A gastric retained dosage form of gabapentin

(Treatment Method Using Gabapentin Administration Held in the Stomach) (Field of Invention) The present invention relates to the use of gabapentin in a dosage form retained in the stomach. More specifically, the present invention relates to the use of such dosage forms for treating epilepsy and other medical conditions.

(Background Technology) Gabapentin (1- (aminomethyl) cyclohexaneacetic acid) is an antiepileptic drug and is currently available in 100 mg, 300 mg and 400 mg hard shell capsule dosage forms, as well as 600 mg and 800 mg tablet dosage forms. A total daily dose of 900 mg to 1800 mg in 3 divided doses is recommended. This oral bioavailability is dose-dependent, about 60% bioavailability for a single dose in the range of 300 mg to 400 mg, but for a dose of 1600 mg. Has only 35% bioavailability (Non-Patent Document 1; Non-Patent Document 2). The decrease in bioavailability with dose was due to carrier-mediated absorption (Non-Patent Document 3).

In an early murine study, Vollmer et al. (Non-Patent Document 4) found that gabapentin was absorbed in the duodenum. Absorption of gabapentin occurs relatively slowly, with maximum plasma concentrations occurring approximately 2 to 6 hours after administration (Non-Patent Document 1). Gabapentin is excreted exclusively through the urinary tract (Non-Patent Document 5; the above-mentioned Non-Patent Document 4; Non-Patent Document 6; Non-Patent Document 7) and has a half-life of 5 to 7 hours (the above-mentioned Non-Patent Document 5). And it is reported that it takes 6 to 7 hours (Non-Patent Document 2 above).

The once-daily or twice-daily dosage form of gabapentin can be expected to improve dosing compliance, and therefore the controlled release dosage form has some obvious advantages over conventional immediate release formulations. Have. In addition, controlled release dosage forms reduce maximal plasma concentrations, which can reduce side effects. Because gabapentin is highly absorbed in the gastrointestinal tract by a supersaturated transport mechanism, gastric-retained dosage forms are particularly advantageous for gabapentin delivery. This form of administration exhibits improved bioavailability due to the ability to retain the drug at the site of absorption and a slower release rate that avoids saturation in carrier-mediated transport of conventional administrations. ..

Permeable forms of administration have been described for the delivery of gabapentin prodrugs. Patent Document 1 to Chen et al. Describes a sustained release formulation that delivers a prodrug of gabapentin by the push-pull permeable pump system described in Patent Document 2 to Wong et al. However, this system is expected to deliver the drug with inadequate bioavailability rather than a gastric-retained dosage form.<patcit num="1"><text>U.S. Pat. No. 6,683,112</text></patcit><patcit num="2"><text>U.S. Pat. No. 4,612,008</text></patcit><nplcit num="1"><text>Bourgeois, Epilepsy: 1995, Addendum 5, 36, S1-S7</text></nplcit><nplcit num="2"><text>Gram, Epilepsy: 1996, Addendum 5, 37, S12-S16</text></nplcit><nplcit num="3"><text>Stewart et al., Pharmaceutical Research: 1993, Vol. 10, No. 2, p.276-281</text></nplcit><nplcit num="4"><text>Vollmer et al., Arzneim-Forsch / Drug Research: 1986, Vol. 36, No. 1, No. 5, p.781-892</text></nplcit><nplcit num="5"><text>Chadwick; The Lancet: 1994, No. 343, p.89-91</text></nplcit><nplcit num="6"><text>Thomson et al., Clin.Pharmacokinet .: 1992, Vol. 23, No. 3, p.216-230</text></nplcit><nplcit num="7"><text>Riva et al., Clin.Pharmacokinet .: 1996, Vol. 31, No. 6, p.470-493</text></nplcit>

<p> In one aspect of the present invention, the present invention relates to an epilepsy treatment method. The method comprises the step of administering a therapeutically effective amount of gabapentin, or a pharmaceutically acceptable salt thereof, to a mammal in need of the procedure in a gastric-held dosage form.</p><p> Yet another aspect of the invention relates to methods of treating neuropathic pain. The method comprises the step of administering a therapeutically effective amount of gabapentin, or a pharmaceutically acceptable salt thereof, to a mammal in need of the procedure in a gastric-held dosage form.</p><p> A further aspect of the invention relates to an improved method of administering a therapeutically effective amount of gabapentin to a patient in need of a therapeutically effective amount of gabapentin. This improvement comprises administering gabapentin, or a pharmaceutically acceptable salt thereof, in a gastric-held dosage form.</p><p> Yet another aspect of the invention relates to sustained release oral dosage forms for releasing gabapentin into the stomach, duodenum and small intestine of mammals. This form comprises a semipermeable membrane that can be porous or non-porous, or a core containing at least 800 mg of gabapentin wrapped by a coating.</p>

(Detailed Description of the Invention) The present invention relates to a method for treating a medical condition such as epilepsy by administering gabapentin once or twice a day in a form of administration held in the stomach. This gastric-held dosage form is particularly advantageous for gabapentin transmission because it takes a long time to pass through the upper gastrointestinal tract. This allows the drug to be well absorbed at the preferred absorption site. In addition, the dosage form retained in the stomach is t_maxAllows for a smoother, longer anticonvulsant effect. This dosage form is also C_maxCan result in a reduction in the incidence and / or severity of CNS side effects caused by drugs such as drowsiness, dysfunction, fatigue and dizziness.

