CA2595470A1 - Pharmaceutical formulations and methods of use - Google Patents

Abstract

This invention relates to new pharmaceutical formulations, and to new medical uses, of gabapentin and pregabalin. The formulations may comprise up to three components including an immediate release component, a sustained release component and a delayed release component. The proportion of each component in the formulation may be adjusted to achieve the desired AUC and therapeutic effect following oral administration in a human subject.

Description

Pharmaceutical Formulations and Methods of Use Cross Reference To Related Applications [001] Priority is claimed to U.S. Provisional Patent Application No.
60/645,857, filed on January 21, 2005, which is fully incorporated herein by reference.
Field of the Invention [002] The present invention relates to new pharmaceutical formulations and to new medical uses of gabapentin and pregabalin.
Background of the Invention [003] Gabapentin (U.S. Patent Nos. 4,024,175 and 4,087,544) is a known GABA
(gainma amino-butyric acid) analogue that has been used clinically to treat epilepsy, neuropathic pain and a number of other conditions. Gabapentin also has potentially useful therapeutic effects in other chronic pain states, e.g., muscular and skeletal pain;
in psychiatric disorders, e.g., panic, anxiety, depression, alcoholism and manic behavior; in movement disorders, e.g., multiple sclerosis, action tremors, tardive dyskinesia, etc.; in migraine; in bipolar disease; in muscle spasm and as an analgesic.
More recently, U.S. Patent No. 6,310,098 demonstrated that gabapentin can be used to treat hot flashes (hot flushes).

[004] For its current clinical uses, gabapentin is formulated as an immediate release unit dose tablet or capsule formulation containing 100, 300, 400, 600 or 800 mg of the active agent. These unit doses are usually administered three times a day (TID) with a maximum dosage of 3,600 mg, or more usually 2,700 mg. TID administration is inconvenient and patient compliance with TID dosages is often erratic.
Depending on the condition to be treated the consequences of missing or mistiming a dose can be serious.

[005] U.S. Patent No. 6,723,340 discloses a tablet formulation of gabapentin that is designed to be retained in the stomach and to release the gabapentin in the stomach.
This formulation provides sustained delivery of gabapentin, but only to the stomach and the upper small intestine. This formulation provides prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and enhanced opportunity for absorption in the stomach and upper GI tract rather than the lower portions of the GI tract. Such a formulation must be taken continuously to maintain therapeutic blood concentrations. Intennittent administration would require a delay in time to reach therapeutic blood concentrations so this formulation is not appropriate for a medication to be taken only as required. All absorption of gabapentin in this formulation would be expected to occur in the stomach and/or upper small intestine, particularly the duodenum.

[006] U.S. Patent No. 6,818,787 discloses certain prodrugs of gabapentin and U.S.
Patent No. 6,465,012 discloses certain improved immediate release fonnulations of gabapentin. The former describes an attempt to provide sustained release of gabapentin by attaching a promoiety to the gainma amino and/or the carboxyl group of gabapentin (and other GABA analogs) to improve bioavailability and transport to the brain. This patent describes new chemical entities that bypass the known active transport mechanism for gabapentin and related compounds delaying absorption to further down the intestinal tract. The '012 patent describes a tablet formulation with improved compressibility characteristics, but does not provide any sustained release of gabapentin.

[007] U.S. Patent No. 5,906,832 discloses a variety of continuous administration formulations of a large number of anti-epileptic drugs focusing on osmotic formulations of phenytoin. It also makes passing reference to gabapentin, but does not disclose the specific parts of the gastrointestinal tract where the drug is to be released, and in particular does not disclose rapid release of the gabapentin in the lower small intestine. This formulation does not include any iinmediate release component and must be taken continuously to maintain therapeutic blood concentrations. Intermittent administration would require a delay in time to reach therapeutic blood concentrations so this fonnulation is not appropriate for a medication to be taken only as required.

[008] The drug, pregabalin, has similar properties to gabapentin. Pregabalin is available only in immediate release form with no sustained release formulation currently available. This drug, therefore, is taken TID to maintain therapeutic blood levels. As with gabapentin, TID administration is inconvenient and patient compliance with TID dosage is often erratic. Depending on the condition to be treated, the consequences of missing or mistiming a dose can be serious.

[009] Thus there is a need for a more convenient and improved dosage regimen not only for the established clinical uses, but also for the use in other treatments, e.g., the treatment of hot flashes. There is also a need for formulations of gabapentin which have more appropriate release patterns and/or which provide ei-fllanced bioavailability of the gabapentin and/or do not lead to saturation of the absorption mechanisms of the body, thereby giving the possibility of reducing dosage for a given effect and so reducing the likelihood of adverse effects.

[0010] Throughout the following parts of this specification (unless it is clear from the context that such is not the case), it is to be understood that where we refer to gabapentin, pregabalin can be substituted for the gabapentin.

[0011] We have now found a means of satisfying some or all of these needs.
Summary of the Invention [0012] The present invention is directed to a composition comprising an active ingredient coated by a pH independent soluble polyiner excipient, an active ingredient coated by a pH independent insoluble polymer excipient, and an active ingredient coated by a pH dependent soluble polymer excipient. The active ingredient may be from gabapentin and pregabalin. The pH independent soluble polymer excipient is hydroxypropylmethyl cellulose. 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.

[0013] The present invention is also directed to the composition wherein the pH
independent insoluble polymer has a thickness of 25 to 150 microns. The pH
dependent soluble polymer has a thickness of 25 to 150 microns. The present invention is also directed to the active ingredient in the form of min-tablets coated by either the pH independent insoluble polymer, the pH independent soluble polymer, or the pH dependent soluble polymer. The present invention is further directed to the composition further comprising a disintegrant, a flavor component, a colorizer, a sweetener, a binder, a lubricant, a plasticizer, or a combination thereof.

