packed in a sachet or are used as an ingredient with optional addition of other pharmaceutically permitted ingredients and excipients to make a solid unit dosage form comprising a tablet and a capsule.