(A. Treatment Method) The present invention includes a step of administering a therapeutically effective amount of gabapentin or a pharmaceutically acceptable salt thereof to a mammal in need of this treatment in a form of administration retained in the stomach. It is a method of treating a medical condition. As used herein, the term "treating" includes treating certain diseases of mammals, (particularly humans), which include: (i) this disease: In subjects who are susceptible to the disease but have not yet been diagnosed with the disease, to prevent the disease, (ii) prevent the disease, i.e. prevent its onset, or ( iii) To alleviate this disease, that is, to regress this disease.

One embodiment of the invention relates to an improved method of administering a therapeutically effective amount of gabapentin to a patient in need of a therapeutically effective amount of gabapentin. This improvement comprises administering gabapentin or a pharmaceutically acceptable salt thereof in a gastric-held dosage form.

Other embodiments of the present invention relate to methods of treating certain medical conditions. The method comprises the step of administering to a mammal in need of this treatment a therapeutically effective amount of gabapentin, or a pharmaceutically acceptable salt thereof, in a gastric-held dosage form. Such methods are currently found to be effective for a number of medical conditions treated with conventional immediate release formulations of gabapentin. This condition includes, for example, epilepsy; neuropathic pain; psychiatric disorders such as bipolar disorder and panic disorder; motor function such as restless lower limb syndrome, periodic sleep movement disorder, essential seismic seizure and acquired nittagmus. Disorders; as well as migraine prevention, but not limited to.

The present invention also contemplates the administration of one or more additional therapeutic agents in conjunction with gabapentin treatment. The choice of these additional therapeutic agents depends on the particular medical condition being treated and is described in detail below.

(B. Active ingredient) The active ingredient in the method of the present invention is gabapentin. Gabapentin is preferably used in the free amphoteric form. It retains the bioeffectiveness and properties of gabapentin and can also be used in the form of pharmaceutically acceptable salts that are not biologically or otherwise undesirable and have excellent bioavailability. Can show ability. As used herein, the term "gabapentin" is intended to include not only the drug itself, but also its pharmaceutically acceptable salt.

The pharmaceutically acceptable salt can be amphoteric and can be present in the form of an internal salt. Gabapentin can form salts with acid addition salts and bases. Representative acids that can be used to form such salts include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, or organic sulfonic acids or organic carboxylic acids. Organic acids include, but are not limited to. Salts formed with inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, for example, primary amines, secondary amines and tertiary amines, substituted amines including naturally occurring substituted amines, and isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, Ethanolamine, 2dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piberazine, piperidine, N-ethylpiperidine, Cyclic amines such as fumaric acid, maleic acid, succinic acid, acetate and oxalate can be mentioned.

(C. Additional Therapeutic Agents) The methods of the invention also consider adding one or more therapeutic agents to the gabapentin treatment.

For embodiments of the invention where the gastrically retained dosage form of gabapentin is administered to treat epilepsy, such additional therapeutic agents may be other antiepileptic or anticonvulsants. .. They include, but are not limited to, hydantoin, iminostilbene, valproic acid, phenyltriazine, barbiturates, deoxybarbiturates, benzodiazepines and carbamates. Such additional therapeutic agents are preferably hydantoin, iminostilbene, valproic acid or phenyltriazine.

The following examples of each of these types of compounds are merely exemplary and are by no means intended to be limiting. Examples of suitable hydantoin anticonvulsants include etotoin, fosphenytoin, mephenytoin and phenytoin, with preference given to phenytoin. An example of a suitable iminostilbene is carbamazepine. Examples of suitable valproates include valproic acid and sodium valproate. A typical suitable phenyltriazine is lamotrigine. A suitable barbiturate is phenobarbital and a typical deoxybarbiturate is primidone. An example of a suitable benzodiazepine is chlorazepine. A suitable carbamate is felbamate.

For embodiments of the invention where the gastrointestinal dosage form of gabapentin is administered to treat neuropathic pain, such additional therapeutic agents are other antidepressants, tricyclics. It can be selected from the group consisting of system antidepressants, levodopa and opioids.