[0014] The present invention is also directed to an oral controlled-release formulation of gabapentin, adapted to a rapid release in part and a sustained release in part of the gabapentin in the stomach and upper small intestine (thereby providing the drug to the stomach and the upper small intestine) and to release in part in the lower or middle to lower small intestine. The formulation is adapted to release the gabapentin or other active ingredients in three phases. In the first phase, gabapentin or other active ingredicnts is released rapidly in the stomach; in the second phase, gabepentin or other active ingredients is released over a sustained release period mainly in the lower stomach, duodenum and jejunum sections of the small intestine; and in the third phase, the release of gabepentin or other active ingredients is delayed until the jejunum and ileum sections of the small intestine, wherein gabepentin or other active ingredients is released rapidly.

[0015] The present invention is also directed to the composition, wherein 20 to 60%, or from 25 to 50%, or from 35 to 45% of gabapentin or other active ingredients are released in the first phase, e.g., within a period of up to 2 or within 3 hours after dosing. These quantities of gabapentin or other active ingredients will for the most part be released in the stomach. The present invention is also directed to the composition, wherein 20 to 60%, or from 25 to 50%, or from 35 to 45% of gabapentin or other active ingredients are released in the second phase, e.g., within a period of up to 12 or within 6 hours or within 1 to 5 hours after dosing. These quantities of the active ingredient will be, for the most part, released in the lower stomach and upper/middle small intestine including the duodenum and jejunum. The present invention is also directed to the composition, wherein 15 to 50%, or from 30 to 45%, or from 30 to 40% of the gabapentin or other active ingredients are released rapidly after a delay of 3 to 10, or 4 to 8 hours after dosing. These quantities of the active ingredient will be, for the most part, released in the middle to lower small intestine include the jejunum and ileum. One objective of the release of the drug in the third phase is to make drug readily available at a time when the blood levels of the drug released in the earlier phases are likely to be decreasing.

[0016] Another aspect of the present invention is directed to the composition comprising an active ingredient encapsulated by a pH independent soluble polymer excipient, an active ingredient encapsulated by a pH independent insoluble polymer excipient, and an active ingredient encapsulated by a pH dependent soluble polymer excipient wherein 20-60% of the active ingredient is released by the pH
independent soluble polymer excipient within a period up to 3 hours after dosing, wherein 20-60%
of the active ingredient is released by the pH independent insoluble polymer excipient within a period up to 12 hours after dosing, and wherein 15-50% of the active ingredient is released by the pH dependent soluble polymer excipient after a delay of 3 to 10 hours after dosing. The present invention is also directed to the composition wherein 25-50% of the active ingredient encapsulated by a pH independent soluble polymer to be released within a period of up to 2 or 3 hours. The present invention is also directed to the composition wherein 35-45% of the active ingredient encapsulated by a pH independent soluble polymer to be released within in a period of up to 2 or 3 hours. These proportions of the active ingredient released by the pH
independent soluble polymer will occur in the stomach.

[0017] Another aspect of the present invention is directed to the composition wherein 25 to 50% of the active ingredient encapsulated by a pH independent insoluble polymer is to be release over a sustained period up to 12 hours or up to 6 hours, or up or between 1 to 5 hours. The present invention is also directed to the composition wherein 25-35% of the active ingredient is released over a sustained period up to 12 hours or up to 6 hours, or between 1 to 5 hours. These proportions of the active ingredient released by the pH independent insoluble polymer will be released in the stomach and upper and middle sections of the small intestine including the duodenum and jejunum.

[0018] The present invention is also directed to the coinposition wherein 30 to 45% of the active ingredient is released from the pH dependent soluble polymer after a delay of 3 to 10, or 4 to 8 hours. The present invention is also directed to the composition wherein 30 to 40% of the active ingredient is released from the pH dependent soluble polymer after a delay of 3 to 12, or 4 to 8 hours. These proportions of the active ingredient released by the pH dependent soluble polyiner will be released in the middle to lower sections of the small intestine including the jejunum and the ileum of the small intestine. The sum of release of the active ingredient over the three phases or from the soluble, insoluble pH independent polymers and the pH dependent polymer is near 100%.

[0019] The present invention is also directed to a composition wherein the AUC
drug plasma level of the gabapentin is greater than 100 to 200% of that obtainable for an equivalent dose of conventional immediate release gabapentin, e.g., that sold under the trademark Neurontin . The present invention may determine AUC as either by the integration of the data points from time zero to time infinity, when those data points are concentrations (levels) of gabapentin in plasma following single doses of gabapentin either as Neurontin0 or as a formulation according to this invention (Xenolev-CRT"') in healthy volunteers, and/or in the target population, or by the integration of the equivalent data points during one dosing interval at the pharmacokinetic steady state in which long-term daily dosing balances daily elimination.

[0020] The present invention determines its formulation kinetics' Tm,,. as the same as, or up to 3.0 times greater than the corresponding Tmax for an equivalent dose of conventional immediate release formulation. The time to Cmax is from 2 to 6 hours from dosing. The peak plasma concentration of gabapentin (Cmax) is lower than for an equivalent dose of conventional immediate release formulation, e.g., as low as 0.5 of that C,l,ax. The plasma concentration of the gabapentin is up to 3 times, or 1.5 to 2.5 times that provided by a conventional release formulation at 8 to 24 hours after dosing. A formulation wherein the time from Cma,, to 50% of C,,,a,, is from 2 to 24 hours, 3 to 12 hours, or 4 to 8 hours. A formulation wherein the time from Clõa~, to 50 percent of Cma,, is greater than the corresponding time for an immediate release gabapentin by a factor of 1.1 to 3, or 1.5 to 2.5. Gabapentin or other active ingredient formulations that are essentially 100% iinmediate release (i.e., not according to this invention) demonstrate nonlinearity in absorption such that the AUC is not doubled with doubling of the dose. The present invention is also directed to the composition wherein the active ingredient or gabapentin is released at a Cmax and AUC
(absolute bioavailability of active ingredient) that is 25-100%, 30-100%, 35-100%, 40-100%, 45%-100%, 50%-100%, 55-100%, 60-100%, 65%-100%, 70%-100%õ 75 00-100%, 80%-100%, 85-100%, 90-100%, 95%-100%, proportional to the dosage strength of gabapentin or an active ingredient. Thus the bioavailability of gabapentin immediate release formulations ranges from over 70% at lower doses to less than 30% at higher doses. Thus, when the present invention comprises using appropriate percentages of all three components and the dose is doubled or tripled, the AUC may correspondingly increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, lx (times), l.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 from the invention is from about 1.0 to about 1.5 that of immediate release gabapentin at lower doses, and from about 1.0 to about 3.0 that of immediate release gabapentin at higher doses.

