JP2008528494A - Pharmaceutical formulations and methods of use - Google Patents

Abstract

The present invention relates to novel pharmaceutical formulations and novel medical uses of gabapentin and pregabalin. The formulation can contain up to three components, including an immediate release component, a sustained release component and a delayed release component. Adjusting the ratio of each component in the formulation can achieve the desired AUC and therapeutic effect after oral administration to the subject. The present invention includes an active ingredient coated with a pH independent soluble polymer excipient, an active ingredient coated with a pH independent insoluble polymer excipient, and an active ingredient coated with a pH dependent soluble polymer excipient Aim for composition.

Description

(Cross-reference to related applications)
Priority is claimed for US Provisional Patent Application No. 60 / 645,857, filed Jan. 21, 2005. US Provisional Patent Application No. 60 / 645,857 is hereby incorporated by reference in its entirety.

(Field of Invention)
The present invention relates to new pharmaceutical formulations and new medical uses of gabapentin and pregabalin.

(Background of the Invention)
Gabapentin (Patent Document 1 and Patent Document 2) is a known GABA (γ-aminobutyric acid) analog that has been used clinically for the treatment of epilepsy, neuropathic pain and many other conditions. Gabapentin is used for other chronic pain conditions such as muscular pain and skeletal pain, panic, anxiety, depression, mental disorders such as alcoholism and mania behavior, multiple sclerosis, motion tremor, delayed dyskinesia, etc. It may have a useful therapeutic effect on disability, migraine, bipolar disease, muscle spasm, and may also have a useful therapeutic effect as an analgesic. Recently, it has been shown in US Pat. No. 6,057,049 that gabapentin can be used to treat hot flashes.

  Gabapentin is formulated as an immediate release unit dose tablet or capsule formulation containing 100 mg, 300 mg, 400 mg, 600 mg or 800 mg of active agent in current clinical applications. These unit doses are usually administered three times a day (TID) and the dosage is usually up to 3,600 mg, or more usually 2,700 mg. TID administration is inconvenient and patients often do not adhere to TID doses. Depending on the condition being treated, forgetting to take or taking the wrong time can have serious consequences.

  Patent Document 4 discloses a tablet formulation that remains in the stomach and releases gabapentin. This formulation continuously delivers gabapentin only to the stomach and upper small intestine. This formulation has a longer sustained release time in the stomach and upper gastrointestinal (GI) tract and is more absorbed in the stomach and upper GI tract than the lower GI tract. Such formulations must be taken continuously to maintain therapeutic blood levels. This formulation is unsuitable for dosing only in a timely manner because intermittent administration results in a delay in the time to reach therapeutic blood levels. All gabapentin in this formulation will be absorbed in the stomach and / or upper small intestine, especially the duodenum.

  U.S. Patent No. 6,057,017 discloses certain prodrugs of gabapentin, and U.S. Patent No. 5,057,017 discloses certain improved immediate release formulations of gabapentin. The former describes attempts to provide sustained release of gabapentin by attaching promoiety to the gamma amino and / or carboxyl groups of gabapentin (and other GABA analogs), improving bioavailability and transport to the brain . This patent describes a novel chemical that bypasses the known active transport mechanism of gabapentin and related compounds and delays absorption below the intestinal tract. Although the tablet formulation described in Patent Document 6 has improved compressibility, it does not provide sustained release of gabapentin.

  U.S. Patent No. 6,057,031 discloses various continuous dosage formulations of a number of antiepileptic drugs, with emphasis on phenytoin osmotic formulations. This specification also refers to gabapentin, but does not disclose in which specific part of the gastrointestinal tract the drug is released, and in particular does not disclose that gabapentin is released rapidly in the lower small intestine. This formulation does not contain an immediate release component and must be taken continuously to maintain therapeutic blood levels. This formulation is unsuitable for dosing only in a timely manner because intermittent administration causes a delay in the time to reach therapeutic blood levels.

  The drug pregabalin has properties similar to gabapentin. Pregabalin is produced only in immediate release form and there is no sustained release preparation at present. This drug is therefore administered TID to maintain therapeutic blood levels. Like gabapentin, TID administration is inconvenient and patients often do not adhere to TID dosages. Depending on the condition being treated, forgetting to take or taking the wrong time can have serious consequences.

  Therefore, not only established clinical uses, but also other treatments such as hot flash treatments require a more convenient and improved drug regimen. The release pattern is more appropriate and / or the bioavailability of gabapentin is improved and / or does not lead to saturation of the body's absorption mechanism, and thus a given effect can be obtained at a lower dosage, resulting in side effects There is also a need for a formulation of gabapentin that also reduces the likelihood of.

  Pregabalin may, of course, be used in place of gabapentin when reference is made to gabapentin throughout the following portions of this specification (unless it is clear from the context).

The inventor has discovered means to meet some or all of these needs.
U.S. Pat. No. 4,024,175 U.S. Pat. No. 4,087,544 US Pat. No. 6,310,098 US Pat. No. 6,723,340 US Pat. No. 6,818,787 US Pat. No. 6,465,012 US Pat. No. 5,906,832

(Summary of the Invention)
The present invention includes an active ingredient coated with a pH independent soluble polymer excipient, an active ingredient coated with a pH independent insoluble polymer excipient, and an active ingredient coated with a pH dependent soluble polymer excipient Aim for composition. The active ingredients are those of gabapentin and pregabalin. The pH independent soluble polymer excipient is hydroxypropyl methylcellulose. The pH independent insoluble polymer excipient may be Eudragit RL30D, Eudragit RS30D or a combination thereof. The pH dependent soluble polymer may be Eudragit L30D-55, Eudragit FS30D or a combination thereof.

  The present invention is also directed to compositions wherein the thickness of the pH independent insoluble polymer is from 25 microns to 150 microns. The thickness of the pH dependent soluble polymer is from 25 microns to 150 microns. The present invention is also directed to an active ingredient in the form of a mini-tablet coated with either a pH independent insoluble polymer, a pH independent soluble polymer or a pH dependent soluble polymer. The present invention is also directed to compositions further comprising disintegrants, flavoring ingredients, colorants, sweeteners, binders, lubricants, plasticizers or combinations thereof.

  The present invention provides a rapid release of a portion of gabapentin in the stomach and upper small intestine, a sustained release (which supplies the stomach and upper small intestine), and a portion in the lower or middle to lower Also intended is an oral sustained release formulation of gabapentin that is released in the small intestine. This formulation is designed to release gabapentin or other active ingredients in three stages. In the first stage, gabapentin or other active ingredient is released rapidly into the stomach. In the second stage, gabapentin or other active ingredient is released continuously, mainly in the lower stomach, duodenum and jejunum of the small intestine. In the third stage, the release of gabapentin or other active ingredient is delayed until it reaches the jejunum and ileum parts of the small intestine where it is rapidly released.

  The present invention further provides that 20% to 60%, or 25% to 50%, or 35% to 45% of gabapentin or other active ingredient is released in the first phase, for example, up to 2 hours or 3 hours after dosing Also contemplated are compositions that are made. Most of these quantities of gabapentin or other active ingredients are released into the stomach. The present invention provides that 20% to 60%, or 25% to 50%, or 35% to 45% of gabapentin or other active ingredient is in a second stage, eg up to 12 hours or 6 hours or 1 hour after dosing Also contemplated are compositions that are released within 5 hours of Most of these quantities of active ingredient are released into the lower stomach and upper / middle small intestine, including the duodenum and jejunum. The invention also provides that 15% to 50%, or 30% to 45%, or 30% to 40% of gabapentin or other active ingredient is rapidly delayed with 3 to 10 hours, or 4 to 8 hours after dosing. Also intended are compositions that are released into the body. Most of these quantities of active ingredient are released from the middle, including the jejunum and ileum, into the lower small intestine. One goal of the third stage drug release is to provide the drug immediately when the blood concentration of the drug released in the first and second stages is likely to decrease.