The following examples of each of these types of compounds are merely examples and are by no means intended to be limiting. Examples of suitable anticonvulsants include carbamazepine, phenytoin and lamotridin. Suitable tricyclic antidepressants include amitriptyline, imipramine, clomipramine and desipramine. Examples of suitable opioids include oxycodone and tramadol.

For embodiments of the invention where the gastrointestinal dosage form of gabapentin is administered to treat a mental disorder, such additional therapeutic agents are lithium, carbamazepine, valproic acid, trifluoroperazine. , Clonazepam, risperidone, lorazapam, benrafaxin, clozapine, olanzapine, benzodiazepines, neuroleptics, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), bupropion and nefazodone.

For embodiments of the invention where the gastrointestinal dosage form of gabapentin is administered to treat bipolar disorder, such additional therapeutic agents include lithium, carbamazepine, valproic acid, trifluoro. It can be selected from the group consisting of perazine, clonazepam, risperidone, lorazapam, benrafaxin, clozapine, olanzapine, benzodiazepines and neuroleptics.

For embodiments of the invention where the gastrointestinal dosage form of gabapentin is administered to treat depression, such additional therapeutic agents are tricyclic antidepressants, selective serotonin. It can be selected from the group consisting of reuptake inhibitors (SSRIs), bupropion and nefazodone.

For embodiments of the invention where the gastrically retained dosage form of gabapentin is administered to treat mania, such additional therapeutic agents may be selected from the group consisting of diazepan and oxazepam.

For embodiments of the invention where the gastrointestinal dosage form of gabapentin is administered to treat motor dysfunction, such additional therapeutic agents are benzodiazepines, dopamine agonists, and opiates. , In particular, may be selected from the group consisting of levodopa / carbidopa and clonazepam.

For embodiments of the invention where the gastrointestinal dosage form of gabapentine is administered for the preventive treatment of migraine, such additional therapeutic agents are tricyclic antidepressants (amitriptyline, It can be selected from the group consisting of doxepin, imipramine, maprotyline, protryptyline, decipramine), SSRI (fluoxetine), triptane (sumatriptan, etc.) and ergotamine.

(D. Dosage) In general, the term "therapeutically effective amount" refers to an amount sufficient for effective treatment when administered to a mammal in need of this treatment. The therapeutically effective amount will vary depending on the subject being treated, the severity of the condition and the mode of administration and may be customarily determined by one of ordinary skill in the art.

In particular, for use in the treatment of epilepsy or neuropathic pain in a gastric-held dosage form, gabapentin is in an immediate release dosage form at a dose suitable for the treatment of epilepsy or neuropathic pain. Can be used. However, gastric-held dosage forms are designed to provide bioavailability of gabapentin at levels of 80% or higher compared to equal doses of immediate release dosage forms. Typically, the methods of the invention require administration of gabapentin on a once-daily or twice-daily basis for as long as the condition persists.

Effective doses of gabapentin for the treatment of epilepsy are typically about 300 mg to 3600 mg daily, typically about 900 mg to 2400 mg daily, and more typically about 900 mg daily. From 1800 mg.

Effective doses of gabapentin for the treatment of neuropathic pain are typically about 100 mg to 4800 mg per day, typically about 300 mg to 3600 mg per day, and more typically 1 It is about 900 mg to 2400 mg per day.

Effective doses of gabapentin for the treatment of psychiatric disorders are typically from about 100 mg to 4800 mg per day, and more typically from about 900 mg to 3600 mg per day.

Effective doses of gabapentin for the treatment of motor dysfunction are typically about 100 mg to 4000 mg per day, typically about 200 mg to 2700 mg per day, and more typically per day. It is about 500 mg to 2700 mg.

Effective doses of gabapentin for migraine prophylaxis are typically about 200 mg to 4000 mg per day, typically about 500 mg to 3600 mg per day, and more typically per day. It is about 900 mg to 2400 mg.

(E. Administration Regimen) The method of the present invention provides once-daily or twice-daily administration of gabapentin in a gastric-held dosage form. This administration can be performed at any time, but is preferably performed at approximately the same time each day and at approximately 12-hour intervals during the treatment period. In addition, the dosage form retained in the stomach is preferably taken with a meal (eg, breakfast or supper).

Thus, in one embodiment of the invention, gabapentin is administered, for example, once daily, in the morning (eg, at wake up or at breakfast), or in the evening (eg, at dinner or just before bedtime). To.

In another embodiment of the invention, gabapentin is administered, for example, twice daily, eg, the first dose in the morning (eg, at wake up or at breakfast) and the second dose in the evening (eg, at wake up or at breakfast). For example, at dinner or just before bedtime).

In another aspect of the invention, the method of administering a therapeutically effective amount of gabapentin in a gastric-held dosage form comprises the step of administering one or more additional therapeutic agents.

