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.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] The present application is a continuation in part of PCT Application PCT/IB2009/007419, filed Oct. 19, 2009, which claims priority to U.S. Provisional Patent Application No. 61/120,051, filed Dec. 4, 2008.

FIELD OF THE INVENTION

[0002] The present invention relates to biodegradable gastroretentive drug formulations for the immediate release and sustained release of baclofen. The gastroretentive baclofen or R-baclofen formulations of the invention may be orally administered to a subject in need thereof for the treatment of spasticity, spastic diplegia, alcoholism, alcohol addiction or alcohol dependence and 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.

BACKGROUND OF THE INVENTION

[0003] Spasticity or muscular hypertonicity is a disorder of the central nervous system (CNS) in which muscles continually tighten and contract, causing stiffness or tightness of the muscles and affecting gait, movement and sometimes speech. Spasticity is characterized by an increased muscle tone, causing resistance to movement. This severe neurological disorder is caused by several diseases and conditions and may be found in most patients suffering from multiple sclerosis (MS), cerebral palsy (CP) and chronic spinal cord injuries. Stroke and traumatic brain injury (TBI) are another common cause of spasticity.

[0004] Spastic diplegia inhibits the proper development of upper motor neuron function, impacting the motor cortex, the basal ganglia and the cortico-spinal tract. The muscles constantly rigidly contract and become permanently hypertonic, creating difficulty with voluntary and passive movement, pain and deformities.

[0005] Multiple sclerosis is an autoimmune disease that affects the brain and spinal cord, causing loss of balance, numbness, pain, vision loss, and impairing brain functions.

[0006] Glossopharyngeal neuralgia is a condition in which there are repeated episodes of severe pain in the tongue, throat, ear and tonsils.

[0007] Since there is no known cure for these diseases, therapies focus on controlling the symptoms. Medicines that reduce muscle spasms include baclofen, tizanidine, and benzodiazepines. Baclofen is a GABA (gamma-amino butyric acid) derivative which is indicated for the treatment of spasticity, spastic diplegia, multiple sclerosis, amyotrophic lateral sclerosis and trigeminal and glossopharyngeal neuralgias, and is commercially available in the US under the trade name Lioresal.RTM. as 0.05, 0.5 and 2 mg/ml intrathecal injectable formulation, or as 10 and 20 mg tablets and oral disintegrating tablets (Kemstro.RTM.). Although baclofen has two known optical isomers, R-baclofen and S-baclofen, only the racemic baclofen is approved for therapeutic use.

[0008] Unfortunately, baclofen is associated with significant and frequent side effects. The most common are sedation (somnolence, drowsiness), weakness (asthenia, fatigue) and dizziness. These undesired side effects might be associated with its considerable fluctuation of blood levels. Moreover, the drug must be administered 3 or 4 times a day, which is a drawback.

[0009] Baclofen has also been shown to be effective for the treatment of alcohol and cocaine addiction in several human studies. However, its usage for these indications is very limited due to its current daily regimen of 3-4 times a day administration. This frequent dosing may result in very poor compliance among alcohol and cocaine abusers.

[0010] Baclofen and other GABA.sub..beta. receptor agonists may also be used as reflux inhibitors for the prevention and treatment of gastrooesophageal reflux disease (GERD), also named "acid reflux disease." However, the required frequent dosing and side effects of baclofen pose a problem and limit its usage.

[0011] Attempts to provide reduced daily treatment with baclofen have encountered two main hurdles: (1) baclofen has a short half life; and (2) the absorption of baclofen into the blood stream is mainly confined to the small intestines by a specialized transport mechanism, whereas its absorption in the colon is negligible (see "Evidence of a specialized transport mechanism for the intestinal absorption of baclofen," Merino et al. Drug Dispos. 10-3: (1989) 279-97). Therefore, typical extended release formulations of baclofen cannot provide a true long-acting baclofen. Once the dosage form has passed the small intestines the drug is poorly absorbed in the distal parts of the GI tract, regardless of its controlled release in the colon.

[0012] Accordingly, there is an urgent need in the art to develop formulations of baclofen with reduced daily dose regimen.

SUMMARY OF THE INVENTION

[0013] It is therefore an object of the invention to provide solutions to the aforementioned deficiencies in the art, enabling the administration of baclofen or R-baclofen with a reduced daily regimen, Another object of this invention is to provide a drug which may be administered fewer times a day, preferably once a day, to a patient in need thereof.

[0014] Further to this object, the invention provides a degradable multi-layered gastroretentive dosage form of baclofen or R-baclofen with a prolonged retention in the stomach and the gastrointestinal tract. In one aspect of the invention, the gastroretentive dosage form provides for the controlled release of baclofen or R-baclofen in the stomach and gastrointestinal tract of a patient. In a preferred aspect of the invention, the gastroretentive dosage form of baclofen or R-baclofen comprises a first dosage of baclofen or R-baclofen for immediate release and a second dosage of baclofen or R-baclofen for controlled release, and the gastroretentive dosage form of baclofen or R-baclofen is compacted or folded into a capsule which is easily swallowed and disintegrates rapidly upon contact with gastric juice. Once the capsule disintegrates, the gastroretentive dosage form of baclofen or R-baclofen unfolds rapidly upon contact with the gastric juice. In an even more preferred aspect of the invention, the gastroretentive dosage form of baclofen or R-baclofen is compacted or folded into a capsule, wherein said gastroretentive dosage form comprises an internal layer comprising a first dosage of baclofen or R-baclofen for controlled release; a rigid frame layer; and one or two outer layers; and the capsule is coated with at least one layer comprising a second dosage of baclofen or R-baclofen for immediate release. In another preferred aspect of the invention, the gastroretentive dosage form of baclofen or R-baclofen comprises an internal layer comprising a first dosage of baclofen or R-baclofen for controlled release and one or two outer layers, and is compacted or folded into a capsule coated with at least one layer comprising a second dosage of baclofen or R-baclofen for immediate release. The capsule disintegrates rapidly upon contact with gastric juice, and the gastroretentive dosage form unfolds rapidly upon contact with the gastric juice. In another preferred embodiment, the gastroretentive dosage form of baclofen or R-baclofen comprises a rigid internal layer comprising a first dosage of baclofen or R-baclofen for controlled release and two outer layers, and is compacted or folded into a capsule coated with at least one layer comprising a second dosage of baclofen for immediate release.

[0015] In one embodiment, the gastroretentive dosage form comprises a dose from about 20 to about 120 mg of baclofen, or R-baclofen divided into a first dosage for immediate release between about 5 and about 30 mg of baclofen or R-baclofen, and a second dosage for controlled-release between about 15 and about 90 mg of baclofen or R-baclofen. In a preferred embodiment, the gastroretentive dosage form comprises a baclofen or R-baclofen dose of 40 mg, divided into a dose of 10 mg in the coating of the capsule for immediate release, and a dose of 30 mg in the inner layer for controlled-release of baclofen.