  Another aspect of the present invention is an active ingredient encased in a pH independent soluble polymer excipient, an active ingredient encased in a pH independent insoluble polymer excipient, and a pH dependent soluble polymer excipient. Containing encapsulated active ingredient, 20% to 60% of the active ingredient is released by the pH independent soluble polymer excipient within a maximum of 3 hours after dosing, and 20% to 60% of the active ingredient is up to 12% from the dosing A composition that is released by a pH-independent insoluble polymer excipient within a time period, and 15% to 50% of the active ingredient is released by a pH-dependent soluble polymer excipient with a delay of 3 to 10 hours after dosing And The present invention is also directed to compositions in which 25% to 50% of the active ingredient encapsulated with a pH independent soluble polymer is released within a maximum of 2 hours or 3 hours. The present invention is further directed to compositions in which 35% to 45% of the active ingredient encapsulated with a pH independent soluble polymer is released within a maximum of 2 hours or 3 hours. Release of the active ingredient in this ratio by the pH-independent soluble polymer occurs in the stomach.

  Another aspect of the present invention is that 25% to 50% of the active ingredient encased in a pH independent insoluble polymer is sustained for up to 12 hours or up to 6 hours, or more or from 1 hour to 5 hours. Aimed at the composition to be released. The present invention is also directed to compositions in which 25% to 35% of the active ingredient is released continuously for up to 12 hours or up to 6 hours, or from 1 hour to 5 hours. Active ingredients released in these ratios by pH independent insoluble polymers are released into the stomach and upper and middle small intestines, including the duodenum and jejunum.

  The present invention is also directed to compositions in which 30% to 45% of the active ingredient is released from the pH-dependent soluble polymer with a delay of 3 to 10 hours, or 4 to 8 hours. The present invention is further directed to compositions in which 30% to 40% of the active ingredient is released from the pH-dependent soluble polymer with a delay of 3 to 12 hours, or 4 to 8 hours. Active ingredients released at these rates by the pH-dependent soluble polymer are released from the middle, including the jejunum and ileum of the small intestine, into the lower small intestine. The total active ingredient release over three steps from soluble, insoluble pH-independent polymers and pH-dependent polymers is close to 100%.

In the present invention, the AUC drug plasma concentration of gabapentin is 100% to 200% of the plasma concentration obtained by administering the same amount of conventional immediate release gabapentin such as gabapentin sold under the trademark Neurontin®. Compositions exceeding are also intended. In the present invention, plasma concentrations (levels) of gabapentin after a single dose of gabapentin in the form of Neurotin® or a formulation according to the present invention (Xenolev-CR ^™ ) to healthy volunteers and / or target populations. Data points from zero to infinite time, or equivalent data points for a single dosing interval in a pharmacokinetic steady state where the long-term daily dose is equal to the excretion, Measure AUC.

The T _max of the formulation kinetics of the present invention is the same as or up to 3.0 times the T _max when the same amount of conventional immediate release formulation is administered. The time to C _max is 2 to 6 hours after dosing. The maximum plasma concentration (C _max ) of gabapentin is lower than when the same amount of the conventional immediate release preparation is administered, for example, about 0.5 of the conventional C _max . The plasma concentration of gabapentin 8 to 24 hours after dosing is up to 3 times, or 1.5 to 2.5 times that of conventional release formulations. C Time from _max up to 50% of the _{C max} is 24 hours 2 hours, formulation 8 hours to 12 hours, or 3-4 hours. Time from C _max ranging to 50% of _{C max} is 3 times 1.1 times than that of immediate release gabapentin, or 2.5 times as long as the formulation from 1.5. Absorption of gabapentin formulations or other active ingredient formulations that are basically 100% immediate release (ie, not according to the present invention) shows non-linearity and doubles the AUC even if the dose is doubled Don't be. In the present invention, the active ingredient or gabapentin is 25-100%, 30-100%, 35-100%, 40-100%, 45% -100%, 50%-in proportion to its dosage strength. 100%, 55-100%, 60-100%, 65% -100%, 70% -100%, 75% -100%, 80% -100%, 85-100%, 90-100%, 95%- Also contemplated are compositions that are released at 100% C _max and AUC (absolute bioavailability of the active ingredient). Thus, the bioavailability of gabapentin immediate release formulations varies from more than 70% at low doses to less than 30% at high doses. Thus, if all three ingredients are used in the present invention in appropriate proportions and the dose is doubled or tripled, the AUC will correspondingly be 0.5 ×, 0.6 ×, 0.7 ×, 0.8 ×, 0.9 ×, 1 × (times), l. Can be lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x or 2.0x . Thus, the bioavailability of gabapentin according to the present invention is about 1.0 to about 1.5 for immediate release gabapentin at low doses and about 1.0 to about 3.0 for immediate release gabapentin at high doses.

  Yet another aspect of the present invention provides a dosage of gabapentin or other active ingredient, wherein the total gabapentin is 900 mg or 800 mg or 700 mg or 600 mg or 500 mg or 400 mg or 375 mg or 350 mg or 325 mg or 300 mg or 275 mg or 250 mg In the first stage, 180 mg to 540 mg, 160 mg to 480 mg, 140 mg to 420 mg, 120 mg to 360 mg, 100 mg to 300 mg, 80 mg to 240 mg, 75 mg to 225 mg, 70 mg to 210 mg, 65 mg to 195 mg, 60 mg to 180 mg, 55 mg to 165 mg, And 50 mg to 150 mg of gabapentin or other active ingredient is a pH independent soluble polymer An object et release composition. The present invention includes 180 mg to 540 mg, 160 mg to 480 mg, 140 mg to 420 mg, 120 mg to 360 mg, 100 mg to 300 mg, 80 mg to 240 mg, 75 mg to 225 mg, 70 mg to 210 mg, 65 mg to 195 mg, 60 mg to 180 mg, 55 mg to 165 mg, and 50 mg. Also contemplated is gabapentin or other active ingredient where from 150 mg is continuously released from the pH independent insoluble polymer during the second stage. The present invention includes 270 mg to 405 mg, 240 mg to 360 mg, 210 mg to 315 mg, 180 mg to 270 mg, 150 mg to 225 mg, 120 mg to 180 mg, 110 mg to 170 mg, 105 mg to 160 mg, 100 mg to 150 mg, 80 mg to 125 mg, and 75 mg to 115 mg. Also contemplated are gabapentin or other active ingredients that are released from the pH-dependent soluble polymer during the three stages. Similarly, reducing the total dose of drug reduces the mg range, which can be easily calculated from the above data.

  The present invention administers 500 mg of gabapentin or active ingredient twice a day as a single unit dose or each 250 mg × 2 unit dose, or 900 mg of gabapentin or active ingredient each 300 mg × 3 unit dose or 450 mg × 2 units Also contemplated is the use of a composition according to a dosage regimen that is administered twice a day as a dose, or 750 mg of gabapentin or active ingredient as a single unit dose or 375 mg × 2 unit doses twice a day.

  Yet another aspect of the present invention is the step of individually mixing the active ingredients with a pH-independent soluble polymer, a pH-independent insoluble polymer, and a pH-dependent soluble polymer, and a minitablet from the resulting mixture. It is intended to be a composition made by a process comprising forming and filling a minitablet of this mixture into a capsule suitable for oral administration. The present invention also includes mixing the active ingredient with a filler, granulating the mixture, blending the granulated mixture with a lubricant, compressing the blended mixture into mini-tablets, Coating a tablet with a pH-independent soluble polymer, a pH-independent insoluble polymer and a pH-dependent soluble polymer excipient, drying the coated mini-tablet, and It is intended to be a composition made by a process comprising preparing a single unit dosage form suitable for administration.