This additional therapeutic agent may be administered at the same time as or at different times as the administration of gabapentin, depending on the disease being treated and the nature of the agent itself. For example, if the additional treatment is another antiepileptic drug, twice daily administration may be sufficient and may be given at the same time as gabapentin or at different times. For the purpose of promoting patient compliance, it is preferable to administer any of the additional therapeutic agents described above at the same time.

(F. Dosage Form) There are a plurality of drug delivery systems suitable for delivering gabapentin in the methods of the invention because they are particularly compatible with the administration form held in the stomach. It is, for example, as follows. Inflatable bilayer as described in US Pat. No. 5,232,704 by Franz et al.; Laminated tablet with band as described in US Pat. No. 6,120,803 by Wong et al.; Described in US Pat. No. 4,996,058 by Sinnreich. Membrane sac and gas generating agent; inflatable polymer system as described in US Pat. No. 5,972,389 of Shell et al. And WO9855107 of Shell et al.; Incorporated inside.

Of particular interest are gastric-held dosage forms that contain a hydrophilic polymer that expands to a size that allows the dosage form to remain in supply. For example, this gastric-held dosage form may contain polymers with high swelling capacity such as polyethylene oxide, hydroxyethyl cellulose, and hydroxypropyl methylcellulose. This polymer is preferably of medium to high molecular weight (4x10) to enhance swelling and control gabapentin release.³From 10⁷To a degree or more). In one embodiment of the invention, such molecular weight hydroxypropyl methylcellulose polymers are used such that the viscosity of a 1% aqueous solution is from about 4000 cps to over 100,000 cps, and examples of suitable polyethylene oxide polymers are: It has a molecular weight (viscosity average) on the order of 2 to 7 million. A typical dosage form should swell to about 115% of the original volume within 1 hour after dosing. Later, it should expand to more than 130% of its original capacity. Fillers, binders, lubricants, and other additives can also be included in dosage forms that are retained in the stomach. Those additives are well known to those of skill in the art.

A typical dosage form provides a drug delivery profile such that gabapentin is delivered at least 5 hours, typically between about 8 and 10 hours, both in vivo and in vitro. To provide sustained release delivery, at least 40% by weight gabapentin is preferably retained in its dosage form after 1 hour. That is, the drug administered in the first hour does not exceed 60% by weight. In addition, dosage forms that deliver virtually all gabapentin over the intended period (typically about 6-8 hours) are used, but may be desired. Here, substantially all is interpreted to mean that at least 85% by weight of gabapentin is administered.

In one embodiment of the invention, the gastric-held dosage form of gabapentin is a capsule dosage form. This capsule dosage form allows sustained release in the stomach, which can: (a) increase on contact with gastric juice and release carbon dioxide or nitrogen, gabapentin or a pharmaceutically acceptable salt thereof. At least one component containing the factor; (b) at least one hydrophilic film in the form of a bag containing component (a), which is augmented by swelling, floats on the gastric juice surface, and is permeable to gastric juice; And (c) a capsule dosage form, comprising components (a) and (b), which decomposes without delay under the action of gastric juice. The components of (a) are low-concentration alkyl ethers of cellulose, starch, water-soluble fatty poly-N-vinylamide or cyclic poly-N-vinylamide, polyvinyl alcohol, polyacrylates, polymethacrylates, polyethylene glycols and mixtures thereof, and pharmaceuticals. Other substances used in the manufacture of dosage forms may also be included. Further details regarding examples of this type of dosage form can be found in Sinnreich's US Pat. No. 4,996,058.

In another embodiment of the invention, the gastric-held dosage form of gabapentin is a sustained-release oral dosage form in the patient's stomach, duodenum and small intestine, gabapentin dispersed in a polymer, or pharmaceuticals thereof. Includes one or more solid particles consisting of an acceptable salt. The solid particles (i) swell to unlimited dimensions by absorbing water from the fluid inside the stomach and increasing the size of the particles, inducing a supply form of gabapentin in the patient (in this patient). ) Promotes retention in the stomach in the stomach; (ii) Over a long period of time, gabapentin diffuses or the polymer corrodes, where gabapentin diffusion or polymer corrosion occurs with the fluid inside the stomach. Initiated by contact; and (iii) at a rate corresponding to the passage of time, gabapentin is released into the patient's stomach, duodenum and small intestine as a result of its diffusion or polymer corrosion. Representative polymers include polyethylene oxide, alkyl-substituted cellulosic materials and combinations thereof, such as ultra-high molecular weight polyethylene oxide and high molecular weight or high viscosity hydroxypropyl methyl cellulose materials. Further details regarding examples of this type of dosage form can be found in US Pat. No. 5,972,389 of Shell et al. And WO9855107 of Shell et al.