[0016] In one embodiment, the outer layers in the gastroretentive dosage form of baclofen or R-baclofen 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. In a preferred embodiment, the polymer insoluble in gastric media comprises one or more types of polymethacrylate USP.

[0017] In another preferred embodiment, the outer layers comprise propylene glycol as a plasticizer. In yet another preferred embodiment, the polymeric combination in the outer layers comprises gelatin, and the amount of gelatin is between about 20% and about 45% of the total outer layer composition.

[0018] In an additional aspect of the invention, the polymer in the frame layer of the gastroretentive dosage form of baclofen or R-baclofen is 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. In an even more preferred embodiment, the polymer in the frame layer is a polymethacrylate copolymer.

[0019] In one embodiment, the frame layer has a mechanical strength described with Young's modulus ranging from about 0.5 to about 15 Kgf/mm.sup.2 and a stress of about 0.03 to about 0.6 Kgf/mm.sup.2 after 1 hour in simulated gastric fluid.

[0020] In a further aspect of the invention, the composition of the frame layer optionally further comprises a filler, a surface-active agent, an additional plasticizer and other suitable materials.

[0021] In one embodiment, the inner layer in the gastroretentive dosage form of baclofen or R-baclofen comprises baclofen and at least one polymer or a combination of polymers. The baclofen or R-baclofen may be substantially uniformly dispersed in the polymer(s) or may form a solid solution therewith, such that the baclofen or R-baclofen is released from the inner layer upon contact of the gastroretentive dosage with the gastric medium. In one embodiment, the polymer in the inner layer is a hydrogel or a polymer composition permeable to water. In a preferred embodiment, the hydrogel is 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. In another preferred embodiment, the polymer composition that is permeable to water is chosen from the group consisting of a single polymer selected from zein, suitably plasticized ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, an enteric polymer and combinations thereof. In a further preferred embodiment, the polymer composition permeable to water comprises a mixture of polymers comprising at least one component soluble in water and at least one component insoluble in water. In yet another preferred embodiment, 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 other similar combinations. In another preferred embodiment, the polymer in the internal layer is chosen from polyvinyl alcohols and polyethylene oxides. In a further aspect of the invention, the polymer composition further comprises 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 may be selected from carbonates, sulfates and stearates, or other similar salts known to one of skill in the art.

[0022] In yet another embodiment, the inner layer composition optionally further comprises a filler, a surface-active agent, and/or other inactive agents.

[0023] In one aspect of the invention, the inner layer comprises baclofen or R-baclofen in the form of a powder, granulated powder, miniature tablets, coated powder, semisolid composition or any other form known to those skilled in the art.

[0024] In one aspect of the invention, a coating comprising at least one layer comprising baclofen is applied onto the capsule of the gastroretentive dosage form. In one embodiment, the coating comprises at least one polymer, which is preferably instantly soluble in the gastric medium. In an additional embodiment, baclofen or R-baclofen is uniformly dispersed or dissolved in the coating. In a further embodiment, the coating further comprises a plasticizer or a combination of plasticizers. In yet another embodiment, the coating further optionally comprises at least one anti-tacking agent.

[0025] In one aspect of the invention, the layers in the gastroretentive dosage form of baclofen or R-baclofen are joined together with ultrasonic welding.

[0026] In another aspect of the invention, the folded multi-layered gastroretentive dosage form of baclofen or R-baclofen unfolds to a length of at least 20 mm within 15 minutes of being exposed to gastric fluid.

[0027] In a further aspect of the invention, the gastroretentive drug formulation of baclofen or R-baclofen is fully degradable within 3 hours in simulated intestinal fluid.

[0028] In a preferred embodiment, the gastroretentive dosage form of baclofen or R-baclofen releases baclofen or R-baclofen upon contact with gastric media and 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. In another preferred embodiment, the multi-layered gastroretentive dosage form releases baclofen or R-baclofen upon contact with gastric media and 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.

[0029] In one embodiment, the controlled release gastroretentive dosage form of baclofen or R-baclofen provides a gastric retention period greater than 6 hours. In a preferred embodiment, the controlled release gastroretentive dosage form of baclofen or R-baclofen provides a gastric retention period of up to 24 hours.

[0030] In a further aspect, the invention provides a method for administering baclofen or R-baclofen and maintaining a therapeutically effective blood plasma concentration of baclofen or R-baclofen over a period of up to 24 hours comprising orally administering to a subject in need thereof a multilayered gastroretentive dosage form of baclofen or R-baclofen. In one aspect of the invention, the method provides a therapeutically effective blood plasma level of baclofen or R-baclofen from about half an hour to about 24 hours after administration.

[0031] In another aspect, the invention provides a method for reducing sharp peaks in the 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 can improve therapeutic activity, which comprises orally administering to a subject in need thereof a multilayered gastroretentive dosage form of baclofen or R-baclofen.

[0032] In yet another embodiment, the invention provides a method for reducing fluctuations in the 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, potentially improving baclofen or R-baclofen therapeutic activity and reducing baclofen or R-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.

[0033] In another aspect, the invention provides 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 per day.

[0034] In a different aspect, the invention provides a kit comprising a number of gastroretentive dosage forms of baclofen or R-baclofen and instructions and precautions for their use.

[0035] In one aspect, the invention provides 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 per day.

[0036] In another aspect, the invention provides 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.

[0037] In yet another aspect, the invention provides 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.

[0038] In a further aspect, the invention provides a method for treating a disease selected from the group consisting of spasticity, spastic diplegia, alcoholism, alcohol addiction, dependence 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.

[0039] The foregoing general description and following brief description of the drawings and the detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG. 1 shows a schematic drawing of the film components of a Baclofen or R-baclofen GRDF and their approximate dimensions.

[0041] FIG. 2 shows the dissolution profile of a 40 mg baclofen GRDF-A

[0042] FIG. 3 provides the dissolution profile of a 40 mg baclofen GRDF-B.

[0043] FIG. 4 depicts the mean plasma concentrations of baclofen for single dose 40 mg Baclofen GRDF A, single dose 40 mg Baclofen GRDF B and single dose 40 mg (4.times.10 mg) Lioresal.RTM. as described in Example 5.

[0044] FIG. 5 provides the dissolution profile of 40 mg Baclofen GRDF-C, a combination of 10 mg immediate release and 30 mg controlled release.

[0045] FIG. 6 provides the pharmaco-kinetics of baclofen GRDF formulation of 40 mg baclofen (10IR/30CR) vs. 10 mg Lioresal in two food protocols

DETAILED DESCRIPTION OF THE INVENTION

[0046] Because of the undesirable side effects and the inconvenient mode of administration of the baclofen commercial product (3-4 times a day), there is a great need for an effective controlled release formulation of baclofen or R-baclofen that can provide steady therapeutic levels. The baclofen or R-baclofen gastroretentive dosage forms of this invention are designed to release baclofen or R-baclofen by a combination of immediate and controlled release mechanisms to provide quick onset and steady therapeutic level of baclofen or R-baclofen over time. Accordingly, the invention provides for the first time successful gastroretentive formulations of baclofen or R-baclofen that can be taken under a regular calorie diet.