  The invention further provides a neurological disease or injury selected from the group consisting of epilepsy, treatment of stroke attacks, head / brain injury or pre-operative neurological symptoms, multiple sclerosis or involuntary movement tremors A composition comprising gabapentin or pregabalin or other active ingredient used in the treatment of. The present invention relates to neuropathy, muscle pain, skeletal pain, tardive dyskinesia or migraine, reflex sympathetic dystrophy syndrome (RSD) [also known as complex local pain syndrome (CRPS)] and chronic associated with fibrosis or muscle disease. Also contemplated are compositions comprising gabapentin or pregabalin or other active ingredients used in the treatment of typical pain. The present invention is also directed to compositions comprising psychiatric disorders including bipolar disease, panic, anxiety, depression, alcoholism and mania behavior. The formulations or compositions of the present invention may have the symptoms described in US Pat. No. 6,310,098 (incorporated herein by reference), and particularly menopausal hormone fluctuations and other It may be used to treat the associated syndromes hot flash, fever, nausea and vomiting. The present invention is also directed to the treatment of postmenopausal female symptoms selected from the group consisting of urge urinary incontinence, vaginal dryness and dry eye syndrome.

(Detailed explanation)
The release pattern is more appropriate and / or the bioavailability of gabapentin is improved and / or does not lead to saturation of the body's absorption mechanism, and thus a given effect can be achieved with a lower dose and possible side effects In order to meet the need for a formulation of gabapentin that also has reduced properties, the present invention provides an active ingredient encased in a pH independent soluble polymer excipient and an active ingredient encased in a pH independent soluble polymer excipient And a composition comprising an active ingredient encased in a pH-dependent soluble polymer excipient. The present invention is directed to a composition or formulation comprising active ingredients such as gabapentin and the drug pregabalin. Other ingredients that can be used in the compositions or formulations of the present invention include, but are not limited to, the following table.

  Table 1. Most commonly formulated active ingredients 150

ガバペンチンを含む組成物の活性成分は、本発明による製剤の経口使用を含めた任意の都合のよい手段で、神経疾患または損傷の治療、慢性的な疼痛の治療、精神障害または精神病の治療、月経関連症状の治療および閉経後関連の症状の治療に使用されればよい。これらの用途の場合の投与量は、癲癇の治療に使用する場合より概して少なく、通常１日１００ｍｇから３，０００ｍｇの範囲で、1日に多くて２回または３回に分けて投与してもよい。即時放出性製剤、または本発明による製剤を使用する場合の投与量は、本発明による製剤に関連して下記に示される通りである。

The active ingredient of the composition comprising gabapentin can be administered by any convenient means, including oral use of the formulations according to the invention, treatment of neurological diseases or injuries, treatment of chronic pain, treatment of mental disorders or psychosis, menstruation. It may be used to treat related symptoms and postmenopausal related symptoms. The dosage for these applications is generally lower than that used for the treatment of epilepsy, usually in the range of 100 mg to 3,000 mg per day, and may be administered at most twice or three times per day. Good. The dosages when using immediate release formulations or formulations according to the invention are as indicated below in connection with the formulations according to the invention.

  A drug (ie, the active ingredient of a particular pharmaceutical formulation) inevitably passes through the digestive tract when administered orally. The active ingredient of the formulation or composition of the invention first enters the strongly acidic environment of the stomach where the pH is between 1 and 3. Nutrient / drug absorption occurs primarily in the small intestine, including the duodenum, jejunum and ileum. The small intestine continues from a strongly acidic environment (pH about 4 to 5 in the duodenum) to a weakly acidic environment (pH about 6 to 7 in the jejunum and ileum). Based on the strongly acidic environment of the stomach, a preparation that prevents the drug or active ingredient from dissolving in the stomach can provide sustained and delayed release of the drug in the small intestine.

  As used herein, an excipient is defined as an inert substance used as a diluent or solvent for a drug. Excipients can be in the form of solid coatings, liquid coatings, or semi-solid capsules that coat an active pharmaceutical ingredient such as gabapentin. The excipients of the present invention are defined in three different coating forms: pH independent soluble polymer, pH independent insoluble polymer and pH dependent soluble polymer. pH dependent soluble polymers are soluble in certain pH environments. Thus, soluble polymers are soluble at a specific pH rather than any pH.

  A pH-independent soluble polymer is defined as a pharmaceutical grade carrier or solvent that dissolves immediately in a soluble environment, including the stomach, and includes calcium phosphate dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, cellulose derivatives , Glucose, gelatin, lactose, anhydrous lactose, spray dried lactose, lactose monohydrate, mannitol, starch, sorbitol, sucrose, and the like. Further examples include acacia, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose acetate butyrate, hydroxyethylcellulose, ethylcellulose, polyvinyl alcohol, polypropylene, dextran, dextrin , Hydroxypropyl-β-cyclodextrin, chitosan, copolymers of lactic acid and glycolic acid, lactic acid polymers, methacrylic acid copolymers containing acidic groups, glycolic acid polymers, polyorthoesters, polyanhydrides, polyvinyl chloride, Polyvinyl acetate, polyvinyl alcohol, polyethylene glycol copolymer , Ethylene vinyl acetate, lectins, carbopols, silicone elastomers, polyacrylic polymers, maltodextrins, fructose, inositol, trehalose, maltosuraffinose, and α-, β-, γ-cyclodextrins, Including suitable mixtures, and the like. These polymers are readily soluble in the low pH environment (pH 1-5), medium pH environment (pH 5-7.5), or high pH environment (pH 7.5 to 10) of the gastrointestinal tract. These polymers are readily soluble and as soon as they come in contact, they dissolve in the liquid medium and release gabapentin or other active ingredients.

  In the composition, a pH independent insoluble polymer is also used to coat the active ingredient. A pH-independent insoluble polymer is a pharmaceutical grade carrier or solvent that coats an active pharmaceutical ingredient such as gabapentin. Examples of pH independent insoluble polymers include hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, aminoacryl methacrylate copolymer E containing methyl cellulose, ethyl cellulose or combinations thereof, and Eudragit RL30D and Eudragit RS30D. Including, but not limited to, aminoalkyl methane acrylate copolymers RS and RL. The pH-independent insoluble polymer may have low permeability and expansibility like Eudragit RS30D, and may have high permeability and expansibility like Eudragit RL30D. Such variations in the permeability of insoluble pH-independent membranes affect the release kinetics of the active ingredient or gabapentin, with sustained release of the active ingredient or gabapentin into the upper small intestine, including the stomach and duodenum, for up to 12 hours from the first dose. It becomes possible to do.

  A pH-dependent soluble polymer is a pharmaceutical grade carrier or solvent that coats an active ingredient such as gabapentin. Examples of pH-dependent soluble polymers include natural polymers such as purified shellac and white shellac, synthetic polymers such as cellulose derivative polymers: hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate acetate, carboxymethyl Acrylic polymers such as those obtained from ethyl cellulose, cellulose trimellitic acetate, cellulose acetate phthalate, acrylic acid and / or methacrylic acid, polymers obtained from acrylic acid and / or methacrylic acid and carboxylic acid esters, polyvinyl acetate phthalic acid Polyvinyl alcohol type polymers such as salts are included, but not limited thereto. Further, the pH-dependent soluble polymers include those having a carboxyl group obtained from acrylic acid and / or methacrylic acid or those obtained from acrylic acid and / or methacrylic acid and carboxylic acid ester. Examples of carboxylic acid esters used herein include methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, t-butyl acrylate, acrylic acid 2-hydroxyethyl, 2-hydroxypropyl acrylate, methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, -2-methacrylic acid methacrylate, 2-hydroxypropyl methacrylate, n-methacrylic acid n- Acrylic esters and methacrylic esters such as butyl, isobutyl methacrylate and t-butyl methacrylate are included.

