Carbidopa/levodopa gastroretentive drug delivery

Abstract

A gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract comprises internal layer or compartment comprising an active agent and one or more pharmaceutical excipients, of which at least one is a polymer and two membranes forming together an envelope around the inner membrane, each membrane comprising at least one polymeric combination of an enteric polymer which is not soluble in gastric juice, and an hydrophilic swelling polymer, and at least one plasticizer.

What is claimed is: 
     
         1 . A degradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the stomach and gastrointestinal tract of a patient, comprising:
 an internal layer comprising an active agent and a degradable polymer composition which is not instantly soluble in gastric fluid, the internal layer including a first side and an opposing second side; and   at least one membrane covering the internal layer, the membrane comprising at least one polymeric combination of a hydrophilic polymer and a polymer, insoluble in gastric media, the membranes being hydratable at a rate greater than the internal layer;   the membrane being directly secured to and covering both sides of the internal layer and having a predetermined length greater than 20 mm in a planar orientation, the membrane and internal layer being arranged in an accordion folded orientation sufficiently compact to be placed within a capsule dissolvable within the stomach;   the membrane and internal layer developing sufficient mechanical force to unfold from the initial accordion folded orientation to a length of at least 20 mm within 30 minutes of being exposed to gastric medium,   the membrane permitting passage of gastric media from the environment to the internal layer and permitting passage of the active agent from the internal layer through the membrane to the environment.   
     
     
         2 . The gastroretentive drug formulation of  claim 1 , wherein the membrane and internal layer unfold to a length of at least 20 mm within 15 minutes of being exposed to gastric fluid. 
     
     
         3 . The gastroretentive drug formulation of  claim 1 , wherein the internal layer has a mechanical strength described with Young's modulus ranging from about 0.5 to 15 Kgf/mm/ 2  and stress of about 0.03 to about 0.6 Kgf/mm 2  after 1 hour in simulated gastric fluid. 
     
     
         4 . The gastroretentive drug formulation of  claim 1 , wherein the membrane includes two separate membranes, each membrane being directly joined together along an outer periphery of the membranes, the entire internal layer being located completely between the membranes, the membranes being secured to the internal layer along a portion of at least one surface of the internal layer. 
     
     
         5 . The gastroretentive drug formulation of  claim 4 , wherein the membranes are joined together with ultrasonic welding. 
     
     
         6 . The gastroretentive drug formulation of  claim 5 , wherein the membranes are joined together with the internal layer with ultrasonic welding along a region adjacent the outer periphery of the internal layer. 
     
     
         7 . The gastroretentive drug formulation of  claim 6 , wherein a central portion of the surface of the internal layer is essentially free from ultrasonic welds. 
     
     
         8 . The gastroretentive drug formulation of  claim 4 , wherein the internal layer and membranes are free of an additional adhesive member. 
     
     
         9 . The gastroretentive drug formulation of  claim 1 , wherein the multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract comprises: 
       an internal layer comprising an active agent and a degradable polymer composition which is not instantly soluble in gastric fluid, the internal layer including a first side and an opposing second side,
 a first and second membrane coveting the internal layer, the membrane including at least one polymeric combination of a hydrophilic polymer and a polymer, insoluble in gastric media, the membranes being hydratable at a rate greater than the internal layer, 
 the first and second membrane having a width and length, greater than a width and length of the internal layer, 
 the first and second membranes being ultrasonically welded or otherwise affixed or attached directly together about the periphery of the first and second membranes, the first membrane being attached to a first side of the internal layer, the second membrane being attached to the second side of the internal layer, 
 the internal layer and first and second membranes having a predetermined length greater than 20 mm in a planar orientation, the membrane and internal layer being arranged in an accordion folded orientation sufficient to be placed within a capsule dissolvable within the stomach, 
 the ultrasonic welds having sufficient mechanical strength to remain intact upon being exposed to gastric medium. 
 
     
     
         10 . The gastroretentive drug formulation of  claim 11 , wherein the internal layer and first and second outer layers include a central region that is substantially free of ultrasonic welds. 
     
     
         11 . The gastroretentive drug formulation of  claim 12 , wherein the ultrasonic welds between the membrane and internal layer do not penetrate entirely through the internal layer. 
     
