Baclofen and r-baclofen gastroretentive drug delivery systems

Abstract

A biodegradable, multi-layered controlled release gastroretentive baclofen or R-baclofen dosage form which is optionally divided into a first dosage of baclofen or R-baclofen for immediate release and a second dosage of baclofen or R-baclofen for controlled release in the stomach and gastrointestinal tract of a patient, folded into a capsule which disintegrates upon contact with gastric juice and the dosage form unfolds rapidly upon contact with gastric juice. The biodegradable, multi-layered gastroretentive dosage forms of the invention provide fast onset of baclofen or R-baclofen activity with prolonged absorption and minimal undesirable side effects.

1 . A biodegradable multi-layered baclofen or R-baclofen gastroretentive dosage form comprising a first dosage of baclofen or R-baclofen for controlled release and optionally a second dosage of baclofen or R-baclofen for immediate release in the stomach and gastrointestinal tract of a subject, wherein the gastroretentive dosage form is compacted or folded into a capsule which disintegrates rapidly upon contact with gastric juice, and wherein the gastroretentive dosage form, upon disintegration of the capsule, unfolds rapidly upon contact with the gastric juice. 
     
     
         2 . The biodegradable, multi-layered baclofen or R-baclofen gastroretentive dosage form of  claim 1 , wherein the dosage form is designed for oral administration and compacted or folded into a standard size capsule which is easily swallowed. 
     
     
         3 . The biodegradable, multi-layered baclofen or R-baclofen gastroretentive dosage form of  claim 1 , comprising:
 a. a first dosage of baclofen or R-baclofen for controlled release in an inner layer;   b. a rigid frame layer; and   c. one or two outer layers;   wherein the inner layer, frame layer and one or two outer layers are compacted or folded into a capsule and the capsule is optionally coated with at least one coating comprising a second dosage of baclofen or R-baclofen for immediate release.   
     
     
         4 . The biodegradable, multi-layered baclofen or R-baclofen gastroretentive dosage form of  claim 1 , comprising:
 a. a rigid inner layer comprising a first dosage of baclofen or R-baclofen for controlled release; and   b. one or two outer layers;   wherein the inner layer and the one or two outer layers are compacted or folded into the capsule and wherein the capsule is optionally coated with at least one layer comprising a second dosage of baclofen or R-baclofen for immediate release.   
     
     
         5 . The biodegradable, multi-layered gastroretentive dosage form of  claim 1 , wherein the gastroretentive dosage form comprises a dose of from about 20 to about 120 mg of baclofen or R-baclofen, optionally divided into a first dosage for controlled release between about 15 and about 90 mg of baclofen or R-baclofen, and a second dosage for immediate-release between about 5 and about 30 mg of baclofen or R-baclofen. 
     
     
         6 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3  or  4 , wherein the gastroretentive dosage form has two outer layers. 
     
     
         7 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the gastroretentive dosage form comprises two outer layers, a rigid frame layer and an inner layer containing baclofen or R-baclofen for controlled release, and wherein the capsule is coated with a coating comprising baclofen or R-baclofen for immediate release. 
     
     
         8 . The biodegradable, multi-layered gastroretentive dosage form of  claim 4 , wherein the gastroretentive dosage form comprises two outer layers and a rigid inner layer containing baclofen or R-baclofen for controlled release, and wherein the capsule is coated with a coating comprising baclofen or R-baclofen for immediate release. 
     
     
         9 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3  or  4 , wherein the gastroretentive dosage form comprises a dose of 40 mg of baclofen or R-baclofen, divided into a dose of 10 mg of baclofen or R-baclofen in the coating of the capsule for immediate release, and a dose of 30 mg in the inner layer for controlled-release of baclofen or R-baclofen. 
     
     
         10 . The biodegradable, multi-layered controlled release gastroretentive dosage form of  claim 1 , wherein the gastroretentive dosage form provides a baclofen or R-baclofen gastric retention period greater than 6 hours. 
     
     
         11 . The biodegradable, multi-layered controlled release gastroretentive dosage form of  claim 1 , wherein the gastroretentive dosage form provides a baclofen or R-baclofen gastric retention period of up to 24 hours. 
     
     
         12 . The biodegradable, multi-layered controlled release gastroretentive dosage form of  claim 1 , wherein the active is baclofen or R-baclofen and wherein the gastroretentive dosage form provides a R-baclofen gastric retention period between 8 and 14 hours. 
     