  Methacrylic acid-methyl methacrylate copolymers include, for example, Eudragit L100 or S100. In addition, the pH dependent soluble polymers Eudragit L30D-55 and Eudragit FS30D may be used in the composition. Such pH-dependent soluble polymers dissolve in a specific pH environment, not due to the solubility of the inclusions. Eudragit L30D-55 is used above pH 5.5 while Eudragit FS30D is used above pH 7.0 to dissolve the active ingredient and provide release into the small intestine including the duodenum, jejunum and ileum. Specifically, Eudragit L30D-55 is easily soluble in active ingredients such as gabapentin at a point where the pH in the duodenum of the small intestine exceeds 5.5, and Eudragit FS30D has a pH in the jejunum and ileum of 7.0. Dissolves at points above. The pH dependent soluble polymer may be combined with disintegrants that affect the release of the active ingredient of the formulation or composition.

  The composition of the present invention may further comprise a disintegrant, a flavoring ingredient, a colorant, a sweetener, a binder, a filler, a lubricant, a glidant, a plasticizer or a combination thereof. Core gabapentin or other active agent mini-tablets can be formed using conventional techniques, such as disintegrants including but not limited to croscarmellose sodium or sodium starch glycolate; A binder including but not limited to microcrystalline cellulose and / or a lubricant including but not limited to magnesium stearate may be included. Examples of glidants include, but are not limited to, talc and colloidal anhydrous silica. The powder form of gabapentin may be directly coated or granulated using known dry or wet techniques (molding) and then screened and tableted as necessary to achieve the desired particle size.

  The coating may further contain a plasticizer or an adjuvant, if necessary. Suitable plasticizers for use in the second and third stage coatings include polyethylene glycol, dibutyl phthalate, diethyl phthalate, dibutyl sebacate and citrate esters, phthalates, phosphates, citrates, Adipate, tartrate, sebacic acid, succinate, glycolic acid, glycerolate, benzoate, myristic acid, polyethylene glycol, polypropylene glycol and halogenated phenyl, triacetin, acetylated monoglyceride, grape seed oil, olive oil , Sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerine sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonic acid, dioctyl phthalate Dibutyl sebacate, triethyl citrate, tributyl citrate, glycerol tributyrate, although their mixtures and include the other same type is not limited thereto. Adjuvants suitable for inclusion in these coatings include talc, silicon dioxide, titanium dioxide, colorants, soy lecithin and magnesium stearate. Barrier coats suitable for bringing the active ingredient into various coated minitablets or other forms as described above include, but are not limited to, hydroxypropyl methylcellulose, methylcellulose and shellac.

  The various coatings used above may include multiple colorants to facilitate identification, and the overall appearance of the formulation may also be noticeably multicolored, eg a mixture of various ingredients in a clear capsule And so on.

  The present invention further provides that a portion of gabapentin is released into the stomach (thus providing drugs to the stomach and upper small intestine), and a portion is released in the lower small intestine, some of which are in the duodenum and some in the jejunum and ileum. The purpose is an oral sustained release formulation of gabapentin that has begun to be released rapidly. The formulation is designed to release gabapentin or other active ingredient in three stages. In the first stage, gabapentin or other active ingredient is released rapidly in the stomach. Release of gabapentin or other active ingredients is controlled by a coating of pH independent soluble polymer. In the second stage, gabapentin or other active ingredient is released continuously, mainly in the lower stomach, duodenum and jejunum of the small intestine. The release of gabapentin or other active ingredient is controlled by the coating of the pH independent insoluble polymer and depends on the water permeability of the coating membrane. In the third stage, the release of gabapentin or other active ingredient is delayed to the jejunum and ileum parts of the small intestine where it is coated with a pH-dependent polymer that dissolves at various pH ranging from pH 4 to 10 The active ingredient is released rapidly.

  An immediate (first stage) releasable component that has rapidly released gabapentin upon entering the stomach can be formed by making a mini-tablet using a pH-independent soluble polymer as a coating. These may or may not contain a disintegrant. These mini-tablets are the core mini-tablets described immediately above for convenience, but are sprayed, for example, in a pan coater or fluidized bed system to protect the barrier coat (gabapentin from subsequent interactions with the coating) To play a role). This barrier coat is obtained using a suitable polymer, such as hydroxypropylmethylcellulose, dissolved or suspended in an organic solvent, a mixture of organic solvents, or a mixture or solution of organic solvent and water, dispersion or aqueous emulsion. It is done.

  The mini-tablet coating thickness may be varied at various stages of production so that as much drug is released from the coating as necessary. The thickness of the coating may be 25 to 150 microns.

  The second stage component aims to achieve a sustained release of gabapentin or other active ingredient using a pH independent insoluble polymer as a coating. For convenience, this may be a mini-tablet containing an immediate release component or other suitable gabapentin with a coating of pH independent insoluble polymer. This coating is, for example, one of pH-independent water-insoluble polymers with high permeability and swellability, such as Eudragit RL30D, and pH-independent water-insoluble polymers with low permeability and swellability, such as Eudragit RS30D. Or it may be mixed. This coating may contain plasticizers or adjuvants as required.

  The third stage components include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic methacrylic acid polymers such as Eudragit L30D-55 which dissolves at pH above 5.5 and Eudragit FS30D which dissolves at pH above 7.0. It can be formed from mini-tablets that can be coated with a pH-dependent soluble polymer or enteric material, including but not limited to, containing a disintegrant. Specifically, Eudragit L30D-55, which is a pH-dependent soluble polymer, dissolves in an environment of pH 5.5 or higher and releases the active ingredient, so that it can target the jejunum where the pH changes from 4 to 7 to the duodenum. Since Eudragit FS30D, a pH-dependent soluble polymer, dissolves in an environment of pH 7.0 or higher and releases the active ingredient, it can target the jejunum and ileum with pH higher than 7.

  Such release of gabapentin in the lower small intestine is achieved by coating with a membrane whose solubility is pH-dependent, especially if the coating is with a membrane that dissolves when the pH is above 5.5. It does not change in the duodenum) and dissolves and releases the drug when the pH is above 5.5 in the lower small intestine (ie jejunum and ileum). Thus, when the formulation is coated with a Eudragit S membrane (which dissolves when the pH is above 7), there is little or no release in solutions up to pH 6. However, as the pH rises above 7, the drug dissolves rapidly.

  The present invention is further directed to a formulation of gabapentin that is administered to achieve a predetermined therapeutic effect. Effective doses of gabapentin are used to give patients (patients with renal failure may need a lower dose than patients with normal renal function), symptoms treated, number of doses, and gabapentin Depending on the specific composition according to the invention. Because each person has different needs, the determination of the optimal range of effective dose of gabapentin is within the skill level. Therefore, the preparation can be administered in the morning to suppress symptoms that occur mainly during the day, or at night to suppress symptoms that occur mainly at night, with a single dose of 100 mg to 1500 mg. Or both morning and evening, so the total dose of gabapentin will be 100 to 3000 mg per day. Alternatively, 250 mg to 750 mg may be administered once daily in the morning and / or night for a total of 250 mg to 1500 mg, or 350 mg to 600 mg may be administered once daily in the morning and / or night for a total of 350 mg to 1200 mg.

  There are many formulations suitable for achieving the release profile and other parameters described above. As is evident from these release profiles, the formulation releases an immediate-release first component, a sustained-release second component (acting on the lower stomach and duodenum), and gabapentin content in the lower small intestine such as the jejunum and ileum It can include three components of a third component that is adapted to do so. These three components can be provided in various ways. One such method is to form the last component core to support (eg, be surrounded by) a layer of sustained release component, and the layer of sustained release component further forms a layer of immediate release component. It is formed so as to be supported (for example, surrounded). Alternatively, a properly blended mixture of three different ingredients with desirable release characteristics can be provided to achieve the desired release pattern. The excipients used to provide the desired properties for the three components may be selected from well known ones.