[0047] Due to the design flexibility afforded by the complex structure of the gastroretentive dosage forms (GRDFs) of this invention, the GRDFs can conveniently release baclofen or R-baclofen in a sustained profile or in a combined immediate and sustained profile over a prolonged period, while maintaining relevant drug plasma levels for extended time intervals.

DEFINITIONS

[0048] As used herein, "Gastroretentive dosage form(s)" (GRDF or GRDFs in the plural) refers to dosage forms with delayed gastric emptying or longer retention in the stomach as compared to food. The GRDFs of this invention are also named "Accordion Pills" or "AP". "Gastroretentive" or "gastric-retentive" dosage forms denote dosage forms comprising multilayer structures including an inner layer, a rigid frame layer and one or two outer layers, or comprising an inner layer, a rigid frame layer, one or two outer layers and one or two supra-outer layers, or comprising the foregoing structures folded or compacted into a capsule. The capsule disintegrates rapidly upon contact with gastric fluid and the structures unfold rapidly upon contact with gastric juice and reside in the stomach of a mammal, preferably a human, for prolonged periods of time, preferably longer than food and small indigestible particles of size below 10 mm in either dimension. "Gastric retention" is therefore the maintenance or withholding of a drug in stomach, for a time period longer than the time it would have been retained in the stomach when delivered in a free form or within a gastro-intestinal (GI) delivery vehicle which is not considered gastroretentive. Gastroretentivity may be characterized by retention in the stomach for a period that is longer than the normal emptying time from the stomach, i.e. longer than about 2 hours, particularly longer than about 3 hours and usually more than about 4, 6, 8 or 10 hours. Gastroretentivity typically means retention in the stomach from about 3, 4, 6, 8, 10, 15, 18 hours and up to about 24 hours.

[0049] In the context of this invention, "baclofen" means racemic baclofen, and the isolated optical isomers of baclofen are designated "R-baclofen" and "S-baclofen". R-baclofen is (R)-4-amino-3-(4-chlorophenyl)butanoic acid, in the free base or salt form. One of the possible salts is the hydrochloride salt.

[0050] R-baclofen in the context of this invention means R-baclofen of substantial optical purity, from 80% to 99.99% optical purity. "Controlled-release drug delivery system" or "CR" as used herein denotes a dosage form of baclofen, or R-baclofen which releases baclofen or R-baclofen in a controlled manner over designable time intervals at needed quantities to produce a prolonged, sustained or delayed pharmacological effect that is otherwise unattainable through conventional non-modified-release dosage forms.

[0051] "Immediate-release drug delivery system" or "instant release" or "IR" as used herein denotes a dosage form of baclofen or R-baclofen which releases most of the baclofen or R-baclofen in a quick or instantaneous way, such as during the first half hour or hour after administration.

[0052] "Simulated gastric fluid" (SGF) and "Simulated intestinal fluid" (SIF) as used herein refers to "Gastric fluid, Simulated, TS" and "Intestinal fluid, Simulated, TS" solutions as defined by the United States Pharmacopeia 30 National Formulary, without enzymes.

[0053] "Gastric medium" and "Intestinal medium" as used herein denote a biological medium of the stomach and intestines, respectively, or an artificial medium, used to mimic the environment of the stomach or intestines.

[0054] The term "biodegradable" as used herein is intended as capable of being chemically and/or physically reduced or broken down in the body of a patient and within a relevant time period.

[0055] The phrase "polymer which is not instantly soluble in gastric fluid" as used herein refers to a polymer that will gradually dissolve in the GI tract during its residence therein.

[0056] The terms "inert" or "inactive" or "inactive ingredient" as used herein refer to components in the internal layer or compartment, outer membranes, optional layers and/or the immediate release layers that do not react with the active ingredient or affect its properties, or cause any biological effect upon administration to a subject.

[0057] The phrase "prolonged period" as used herein intends a period of delivery of at least 80% of the dose that lasts for several hours to about 24 hours.

[0058] The terms "swellable" and "swelling" mean, with respect to a polymer, that the polymer is capable of imbibing fluid and expanding when in contact with fluid present in the environment of use.

[0059] A "patient" or "subject" as referenced herein is an animal who may receive the gastroretentive drug formulations of the present invention. In a preferred aspect of the invention, the "patient" or "subject" is a human or non-human mammal.

[0060] "Treating" or "treatment," and the like are used herein to refer to obtaining a desired pharmacological and physiological effect. The effect may be prophylactic for preventing or partially preventing a disease, symptom or pathological condition and/or may be therapeutic for a partial or complete cure of a disease, condition, symptom or adverse effect attributed to a pathological condition. Thus, "treatment" covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing a pathological condition from occurring in an individual which may be predisposed to develop a pathological condition but has not yet been diagnosed as having it, i.e., causing the clinical symptoms of a pathological condition not to develop in a subject that may be predisposed to develop the condition but does not yet experience or display symptoms of the condition; (b) inhibiting, i.e., arresting or reducing the development of the pathological condition or its clinical symptoms; or (c) relieving symptoms associating with the pathological condition.

[0061] "Drug," "active pharmaceutical ingredient," "API," "active agent," "active ingredient," "active," and the like, are used in connection with the present invention as pure chemical substances, mixtures of pure chemical substances or crude extracts from various sources, which are used to treat pathological conditions of a person in need or such treatment. "Inactive ingredient," "excipient," "material," "component," "ingredient," "inactive material," "inactive," "agent," and the like as used interchangeably herein, refer to materials or ingredients that are not drugs, but are employed in pharmaceutical compounding in connection with the present invention with intention to impart the final dosage form specific characteristics, as known to the skilled in the art.

[0062] "Film" or "layer" or membrane" is used interchangeably in connection with the components of the multi-layered GRDF of this invention and their formulation and preparation is described herein.

[0063] As used in the specification and claims, the forms "a," "an" and "the" include singular as well as plural references unless the context clearly dictates otherwise.

[0064] Further, as used herein, the term "comprising" is intended to mean that the system includes the recited elements, but not excluding others which may be optional in the design of the system, such as fillers and the like. The term "consisting essentially of" is used to define a system that includes the recited elements but exclude other elements that may have an essential significant effect on the performance of the system. "Consisting of" shall thus mean excluding more than traces of other elements. Embodiments defined by each of these transition terms are within the scope of this invention.

[0065] Pro-drugs of R-baclofen have been suggested as possible treatment for a disease selected from spasticity, gastro-esophageal reflux disease, emesis, cough, narcotic addiction or abuse, alcohol addiction or abuse, nicotine addiction or abuse, neuropathic pain and musculoskeletal pain (US Patent Application 2009/0197958).

[0066] Various drug delivery forms of R-baclofen or enriched R-baclofen have been suggested for use in treating gastroparesis and nonulcer dyspepsia (US Patent Application No. 2009/0246233).