     
         13 . The biodegradable, multi-layered controlled release gastroretentive dosage form of  claim 1 , wherein the active is baclofen and wherein one administration of a 40 mg GRDF provides baclofen plasma levels of 50-175 ng/ml for 12-20 hours. 
     
     
         14 . A method for providing a therapeutic blood plasma concentration of baclofen or R-baclofen over a period of up to 24 hours resulting in improved therapeutic activity which comprises orally administering to a subject in need thereof a baclofen or R-baclofen biodegradable, multilayered gastroretentive dosage form, wherein the gastroretentive dosage form provides a therapeutically effective blood plasma level of baclofen or R-baclofen from about half an hour to about 24 hours after administration. 
     
     
         15 . A method for reducing sharp peaks in the therapeutic blood plasma concentration of baclofen or R-baclofen after administration of baclofen or R-baclofen to a subject in need thereof over a period of up to 24 hours and improving therapeutic activity, which comprises orally administering to the subject a baclofen or R-baclofen biodegradable, multilayered gastroretentive dosage form. 
     
     
         16 . A method for reducing fluctuations in the therapeutic blood plasma concentration of baclofen after administration of baclofen or R-baclofen to a subject in need thereof over a period of up to 24 hours, improving baclofen or R-baclofen therapeutic activity and reducing baclofen side-effects in comparison to side effects produced by immediate release administration of an equivalent dose of baclofen or R-baclofen comprising orally administering to the subject a baclofen or R-baclofen biodegradable multilayered gastroretentive dosage form. 
     
     
         17 . A method for treating a disease selected from the group consisting of spasticity, spastic diplegia, multiple sclerosis, amyotrophic lateral sclerosis and trigeminal and glossopharyngeal neuralgias in a subject in need thereof, comprising orally administering one or more baclofen or R-baclofen gastroretentive dosage forms of  claim 1  per day. 
     
     
         18 . A kit comprising a number of baclofen or R-baclofen gastroretentive dosage forms of  claim 1  and instructions and precautions for their use. 
     
     
         19 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the outer layers are hydratable at a rate greater than the frame layer, and comprise at least one polymeric combination of a hydrophilic polymer and a polymer insoluble in gastric media. 
     
     
         20 . The biodegradable, multi-layered gastroretentive dosage form of  claim 19 , wherein the polymer insoluble in gastric media is selected from the group consisting of one or more types of polymethacrylate USP. 
     
     
         21 . The biodegradable, multi-layered gastroretentive dosage form of  claim 19 , wherein the outer layers comprise propylene glycol as a plasticizer. 
     
     
         22 . The biodegradable, multi-layered gastroretentive dosage form of  claim 19 , wherein the polymeric combination in the outer layers comprises gelatin. 
     
     
         23 . The biodegradable, multi-layered gastroretentive dosage form of  claim 22 , wherein the amount of gelatin in the outer layers is between about 20% and about 45% of the total outer layer composition. 
     
     
         24 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the rigid frame layer comprises an enteric polymer selected from the group consisting of cellulose acetate phthalate, hypromelose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methylmethacrylate-methacrylic acid copolymers. 
     
     
         25 . The biodegradable, multi-layered gastroretentive dosage form of  claim 4 , wherein the inner layer comprises an enteric polymer selected from the group consisting of cellulose acetate phthalate, hypromelose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methylmethacrylate-methacrylic acid copolymers. 
     
     
         26 . The biodegradable, multi-layered gastroretentive dosage form of  claim 24 , wherein the polymer in the rigid frame layer is polymethacrylate copolymer. 
     
     
         27 . The biodegradable, multi-layered gastroretentive dosage form of  claim 24 , wherein the rigid frame layer has a mechanical strength described with Young's modulus ranging from about 0.5 to about 15 Kgf/mm 2  and stress of about 0.03 to about 0.6 Kgf/mm 2  after 1 hour in simulated gastric fluid. 
     
     
         28 . The biodegradable, multi-layered gastroretentive dosage form of  claim 24 , wherein the frame layer optionally further comprises a filler, a surface-active agent, an additional plasticizer and other suitable materials. 
     
     
         29 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the inner layer comprises baclofen or R-baclofen and at least one polymer, wherein baclofen or R-baclofen is substantially uniformly dispersed in the polymer or forms a solid solution therewith and wherein baclofen or R-baclofen is released from the inner layer upon contact of the gastroretentive dosage form with gastric medium. 
     