  The present invention further includes the formulation of a formulation according to the invention comprising mixing the active ingredient with one or more suitable excipients, diluents or carriers and forming a suitable sustained release formulation from the resulting mixture. Provide production methods. Each unit dose contains 50% to 95% or 60% to 80% w / w of gabapentin.

  The formulation of the present invention is a multi-dose formulation shaped like a mini tablet. Multi-dose formulations contain multiple small units (tablets), where each unit of the unit dose is dispersed over a wide area of the gastrointestinal tract, thereby avoiding or reducing the concentration of the formulation and causing irritation of the mucosa To do. The multidose shape of gabapentin may be in the form of crystals, granules, pellets, or very small tablets (mini-tablets), some or all of which are coated as follows . The size of the multi-dose-shaped small unit, that is, the size of the single crystal granule, pellet or mini-tablet may be in the range of 0.1 mm to 3.5 mm, but is 5 mm or less. The smaller these small units, the wider they spread within the gastrointestinal tract. In addition, units larger than 5 mm will stay in the stomach, while units smaller than 5 mm will pass through the stomach more like a liquid.

  The description that follows uses gabapentin in the form of mini-tablets, but the same applies to other multi-dose shapes such as crystals, pellets and granules. The coated mini-tablets may be dried with warm air (eg, about 30 ° C.) for an appropriate time (eg, about 30 minutes).

  More specifically, the gabapentin mini-tablet is a first step where the drug is mixed with an appropriate filler, the mixture is granulated using a binder solution, the granules are dried, screened as necessary, and the lubricant and Formed by blending, blending with disintegrant, if necessary, and compressing the mixture using, for example, a rotary or single punch tablet machine with a punch diameter of about 3 mm. Following this, in the second step, a solution / suspension of an appropriate polymer mixture, such as an alcohol or aqueous solution, and optionally plasticizers and / or adjuvants are sprayed, for example in a pan coating machine. A portion of the mini-tablet obtained in one step is coated and dried to form the inner coating of the tablet. The coating applied in this step provides a barrier that protects the active ingredient from subsequent interaction with the coating. After drying, a third step may be performed in which a part of these tablets is further coated to achieve sustained release of the drug. The fourth step of applying the enteric coating by spraying a solution or suspension of the enteric coating substance using a part of the mini-tablet obtained in the second step may be performed. Thereafter, the products of the second and / or third and fourth steps are mixed in a ratio such that the overall release profile is appropriate, and the mixture is packed into, for example, capsules or sachets, or administered orally. Other dosage forms suitable for the preparation may be prepared into a single unit dosage form to produce the final composition.

  The amount of drug released in vivo at each of these times can be predicted using the appropriate combination of in vitro dissolution rate measurements described in US Pharmacopoeia, eg, the test presented in Example 5. Thus, a formulation having the dissolution rate of Example 5 and the release rate as described above is provided.

  Healthy volunteers screened first for acute or recurrent disease classification, prescription, over-the-counter (OTC) or illegal drug use, and / or any other reason not suitable for participation in pharmacokinetic studies, in vivo The amount of drug released can be evaluated.

Volunteers are fasted, sent to treatment, and a catheter is placed in the vein for blood collection. Dosing is done at time zero, and blood samples are collected at predetermined intervals through the catheter for 48 hours thereafter. Plasma is separated from blood by centrifugation and tested for gabapentin content using proven analytical methods. Display data and use pharmacokinetic software to evaluate C _max (maximum plasma concentration), T _max (maximum plasma concentration arrival time), AUC (area under the plasma concentration time curve) and other pharmacokinetic parameters To do.

The present invention also provides a composition wherein the plasma concentration of gabapentin in the AUC drug exceeds 100-200% when the same amount of conventional immediate release gabapentin such as gabapentin sold under the trademark Neurontin® is administered. With the goal. AUC is the plasma concentration (level) data of gabapentin after a single dose of gabapentin in the form of Neurotin® or a formulation according to the present invention (Xenolev-CR ^™ ) to healthy volunteers and / or target populations. Measured by integrating points from zero to infinite time or by integrating equivalent data points for a single dosing interval in a pharmacokinetic steady state where the long-term daily dose is equal to the excretion The T _max is the same or up to 3.0 times T _max when the same amount of conventional immediate release formulation is administered. The time to C _max is desirably 2 to 6 hours after dosing. The maximum plasma concentration (C _max ) of gabapentin is lower than the C _max when the same amount of a conventional immediate release preparation is administered, for example, about 0.5 times that. The clot concentration of gabapentin 8 to 24 hours after dosing is 1.5 to 2.0 times and 3.0 times that of conventional release formulations. Time from C _max to 50% of the _{C max} is 24 hours 2 hours, or 12 hours 3 hours, or estimated from 4 hours and 8 hours. Time from C _max to 50% of the _{C max} is 3 times 1.1 times than that of immediate release gabapentin, or 2.5 times longer formulation from 1.5 envisioned. Absorption of gabapentin (ie, not according to the invention), which is essentially 100% immediate release, is non-linear, and doubling the dose does not double the AUC.

The active ingredient of the present invention or gabapentin is 25-100%, 30-100%, 35-100%, 40-100%, 45% -100%, 50% -100%, 55- C _{max of} 100%, 60-100%, 65% -100%, 70% -100%, 75% -100%, 80% -100%, 85-100%, 90-100%, 95-100% And AUC (absolute bioavailability of the active ingredient). Thus, the bioavailability of gabapentin immediate release formulations varies from more than 70% at low doses to less than 30% at high doses. Thus, if all three ingredients are used in the present invention in appropriate proportions and the dose is doubled or tripled, the AUC is accordingly 0.5 ×, 0.6 ×, 0.7 ×, 0 .8x, 0.9x, 1x (times), l. Increased to lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x or 2.0x sell. Similarly, when the dose is doubled or tripled, C _max is accordingly 0.5 ×, 0.6 ×, 0.7 ×, 0.8 ×, 0.9 ×, 1 × (fold). l. Increased to lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x or 2.0x sell. Thus, the bioavailability of the gabapentin of the present invention is about 1.0 to about 1.5 times that of immediate release gabapentin at low doses and about 1.0 to about 3.0 times that of immediate release gabapentin at high doses. is there.

Conversely, T _max does not change with increasing or decreasing dosage. Equivalence of other pharmacological and physiological situations is also assessed using clot concentrations. For example, it is well known from the medical literature where there is a paper review that food does not affect the plasma concentration of gabapentin after oral administration.

  Thus, when 900 mg of gabapentin (eg, 450 mg × 2 unit dose or 300 mg × 3 unit dose) can be administered twice a day according to the formulation of the present invention, the plasma concentration The maximum and minimum values are about 4.4 mg / ml and 2.3 mg / ml, respectively, the maximum value reaching time is about 5 hours after each administration, and the minimum value reaching time is immediately before the next administration. In contrast, when 900 mg was administered twice daily with an immediate release formulation, it reached its maximum 3 to 4 hours after each dose, the maximum was about 6.3 mg / ml, and the minimum was about 2 mg / ml, the minimum time to reach is again just before the next dose. The highest and lowest values are about 4.7 mg / ml and 1.95 mg / ml, respectively, when the 600 mg immediate release formulation is administered three times a day. Therefore, when 900 mg is administered twice a day (bd), it can be approximated to the maximum value and the minimum value when 600 mg is administered as TID. The figures given in this paragraph are for an average adult.

  In making the final formulation from different ingredients, each ingredient can be administered separately to healthy volunteers and pharmacokinetic analysis can be performed as described above to determine the desired ratio of the ingredients. Simple mathematical calculations can be used to determine the exact ratio of each component to achieve the desired overall release profile of the active ingredient.

  The unit dose of the formulation according to the invention may contain up to 500 mg of gabapentin. One dose administered at any time may include one or more of these unit doses. Unit doses containing 500 mg or more of gabapentin may not be completely followed by the desired drug regimen because some patients are difficult to swallow. The unit dose is a solid shape.