[0021] As yet another aspect of this invention is directed to the composition wherein gabapentin or other active ingredient is in a single dose of a formulation totaling 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 of gabapentin, wherein 180 mg to 540 mg, 160 to 480 mg, 140 to 420 mg, 120 to 360 mg, 100 to 300 mg, 80 to 240 mg, 75 to 225 mg, 70 to 210 mg, 65 to 195 mg, 60 to 180 mg, 55 to 165 mg, and 50 to 150 mg of gabapentin or other active ingredient is released in the first phase from the pH
independent soluble polymer. The present invention also is directed to 180 mg to 540 mg, 160 to 480 mg, 140 to 420 mg, 120 to 360 mg, 100 to 300 mg, 80 to 240 mg, to 225 mg, 70 to 210 mg, 65 to 195 mg, 60 to 180 mg, 55 to 165 mg, and 50 to mg of gabapentin or other active ingredient is released over a sustained period during the second phase from the pH independent insoluble polymer. The present invention is also directed to 270 to 405 mg, 240 to 360 mg, 210 to 315 mg, 180 to 270 mg, 150 to 225 mg, 120 to 180 mg, 110 to 170 mg, 105 to 160 mg, 100 to 150 mg, 80 to mg, and 75 to 115 mg of the gabapentin or other active ingredient is released during third phase from the pH dependent soluble polymer. Correspondingly, lower mg ranges will be required, and can be simply calculated from the above data for smaller overall dosages of the drug.

[0022] The present invention is also directed to using the composition in dosing regimens of 500 mg of gabapentin or an active ingredient administered twice daily as a single unit dose or as two unit doses of 250 mg each, or 900 mg of gabapentin or active ingredient administered twice daily as three unit doses of 300 mg each or as two unit doses of 450 mg each or 750 mg of gabapentin or active ingredient administered twice daily as single unit doses or as two unit doses of 375 mg each.

[0023] As yet another aspect of the present invention is directed to a composition produced by a process comprising the steps of separately mixing an active ingredient a pH independent soluble polymer, a pH independent insoluble polymer, and a pH
dependent soluble polymer, forming the resulting mixtures into mini-tablets, and filling the mixture of mini-tablets into a capsule suitable for oral administration. The present invention is also directed to a composition produced by the process comprising the steps of mixing an active ingredient with a filler, granulating the mixture, blending the granulated mixture with a lubricant, compressing the blended mixture into mini-tablets, coating the mini-tablets with excipients from a pH
independent soluble polymer, a pH independent insoluble polymer, and a pH
dependent soluble polymer, drying the coated mini-tables, and formulating the mixture of coated mini-tablets into a single unit dosage form suitable for oral administration.

[0024] The present invention is also directed to a composition comprising gabapentin or pregabalin or other active ingredient used for the treatment of a neurological disorder or injury selected from the group consisting of epilepsy, in the treatment of seizures secondary to stroke, head/brain trauma or peri- or post-operative neurosurgery, multiple sclerosis, or involuntary action tremors. The present invention is also directed to a composition comprising gabapentin or pregabalin or other active ingredient used for the treatment of chronic pain associated with neuropathic, muscular and skeletal pain, tardive dyskinesia or migraines, reflex sympathetic dystrophy syndrome (RSD) [also known as complex regional pain syndrome (CRPS)] and fibromyalgia or muscle disorders. The present invention is also directed to a composition comprising psychiatric disorders such as, but not limited, to bipolar disease, panic, anxiety, depression, alcoholism and manic behavior.
The formulations or compositions may also be used to treat the conditions described in U.S. Patent No. 6,310,098 (which is incorporated herein by reference) and in particular hormonal variation in menopausal other related syndromes of hot flashes, fever, nausea and emesis. The present invention is also directed to treatment of symptoms of post menopausal woman selected from the group consisting of urge incontinence, vaginal dryness, and dry eye syndrome.
Brief Description of the Drawings [0025] Figure 1 shows the cumulative in vitro dissolution profile for a formulation comprising 80% percent of the Batch B mini-tablets, 10% of the Batch C mini-tablets wherein Eudragit RL30D and Eudragit RS30D are at a ratio of 2:8, and 10% Batch D
mini-tablets with a 15% Eudragit L30D-55 content. Figure 1 shows three different tests of the gabapentin capsules with milligrams of gabapentin released shown on the y axis.

[0026] Fig. 2 shows the cumulative in vitf o dissolution profile for a formulation comprising 20% percent of the Batch B mini-tablets, 40% of the Batch C mini-tablets wherein Eudragit RL30D and Eudragit RS30D are at a ratio of 2:8, and 40% Batch D
mini-tablets with a 15% Eudragit L30D-55 content. Figure 2 shows three different tests of the gabapentin capsules with milligrams of gabapentin released shown on the y axis.