In yet another embodiment, the bilayer tablet releases gabapentin from the layer containing the active ingredient into the upper gastrointestinal tract, while the other layer is the swelling layer or floating layer. Details on this type of dosage form can be found in Franz et al., US Pat. No. 5,232,704. This dosage form is covered with a band of insoluble material, as described in Wong et al., US Pat. No. 6,120,803.

In another embodiment of the invention, a gastrically retained swelling sustained release tablet with a substrate consisting of poly (ethylene oxide) and hydroxypropyl methylcellulose is used. This dosage form is shown in Example 1, further details can be found in Gusler et al., US Patent Application Publication No. 20030104053.

Yet another embodiment of the invention relates to an dosage form that is formulated to have a size sufficient to provide long-term passage in the upper gastrointestinal tract. Such tablets contain at least 800 mg, typically 800 mg to 1600 mg of gabapentin. Typically, such dosage forms are film-coated or capsule dosage forms that allow controlled release and sustained release of gabapentin in the stomach. In a preferred embodiment, the dosage form is a drug-containing core wrapped in a controlled release film coating that provides controlled drug release or sustained drug release (ie, continuous drug diffusion from the core to the upper gastrointestinal tract). ..

Numerous substances useful in producing these large dosage forms are Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott Williams &amp; Wilkins, 2000) and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems. , 6th Edition (Media, PA: Williams &amp; Wilkins, 1995), explained in the sixth edition. In addition to gabapentin, the core may contain pharmaceutically acceptable additives or excipients to facilitate production. These include binders (eg, ethyl cellulose, gelatin, rubber, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, starch, sugar, wax), colorants, diluents (eg, calcium sulfate, cellulose, dicalcium phosphate, kaolin). , Lactose, mannitol, microcrystalline cellulose, sodium chloride, sorbitol, starch, sucrose) Fragrances, flow promoters (eg colloidal silicon dioxide, talc) and lubricants (eg calcium stearate, glyceryl behenate, vegetable) Hydrous oil, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, behenate stearate, talc) are mentioned. The core may also contain pharmaceutically acceptable additives or excipients that help add the desired physical properties to the dosage form. These include sweeteners, polymers, waxes and solubilizers. These administration forms can be performed by a technique well established in the art including a wet granulation method, a fluidized bed granulation method, a dry granulation method, a direct compression method and the like.

Controlled release film coatings are made by dissolving the material in a suitable solvent such as acetone or methylene chloride and then molding, air spraying, dipping or brushing a solvent-based solution of this material into the core. A coating can be applied to the dosage form. Suitable substances for use in controlled release film coatings include, for example, wax mixtures such as beeswax and carnauba wax, cellulose such as cellac and zein wax, cellulose such as ethyl cellulose, acrylic resins, diacetates, triacetates and other cellulose esters. Examples include cellulose acetate and silicon elastomers. Further examples are shown below.

Controlled release film coating materials that can form semipermeable membranes or semipermeable coatings are of particular interest. This controlled release film coating material can be porous or non-porous, is permeable to external liquids, and is opaque to the non-solubilized drugs contained inside the core. possible. Typically, this external liquid is an aqueous solution or a biological liquid in a usage environment such as the upper gastrointestinal tract. This external liquid passes through the semipermeable membrane into the core, where it solubilizes the drug. The solubilized drug then travels from the core through the semipermeable membrane to the gastrointestinal tract.

After applying the controlled release film coating to the core, a drying step is required and then a suitable outlet means for gabapentin must be formed. Depending on the properties of gabapentin, other components within the internal compartment and the desired release rate for the dosage form, one or more openings for delivery of gabapentin can be formed through the membrane, such as by mechanical or laser perforation. .. This opening, in size, can range from one large opening that includes substantially the entire surface of the dosage form to one or more small openings selectively located on the surface of the semipermeable membrane. One specific embodiment of the semipermeable membrane coated core is a rudimentary osmotic pump. The membrane comprises, for example, one or more delivery openings perforated to create one or more delivery openings. The liquid passing from the membrane to the core creates an osmotic pressure that helps to "pump" the solubilized drug through the delivery opening. See, for example, US Pat. No. 3,845,770 to Theeuwes et al. And US Pat. No. 3,977,404 to Theeuwes et al.

The material used in the formation of the semipermeable membrane is either substantially insoluble in the external liquid or corrodes at the end of the gabapentin release time and can corrode after a predetermined time. Suitable substances include, but are not limited to, examples: acetaldehyde dimethyl acetate and acetaldehyde dimethyl cellulose acetate; agar acetate; copolymer of alkylene oxide and alkyl glycidyl ether; amylose triacetate; beta-glucan acetate and beta-glucan triacetate;

Preferred substances used to form semipermeable membranes include, but are not limited to, examples: cellulose esters, cellulose ethers, polyvinylpyrrolidones, polyvinyl alcohols, polyalkylene oxides and combinations thereof.