[0067] The baclofen or R-baclofen GRDFs of this invention are provided in the form ocapsule containing a multi-layer planar structure composed of films, folded in a wavy way ("Accordion Pill" or AP), which unfolds rapidly upon contact with gastric juice and releases baclofen or R-baclofen in the stomach for prolonged time periods. The "Accordion Pill" technology has been described in detail in previous publications, for example U.S. Pat. No. 6,685,962, PCT application WP 2007/093999 and PCT application WO07083309, which are incorporated herein by reference in their entirety.

[0068] The "Accordion Pill" technology, however, cannot uniformly be applied to any drug. Each "Accordion Pill" is a product in itself, because different actives require different solutions, due to the different physicochemical properties of the active, the pharmacokinetic requirements, bioavailability, dosages, etc.

[0069] Pharmacokinetic requirements specific to each active require different, innovative solutions that fit the specific product. These solutions vary according to case and they may involve different dosages, drug delivery by more than one mechanism (like immediate release and delayed release), with or without supra-outer layers, with or without coating, with or without orifices in various numbers, positions and sizes, different layer compositions, layer thicknesses and sizes and combinations of the above. The possible combinations are endless and success cannot be accurately predicted.

[0070] It was an aim of this invention to develop baclofen or R-baclofen GRDFs that would have a rapid onset of action and an extended period of relevant baclofen or R-baclofen blood levels. The inventors of the present application overcome baclofen or R-baclofen formulations problems by devising GRDF formulations that combine the special physicochemical properties of baclofen or R-baclofen with extended gastric retention, to obtain a baclofen or R-baclofen GRDF that is slowly releasing the active in controlled manner and result in more stable plasma levels for prolonged time, which may result in improved therapeutic activity with reduced frequent daily dosing and reduced undesirable side effects.

[0071] The present invention provides a baclofen or R-baclofen gastroretentive dosage form that exhibit prolonged retention in the stomach and gastrointestinal tract and are suitable for the treatment of a number of diseases and disorders.

Treatment of Ethanol and Drug Addiction

[0072] In some embodiments, the baclofen or R-baclofen GRDFs of this invention have the following advantages over the commercial products containing baclofen:

[0073] 1. The controlled release profile of the present invention is substantially insensitive to ethyl alcohol presence in the dissolution medium with concentrations increasing from 0% v/v up to 20-30%.

[0074] 2. The pharmacokinetic (PK) profile of the system of the present invention is superior to the pharmacokinetic (PK) profile of the marketed baclofen products, affords reduced dosing frequency and improves compliance to the treatment.

Spasticity

[0075] Spasticity or muscular hypertonicity is a disorder of the central nervous system (CNS) in which certain muscles continually receive a stimulation to tighten and contract. Spasticity is most common in spastic diplegia and other forms of spastic cerebral palsy. It is also present in multiple sclerosis and in most neuromuscular diseases, both progressive and not. The GRDF of this invention enables longer baclofen or R-baclofen absorption through retention in stomach and gastrointestinal tract and, as a result, enables administration of the drug once or twice daily instead of 3-4 times daily, reducing baclofen or R-baclofen blood level fluctuations and potentially reducing the side-effects encountered with the current commercial baclofen products.

Gastrooesophageal Reflux Disease (GERD)

[0076] GERD is being treated mainly by proton pump inhibitors (PPI) and gastric histamine (H.sub.2) receptor blocker.

[0077] The baclofen or R-baclofen GRDFs of this invention can provide products for GERD treatment.

Other Diseases

[0078] The baclofen or R-baclofen GRDFs of the invention provide treatment of additional diseases, including but not limited to nocturnal acid breakthrough, chronic hiccups, emesis, dyspepsia, gastric motility disorder, migraine, PTSD (Posttraumatic Stress Disorder), depression, anxiety, lower urinary tract dysfunction and neuropathic pain, with high efficiency and potentially reduced undesirable side effects.

The Development of Baclofen or R-Baclofen GRDFs

[0079] The aim of the present invention was to develop a baclofen or R-baclofen GRDF that would have a rapid onset of action and an extended period of relevant baclofen or R-baclofen blood plasma levels, and exhibit no or short lag-time and a sustained-release effect over a longer period of time than the commercial baclofen product on the market (Lioresal.RTM.).

[0080] The first attempt to produce a baclofen GRDF used an outer layer-inner layer-outer layer GRDF configuration, without a frame layer (Baclofen GRDF-A) and a total baclofen dosage of 40 mg, all of which was in the internal layer. The inner layer possessed substantially rigid properties that are usually found in the frame layer. FIG. 1 depicts a general GRDF configuration that includes the frame layer and Example 1 details the compositions of the formulations of the inner and outer layers. FIG. 2 shows the dissolution profile of the baclofen GRDF A configuration at very acidic pH (1.2) and moderately acid pH (4.1). As shown in FIG. 2, the extended release was seen for 4 hours at pH 1.2 and for more than 16 for pH 4.1.

[0081] A further attempt used an outer-frame inner outer layers GRDF configuration (Baclofen GRDF-B), at a total baclofen dosage of 40 mg. Example 3 shows the compositions of the layers. FIG. 3 shows the dissolution profile of the Baclofen GRDF B configuration at very acidic pH (1.2) and moderately acidic pH (4.1). As shown in FIG. 3, the extended release was seen for 5 hours at pH 1.2 and for 12 hours at pH 4.1 (see also Example 4).

[0082] In order to evaluate the advantages and disadvantages of the baclofen GRDFs, a single-dose, three-way crossover study comparing the pharmacokinetics of gastric retentive controlled release baclofen (Accordion Pill Baclofen or AP-BC) versus Lioresal.RTM. was carried on in 12 healthy volunteers (see Example 5). The primary objective was to evaluate of pharmacokinetic parameters (Cmax, Tmax and AUC) from plasma concentrations of following oral administration of the test formulations and reference. Study design was a single center, single-dose, open label, three-way crossover, comparative pharmacokinetic study in healthy volunteers.

Test Formulation:

[0083] GRDF-BC 40 mg A--Example 1 [0084] GRDF-BC 40 mg B--Example 3 [0085] Reference Formulation Lioresal.RTM. Novartis Pharma S.p.A 40 mg (4.times.10 mg baclofen) immediate release.

[0086] All oral formulations were swallowed whole with 240 ml water after a medium calorie breakfast. Standardized meals were given to all subjects throughout the study days.

[0087] Venous blood samples was drawn before dosing and then at frequent intervals to match the pharmacokinetic behavior of the drug. Baclofen plasma levels were analyzed. The results of the study, shown in Example 5 and in FIG. 4, indicated that:

[0088] 1. Both GRDF formulations increased the absorption phase for 5 hours in comparison to 2 hours in the instant release (IR) formulation Lioresal.RTM.;

[0089] 2. Both GRDF formulations decreased the Cmax and maintained the AUC constant in comparison to the IR formulation.

[0090] 3. The results were achieved under a regular calorie diet.

[0091] 4. Both GRDF formulations presented a lag time of about 1.5 hours in their PK profiles.