  Hot melt extrusion is known as a method of making polymer-based sustained release pharmaceutical formulations. Suitable polymers include cellulose derivatives, poly (methacrylic acid) derivatives, poly (ethylene-co-vinyl acetate), poly (ethylene), poly (vinyl acetate-co-methacrylic acid), epoxy resins and caprolactones. included. In the hot melt extrusion process, an effective amount of powdered gabapentin is mixed with a polymer and optionally a plasticizer such as polyethylene glycol. Other components may be added as necessary. The ratio of gabapentin to excipient is usually from about 0.01% to about 99.99%, or from about 20% to about 80% w / w, depending on the desired release profile. The mixture is then placed in the hopper of the extruder and passed through an area of the extruder heated at a temperature at which the mixture dissolves or softens to form a matrix in which gabapentin is dispersed. The dissolved or softened mixture is extruded through a die or other similar member, while the mixture (referred to herein as the extrudate) begins to cure. The extrudate from the die is still warm or hot, so it can be easily molded, molded, cut, ground, spheroidized into beads, cut into fibers, tablets, or other Can be processed to the desired physical form.

  In addition, one formulation technique that can be used to obtain the desired release profile is known as hot melt extrusion. Such a formulation has the advantage of being able to incorporate a high proportion of gabapentin.

  The equipment used to make the hot melt formulation handles dry feed and may be any commercially available model with a zone for transporting solids, one or more heating zones and an extrusion die. One such device includes C.I. W. There are two-stage single screw extruders manufactured by Brabender Instruments Incorporated (NJ). It is particularly advantageous if the extruder is equipped with a plurality of independent temperature controllable heating zones.

  Many conditions may be changed in the extrusion process to reach a particularly desirable release pattern. Such conditions include, for example, formulation composition, flow rate, operating temperature, extrusion screw RPM, residence time, die shape, heating zone length and extruder torque and / or pressure. Methods for optimizing such conditions are known to skilled technicians.

  In hot melt extrusion, if a very high molecular weight excipient is used, the processing temperature, pressure and / or torque can be higher than if a low molecular weight excipient is used. By including a plasticizer and, optionally, an antioxidant in a formulation that includes an excipient with a very high molecular weight, the processing temperature, pressure and / or torque can be lowered. Hot melt formulations may be selectively covered with various coatings as described above.

  Administration of gabapentin can be in combination with other suitable therapeutic treatments that are effective in treating the condition being treated. This treatment may be therapeutic, but is often prophylactic.

  For example, humans may be treated patients. The patient may be female or male. Hot flushes in female patients can be the first symptoms of menopausal or postmenopausal hormonal changes. However, hot flashes can be drug-induced by anti-follicular hormone compounds (tamoxifen, leuprolide acetate, etc.), or removal of tissues that produce estrogen (abdominal hysterectomy, bitubular ovariectomy) Etc.) may be induced surgically. Hot flushes in male patients usually occur as a side effect of the treatment of androgen-dependent metastatic prostate cancer. They may be induced surgically (such as bilateral orchiectomy) or by drugs (such as treatment with gonadotropin releasing hormone agonists, leuprolide acetate, etc.).

  The present invention includes reducing the frequency of symptoms, the severity of symptoms, or both with the treatments described herein, including treatment of symptoms due to hormonal fluctuations such as hot flashes.

  Gabapentin acts as an antipyretic and can also adjust the patient's body temperature appropriately. Accordingly, the present invention also provides a method of treating a patient's fever by administering a composition according to the present invention to a patient with fever in a state where fever treatment is effective. The invention includes treating the heat to reduce or eliminate the heat completely after each administration or for a period of time (eg up to about 24 hours after administration).

  Gabapentin can also act as an antiemetic for the treatment of nausea and vomiting. Nausea and vomiting are often induced by stimulation of the central nervous system (CNS) chemoreceptor triggering or vomiting (or vomiting) centers. Such stimuli may be due to afferent stimuli (tactile pharyngeal stimulation, labyrinth disturbances, exercise, increased intracranial pressure, pain, visceral or psychological spread, etc.) or in the blood Emetics (eg, pregnancy, cancer chemotherapy, uremia, radiation therapy, electrolyte imbalance and endocrine disorders or found in the presence of chemical emetics) can also be the cause. Nausea and vomiting are also common postoperative side effects resulting from the use of anesthetics.

  Accordingly, a further aspect of the invention relates to a method of treating nausea and / or vomiting by administering a composition according to the invention to a patient with nausea and / or vomiting in a state where the treatment of nausea and / or vomiting is effective. The present invention includes treating nausea and vomiting to reduce or eliminate the frequency of nausea and vomiting completely or for a period of time (eg, up to 24 hours) after each administration. Administration of the formulation can be done to patients who are or are expected to experience nausea or vomiting.

  US Pat. No. 6,310,098 refers to the use of gabapentin in the treatment of hormonal fluctuations, but greatly emphasizes its use in postmenopausal or menopausal women. The inventors have discovered that gabapentin can be used to treat dysmenorrhea and / or reduce or eliminate discomfort caused by menstruation such as premenstrual tension, mood swings, and pain in the lower abdomen.

  Accordingly, it is a further feature of the present invention to provide the use of gabapentin to prevent or reduce menstrual side effects. Gabapentin for this use may be used before the onset of menstruation or when there are first signs, or may be used to treat side effects after the onset of menstruation. Treatment should continue for the duration of menstruation.

  The features of the present invention further provide for the treatment of side effects of Hodgkin's disease, pheochromocytoma, sleep apnea, allergic symptoms, particularly food allergies, diabetes and hyperthyroidism.

  According to other features of the invention, there is further provided the use of gabapentin for the treatment of women, such as postmenopausal women suffering from urge incontinence, vaginal dryness, ataxia such as dry eye syndrome.

  The following examples illustrate the formulation and characteristics of compositions according to the present invention with respect to dispersion of gabapentin or other active ingredients. Many advances and further aspects of the invention will become apparent when the skilled artisan considers the following examples.

(Example 1-Uncoated gabapentin-Preparation of batch A)
In a high shear mixer-granulator, powdered gabapentin was blended with microcrystalline cellulose (Avicel pH 101). Thereafter, the powder mixture containing the desired amount of gabapentin was granulated using a binder solution of polyvinylpyrrolidone (Kollidon K30 BASF). The binder solution was added to the powder mixture in divided portions over a period of time (usually 5 minutes but depending on the batch size) until the appropriate amount was granulated. Thereafter, the wet granules were taken out of the granulator and dried in a hot air oven (Gallenkamp Hotbox) to form dry granules. Screen dry granules with sieve (1000 μm Erweka), blend with sodium starch glycolate super disintegrant (Explotab), blend with magnesium stearate as lubricant (BP Thew Arnott), analyze drug content, Then, it was sent to a rotary tablet molding machine (F3 Manesty) equipped with a single punch hopper (coaxial cam) or a concave punch with a depth of 3.0 mm to form a tablet (batch A mini tablet) with a thickness of about 2.3 mm. . These tablets have the following composition:
Table 2. Batch A Mini Tablet Composition

これらのバッチＡミニ錠剤の累積的なｉｎ ｖｉｔｒｏ溶解プロフィールは、実施例５に示されている。

The cumulative in vitro dissolution profile of these batch A mini-tablets is shown in Example 5.

Example 2-Gabapentin coated with a pH independent soluble polymer-Preparation of Batch B
Batch B, another batch of mini-tablets, was prepared by a method similar to Batch A. However, Batch B was coated with a barrier coat of a pH-independent soluble polymer Methocel E5 (hydroxylpropylmethylcellulose-Colorcon) that protects the active ingredient from subsequent interactions with the coating (Hutlin Microlab fluid bed coater). Batch B forms the immediate release (first stage) component of the drug delivery system. Batch B tablets have the same composition as Batch A tablets, except that hydroxypropyl methylcellulose constitutes 5% of the total weight of the tablet, with an average thickness of 2.5 mm. The results of the cumulative in vitro dissolution profile of these batch B mini tablets are shown in Example 5.