     
         12 . The gastroretentive drug formulation of  claim 11 , wherein the ultrasonic weld pattern between the membranes and internal layer is not continuous. 
     
     
         13 . The gastroretentive drug formulation of  claim 12 , wherein the ultrasonic welds on the periphery of the membranes form a skirt region that surrounds but does not capture the internal layer. 
     
     
         14 . The gastroretentive drug formulation of  claim 13 , wherein the internal layer and first and second outer layers include a central region that is substantially free of ultrasonic welds. 
     
     
         15 . The gastroretentive drug formulation of  claim 11 , wherein the ultrasonically welded internal layer and membranes have a mechanical strength, described with Young's modulus from about 0.05 to 0.4 Kgf/mm 2  after 1 hour in simulated gastric fluid. 
     
     
         16 . The gastroretentive drug formulation of  claim 15 , wherein the membrane and. internal layer unfold to a length of at least 20 mm within 15 minutes of being exposed to gastric fluid. 
     
     
         17 . The gastroretentive drug formulation of  claim 16 , wherein the length of the membrane in the planar orientation is at least 30 mm. 
     
     
         18 . A biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract, comprising:
 an internal layer comprising an active agent and a degradable hydrophilic polymer and a degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer, at least one membrane covering the internal layer, the membrane including at least one polymeric combination of a hydrophilic polymer and a polymer, insoluble in gastric media, and at least one plasticizer, the membrane swelling in the presence of gastric medium   one of the materials in each of the internal layer and membrane being capable of being ultrasonically welded together,   the membrane being directly secured to and covering both sides of the internal layer and having a predetermined length greater than 20 mm in a planar orientation, the membrane and internal layer being arranged in an accordion folded orientation sufficient to be placed within a capsule dissolvable within the stomach, the membrane permitting passage of gastric fluid from the stomach to the internal layer and permitting passage of gastric fluid and the active agent from the internal layer through the membrane to the stomach,   the membrane and internal layer develop sufficient mechanical force to unfold from the accordion folded orientation to a length of at least 20 mm within 30 minutes of being exposed to gastric fluid.   
     
     
         19 . The gastroretentive drug formulation of  claim 18 , wherein the enteric polymer in the internal layer is selected from the group consisting of cellulose acetate phthalate, hypromelose phthalate, hydroxy-propyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methylmethacrylate-methacrylic acid copolymers. 
     
     
         20 . The gastroretentive drug formulation of  claim 18 , wherein the polymeric combination in the outer membranes comprises gelatin. 
     
     
         21 . The gastroretentive drug formulation of  claim 18 , wherein the enteric polymer in the membrane is selected from the group consisting of one or more type of polymethacrylate USP. 
     
     
         22 . The gastroretentive drug formulation of  claim 18 , wherein the membranes comprise propylene glycol as a plasticizer. 
     
     
         23 . The gastroretentive drug formulation of  claim 22 , wherein the amount of gelatin in the membrane is an amount of between about 20% and about 45% of the total outer membrane composition. 
     
     
         24 . The gastroretentive drug formulation of  claim 18 , wherein the internal layer has a mechanical strength described with Young's modulus of from about 0.5 to about 15 Kgf/mm 2  find stress of from about 0.03 to about 0.6 Kgf/mm 2  after 1 hour in simulated gastric fluid. 
     
     
         25 . The gastroretentive drug formulation of  claim 18 , wherein the outer membrane swells at a rate faster than the inner membrane causing the accordion folded membrane and internal layer to unfold in gastric medium. 
     
     
         26 . The gastroretentive drug formulation, of  claim 25 , wherein the outer membrane that swells at a rate faster than the inner membrane thus causing the accordion folded membrane and internal layer to unfold in gastric medium is lightly affixed or attached to the said inner membrane to exert the force resulting in unfolding. 
     
     
         27 . The gastroretentive drug formulation of  claim 1 , wherein the gastroretentive drug formulation is fully degradable within 3 hours in simulated intestinal fluid. 
     
     
         28 . The gastroretentive drug formulation of  claim 1 , wherein the gastroretentive drug formulation provides gastric retention of an active agent for up to 24 hours under low or medium calorie diet to humans. 
     
     
         29 . The gastroretentive drug formulation of  claim 1 , wherein the active agent is a drug for the local treatment of the gastrointestinal tract, such as drugs for the treatment of local infections, obesity and GI pathologies. 
     