Detailed Description [0027] To fulfill the need for formulations of gabapentin which have more appropriate release patterns and/or which provide enhanced bioavailability of the gabapentin and/or do not lead to saturation of the absorption mechanisms of the body, thereby giving the possibility of reducing dosage for a given effect and so reducing the likelihood of adverse effects, the present invention is directed to a composition comprising an active ingredient coated by a pH independent soluble polymer excipient, an active ingredient coated by a pH independent soluble polymer excipient, and an active ingredient coated by a pH dependent soluble polymer excipient.
The present invention is directed to a composition or formulation comprising an active ingredient such as gabapentin, and the drug pregablin.
Other ingredients that could be used in the composition or formulation of the present invention include, but are not limited to the table below.

Table 1 150 of the most prescribe active ingredients ~.._,... ..............._.. ~ ~...~.._._._.. ~.....__ 1. Hydrocodone* 2. Lexa~ro 3. Vicodin 4. anax 5. d~........~.~._.... ~...~
............. .........._.,_............... _........ _.
6 Effexor ~Zoloft axil Wellbutrin Bextra Neurontin LipitorOcodone {oc ~~~_. ~~_..
.._.. __. _. _ . ... ~._.... ~ . -......~.. [Ambien __..~ _.._.__........._..
~.. .
Valium rNaProxenTramadolM[ "- orphine .............
_..._.. ....._...... ..,.........._..._......_.....n..._....... _....
_ Celexa Tylenol Oxycontm ~Celebrex Prednisone Prozac Ultracet Protonix Soma Atenolol ..
.....
. ... .. ........_ _~..._._.._ .
.......,_ ........... _ ................. .__.._---- ..... ......... _. _ ...
. ..........._._......__....._.... . . . .
._.__._......._......... IL0Lisinopril Darvocet ipro Levauin :Ativan Fexium Cyclobenza rp ine Ultram Alprazolain' .
........... ........... ...._._._...._ .._._...... ........................
.... .............
Trazodone Norvasc Biaxin Codeine Clonazepam Toprol Zyprexa Zocor Zithromax F~i:o:van ~.-.
.._ .........____..
;_._.m..__._ _._...._..._..__nr_.__._..._......_._._.__....._.~... .' . . .
_~_._.,_..~. .
Skelaxin Klonopin Lorazepam De akote Diazepam Albuterol Topamax Seroquel Amoxicillin~ Ritalin revacid Methadone Au~mentin -Ztia - _ C~halexin FE

_.-Flexeril Via~ra ~Z ec Synthroid Promethazine , ?.
~~ [i3rcYcline Phentermine Plavix MetforminAn Remeron ~Metoprolol ~~ i~Ibuprofen .. .
__._ ........._..._.__._ . ...._ _. ...__.._._._.__ ~ .... .... . . .... .
....... .. _ .._..... gHydrochlorothiazide Crestor Prilosec Acetaminophen Altace .._.. , ~ .. ....___-__......._....._._ .._..
{iiiim ,.... . .
Concerta Alleg a Clonidine trattera . . ..... . . .. .. .. . ....... . . ..........._....__.._,._..__.
i............_........_....Norco __........ _._ ....................._...,...._....._........_... _._.......................
Elavil ...... _..........................__..I......<......_........._.._ Abilify......_ _. ..... m.............-. Mobic Risperdal E .. .... .~,. ' ~ . _........
Ranitidine Lasix [-. Fluoxetine ~Levitra ~ Coumadin .. ...... . ....... .. ... .......... ..,...... ~ ..~.__ . .......... ...
.., ~.~ .. .. .. ..m.. ...
................... ........._...........,...... ._... ... _.,. ......_.~_.
_.a_._-. .. . ........ . ~. . ._..e.. .. . .
Hydroxyzine Phenergan Lamictal Verapamil Diclofenac Guaifenesin Aciphex Furosemide lEntex Metronidazole _..... ~ __. ..__ _.__ __.._.~., ._.. _..__...____...~.._...~ .,_._ ,._.._ ~..
.. ~ __._.._._, ___._.. .. _.~. _ _ Carisoprodol IPropoxyphene Insulin Digoxnn IZanaflex Clindamycin ~Trileptal Buspar Keflex Bactnm . .._. _..~. .._ _._ .... ~.._..._ _..._~ ..~.. _._k ._._.. ar Baclofen Endocet Dilantin F~loinax Bemc _..._......_....._...._._....._....._..........__.....__.. _.__ ~ _ ._. . .. .
.......... _.._....... . . ............................. .._......._.._ ..............
Avelox Lotrel Inderal Provigil ~Glucophage Demerol [Zantac ~ ~Fentanyl ~ Premarin ~~~Fosamax __....._.._.._._..._.__._,_.._...._..._......_.._._...._...._...,.._........_..
........__,__._._,.___~...._..
.___._..__.___._.....___._.._.___...._....__._._ ..__,__........_.....__...__.....____......__._._ __ ........_____.._,...__.... _ ............... _ Penicillin Claritin R~e lan. Enalapril Tricor Methotrexate 'Pravachol Amiodarone Zelnorm ~ ~ rythrom~cin _..__.~.._._.~ _.. _..._.._.~.._... ~ ...___.._.
146. HCTZ Potassium ,Te retol Omeprazole ~Meclizine#

[0028] The composition's active ingredients including gabapentin may be applied for uses by any convenient means, including orally using a formulation according to the invention for the treatment of neurological disorders or injury, treatment of chronic pain, treatment of psychiatric disorders or mental disease, treatment of menstrual related symptoms, and post-menopausal related symptoms. The dosage for these uses will generally be lower than that used for epilepsy and will generally be in the range of 100 to 3,000 mg per day which may be given in divided doses up to 2 or 3 times per day. When an immediate release formulation, or a formulation according to the invention, is used, the dosages are as given below in relation to the formulation according to the invention.