The semipermeable membrane also contains one or more plasticizers. The plasticizers include: acetylated monoglycerol; dibutyl phthalate, diethyl phthalate, isopropyl phthalate, dimethyl phthalate and dactyl phthalate; dibutyl sebacate and dimethyl sebacate; acetyltrimethyl citrate, acetyltributyl citrate, citric acid. Esters such as esters, dibutyl sevacate, tetraethyl acetate, triethyl citrate and other citrate esters; fatty acids such as stearic acid; glyceryl behenate; 1,2-butylene glycol, 2,3-butylene glycol, diethylene glycol, Polyalkylene glycols such as ethylene glycol, propylene glycol, tetraethylene glycol, triethylene glycol, polyethylene glycol; oils such as castor oil and distillate coconut oil; glycerin; glycerol and glycerol monoesterates; triacetin; etc. and theirs. Combinations can be mentioned.

Preferred plasticizers include esters and fatty acids.

A particularly well-suited example of a core / coating system that can be used with gabapentin to provide a gastrically retained dosage form is the delayed release tablet described in US Pat. No. 6,350,471 to Seth. The tablet consists of a drug core and a water-insoluble coating, a water-permeable film-forming polymer such as ethyl cellulose, a plasticizer such as stearic acid and a water-soluble polymer such as polyvinylpyrrolidone or hydroxypropyl cellulose.

Another suitable core / coating system is polyvinyl alcohol coating. This is either water-soluble polyvinyl alcohol mixed with water-insoluble polyvinyl alcohol, or polyvinyl alcohol cross-linked with a substance such as boric acid or sodium borate.

In embodiments of the invention in which additional therapeutic agents are administered at the same time as gabapentin, these agents are administered in a gastric-held dosage form containing gabapentin or in a dosage regime different from gabapentin. obtain. Typical dosage forms are described below.

(H. Dosage Form of Additional Therapeutic Agent) For embodiments of the invention comprising further administration of one or more additional therapeutic agents, such dosage is any suitable formulation known in the art. Can be. For additional therapeutic agents for which controlled release is desirable, the drug may be incorporated into gastric-held dosage forms of gabapentin, or individual dosage forms or other controlled-release formulation dosage forms that are retained in the stomach. May be administered at. If immediate release is desired, for those additional therapies, the drug may be incorporated into the coating around the gastric-retained dosage form of gabapentin or the separate layer of the bilayer tablet, or the drug. May be simply encapsulated in a capsule dosage form that is held in the stomach of gabapentin, or the drug may be administered in separate immediate release dosage forms.

Typically, dosage forms include additional therapeutic agents (another antiepileptic or anticonvulsant) in combination with one or more pharmaceutically acceptable ingredients. The carrier can be in the form of a solid, semi-solid, or liquid diluent or capsule. Generally, the amount of active agent is from about 0.1% to 95% by weight, more typically from about 1% to 50% by weight. Practical methods of preparing such dosage forms are known or obvious to those of skill in the art; for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa: Volume 18, 1990, Volume 18. checking ... The dosage form administered is in any case an amount effective in alleviating the symptoms of the subject being treated and comprises a certain amount of additional therapeutic agent.

In the preparation of pharmaceutical formulations containing additional therapeutic agents in the form of dosage units for oral administration, the agents include lactose, microcrystalline cellulose, maltodextrin, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose induction. It can be mixed with solid powdery ingredients such as the product, gelatin or other suitable ingredients. Similarly, the agent can be mixed with degrading agents as well as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. The mixture is then granulated or compressed into tablets such as chewing tablets and orally disintegrating tablets.

Soft gelatin capsules can be prepared by mixing activators with vegetable oils, fats or other suitable vehicles. Hard gelatin capsules may contain granules of activator alone or in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Liquid preparations for oral administration can be prepared in the form of syrups or suspensions. This is, for example, a solution or suspension containing about 0.2% to 20% by weight of activator and a residue consisting of sugar or sugar alcohol and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may include colorants, air fresheners, saccharin and carboxymethyl cellulose or other concentrates. Liquid preparations for oral administration can be prepared in the form of dry powders for reconstitution with a suitable solvent prior to use.

If the methods of the invention include the step of administering another antiepileptic or anticonvulsant, there are numerous commercially available forms of administration that can be administered. In addition, other formulations can be readily designed based on knowledge in the art and include the gastric retention delivery system described above.