[0092] An additional clinical study was carried out in order to evaluate the pharmacokinetic profiles of a gastric retentive IR/CR GRDF (Accordion Pill-Baclofen or AP-BC) vs. IR baclofen (Lioresal) in healthy volunteers. This study was meant to compare the pharmacokinetic profiles of 40 mg Baclofen, following oral administration of a single-dose of an IR/CR gastric retentive formulation with those obtained following oral ingestion of a single-dose of the reference formulation, Baclofen IR 10 mg (Lioresal), using different diets and, in addition, to monitor the subjects for adverse events during the study period and to compare the safety of the test formulation with the reference formulation.

[0093] This study proved that the absorption phase of Baclofen was prolonged, by using the Accordion Pill, to 11 hours in comparison to the 2.5 hours provided by the marketed Lioresal.RTM..

[0094] One administration of an Accordion Pill-Baclofen (40 mg) provided drug plasma levels of 50-175 ng/ml for 16.5 hours. These plasma levels are currently provided by TID administration of 10 mg Lioresal.RTM.. In one embodiment, there are provided biodegradable, multi-layered controlled release gastroretentive dosage form of this invention, 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.

[0095] In another embodiment, there are provided biodegradable, multi-layered controlled release gastroretentive dosage form of this invention, wherein the active is baclofen or R-baclofen and wherein one administration of a 40 mg GRDF provides baclofen plasma levels of 50-175 ng/ml for 12-20 hours.

[0096] In yet another embodiment, there is provided 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 or R-baclofen gastroretentive dosage forms.

[0097] The Baclofen or R-Baclofen GRDF Formulations of the Invention

[0098] The present inventors devised a combination of a first baclofen or R-baclofen dosage in the inner GRDF layer with a second baclofen or R-baclofen dosage applied as a coating on the GRDF's capsule, which resulted in baclofen or R-baclofen GRDFs with attractive in-vitro release profile, as shown in Examples 6 and 7 and FIG. 5. Specific layer formulations, GRDF configurations, layer thicknesses, dosages, and other design and formulation particulars lead to the best results, as detailed herein.

[0099] As shown in FIG. 5, the immediate release occurred within 10 minutes and the extended release was seen for 16 hours for both pH 1.2 and 4.1.

[0100] In a preferred embodiment, the baclofen or R-baclofen gastroretentive dosage forms of this invention comprise two outer layers, a frame layer and an inner layer comprising baclofen or R-baclofen and additional ingredients for the controlled-delivery of baclofen or R-baclofen. This structure is compacted or folded into a capsule and unfolds rapidly upon contact with gastric juice. A schematic of this GRDF is detailed in FIG. 1.

[0101] In another preferred embodiment, the baclofen or R-baclofen GRDFs of this invention comprise in addition to the above an external coating of the capsule, comprising a second dose of baclofen or R-baclofen and additional ingredients, for the immediate release of baclofen or R-baclofen.

[0102] In one embodiment, there is provided a degradable multi-layered baclofen or R-baclofen gastroretentive dosage form for the controlled release of baclofen or R-baclofen in the stomach and gastrointestinal tract of a patient comprising a first dosage of baclofen or R-baclofen for immediate release and a second dosage of baclofen for controlled release, and compacted or folded into a capsule which disintegrates rapidly upon contact with gastric juice, such that the gastroretentive dosage form unfolds rapidly upon contact with gastric juice.

[0103] In another embodiment, the above gastroretentive baclofen dosage form is designed for oral administration and compacted or folded into a standard size capsule, which is easily swallowed.

[0104] In a preferred embodiment, there is provided a degradable multi-layered baclofen or R-baclofen gastroretentive dosage forms comprising

[0105] a. a first dosage of baclofen or R-baclofen for controlled release in an internal layer;

[0106] b. a rigid frame layer; and

[0107] c. one or two outer layers;

[0108] wherein the gastroretentive dosage form is compacted or folded into a capsule which is coated with at least one layer comprising a second dosage of baclofen or R-baclofen for immediate release, the capsule disintegrates and the gastroretentive dosage form unfolds rapidly upon contact with gastric juice.

[0109] In another preferred embodiment, there is provided a degradable, multi-layered baclofen or R-baclofen gastroretentive dosage form comprising

[0110] a. a first dosage of baclofen or R-baclofen for controlled release in a rigid internal layer; and

[0111] b. one or two outer layers;

[0112] wherein the gastroretentive dosage form is compacted or folded into a capsule which is coated with at least one layer comprising a second dosage of baclofen or R-baclofen for immediate release, the capsule disintegrates and the gastroretentive dosage form unfolds rapidly upon contact with gastric juice.

[0113] In other embodiments, 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 form of a powder, a granulated powder, a coated multi-particulate dosage form, a mini-tablet, or a combination of one or more thereof, wherein the capsule is optionally coated with at least one layer comprising an additional dosage of baclofen or R-baclofen for immediate release.

[0114] In further embodiments, 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 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. The capsule may be optionally coated with a pharmaceutical coating.

[0115] Preferably, the biodegradable multi-layered baclofen gastroretentive dosage forms comprises a total baclofen dose between about 20 and about 120 mg, divided into a first dosage for immediate release between 5-30 mg of baclofen and a second dosage for controlled-release between 15-90 mg of baclofen.

[0116] Replacing racemic baclofen with R-baclofen in the above GRDFs may allow reducing the dosage as compared to the racemic baclofen GRDFs, possibly halving the dosage. As we envisage that S-baclofen is not only inactive but also possibly having a negative effect, a further dosage decrease may be possible, between one half and one quarter of the racemic baclofen dosage.

[0117] The biodegradable multi-layered R-baclofen gastroretentive dosage forms may comprise a total R-baclofen dose between about 10 and about 60 mg, divided into a first dosage for immediate release between 2.5-15 mg of R-baclofen and a second dosage for controlled-release between 7.5-45 mg of R-baclofen.

[0118] Alternatively, the biodegradable multi-layered R-baclofen gastroretentive dosage forms may comprise a total R-baclofen dose between about 5 and about 30 mg, divided into a first dosage for immediate release between 1.25-7.5 mg of R-baclofen and a second dosage for controlled-release between 3.75-22.5 mg of R-baclofen.

[0119] In a preferred embodiment, the biodegradable multi-layered baclofen or R-baclofen gastroretentive dosage form has two outer layers.

[0120] In a preferred embodiment, the biodegradable multi-layered baclofen or R-baclofen gastroretentive dosage form comprises two outer layers, a frame and an inner layer containing baclofen or R-baclofen for controlled release, and is folded into a capsule coated with a coating comprising baclofen or R-baclofen for immediate release.

[0121] In another preferred embodiment, the biodegradable multi-layered baclofen or R-baclofen gastroretentive dosage form comprises two outer layers and a rigid inner layer containing baclofen or R-baclofen for controlled release, and is folded into a capsule coated with a coating comprising baclofen or R-baclofen for immediate release.

[0122] In another embodiment, the biodegradable multi-layered baclofen gastroretentive dosage form comprises a total baclofen dose of 40 mg divided into an immediate release coating of the capsule containing 10 mg of baclofen and a controlled-release inner layer containing 30 mg of baclofen.