[0029] When drugs (i.e., active ingredients in particular pharmaceutical formulations) are administered orally, they necessarily pass through the gastrointestinal tract.
Active ingredients in a formulation or composition of the present invention first enter the higlily acidic enviromnent of the stomach, where the pH ranges from pH 1-3. The small intestine, comprising of the duodenum, jejunum and ileum, is predominantly where nutrient/drug absorption occurs. The small intestine progresses from a highly acidic environment (- pH 4-5 in the duodenuin) to a less acidic environment (-pH 6-7 in the jejunum and ileuni). Based on the highly acidic environment, formulation which prevent the dissolutions of drugs or active ingredient in the stomach can provide a sustained and delayed release of the drug while in the small intestine.

[0030] As used in the application herein, an excipient is defmed as an inert substance used as a diluent or vehicle for a drug. The excipient may be in a form of a solid forming coating, or a liquid coating, or semi-solid capsule that coats an active drug ingredient such as gabapentin. The excipients in the present invention are defined in three different coating forms being a pH independent soluble polymer, a pH
independent insoluble polymer, and a pH dependent soluble polyiner. The pH
dependent soluble polymer is soluble in a particular pH environment.
Accordingly, the soluble polymer becomes soluble at a particular pH rather than a soluble at any pH.

[0031] A pH independent soluble polymer is defined as pharmaceutically grade carrier or vehicle that readily dissolves in the soluble enviromnent including the stomach, and include, for example and without limitation, calcium phosphate dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, cellulose derivatives, dextrose, gelatin, lactose, anhydrous lactose, spray-dried lactose, lactose monoliydrate, mannitol, starches, sorbitol and sucrose. Further examples include acacia, hydroxypropylmethylcellulose, hydroxypropylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, polypropylene, dextrans, dextrins, hydroxypropyl-beta-cyclodextrin, chitosan, copolymers of lactic and glycolic acid, lactic acid polymers, methacrylic acid co-polymer containing acidic groups, glycolic acid polymers, polyorthoesters, polyanyhydrides, polyvinyl chloride, polyvinyl acetate, polyvinylalcohol, polyethylene glycol co-polymer, ethylene vinyl acetate, lectins, carbopols, silicon elastomers, polyacrylic polymers, maltodextrins, fructose, inositol, trehalose, maltose raffinose, and alpha-, beta-, and gamma-cyclodextrins, suitable mixtures of the foregoing, and the like. These polymers are susceptible to dissolution in low pH (pH 1-5), middle pH (pH 5-7.5), or high pH (pH 7.5 to 10) environments of the gastrointestinal tract. These polymers are readily soluble and upon contact in a liquid medium dissolve and release gabapentin or other active ingredients.

[0032] A pH independent insoluble polymer is also used in the coinposition to coat the active ingredient. A pH independent insoluble polymer is a pharmaceutically grade carrier or vehicle that coats an active drug ingredient such as gabapentin.
Examples of the pH independent insoluble polymer include, but are not limited to, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, aminoacryl methacrylate co-polymer E including methyl cellulose, ethyl cellulose, or a combination thereof and aminoalkylmethane acrylate co-polymers RS and RL, including Eudgragit RL30D, and Eudragit RS30 D. The pH independent insoluble polymer may have a low perineability and swelling such as Eudragit RS30D or a pH
independent insoluble polymer having a high perineability and swelling such as Eudragit RL30D. Such variations in the permeability of the insoluble pH
independent membrane affect the release kinetics of the active ingredient or gabapentin allowing for a sustained release up to 12 hours after original dosing in the stomach and upper small intestine including the duodenum.

[0033] A pH dependent soluble polymer is a pharmaceutically grade carrier or vehicle that coats an active ingredient such as gabapentin. Examples of the pH
dependent soluble polymer include, but are not limited to, natural polymers such as purified shellac and white shellac, synthetic polyniers such as cellulose derivative polymers:
hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxyinethylethyl cellulose, cellulose acetate trimellitate, cellulose acetate phthalate, acrylic polymers such as those obtained from acrylic acid and/or methacrylic acid, polymers obtained from acrylic acid and/or methacrylic acid and a carboxylic ester, and polyvinyl alcohol type polymers such as polyvinyl acetate phthalate. In addition, pH dependent soluble polymers include those with a carboxyl group obtained from acrylic acid and/or methacrylic acid or those obtained from acrylic acid and/or methacrylic acid and a carboxylic ester. Examples of the carboxylic ester used herein include acrylic esters and methacrylic esters such as methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, t-butyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate and t-butyl methacrylate.

[0034] Examples of methacrylic acid-methyl methacrylate co-polymers include Eudragit L100 or S100. In addition, the pH dependent soluble polymer Eudragit L30D-55 and Eudragit FS30D may be used in the composition. Such pH dependent soluble polymers dissolve in a certain pH environment rather than upon the soluble contents. Eudragit L30D-55 can be used for dissolution of the active ingredient above pH 5.5, while Eudragit FS30D may be used for dissolution of the active ingredient above pH 7.0 to provide a release in the small intestine including the duodenum, jejunum, and ileum. Specifically, Eudragit L30D-55 would be susceptible to dissolution of the active ingredient such as gabapentin when pH changes to over pH
5.5 at some point in the duodenum of the small intestine while Eudragit FS30D
would dissolve above pH 7.0 at some point in tlle jejunum and ileum. The pH
dependent soluble polymer may also be combined with a disintegrant, which will affect the release of the active ingredient of the formulation or composition.

[0035] The composition of the present invention may further comprise a disintegrant, a flavor component, a colorizer, a sweetener a binder, a filler, a lubricant, a glidant, a plasticizer or a combination thereof. The core mini-tablets of gabapentin or other active agents may be formed using conventional techniques, e.g., they may contain disintegrants; including, but not limited to, croscannellose sodium or sodium starch glycolate; binders, including, but not limited to, polyvinylpyrrolidone;
fillers including, but not limited to microcrystalline cellulose and/or lubricants including, but not limited to, magnesium stearate. Examples of glidant include, but are not limited to, talc, and colloidal anhydrous silica. Gabapentin in powder form may be coated directly or may be granulated, using known dry or wet techniques (compacting), followed if desired by screening and tabletting to obtain the desired particle size.