Typical forms of administration of other antiepileptic drugs or anticonvulsants suitable for use in the present invention include tablets, capsules, oral suspensions and syrups. One of ordinary skill in the art can readily prepare one of these representative formulations, or the other antiepileptic drug can be administered by one of a number of commercial products. Examples of them are provided below.

Commercially available hydantoin anticonvulsants include, for example, Peganone® (Abbott); Mesantoin® (Mephenytoin, Sandoz); and Dilantin® (Phenytoin, Warner-Lambert). ..

Typical dosage forms of anti-neuralgia agents suitable for use in the present invention include tablets, capsules and oral suspensions. One of ordinary skill in the art can readily prepare one of these representative formulations, or the anti-neuralgia agent can be administered by one of the commercially available products. Examples of them are provided below.

Commercially available anti-neuralgia agents include, for example, Atretol® (carbamazepine, Elan).

Specific examples of suitable antiepileptic drugs, anticonvulsants and anticonvulsants have been described above, but there are many other antiepileptic drugs or other preparations that can be used to deliver anticonvulsants. As such, it is understood that the present invention is not limited to those examples.

The general method of the present invention is best understood by reference to the following examples intended to allow one of ordinary skill in the art to better understand and practice the product. These examples are not intended to limit the scope of the invention and should not be construed as such. They are merely examples and typical examples.

(Example 1) Tablets were produced using a dry blending process and manually produced with a Carver Auto C press (Fred Carver, Inc., Indiana). This dry blending process involves mixing all ingredients in a plastic bag and compressing to 1000 mg tablets (600 mg gabapentin dose) using a 0.7086 inch x 0.3937 inch Mod Oval type (Natoli Engineering). It consisted of. The parameters for the Carver Auto C press operation were as follows: pressure 4000 lbs, holding time 0 seconds (setting on this Carver Press) and pump speed 100%.

<tables num="1"><img file="JP2008508317A_D0001.tif" /></tables>In the table: Active Ingredient = Gabapentin Polyethylene Oxide Coagulant = Poly (ethylene oxide), Polyoxide Coagulant Grade, NFFP Grade manufactured by Union Carbide / Dow Chemical. Methocel K100M = Hydroxypropyl Methyl Cellulose Manufactured by Dow Chemical, Methocel K100M Grade, Premium. M. St. = Magnesium stearate, NF supplied by Spectrum Chemical.

This dissolution was quantified in UPS instrument 1 (40 mesh basket) at 100 rpm in deionized water. After 1 hour, 4 hours and 8 hours, samples were taken at 5 ml at each time point without changing the medium.

Based on the theoretical percentage of active ingredient added to the formulation, the cumulative dissolution profile obtained is shown in the table below.

<tables num="2"><img file="JP2008508317A_D0002.tif" /></tables> (Example 2) Tablets were produced using a dry blending process and manually produced by Carver Auto C Press (Fred Carver, Inc., Indiana). This dry blending process consists of mixing all ingredients in a plastic bag and compressing into 600 mg tablets (300 mg gabapentin) using a 0.6299 inch x 0.3937 inch Mod Oval type (Natoli Engineering). Was there. The parameters for the Carver Auto C press operation were: pressure approx. 2000-2500 lbs, holding time 0 seconds (setting on this Carver Press) and pump speed 100%.

<tables num="3"><img file="JP2008508317A_D0003.tif" /></tables>In the table: Active Ingredient = Gabapentin Polyethylene Oxide Coagulant = Poly (ethylene oxide), Polyoxide Coagulant Grade, NFFP Grade manufactured by Union Carbide / Dow Chemical. Methocel K15M = Hydroxypropyl Methyl Cellulose, Methocel K15M Grade, Premium manufactured by Dow Chemical. M. St. = Magnesium stearate, NF supplied by Spectrum Chemical.

This dissolution was quantified in USP instrument 1 (40 mesh basket) at 100 rpm in deionized water. After 1 hour, 2 hours, 4 hours and 8 hours, samples were taken at 5 ml at each time point without changing the medium.

Based on the theoretical percentage of active ingredient added to the formulation, the cumulative dissolution profile obtained is shown in tabular form below.

<tables num="4"><img file="JP2008508317A_D0004.tif" /></tables> (Example 3) Three Gastric Retentive (GR)^TM) Gabapentin preparation was produced using standard granulation techniques. The manufactured formulation is shown in tabular form below.