[0123] In yet another embodiment, the biodegradable multi-layered R-baclofen gastroretentive dosage form comprises a total R-baclofen dose of 20 mg divided into an immediate release coating of the capsule containing 5 mg of R-baclofen and a controlled-release inner layer containing 15 mg of R-baclofen. Alternatively, the biodegradable multi-layered R-baclofen gastroretentive dosage form comprises a total R-baclofen dose of 10 mg divided into an immediate release coating of the capsule containing 2.5 mg of R-baclofen and a controlled-release inner layer containing 7.5 mg of R-baclofen.

[0124] In one embodiment, the biodegradable gastroretentive dosage form of the invention provides a baclofen or R-baclofen gastric retention period greater than 6 hours.

[0125] In another embodiment, the biodegradable gastroretentive dosage form provides a baclofen or R-baclofen gastric retention period of up to 24 hours.

[0126] In one embodiment, there is provided a method for providing a therapeutic blood plasma concentration of baclofen or R-baclofen over a period of up to 24 hours, potentially resulting in improved therapeutic activity, which comprises orally administering to a subject in need thereof a baclofen or R-baclofen multilayered gastroretentive dosage form, which maintains a therapeutically effective blood plasma level of baclofen or R-baclofen from about 0.5 hours to about 24 hours.

[0127] In another embodiment, there is provided a method for reducing sharp peaks in the 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 with potentially improved therapeutic activity, which comprises orally administering to the subject a baclofen or R-baclofen multilayered gastroretentive dosage form.

[0128] In yet another embodiment, there is provided a method for reducing fluctuations in the 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 with potentially improved therapeutic activity and reduced undesirable side-effects compared to an equivalent dose of an immediate release formulation, which comprises administering orally to the subject a baclofen or R-baclofen multilayered gastroretentive dosage form.

[0129] In one embodiment, there is provided a method of treatment of a disease in a subject in need thereof, comprising orally administering one or more baclofen or R-baclofen gastroretentive dosage forms of the invention per day.

[0130] In another embodiment, there is provided a kit comprising a number of baclofen or R-baclofen gastroretentive dosage forms of this invention and instructions and precautions for their use.

[0131] The outer layers comprise at least one polymeric combination of a hydrophilic polymer and a polymer insoluble in gastric media, and said layers are hydratable at a rate greater than the frame layer.

[0132] In one embodiment, a polymer insoluble in gastric acid media in the outer layer is selected from the group consisting of one or more types of polymethacrylate USP.

[0133] The outer layers may further comprise propylene glycol as a plasticizer.

[0134] The polymeric combination in the outer layers may comprise gelatin. The amount of gelatin in the outer layer is between about 20% and about 45% of the total outer layer composition.

[0135] The frame layer may comprise 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. In further preferred embodiments, the frame layer may comprise a suitable plasticizer.

[0136] The rigid inner layer may comprise 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.

[0137] The polymer in the frame layer may be a polymethacrylate copolymer USP.

[0138] In one embodiment, the frame layer or the rigid inner layer in the gastroretentive dosage form have a mechanical strength described with Young's modulus ranging from about 0.5 to 15 Kgf/mm.sup.2 and stress of about 0.03 to about 0.6 Kgf/mm.sup.2 after 1 hour in simulated gastric fluid.

[0139] In another embodiment, the composition of the frame layer optionally further comprises a filler, a surface-active agent, an additional plasticizer and other materials suitable for such composition.

[0140] In one embodiment, the inner layer comprises baclofen or R-baclofen and at least one polymer, whereas baclofen or R-baclofen is substantially uniformly dispersed in the polymer or forms a solid solution therewith and wherefrom baclofen or R-baclofen is released upon subjecting the gastroretentive dosage form into a gastric medium. The at least one polymer is chosen from hydrogels and polymer compositions, permeable to water. The film or layer may optionally further comprise a plasticizer.

[0141] The hydrogels are chosen from carboxymethyl cellulose, including sodium salt, alginic acid, including sodium salt, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromelose, a gum, i.e. guar gum, xanthan gum and others, a protein, i.e. albumin, casein, gelatin or collagen, or a cross-linked polyacrylic acid.

[0142] The polymer compositions permeable to water are chosen from a polymer such as zein, suitably plasticized ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, an enteric polymer and combinations thereof.

[0143] Alternatively, the polymer compositions permeable to water comprise a mixture of polymers, wherein at least one component is soluble in water and at least one component is insoluble in water, such as a mixture of polyvinyl acetate and polyvinyl pyrrolidone, a mixture of ethyl cellulose and polyethylene glycol and similar combinations.

[0144] In another embodiment, the polymer is chosen from polyvinyl alcohols and polyethylene oxides.

[0145] The polymers composition may further comprise buffering agents selected from acidifying agents selected from citric acid, tartaric acid, sorbic acid, fumaric acid, hydrochloric acid and sulfuric acid, or alkalizing agents selected from divalent cations selected from but not limited to calcium, magnesium, zinc and others, hydroxides, oxides, and their salts selected from but not limited to carbonates, sulfates and stearates.

[0146] The inner layer composition optionally may further comprise a filler, a surface-active agent and/or other inactive ingredients.

[0147] In a preferred embodiment, baclofen or R-baclofen is released from the gastroretentive dosage forms of the invention upon contact with gastric media and the release profile is substantially insensitive to changes of the environment of release in pH ranges between 1.2 and 5.5, or more preferably between 1.2 and 5.0 or even more preferably between 1.2 and 4.1.

[0148] In another embodiment, baclofen or R-baclofen is released from the gastroretentive dosage forms of this invention upon contact with gastric media and the release profile is substantially insensitive to changes of the environment of release in the presence of ethyl alcohol from 0% to about 30% or between 0% and 25% or between 0% and equal or below 20% v/v.

[0149] The inner layer of the gastroretentive dosage forms of the invention comprises baclofen, whereas baclofen or R-baclofen is present in form of a powder, granulated powder, miniature tablets, coated powder, semisolid composition or any other form known to those skilled in the art.

[0150] In some embodiments, the coating comprising baclofen or R-baclofen is applied onto the capsule of the gastroretentive dosage forms of this invention, and the coating comprises at least one layer.

[0151] The coating comprises at least one polymer, whereof the at least one polymer is instantly soluble in gastric medium.

[0152] In one embodiment, baclofen or R-baclofen is uniformly dispersed or dissolved in the coating.

[0153] The coating may further optionally comprise a plasticizer or a combination of plasticizers.

[0154] The coating may further optionally comprise at least one anti-tacking agent.

[0155] In one embodiment, there is provided a method for joining together the layers of the gastroretentive dosage forms of this invention with ultrasonic welding. In other embodiments, the layered are joined together with a solvent, with a suitable adhesive composition or due to sufficient tackiness of one or more of the said layers.

[0156] In another embodiment, the folded multilayered gastroretentive dosage form unfolds to a length of at least 20 mm within 15 minutes of being exposed to gastric fluid.

[0157] In yet another embodiment, the gastroretentive drug formulation of this invention is fully degradable within 3 hours in simulated intestinal fluid.