Example 3-Gabapentin Coated with pH Independent Insoluble Polymer-Preparation of Batch C
To achieve sustained drug release, the Batch B mini-tablets of Example 2 were coated with a Eudragit polymer (Degussa AG) membrane. Mini tablets are placed in a coating machine (bottom spray Wurster) and Eudragit RL30D (water-insoluble polymer with high permeability and swellability which is a pH-independent insoluble polymer, ie a methacrylic acid copolymer having trimethylammonioethyl methacrylate functionality) ) And Eudragit RS30D (water-insoluble polymer with low pH-independent permeability and swellability—methacrylic acid copolymer with trimethylammonioethyl methacrylate functionality). Talc (gridant) and triethyl citrate (plasticizer) were added to the polymer dispersed in water to make a coating suspension. The coating suspension was sprayed onto the surface of the tablet while the tablet was fluidized in the coating machine. The resulting membrane was dried in situ to provide the specified weight percent (10% or 15%) coating material around the mini-tablets (a mixture of RL30D / RS30D 10:90 or 20:80, respectively). .

  Table 3. Batch3 mini-tablet composition

この工程の生成物は、製剤（バッチＣ）の調整放出または持続放出（第二段階）部分を形成する。これらのバッチＣミニ錠剤の累積的なｉｎ ｖｉｔｒｏ溶解プロフィールの結果は、実施例５に示される。

The product of this process forms the modified or sustained release (second stage) portion of the formulation (Batch C). The results of the cumulative in vitro dissolution profile of these batch C mini tablets are shown in Example 5.

Example 4-Gabapentin Coated with pH Dependent Soluble Polymer-Preparation of Batch D
The batch B mini-tablets of Example 2 can be further dissolved in L30D-55 (anionic polymer having methacrylic acid as a functional group) that dissolves at pH above 5.5 or FS30D (Degussa AG, functionalized in methacrylic acid that dissolves at pH above 7.0 Anionic polymer having as a group).

These tablets are based on 15% w / w polymer addition and have the following composition:
Table 4. Composition of batch D mini tablets

これらのバッチＤ遅延放出（第三段階）ミニ錠剤の累積的なｉｎ ｖｉｔｒｏ溶解プロフィールの結果は、実施例５に示される。

The results of the cumulative in vitro dissolution profile of these batch D delayed release (third stage) mini-tablets are shown in Example 5.

Example 5-Evaluation of dissolution characteristics of batches A, B, C and D
USP dissolution apparatus II (paddle) USP 28 2005 [711] was used at 75 rpm to evaluate the in vitro dissolution characteristics of batch A, B, C, D mini tablets. The dissolution media for batches B, C and D of the formulation was a pH 7.6 phosphate buffer solution (BP2004 phosphate buffer pH 7.6). The dissolution results of each component are shown in Tables 3 to 5, respectively, where t ₅₀ is the time to 50% release, t ₉₀ is the time to 90% release, and the ratio is w / w.

（実施例６―バッチＢ、Ｃ、Ｄの様々な製剤の溶解）
バッチＢミニ錠剤を８０％、バッチＣミニ錠剤を１０％（１０％ＲＬ／ＲＳ（２：８））、およびバッチＤミニ錠剤を１０％（１５％Ｌ３０Ｄ―５５）含む製剤（比率はｗ／ｗ）を、ガバペンチンの全量が３７５ｍｇとなるように、サイズ００の硬質ゼラチンカプセル（カプスゲル）に充填した。この製剤全体の溶解試験は、まずｐＨ約１．２（０．１Ｍ ＨＣｌ）で２時間、７５ｒｐｍで実施した；２時間全体にわたってサンプルをとった。１２０分のサンプリングの後、溶解ポットをろ過し、残りの錠剤を除イオン水ですすいだ。その後残りの錠剤を５００ｍｌのｐＨ６．８リン酸緩衝液（ＢＰ２００４）（３７°Ｃ）に加え、７５ｒｐｍでさらに４時間にわたりサンプリングした（図１を参照）。試験を三度繰り返した。

Example 6-Dissolution of various formulations in batches B, C, D
Formulation containing 80% batch B mini-tablets, 10% batch C mini-tablets (10% RL / RS (2: 8)), and 10% batch D mini-tablets (15% L30D-55) (ratio is w / w) was filled into size 00 hard gelatin capsules (caps gel) so that the total amount of gabapentin was 375 mg. The dissolution test for the entire formulation was first performed at pH 1.2 (0.1 M HCl) for 2 hours at 75 rpm; samples were taken over the entire 2 hours. After 120 minutes of sampling, the dissolution pot was filtered and the remaining tablets were rinsed with deionized water. The remaining tablets were then added to 500 ml of pH 6.8 phosphate buffer (BP2004) (37 ° C.) and sampled at 75 rpm for an additional 4 hours (see FIG. 1). The test was repeated three times.

Example 7-Dissolution of various formulations in batches B, C, D
Formulation containing 20% batch B mini-tablets, 40% batch C mini-tablets (10% RL / RS (2: 8)), 40% batch D mini-tablets (15% L30D-55) (ratio is w / w ) Was added to a size 00 gelatin capsule so that the total amount of gabapentin was 375 mg. The same dissolution conditions as in Example 6 were used. The test was repeated three times (see FIG. 2).

Example 8-In vivo pharmacological properties of formulations comprising Batch B, Batch C, and Batch D
The properties of Examples 6 and 7 when used in humans are expected to be as shown in the table below. The table also shows the properties of a single dose of human immediate release (IR) gabapentin 600 mg for comparison. Delayed dissolution in the experiment can be used to predict delayed dissolution in vivo. The numerical values of these simulations reflect the physical properties shown in Example 5 and the dissolution test of FIGS.

＊ＩＲ成分のＣ_ｍａｘへの寄与。
対照標準のデータは、臨床観察からの実際のデータである。他のデータは予測（シミュレーション）値であり、各ケースでＩＲ、ＳＲおよびＤＲを所定通りに混合した数値である。シミュレーションの投与量は３７５ｍｇである。

* Contribution of IR component to _Cmax .
Control data are actual data from clinical observations. The other data is a predicted (simulated) value, and is a numerical value obtained by mixing IR, SR, and DR as prescribed in each case. The simulation dose is 375 mg.

Example 9-Capsules of formulations containing Batch B, Batch C and Batch D are administered to humans
Gabapentin 375 mg was administered to healthy human volunteers via the batch B mini-tablets of example 2, the batch C mini-tablets of example 3, the capsules of the batch D mini-tablets of example 4 and the capsules of examples 6 and 7, Take blood samples at appropriate time intervals. These samples are then analyzed to obtain a pharmacokinetic profile of the batch or capsule being tested.

Example 10-Analysis of gabapentin using reverse phase gradient
Analysis of the gabapentin-dissolved sample is performed by reverse phase gradient HPLC using pH 7.8 phosphate buffer and methanol as the mobile phase in various ratios. Gabapentin is derivatized with orthophthalaldehyde (OPA) to improve UV absorption and phenylalanine is used as an internal standard. A derivatization reaction takes place in the autosampler. Separation is performed on a Zorbax Eclipse AAA 4.6 × 150 mm HPLC column (Agilent part number 994400-902) with a particle size of 5 μm, and UV absorption at 338 nm is detected. The gabapentin in the sample is quantified based on the peak area measurement and calibrated using a known standard concentration of gabapentin.