<tables num="5"><img file="JP2008508317A_D0005.tif" /></tables> Gabapentin was obtained from Plantex USA (Englewood Cliffs, NJ). Methocel® brand hydroxypropylmethylcellulose (also known as Hypromellose) and Sentry® PolyOx® brand polyethylene oxide were obtained from Dow Chemical (Midland, Mich.). Methocel E5 Premium is a USP 2910 type hydroxypropyl methylcellulose with a number average molecular weight on the order of 6000 to 8000 and a viscosity of 5 cps in a 2% aqueous solution at 20 ° C. Methocel® K4M and Methocel® K15M are USP2208 type hydroxypropyl methylcellulose with viscosities of 4000 cps and 15,000 cps, respectively, in a 2% aqueous solution at 20 ° C. It is on the order of 100,000. Sentry PolyOx® WSR301 (NFFP), Sentry® PolyOx® WSR Coagulant (NFFP), and Sentry® PolyOx® WSR303 (NFFP) are approximately 4,000,000, 5,000,000, respectively. And has a viscosity average molecular weight of 7,000,000. Avicel PH-101 (NF) is a microcrystalline cellulose supplied by FMC Corporation (Philadelphia, Pa.). Magnesium stearate (NF) was supplied by Spectrum Quality Products (New Brunswick, NJ).

Three (GR) quantified with USP instrument 1 (100 rpm) in modified simulated gastric juice^TMThe dissolution profile of the prototype of the formulation is shown in Figure 1.

(Example 4) The pharmacodynamic profile of the three formulations described in Example 3 administered at a dose of 600 mg was taken in Neurontin in four randomized crossover studies involving 15 healthy volunteers. (Registered Trademark) Compared with immediate release capsule. For each subject, within 5 minutes of completing the high-fat breakfast (FDA breakfast), 3 GRs^TMOne of the formulations (1 x 600 mg tablets or 2 x 300 mg tablets) or as a Neurontin® capsule (2 x 300 mg) was treated with 600 mg gabapentin. Plasma samples were taken up to 48 hours after administration. Figure 2 shows the mean plasma distribution of the four treatments performed, and the pharmacodynamic data are summarized in tabular form below.

<tables num="6"><img file="JP2008508317A_D0006.tif" /></tables> GR as shown in Figure 2 and in tabular form^TMThe formulation is AUC_infShows sustained release when the maximum plasma concentration is low and the maximum concentration time value is large as compared to the immediate release capsule in the absence of loss in bioavailability as measured by.

(Example 5) A tablet containing 900 mg gabapentin was prepared by granulating with 90 mg polyvinylpyrrolidone and 10 mg magnesium stearate, and then to 1000 mg tablets with a Carver press at a pressure of 4000 pounds and a holding time of 0 seconds. Tablet. The cores of these tablets are then dry coated with an aqueous alcoholic solution of 10 mg ethyl cellulose, 7 mg popidone (PVP) and 3 mg stearic acid, which when dried results in a coating dry weight of approximately 2%.

(Example 6) A tablet containing 1200 mg gabapentin was prepared by granulating with 120 mg polyvinylpyrrolidone and 10 mg magnesium stearate, and then to a 1330 mg tablet with a Carver press at a pressure of 4000 pounds and a holding time of 0 seconds. Tablet. The cores of these tablets are then dry coated with 10 mg of ethyl cellulose, 10 mg of hydroxypropyl cellulose and 5 mg of glycervehenate in alcohol, which when dried results in a dry coating weight of approximately 25 mg.

(Example 7) A tablet containing 900 mg gabapentin was prepared by granulating with 90 mg polyvinylpyrrolidone and 10 mg magnesium stearate, and then to 1000 mg tablets with a Carver press at a pressure of 4000 pounds and a holding time of 0 seconds. Tablet. The cores of these tablets are then dry coated with an aqueous solution of 15 mg polyvinyl alcohol (PVA), 5 mg popidone (PVP) and 3 mg stearic acid, which when dried results in a coating dry weight of approximately 2%. In addition, these coated tablets are sprayed with 1% aqueous sodium borate solution to crosslink polyvinyl alcohol (PVA) and dried.

Example 8 A tablet containing 900 mg gabapentin was prepared by granulating with 90 mg polyvinylpyrrolidone, 250 mg microcrystalline cellulose and 10 mg magnesium stearate, followed by a pressure of 4000 pounds and a holding time of 0 seconds. Tablet into 1250 mg tablets with Carver press. The cores of these tablets are then dry coated with an aqueous alcoholic solution of 10 mg ethyl cellulose, 7 mg popidone (PVP) and 3 mg stearic acid, which when dried results in a coating dry weight of approximately 2%.

Even though the invention is described with reference to its particular embodiment, various modifications can be made and equivalents can be substituted without departing from the true spirit and scope of the invention. However, it should be understood by the parties. In addition, many improvements can be made to adapt a particular condition, substance, composition of material, process, or step of process to the object, purpose and scope of the invention. All such improvements are intended to be within the scope of the claims attached herein.

<figref num="1">3 GR^TMThe dissolution profile of the pharmaceutical product is shown.</figref><figref num="2">3 GR^TMThe average plasma profile of the formulation and Neurontin® is shown.</figref>