[0036] The coating may, if desired also contain a plasticizer or adjuvant.
Suitable plasticizers for use in the second and third phase coating including but not limited to, polyethylene glycol, dibutyl phthalate, diethyl phthalate, dibutyl sebecate and citric acid esters,phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates, myristates, polyethylene glycols, polypropylene glycols, and halogenated phenyl, triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, mixtures thereof, and the like.. Suitable adjuvants for inclusion in these coatings include talc, silicon dioxide, titanium dioxide, coloring agents, soya lecithin and magnesium stearate. Suitable barrier coatings for placing each of the various coated mini-tables or other power forms of the active ingredient as described above include, but are not limited to, hydroxypropylmethylcellulose, methycellulose, and shellac.

[0037] The various coatings used above may contain different coloring agents to enable them to be readily distinguished and also to provide a distinguishing multi-colored appearance to the overall formulation, e.g., where the mixture of the various components is put up in a clear capsule.

[0038] The present invention is also directed to an oral controlled-release formulation of gabapentin, adapted to release part of the gabapentin in the stomach (thereby providing the drug to the stomach and the upper small intestine) and to begin to rapidly release in part in the lower small intestine including in part in the duodenum, and in part in the jejunum and ileum. The formulation is adapted to release the gabapentin or other active ingredients in three phases. In the first phase, gabepentin or other active ingredients is released rapidly in the stomach. The release of gabapentin or other active ingredients is controlled by a pH independent soluble polyiner coating. In the second phase, gabepentin or other active ingredients is released over a sustained period mainly in the lower stomach, duodenum and jejunum sections of the small intestine. The release of gabapentin or other active ingredients is controlled by the pH independent insoluble polymer coating and is dependent upon the water penneability of said coating membrane. In the third phase, the release of gabepentin or other active ingredients is delayed until the j ejunum and ileum sections of the small intestine, wherein gabepentin or other active ingredients is released rapidly dependent upon the pH dependent polymer coating that dissolves in various pH's ranging from 4 to 10.

[0039] The immediate (first phase) release component, which are designed to release the gabapentin quickly when ingested into the stomach, may be fonned by making mini-tablets using a pH-independent soluble polymer as the coating. These may or may not incorporate a disintegrant. These mini-tablets, which may for convenience be the core mini-tablets described immediately above, may be provided with a barrier coat (which can serve to protect the gabapentin from interaction with any subsequent coatings), e.g., in a pan coater or by spraying in a fluid bed system. This barrier coat may be provided by use of a suitable polymer, e.g., hydroxpropylmethylcellulose, dissolved or suspended in an organic solvent, or a mixture of organic solvents, or a mixture of organic solvents and water, or in solution, dispersion or aqueous emulsion.

[0040] The thickness of the mini-tablet coating at the various stages of its production may also be varied to achieve the required release characteristics of the drug through the coating. The coatings may have a thickness of 25 to 150 microns.

[0041] The second phase component is designed to achieve a timed release of the gabapentin or other active ingredient using a pH independent insoluble polymer as the coating. This may, for convenience, be the immediate release component or some other suitable gabapentin-containing mini-tablet, carrying a coating of pH
independent insoluble polymer. This coating may for example be one or a mixture of a water-insoluble polymer having high permeability and swelling that is pH
independent, e.g., Eudragit RL30D, and a water-insoluble polymer having low perineability and swelling that is pH independent, e.g., Eudragit RS30D. This coating may, if desired, contain a plasticizer or adjuvant.

[0042] The third phase component may be formed from mini-tablets, which may contain a disintegrant, which are coated with a pH-dependent soluble polymer or enteric material including, but not limited to, cellulose acetate phthalate, hydroxypropylmethylcellullose phthalate or an anionic methacrylic acid polymer such as Eudragit L30D-55 for dissolution above pH 5.5, or Eudragit FS30D for dissolution above pH 7Ø Specifically, the pH dependent soluble polymer Eudragit L30D-55 dissolves and releases the active ingredient in environments with pH 5.5 or above, and can be targeted for the duodenum to the jejunum wherein the environmental pH
changes from 4 to 7. The pH dependent soluble polymer Eudragit FS30D dissolves and releases the active ingredient in environments with pH 7.0 or higher, and can be targeted for the jejunum and ileum, wherein the pH environment changes to over 7.

[0043] This release of the gabapentin in the lower small intestine is achieved by coating with a membrane with pH-dependent solubility, and more particularly with a membrane which is soluble at a pH greater than 5.5, so that it remains intact in the stomach and the upper part of the small intestine (duodenum) and dissolves when a pH of greater than 5.5 is reached in the lower small intestine (i.e., the jejunum and ileum), thus releasing the drug. Thus, if the formulation is coated with an Eudragit S
membrane (which dissolves at a pH higher than 7), there is little or no release in solutions up to pH 6. But when the pH increases to greater than 7, a rapid dissolution of the drug occurs.

[0044] The present invention is also directed to a formulation of gabapentin administered such that it is effective for the desired treatment. Effective amounts of the gabapentin will depend upon the patient (patients with renal insufficiency may need lower doses than those with normal kidney function), the condition to be treated, the frequency of administration, and the specific composition according to the invention used to deliver the gabapentin. While individual needs vary, determination of optimal ranges of effective amounts of gabapentin is within the skill of the art.
Thus, the fonnulation may be administered in doses of between 100 and 1500 mg to be taken either in the morning for the suppression of symptoms occurring mostly during the daytime, or at night for the suppression of symptoms occurring mostly at night, or both, thus giving a total daily dose of from 100 to 3000 mg of gabapentin.
Doses of 250 to 750 mg morning and/or night giving a total daily dose of 250 to 1500 mg, and doses of 350 to 600 mg morning and/or night giving a daily dose of 350 to 1200 mg may also be administered.