[0158] In one embodiment, there is provided a method of treatment of a disease in a subject in need thereof, comprising administering to the subject one or more gastroretentive dosage forms of this invention per day.

[0159] In another embodiment, there is provided a method of treatment of a disease in a subject in need thereof suffering from a disease treatable with baclofen or R-baclofen, which comprises administering orally to the subject a baclofen or R-baclofen multilayered gastroretentive dosage form of this invention with improved therapeutic activity.

[0160] In one embodiment, there is provided a method of treatment of a spasticity disease selected from spasticity, spastic diplegia, multiple sclerosis, amyotrophic lateral sclerosis and trigeminal and glossopharyngeal neuralgia in a subject in need thereof, which comprises administering orally to the subject a baclofen or R-baclofen multilayered gastroretentive dosage form of this invention.

[0161] In another embodiment, there is provided a method of treatment of alcohol or abuse drug addiction in a subject in need thereof, which comprises administering orally to the subject a baclofen or R-baclofen multilayered gastroretentive dosage form of this invention.

[0162] In yet another embodiment, there is provided a method of treatment of gastrooesophageal reflux disease in a subject in need thereof, which comprises administering orally to the subject a baclofen or R-baclofen multilayered gastroretentive dosage form of this invention.

[0163] In a further embodiment, there is provided a method of treatment of a disease selected from nocturnal acid breakthrough, chronic hiccups, emesis, dyspepsia, gastric motility disorder migraine, PTSD (Posttraumatic Stress Disorder), depression, anxiety, lower urinary tract dysfunction or neuropathic pain in a subject in need thereof, which comprises administering orally to the subject a baclofen or R-baclofen multilayered gastroretentive dosage form of this invention.

[0164] All films, layers and membranes of this invention were made by methods that are well known to those of skill in the art.

[0165] In a preferred embodiment, the films of this invention are prepared by the film casting technique. A solution or suspension of the film composition is cast on trays and dried in an oven until the solvent evaporates. The dried film in then cut according to the needed shape.

[0166] In the preferred current embodiments, the gastroretentive dosage form of this invention includes a frame layer, an internal layer and two outer layers. The outer layers are two films which are slightly larger than the frame layer and which are sealed or welded together around their perimeter and completely envelope the frame and the internal layer. Along with welding which connects the outer layers together, the outer portion of the frame layer is also welded to the outer layers. The compositions, ingredients and structure of the various layers forming the GRDF are detailed in the following illustrative examples of the formulations.

[0167] In some embodiments, the rigid frame layer of the GRDF (also referred to as "frame" or "backbone") provides mechanical strength to the GRDF.

[0168] The gastroretentive dosage form may comprise a baclofen or R-baclofen--comprising coating applied onto the capsule of the gastroretentive dosage form, and said coating comprises at least one layer.

[0169] Some of the GRDF of this invention may have in addition to the inner layer, frame layer and outer layer or layers, one or two additional external layers, named "supra-outer layers."

[0170] In current embodiments, the gastroretentive dosage form may optionally comprise an additional layer covering each outer layer or each supra-outer layer, comprising a powder or a film that prevents adherence of the outer membrane onto itself when folded inside the capsule, wherein said layer comprises a powder, a polymer, or a combination thereof.

[0171] In another embodiment, the one or two supra-outer layers are affixed to the outer layers on one or two sides of the gastroretentive dosage form, and comprise baclofen or R-baclofen and one or more inactive ingredients selected from the group consisting of polymers, preferably water soluble polymers, a plasticizer, a solubilizing agent intended for immediate release of the drug in the stomach, a disintegrant and a glidant, or any combination of ingredients capable of performing one or more of the said functions.

[0172] The detailed description of the present invention is further illustrated by the following examples, which are illustrative only and are not to be construed as limiting the scope of the invention. Variations and equivalents of these examples will be apparent to those skilled in the art in light of the present disclosure, the drawings and the claims herein.

[0173] It is appreciated that certain features of the invention which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0174] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0175] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent and patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

EXAMPLES

Racemic Baclofen Examples

Example 1

AP-Baclofen 40 mg Formulation A

[0176] GRDF Type: Outer-Inner-Outer

TABLE-US-00001 TABLE 1 mg Outer Film 4.1 Potassium hydroxide 63.9 Propylene glycol 63.9 Gelatin (Fish) 16 Eudragit L100-55 16 Eudragit L100 32 Eudragit S100

TABLE-US-00002 TABLE 2 mg Inner film 25.0 PEG 400 71.5 Lutrol F127 178.5 Eudragit L100 40.0 Baclofen

Example 2

GRDF-Baclofen 40 mg A Release Profile

[0177] In order to illustrate the ability of the GRDF to provide controlled release of active ingredient, the release profile for the above (Example 1) Baclofen GRDF was determined. Baclofen was present in a total amount of 40 mg, all of which is in the internal layer.

[0178] Experiments were conducted in SGF (USP) pH 1.2 and in Acetate buffer (USP) pH 4.1 in a USP Apparatus 2, 50 rpm.

[0179] As shown in FIG. 2, the extended release was seen for 4 hours at pH 1.2 and for more than 16 for pH 4.1.

Example 3

AP-Baclofen 40 mg Formulation B

[0180] GRDF Type: Outer-Frame-Inner-Outer

TABLE-US-00003 TABLE 3 mg Outer Film 4.1 Potassium hydroxide 63.9 Propylene glycol 63.9 Gelatin (Fish) 16 Eudragit L100-55 16 Eudragit L100 32 Eudragit S100

TABLE-US-00004 TABLE 4 mg Frame film 50 Lutrol F127 29.2 Eudragit L100-55 117.1 Eudragit L100 62.3 Lactose 15.6 Talc

TABLE-US-00005 TABLE 5 mg Inner film 8.97 PEG 400 89.74 Klucel EF 67.31 CMC 7H3SXF 40.0 Baclofen

Example 4

GRDF-Baclofen 40 mg B Release Profile

[0181] In order to illustrate the ability of the GRDF to provide controlled release of active ingredient, the release profile for the above (Example 3) Baclofen GRDF was determined. Baclofen was present in total amount of 40 mg which are all in the internal layer.

[0182] Experiments were conducted in SGF (USP) pH 1.2 and in Acetate buffer (USP) pH 4.1 in a USP Apparatus 2, 50 rpm.

[0183] As shown in FIG. 3, the extended release was seen for 5 hours at pH 1.2 and for 12 hours for pH 4.1.

Example 5

Evaluation of the Pharmacokinetic Profiles of Gastric Retentive, Controlled Release, Accordion Pill-Baclofen (AP-BC) Vs. Immediate Release Baclofen in Healthy Volunteers

[0184] The primary objective was to evaluate of pharmacokinetic parameters (Cmax, Tmax, AUC) from plasma concentrations of baclofen following oral administration of the test formulations and reference.

[0185] Study design was a single center, single-dose, open label, three-way crossover, comparative pharmacokinetic study in healthy volunteers.