Example 11-Treatment of hot flush with gabapentin formulation
The following formulation is used to treat a hot flush, for example with 900 mg of gabapentin. Approximately 360 mg of gabapentin is coated with a suitable pH-independent soluble polymer such as hydroxypropylmethylcellulose. Next, 270 mg of gabapentin is coated with two different water-insoluble polymers. One of them has low permeability and the other has high permeability, but both have pH independent swelling properties. For the purposes of this experiment, Eudragit RL30D (high permeability) and Eudragit RS30D (low permeability) meet these requirements. Finally, 270 mg of gabapentin is coated with Eudragit L30D-55 and Eudragit FS30D. The coated gabapentin tablets are dried and packed into a single unit dosage form for oral administration. As a result of ingestion, (1) gabapentin coated with hydroxypropylmethylcellulose is released immediately in the stomach, (2) gabapentin coated with water insoluble is sustained released in the stomach and upper small intestine, and (3) Eudragit L30D-55 (pH 5). The dissolution properties of Eudragit FS30D (dissolved above pH 7.0) delay release of gabapentin into the upper and lower small intestines.

Example 12-Dissolution rate of pregabalin and pregabalin preparation in vitro and in vivo
For testing in vitro and in vivo dissolution rates of pregabalin, the batch B, C, D gabapentin described in Examples 2 to 4 may be replaced with the active ingredient pregabalin. The in vitro test for pregabalin may be performed in the same manner as in Example 5. The in vivo test may be performed using 900 mg of pregabalin preparation. About 360 mg of pregabalin is coated with a suitable pH independent soluble polymer such as hydroxypropylmethylcellulose. Next, 270 mg of pregabalin is coated with two different water-insoluble polymers. One of them has low permeability and the other has high permeability, but both have pH independent swelling properties. For the purposes of this experiment, Eudragit RL30D (high permeability) and Eudragit RS30D (low permeability) meet these requirements. Finally, 270 mg pregabalin is coated with Eudragit L30D-55 and Eudragit FS30D. The tablets of coated pregabalin are dried and packed into a single unit dosage form for oral administration. As a result of oral ingestion, (1) pregabalin coated with hydroxypropylmethylcellulose is released immediately in the stomach, (2) pregabalin coated with water insoluble is sustained released in the stomach and upper small intestine, and (3) Eudragit L30D-55 (pH 5). The dissolution characteristics of Eudragit FS30D (dissolved above pH 7.0) cause delayed release of pregabalin into the upper and lower small intestines.

Figure 1 shows 80% batch B mini-tablets and 10% batch C mini-tablets, the ratio of Eudragit RL30D to Eudragit RS30D is 2: 8, and 15% Eudragit L30D-55 for 10% Batch D mini-tablets. 2 shows the cumulative in vitro dissolution profile of a formulation containing FIG. 1 shows three different tests of gabapentin capsules, where the y-axis shows the amount of gabapentin released in milligrams. FIG. 2 shows 20% batch B mini-tablets and 40% batch C mini-tablets, the ratio of Eudragit RL30D to Eudragit RS30D is 2: 8, and 15% Eudragit L30D-55 in 40% batch D mini-tablets. 2 shows the cumulative in vitro dissolution profile of a formulation containing FIG. 2 shows three different tests of gabapentin capsules, where the y-axis shows the amount of gabapentin released in milligrams.

Claims (27)

(A) an active ingredient selected from the group consisting of gabapentin and pregabalin coated with a pH-independent soluble polymer excipient;
(B) an active ingredient selected from the group consisting of gabapentin and pregabalin coated with a pH independent insoluble polymer excipient;
(C) an active ingredient selected from the group consisting of gabapentin and pregabalin coated with a pH-dependent soluble polymer excipient;
A composition comprising: The composition of claim 1, wherein the pH independent soluble polymer excipient is hydroxypropyl methylcellulose. The composition of claim 1, wherein the pH independent insoluble polymer excipient is selected from the group consisting of Eudragit RL30D, Eudragit RS30D, and combinations thereof. 4. The composition of claim 3, wherein the pH independent insoluble polymer excipient has a thickness of 25 microns to 150 microns. 2. The composition of claim 1, wherein the pH dependent excipient is selected from the group consisting of Eudragit L30D-55, Eudragit FS30D, and combinations thereof. 6. The composition of claim 5, wherein the pH dependent excipient has a thickness of 25 microns to 150 microns. The composition of claim 1 wherein 20% to 60% of the active ingredient is released by the pH-independent soluble polymer excipient within a maximum of 3 hours after dosing. 8. The composition of claim 7, wherein 20 to 60% of the active ingredient is released by the pH independent insoluble polymer excipient within a maximum of 12 hours after dosing. 9. A composition according to claim 8, wherein 15% to 50% of the active ingredient is released by the pH dependent soluble polymer excipient 3 to 10 hours after dosing. The composition of claim 1, wherein 250 mg of gabapentin is a solid unit dosage form. The composition of claim 1, wherein 375 mg of gabapentin is a solid unit dosage form. The composition of claim 1, wherein the active ingredient is released at a _Cmax and an AUC (Absolute Bioavailability of the active ingredient) that is 50% proportional to the dose intensity of the active ingredient. The release of the active ingredient consisting of _{C max} to _{50% C max} within 24 hours 2 hours The composition of claim 12. The composition according to claim 1, wherein the active ingredient is coated in the form of minitablets. The composition of claim 1 further comprising a disintegrant, flavoring ingredient, colorant, sweetener, binder, filler, lubricant, plasticizer or combinations thereof. (A) gabapentin coated with hydroxypropylmethylcellulose;
(B) gabapentin coated with a pH independent insoluble polymer mold release agent selected from the group consisting of Eudragit RL30D, Eudragit RS30D and combinations thereof;
(C) gabapentin coated with a pH-dependent soluble polymer release agent selected from the group consisting of Eudragit L30D-55, Eudragit FS30D and combinations thereof;
A composition comprising: 17. The composition of claim 16, wherein the pH independent insoluble polymer excipient has a thickness of 25 microns to 150 microns. 17. The composition of claim 16, wherein the pH dependent excipient has a thickness of 25 microns to 150 microns. (A) individually mixing the active ingredients with a pH independent soluble polymer;
(B) individually mixing the active ingredients with a pH independent insoluble polymer;
(C) individually mixing the active ingredients with the pH-dependent soluble polymer;
(D) converting the mixture obtained from steps (a)-(c) into mini-tablets;
(E) filling the mixture minitablets obtained from step (d) into a single unit dosage form suitable for oral administration;
A composition made by a process comprising: (A) mixing the active ingredient with a filler;
(B) a step of granulating the mixture of step (a);
(C) blending the granulated mixture of step (b) with a lubricant;
(D) compressing the blended mixture of step (c) into mini-tablets;
(E) The mini-tablet of step (d)
(I) a pH-independent soluble polymer;
Coating with an excipient in the group consisting of (ii) a pH independent insoluble polymer, and (iii) a pH dependent soluble polymer;
(F) drying the coated mini-tablet of step (e);
(G) preparing the coated mini-tablets into a single unit dosage form suitable for oral administration;
A composition made by a process comprising: 17. The composition of claim 16, for treating a neurological disease or injury selected from the group consisting of epilepsy, stroke attacks, and head / brain injury. 17. The composition of claim 16, for treating chronic pain associated with the group consisting of neuropathy, muscle pain, skeletal pain, tardive dyskinesia or migraine, reflex sympathetic dystrophy syndrome (RSD) and fibrosis. object. 17. The composition of claim 16, for treating a mental disorder selected from the group consisting of bipolar disease, panic, anxiety, depression, alcoholism, and timid behavior. 17. The composition of claim 16, for treating menstrual-related symptoms selected from the group consisting of premenstrual tension, mood swings, hot flushes and pain. 17. The composition of claim 16, for treating postmenopausal related symptoms selected from the group consisting of urge incontinence, vaginal dryness and dry eye syndrome. The composition of claim 1, wherein the composition is administered once or twice daily. 17. The composition of claim 16, wherein the composition is administered once or twice daily.

Images