     
         30 . The gastroretentive dosage form of  claim 29 , wherein the at least one polymer is chosen from hydrogels and polymer compositions permeable to water. 
     
     
         31 . The biodegradable, multi-layered gastroretentive dosage form of  claim 29 , wherein the at least one polymer optionally further comprises a plasticizer. 
     
     
         32 . The biodegradable, multi-layered gastroretentive dosage form of  claim 30 , wherein the hydrogels are chosen from the group consisting of carboxymethyl cellulose, including sodium salt, alginic acid, including sodium salt, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromelose, a gum, including guar gum, xanthan gum and others, a protein, including albumin, casein, gelatin or collagen, and a cross-linked polyacrylic acid. 
     
     
         33 . The biodegradable, multi-layered gastroretentive dosage form of  claim 30 , wherein the polymer compositions permeable to water are selected from the group consisting of a polymer, selected from zein, suitably plasticized ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, an enteric polymer and combinations thereof. 
     
     
         34 . The biodegradable, multi-layered gastroretentive dosage form of  claim 30 , wherein the polymer compositions permeable to water comprise a mixture of polymers comprising at least one component soluble in water and at least one component insoluble in water, and wherein the mixture of polymers is selected from the group consisting of a mixture of polyvinyl acetate and polyvinyl pyrrolidone, a mixture of ethyl cellulose and polyethylene glycol and similar combinations. 
     
     
         35 . The biodegradable, multi-layered gastroretentive dosage form of  claim 30 , wherein the at least one polymer is chosen from polyvinyl alcohols and polyethylene oxides. 
     
     
         36 . The biodegradable, multi-layered gastroretentive dosage form of  claim 30 , wherein the polymer compositions further comprise buffering agents selected from acidifying agents selected from citric acid, tartaric acid, sorbic acid, fumaric acid, hydrochloric acid and sulfuric acid, and alkalizing agents selected from divalent cations hydroxides, oxides, and their salts, wherein said divalent cations include but are not limited to calcium, magnesium and zinc, and their salts are selected from but not limited to carbonates, sulfates and stearates. 
     
     
         37 . The biodegradable, multi-layered gastroretentive dosage form of  claim 29 , wherein the inner layer optionally further comprises a filler, a surface-active agent and/or other inactive ingredients. 
     
     
         38 . The gastroretentive dosage form of  claim 3 , wherein baclofen or R-baclofen is released upon contact with gastric media and wherein the release profile is substantially insensitive to changes of the environment of release in pH ranges selected from the group consisting of between about 1.2 and about 5.5, between about 1.2 and about 5.0 and between about 1.2 and about 4.1. 
     
     
         39 . The biodegradable, multi-layered gastroretentive dosage form of  claim 1 , wherein baclofen or R-baclofen is released upon contact with gastric media and wherein the release profile is substantially insensitive to changes of the environment of release in the presence of ethyl alcohol in an amount selected from the group consisting of from about 0% to about 30%, from about 0% and about 25% and from about 0% and equal or below 20% v/v. 
     
     
         40 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the inner layer comprises baclofen or R-baclofen in a form selected from the group consisting of a powder, granulated powder, miniature tablets, coated powder, semisolid composition and combinations thereof. 
     
     
         41 . The biodegradable, multi-layered gastroretentive dosage form of  claim 4 , wherein the inner layer comprises baclofen or R-baclofen in a form selected from the group consisting of a powder, granulated powder, miniature tablets, coated powder, and combinations thereof. 
     
     
         42 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the coating on the capsule comprises at least one layer. 
     
     
         43 . The biodegradable, multi-layered gastroretentive dosage form of  claim 42 , wherein the coating comprises at least one polymer which is instantly soluble in gastric medium. 
     
     
         44 . The biodegradable, multi-layered gastroretentive dosage form of  claim 42 , wherein baclofen is uniformly dispersed or dissolved in the coating. 
     
     
         45 . The biodegradable, multi-layered gastroretentive dosage form of  claim 42 , wherein the coating further comprises a plasticizer or a combination of plasticizers. 
     
     
         46 . The biodegradable, multi-layered gastroretentive dosage form of  claim 42 , wherein the coating further optionally comprises at least one anti-tacking agent. 
     
     
         47 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the inner layer, rigid frame layer and one or two outer layers are joined together with ultrasonic welding. 
     