Test Formulation:

[0186] A) GRDF-BC 40 mg A--Example 1

[0187] B) GRDF-BC 40 mg B--Example 3

[0188] Reference Formulation: Lioresal.RTM. Novartis Pharma S.p.A. 40 mg (4.times.10 mg) immediate release.

[0189] All oral formulations were swallowed whole with 240 ml water after a medium calorie breakfast. Standardized meals were given to all subjects throughout the study days.

[0190] Venous blood samples was drawn before dosing and then at frequent intervals to match the pharmacokinetic behavior of the drug. Baclofen plasma levels were analyzed.

[0191] The results of the study are shown in the Tables below and in FIG. 4:

TABLE-US-00006 TABLE 6 GRDF-BC 40 mg GRDF-BC 40 mg B A IR dose 2750 2747 2865 AUC (.mu.g*h/L)t.fwdarw.0 2953 2944 3021 AUC (.mu.g*h/L)t.fwdarw..infin. 97.7% 97.4% -- FIR (%) 352.8 361.0 427.0 C.sub.max ng/ml 5.55 5.49 5.54 t1/2 (h)

The results indicated the following: [0192] Both formulations increased the absorption phase for 5 hours in comparison to 2 hours in the IR formulation. [0193] In both formulations Cmax was decreased while the AUC was preserved in comparison to the IR formulation. [0194] Results were achieved under a regular calorie diet. [0195] There is a lag time of about 1.5 hours in both PK profile.

[0196] In order to further improve the PK profile by increasing the time of steady plasma levels and decreasing the lag time, there was a need to add an IR component to the GRDF and to prolong of the CR release profile. These changes were implemented in the formulation described in example 6.

Example 6

AP-Baclofen-C 40 mg Formulation

[0197] GRDF Type: IR Capsule Coating, Outer-Frame-Inner-Outer

TABLE-US-00007 TABLE 7 (mg per capsule) IR by Coating 2.0 Triethyl Citrate (TEC) 1.0 PEG 400 10.0 Eudragit E PO 4 Talc Extra fine 10.0 Baclofen

TABLE-US-00008 TABLE 8 Outer Film mg KOH 4.1 Propylene glycol 63.9 Gelatin (Fish) 63.9 Eudragit L100-55 16 Eudragit L100 16 Eudragit S100 32

TABLE-US-00009 TABLE 9 Frame film mg Lutrol F127 43.9 Eudragit L100-55 29.2 Eudragit L100 117.1 Lactose 62.3 Talc 15.6

TABLE-US-00010 TABLE 10 Inner film mg Kollidon .RTM. SR 125.0 Magnesium Hydroxide 50.0 Baclofen 30.0

Example 7

GRDF-Baclofen-C 40 mg Release Profile

[0198] In order to illustrate the ability of the GRDF to provide both immediate release and controlled release of active ingredient, the release profile for the above (Example 6) baclofen GRDF was determined. Baclofen present in total amount of 40 mg. Specifically, there are 10 mg Baclofen in the immediate release coating layer of the capsule and 30 mg in the internal layer which are provided to the patient as a controlled release.

[0199] Experiments were conducted in SGF (USP) pH 1.2 and in Acetate buffer (USP) pH 4.1 in a USP Apparatus 2, 50 rpm.

[0200] As shown in FIG. 5, immediate release occurred within 10 minutes and extended release was seen for 16 hours for both pH 1.2 and 4.1.

R-Baclofen Examples

Example 8

AP-Baclofen-C 20 mg Formulation

[0201] GRDF type: IR Capsule Coating, Outer-Frame-Inner-Outer

TABLE-US-00011 TABLE 7 (mg per capsule) IR by Coating 1.0 Triethyl Citrate (TEC) 0.5 PEG 400 5.0 Eudragit E PO 2 Talc Extra fine 5.0 R-Baclofen

TABLE-US-00012 TABLE 8 Outer Film mg KOH 4.1 Propylene glycol 63.9 Gelatin (Fish) 63.9 Eudragit L100-55 16 Eudragit L100 16 Eudragit S100 32

TABLE-US-00013 TABLE 9 Frame film mg Lutrol F127 43.9 Eudragit L100-55 29.2 Eudragit L100 117.1 Lactose 62.3 Talc 15.6

TABLE-US-00014 TABLE 10 Inner film mg Kollidon .RTM. SR 62.5 Magnesium Hydroxide 25.0 R-Baclofen 15.0

Example 9

GRDF-Baclofen-C 20 mg Release Profile

[0202] In order to illustrate the ability of the GRDF to provide both immediate release and controlled release of active ingredient, the release profile for the above (Example 8) R-baclofen GRDF was determined. R-baclofen present in total amount of 20 mg. Specifically, there are 5 mg R-baclofen in the immediate release coating layer of the capsule and 15 mg in the internal layer which are provided to the patient as a controlled release.

[0203] Experiments are to be conducted in SGF (USP) pH 1.2 and in Acetate buffer (USP) pH 4.1 in a USP Apparatus 2, 50 rpm.

Examples 10-11

GRDF-R-Baclofen Formulations A, B, C-10 mg

[0204] These examples are to be carried out according to the procedures detailed in Examples 8-9, with half their total and layer dosages.

Example 12

Pharmacokinetic Clinical Study: AP-Baclofen 40 mg (10 mg IR, 30 mg CR

[0205] The PK study had three arms crossover, and was carried out on 12 healthy volunteers (full crossover on 9 volunteers, in arm 2). The volunteers were healthy males aged between 18-55 years inclusive. 12 subjects participated in periods 1 and 2. Out of those 9 subjects also participated in period 3. Three new subjects were enrolled for period 3.

[0206] Pharmacokinetic parameters (Cmax, Tmax and AUC) were determined from plasma concentrations of Baclofen following oral administration of each of the drug administrations.

[0207] The three arms were:

[0208] 1. AP-BC 40 mg (10 mg IR, 30 mg CR), Food protocol 1

[0209] 2. AP-BC 40 mg (10 mg IR, 30 mg CR), Food protocol 2

[0210] 3. Lioresal 10 mg IR, Food protocol 1

[0211] Hours of blood sampling: Pre dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 18.0, 22.0 24.0, 26.0 except for--Arm 1 and 3 had sampling at hour 26 but not at 22. Arm 2 had sampling at hour 22 but not at 26.

TABLE-US-00015 PK results AP-BC 40 mg AP-BC 40 mg Lioresal .RTM. 10 mg Food protocol 1 Food protocol 2 Food protocol 1 AUC 0-t 2254 2033 824 AUCinf 2673 2646 861 Cmax (ng/mL) 211 168 134 Tmax (hour) 4.75 4.48 1.88 .lamda..sub.z (1/hour) 0.0920 0.0813 0.1169 T1/2 (hour) 8.80 10.2 6.09 MRT 0-t (hour) 9.38 10.2 6.79 MRT inf (hour) 13.6 16.4 8.00

See also FIG. 6.

Claims

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.sup.2 and stress of about 0.03 to about 0.6 Kgf/mm.sup.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.