     
         30 . The gastroretentive drug formulation of  claim 1 , wherein at least one additional layer is affixed to the outer membrane on one or two sides of the gastroretentive drug formulation, and where this layer comprises a drug or a combination of drugs, together with one or more additives selected from the group consisting of water soluble polymers, a plasticizer, a solubilizing agent intended for immediate release of the drug in the stomach, a disintegrant and a glidant. 
     
     
         31 . The gastroretentive drug formulation of  claim 29 , wherein the active agent comprises a drug selected from the group consisting of levodopa and carbidopa. 
     
     
         32 . The gastroretentive drug formulation of  claim 31 , where the formulation contains 250 mg of levodopa and 50 mg of carbidopa. 
     
     
         33 . The gastroretentive drug formulation of  claim 32 , wherein 70 mg of the levodopa and 25 mg carbidopa are formulated as an immediate release component, whereas the rest of the carbidopa and the levodopa are released in a controlled manner over 8-10 hours. 
     
     
         34 . The gastroretentive drug formulation of  claim 31 , where the formulation contains 375 mg of levodopa and 50 mg of carbidopa. 
     
     
         35 . The gastroretentive drug formulation of  claim 34 , wherein 100 mg of the levodopa and 25 mg carbidopa are formulated as ail immediate release component, and wherein the rest of the carbidopa and the levodopa are released in a controlled manner over 8-10 hours. 
     
     
         36 . The gastroretentive drug formulation of  claim 1 , wherein the inner compartment comprises one layer intended as backbone to increase the mechanical strength of the formulation, and to this layer are attached on one or two sides additional layer or layers containing the active ingredient or ingredients and an inactive ingredient and intended for the controlled release of the drug and wherein these layers are covered by and contained between two layers of outer membrane as described previously in these claims. 
     
     
         37 . A biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract, comprising:
 an internal layer comprising an active agent and a degradable hydrophilic polymer which is not instantly soluble in gastric fluid and a degradable enteric polymer which is substantially insoluble at pH less than 5.5, and a plasticizer, the internal layer including a first side and an opposing second side,   a first and second membrane covering the internal layer, the membranes including at least one polymeric combination of a hydratable swelling polymer and an enteric polymer, and at least one plasticizer, the membrane swelling in the presence of gastric fluid,   one of the materials in each of the internal layer and membranes being capable of being ultrasonically welded together,   the membranes being directly secured to and covering both sides of the internal, layer and having a predetermined length, greater than 20 mm in a planar orientation, the membranes and internal layer being arranged in an accordion folded orientation sufficient to be placed within a capsule dissolvable within the stomach,   the membranes and internal layer developing sufficient mechanical force to unfold from the accordion folded orientation to a length of at least 20 mm within 30 minutes of being exposed to gastric fluid,   the first and second membranes having a width and length greater than a width and length of the internal layer,   the first and second membranes being ultrasonically welded directly together about the periphery of the first and second membranes, the first membrane being ultrasonically welded to a first side of the internal layer, the second membrane being ultrasonically welded to the second side of the internal layer, the membrane permitting passage of gastric fluid from the stomach to the internal layer and permitting passage of gastric fluid and the active agent from the internal layer through the membrane to the stomach,   the internal layer and first and second membranes having a predetermined length greater than 20 mm in a planar orientation, the membrane and internal layer being arranged in an accordion folded orientation sufficient to be placed within a capsule dissolvable within the stomach,   the ultrasonic welds having sufficient mechanical strength to remain intact upon being exposed to gastric medium.   
     
     
         38 . A gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract comprising:
 i.) an internal layer or compartment comprising an active agent, and one or more pharmaceutical excipients, of which at least one is a polymer;   i.i.) two membranes forming together an envelope around the inner membrane, each membrane comprising at least one polymeric combination of an hydrophilic polymer and a polymer, insoluble in gastric media, and at least one plasticizer; and   iii.) optionally an additional layer covering each outer membrane comprising a powder or a film that prevents adherence of the outer membrane onto itself when folded inside the capsule.   
     
     
         39 . The gastroretentive drug formulation of  claim 38  further including one or two layers comprising the active agent and a soluble polymer that provides for the immediate release of the active agent and being attached to the outside of one outer membrane or two outer membranes or part of the outer membrane. 
     