     
         48 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the folded multi-layered gastroretentive dosage form unfolds to a length of at least 20 mm within 15 minutes of being exposed to gastric fluid. 
     
     
         49 . The biodegradable, multi-layered gastroretentive dosage form of  claim 3 , wherein the gastroretentive drug formulation is fully degradable within 3 hours in simulated intestinal fluid. 
     
     
         50 . A method for treating a disease selected from the group consisting of spasticity, spastic diplegia, multiple sclerosis, amyotrophic lateral sclerosis and trigeminal and glossopharyngeal neuralgias in a subject in need thereof, comprising orally administering to the subject one or more baclofen or R-baclofen gastroretentive dosage forms of  claim 3  per day. 
     
     
         51 . A method for treating a disease treatable with baclofen or R-baclofen in a subject in need thereof, comprising orally administering to the subject one or more baclofen or R-baclofen gastroretentive dosage forms of  claim 1  per day. 
     
     
         52 . A method for treating a disease selected from the group consisting of spasticity, spastic diplegia, alcoholism, alcohol addiction, dependance or alcohol abuse, gastro-esophageal reflux disease (GERD), emesis, cough, narcotic addiction or abuse, nicotine addiction or abuse, neuropathic pain and musculoskeletal pain, nocturnal acid breakthrough, chronic hiccups, dyspepsia, gastric motility disorder, migraine, PTSD (Post-traumatic Stress Disorder), depression, anxiety, lower urinary tract dysfunction, multiple sclerosis, amyotrophic lateral sclerosis and trigeminal and glossopharyngeal neuralgias in a subject in need thereof, comprising orally administering to the subject one or more baclofen or R-baclofen gastroretentive dosage forms of  claim 3  or  4 . 
     
     
         53 . A method for treating an alcohol or abuse drug addiction in a subject in need thereof, comprising orally administering to the subject one or more baclofen or R-baclofen gastroretentive dosage forms of  claim 1 . 
     
     
         54 . A method for treating gastroesophageal reflux disease in a subject in need thereof, comprising orally administering to the subject one or more baclofen or R-baclofen gastroretentive dosage forms of  claim 1 . 
     
     
         55 . A method for treating a disease selected from the group consisting of spasticity, spastic diplegia, alcoholism, alcohol addiction, depndance or abuse, gastro-esophageal reflux disease (GERD), emesis, cough, narcotic addiction or abuse, nicotine addiction or abuse, neuropathic pain and musculoskeletal pain, nocturnal acid breakthrough, chronic hiccups, dyspepsia, gastric motility disorder, migraine, PTSD (Post-traumatic Stress Disorder), depression, anxiety, lower urinary tract dysfunction, multiple sclerosis, amyotrophic lateral sclerosis and trigeminal and glossopharyngeal neuralgias. in a subject in need thereof, comprising orally administering to the subject one or more baclofen or R-baclofen gastroretentive dosage forms of  claim 1 . 
     
     
         56 . A method for treating a disease selected from the group consisting of gastro-esophageal reflux disease (GERD), cough, narcotic addiction or abuse, nicotine addiction or abuse, musculoskeletal pain, migraine, PTSD (Post-traumatic Stress Disorder), depression, anxiety, lower urinary tract dysfunction in a subject in need thereof, comprising orally administering to the subject one or more baclofen gastroretentive dosage forms. 
     
     
         57 . The biodegradable, multi-layered baclofen or R-baclofen gastroretentive dosage form of  claim 1 , wherein the gastroretentive dosage form is compacted or folded into a capsule and the second dosage for immediate release is formed by filling into the capsule a portion or a whole dose of baclofen or R-baclofen in the form of a powder, a granulated powder, a coated multi-particulate dosage form, a mini-tablet, or a combination of one or more thereof, and wherein the capsule is optionally coated with at least one layer comprising an additional dosage of baclofen or R-baclofen for immediate release. 
     
     
         58 . The biodegradable, multi-layered baclofen or R-baclofen gastroretentive dosage form of  claim 1 , wherein the gastroretentive dosage form is compacted or folded into a capsule and the second dosage for immediate release is formed by incorporating a portion or a whole dose of baclofen or R-baclofen into the capsule shell in the form of a powder, a granulated powder, a coated multi-particulate dosage form, or a combination of one or more thereof during the manufacturing process and wherein the capsule may be optionally coated with a pharmaceutical coating.