[0045] There are many formulations suitable for achieving the release profiles, and other parameters, which are described above. As will be appreciated from these release profiles, the formulation may have three components, a first immediate release component, a second sustained release component (over the lower stomach and duodenum) and a third component designed to release its gabapentin content in the lower small intestine such as the jejunum and ileum. The provision of these three components may be achieved in a number of different ways. One such way is by forming a core of the last component bearing (e.g., surrounded by) a layer of the sustained release component, which in turn bears (e.g., is surrounded by) a further layer of the immediate release component. Alternatively, the desired release pattern may be achieved by providing a mixture, in appropriate proportions, of three separate components having the desired release characteristics. The excipients to be used in the three components may be chosen from those known in the art to provide the desired properties to that component.

[0046] According to the invention we also provide a process for the production of a formulation according to the invention, which comprises mixing the active ingredient with one or more suitable excipients, diluents or carriers and forming the resulting mixture into a suitable controlled release formulation. Each unit dose contains from 50 to 95%, or 60% to 80% w/w of the gabapentin.

[0047] The formulation of the present invention is a multidose formulation in the form of mini tablets for example. Multidose formulations comprise a plurality of small units (tablets) in which the individual units that make up a unit dose spread in a wide area of the gastrointestinal tract thus avoiding or reducing any possible problems of irritation of the mucosa due to a high concentration of the formulation.
Multidose forms of the gabapentin may be in the form of crystals, granules, pellets or tablets of very small dimensions (mini-tablets), some or all of which are coated as described below. The size of the small units of the multidose forms, that is of the single crystals, granules, pellets or mini tablets, may vary from 0.1 to 3.5 mm, but does not exceed 5 mm. The smaller these small units are, the wider the distribution in the gastrointestinal tract. In addition, while units greater than 5 min are retained in a fiill stomach, units smaller than 5 mm pass through the stomach much more rapidly and in a similar way to liquids.

[0048] The description that follows refers to gabapentin in mini-tablet form, but it is also valid for the other multidose forms, e.g., crystals, pellets and granules. The coated inini-tablets may be dried with hot air, e.g., at about 30 C, for a suitable time, e.g., about 30 minutes.

[0049] More specifically, mini-tablets of gabapentin may be formed by a first step involving mixing the drug with a suitable filler, granulating the mixture using a binder solution, drying the granules and, if desired screening them, blending with a lubricant, and where desired a disintegrant, and compressing the mixture, e.g., using a rotary or single punch tableting machine with punches having a diameter of say 3 mm.
This is followed by a second step in which some of these mini-tablets are coated, e.g., by spraying in a coating pan, with a solution/suspension, e.g., an alcoholic or aqueous solution, of a suitable polymer mixture, optionally together with a plasticizer and/or adjuvant and drying to form an inner coating on the tablets. The coating applied in this step provides a barrier to protect the active ingredient from interacting with subsequent coatings. After drying, some of these tablets may be subjected to a third step in which a further coating designed to achieve a timed release of the drug is applied. Some of the mini-tablets product of the second step may be provided, in a fourth step, with an enteric coating, e.g., by spraying the mini-tablets with a solution or suspension of enteric coating material. The final composition may then be made up by mixing the products of the second and/or third and fourth steps in such proportions as to give the desired overall release profile, and then formulating the mixture into a single unit dosage form, e.g., by filling into capsules or monodose sachets, or in other phannaceutical forms suitable for oral administration.

[0050] The ainount of drug released in vivo at each of these times may be predicted by use of the in vitro dissolution rate method described in the US
Phannacopoeia, e.g., a suitable combination of the tests set out in Example 5. Accordingly, we provide formulations having dissolution rates in Example 5 and corresponding to the percentages to be released as set out above.

[0051] The amount of drug released in vivo can be evaluated in healthy volunteers who are first screened for acute or recurrent illness, for prescription, over the counter (OTC) or illegal drug use, and/or for any other reasons making them unsuitable for participation in pharmacokinetic studies.

[0052] Having fasted, volunteers are assigned to the treatment to be received and equipped with an in-dwelling venous catheter for blood collection. The doses are given at time zero, and blood samples are collected through the catheter at pre-determined intervals over the next 48 hours. The plasma is separated from the blood by centrifugation, and then assayed for gabapentin content using a validated analytical method. Data are displayed, and evaluated using pharmacokinetic software for C,x,~
(maximum concentration), Tm,,, (time to maximum concentration), AUC (area under the curve) and other pharmacokinetic parameters.

[0053] The present invention is also directed to a composition wherein the AUC
drug plasma level of the gabapentin is greater than 100 to 200% of, that obtainable for an equivalent dose of conventional immediate release gabapentin, e.g., that sold under the trademark Neurontin . AUC is evaluated either by the integration of the data points from time zero to time infinity, when those data points are concentrations (levels) of gabapentin in plasma following single doses of gabapentin either as Neurontin or as a formulation according to this invention (Xenolev-CRT"") in healthy volunteers, and/or in the target population, or by the integration of the equivalent data points during one dosing interval at the pharmacolcinetic steady state in which long-term daily dosing balances daily elimination. The Tmax is the same as, or up to 3.0 times greater than, the corresponding Tmax for an equivalent dose of conventional immediate release formulation. The time to C,7,a, is desirably from 2 to 6 hours from dosing. The peak plasma concentration of gabapentin (Cmax) is lower than for an equivalent dose of conventional immediate release formulation, e.g., as low as 0.5 of that C,,,ax. The plasma concentration of the gabapentin is 1.5 to 2.0 to 3.0 times that provided by a conventional release formulation at 8 to 24 hours after dosing.
A
formulation wherein the time from Cma3, to 50% of C,,,a,, is from 2 to 24 hours, or 3 to 12 hours, or 4 to 8 hours is envisioned. A formulation wherein the time from Cmax to 50 percent of C,7,a, is greater than the corresponding time for an immediate release gabapentin by a factor of 1.1 to 3, or 1.5 to 2.5, is further envisioned.
Gabapentin formulations that are essentially 100% immediate release (i.e., not according to this invention) demonstrate nonlinearity in absorption such that the AUC is not doubled with doubling of the dose.