     
         40 . The gastroretentive drug formulation of  claim 38  wherein, the internal layer and membranes effectively unfold from an accordion folded orientation and are stable in acidic pH for up to 24 hours and completely biodegrade after 3 hours in simulated intestinal fluid. 
     
     
         41 . The gastroretentive drug formulation of  claim 39 , wherein,, the polymer in the internal layer is selected from the group consisting of a degradable hydrophilic polymer which is not instantly soluble in gastric fluid and a degradable enteric polymer which is substantially insoluble at pH less than 5.5. 
     
     
         42 . The gastroretentive drug formulation of  claim 41 , wherein the enteric polymer in the internal layer is polymethacrylate copolymer. 
     
     
         43 . The gastroretentive drug formulation of  claim 41 , wherein the enteric polymer is at least one of cellulose acetate phthalate, hypromelose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate or cellulose acetate trimellitate. 
     
     
         44 . The gastroretentive drug formulation of  claim 38 , wherein the active agent and the polymer are uniformly distributed in the internal layer. 
     
     
         45 . The gastroretentive drug formulation of  claim 38 , wherein the polymeric combination in the outer membranes comprises gelatin and cellulose acetate succinate. 
     
     
         46 . The gastroretentive drug formulation of  claim 38 , wherein the enteric polymer in the membranes is polymethacrylate copolymer USP type A. 
     
     
         47 . The gastroretentive drug formulation of  claim 38 , wherein the enteric polymer in the membranes is polymethacrylate copolymer USP type C. 
     
     
         48 . The gastroretentive drug formulation of  claim 38 , wherein, the plasticizer in the outer membranes is propylene glycol. 
     
     
         49 . The gastroretentive drug formulation of  claim 38 , wherein the internal layer or compartment, the membranes and the optional additional layers or the immediate release layers are joined by applying ultrasonic welding. 
     
     
         50 . The gastroretentive drug formulation of  claim 38 , wherein, the internal layer provides at least 50% of the mechanical strength of the welded internal layer and membranes when wetted with gastric medium. 
     
     
         51 . The gastroretentive drug formulation of  claim 38 , wherein the GRDF reaches its eventual maximum strength within less than two hours in simulated gastric fluid. 
     
     
         52 . The gastroretentive drug formulation of  claim 38 , wherein, the internal layer has a planar-accordion geometry that unfolds to at least 50% of its original length within 30 minutes in simulated gastric fluid. 
     
     
         53 . The gastroretentive drug formulation of  claim 38 , wherein the internal layer and membranes are fully degradable within 3 hours in simulated intestinal fluid. 
     
     
         54 . The gastroretentive drug formulation of  claim 38 , wherein the GRDF comprises an internal layer that provides gastric retention for up to 24 hours under low or medium calorie diet. 
     
     
         55 . The gastroretentive drug formulation of  claim 38  is designed for oral administration and are compacted or folded into a standard size capsule which is easily swallowed. 
     
     
         56 . The gastroretentive drug formulation of  claim 38 , wherein the active ingredient or ingredients are incorporated in the internal layer as one or more of solid solutions, powders, grains, spheres, particles, microparticles, nanoparticles, multiparticulates, or microcapsules. 
     
     
         57 . The gastroretentive drug formulation of  claim 38 , wherein the active agent has a narrow window of absorption in the gastrointestinal tract, the active agent being one or more of a therapeutic nucleic acid sequence, a therapeutic protein or peptide, a peptidomimetic drug, a nucleoside analogue, an aminoacid analogue, an antibiotic, a therapeutic ion, a vitamin, a bronchodilator, an anti-gout agent, an anti-hypertensive agent, a diuretic agent, an anti-hyperlipidemic agent, an ACE inhibitor, a CNS active agent, an anti-tumor agent, an histamine (H2) blocker, a bismuth salt or a synthetic prostaglandin. 
     
     
         58 . The gastroretentive drug formulation of  claim 57 , wherein the active agent is levodopa. 
     
     
         59 . The gastroretentive drug formulation of  claim 57 , wherein the active agent is a drug for the local treatment in the gastrointestinal tract, or for the treatment of local infections, gastrointestinal diseases and symptoms, metabolic disorders, local cancers or cancer-related diseases.