[0054] The present invention active ingredients or gabapentin is released at a C,t,ax and AUC (absolute bioavailability of active ingredient) that is 25-100%, 30-100%, 35-100 / , 40-100%, 45%-100%, 50%-100%, 55-100%, 60-100%, 65%-100%, 70%-100%õ 75%-100%, 80%-100%, 85-100%, 90-100%, 95%-100%, proportional to the dosage strength of gabapentin or an active ingredient. Thus the bioavailability of gabapentin immediate release formulations ranges from over 70% at lower doses to less than 30% at higher doses. Thus, when the present invention comprises using appropriate percentages of all three components and the dose is doubled or tripled, the AUC may correspondingly increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, lx (times), l.lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, or 2.0x. By the same standard, when the doses are double or tripled, the Cma,, may correspondingly increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, lx (times), l.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 from the invention is from about 1.0 to about 1.5 that of immediate release gabapentin at lower doses, and from about 1.0 to about 3.0 that of immediate release gabapentin at higher doses.

[0055] In contrast, T~õa,. should be unchanged with increase or decrease in dose.
Equivalence in other pharmacological and physiological situations is also evaluated using plasma concentrations. For example, it is well known from peer-reviewed medical literature that there is no effect of food on the concentrations of gabapentin in plasma following oral administration.

[0056] Thus, a dose of a formulation according to the invention providing 900 mg of gabapentin (which may be administered as, e.g., 2 unit doses of 450 mg or 3 unit doses of 300 mg each) and given twice daily can give plasma peaks and troughs, after dosing to steady state, of approximately 4.4 and 2.3 micrograms per ml respectively, with the peaks approximately 5 hours after each dosage and the troughs just before each subsequent dose. In contrast, an immediate release dosage of 900 mg given twice daily will give a peak at 3 to 4 hours after each dosage the peak being approximately 6.3 micrograms per ml, and the troughs being approximately 2 micrograms per ml, the trough again being just before the subsequent dose. The peaks and troughs with 600 mg of an immediate release formulation given three times per day have values of approximately 4.7 and 1.95 micrograms per ml respectively.
Thus a formulation according to the invention administered as 900 mg doses twice a day (bd) can match closely the peaks and troughs of 600 mg doses administered TID.
The values given in this paragraph are for an average adult human.

[0057] When the final formulation is to be made up of separate components, the desired proportion of those components can be determined by administration of each component separately to healthy volunteers and performing the pharmacokinetic analyses as described above. Straightforward mathematical calculations can then be used to define the exact proportion of each component to achieve the desired overall release profile of the active ingredient.

[0058] Unit doses of the formulation according to the invention can contain 500 mg or less of gabapentin. One or more of these unit doses may be used to make up the dose to be administered at any one time. Unit doses containing more than 500 mg of gabapentin can be difficult for some patients to swallow and may lead to erratic compliance with the desired dosage regimen. The unit doses are in solid form.

[0059] Hot-melt extrusion is known as a method for producing polymer-based sustained-release pharmaceutical formulations. Suitable polymers include derivatized cellulose, poly(methacrylate) derivatives, poly(ethylene-co-vinyl acetate), poly(ethylene), poly(vinyl acetate-co-methacrylic acid), epoxy resins and caprolactones. In the hot-melt extrusion process an effective amount of powdered gabapentin is mixed with a polymer, and optionally with a plasticizer such as polyethylene glycol. Other components may be added as required. The ratio of the gabapentin to the excipients is generally 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 an extruder and passed through the heated area of the extruder at a temperature that will melt or soften the mixture to form a matrix throughout which the gabapentin is dispersed. The molten or softened mixture is then extruded through a die, or other such element, at which time, the mixture (now called the extrudate) begins to harden. Since the extrudate is still warm or hot upon leaving the die, it may be easily shaped, molded, chopped, ground, spheronized into beads, cut into strands, tabletted or otherwise processed to the desired physical form.

[0060] A further formulation technique that may be used to provide the desired release profile is that known as hot melt extrusion. Such formulations have the advantage that they enable the incorporation of high percentages of gabapentin.

[0061] The equipment used to produce the hot melt formulation may be any commercially available model equipped to handle dry feed and having a solid conveying zone, one or more heating zones, and an extrusion die. A two-stage single screw extruder, such as that manufactured by C.W. Brabender Instruments Incorporated (NJ) is one such apparatus. It is particularly advantageous for the extruder to possess multiple separate temperature controllable heating zones.

[0062] Many conditions may be varied during the extrusion process to arrive at a particularly desired release pattern. Such conditions include, by way of example, composition of the formulation, feed rate, operating temperature, extruder screw RPM, residence time, die configuration, heating zone length and extruder torque and/or pressure. Methods for the optimization of such conditions are known to the skilled artisan.

[0063] When very high molecular weight excipients are employed, the hot-melt extrusion may require higher processing temperature, pressure and/or torque than when an excipient having a lower molecular weight is employed. By including a plasticizer, and, optionally, an antioxidant, in a formulation comprising very high molecular weight excipients, processing temperature, pressure and/or torque may be reduced. The hot melt formulations may optionally be covered with various coatings as described above.

[0064] The administration of the gabapentin can be carried out in combination with other suitable therapeutic treatments that are useful for treating the condition(s) to be treated. The treatments may be curative, but more usually will be prophylactic.

[0065] The patient to be treated may be e.g., a human. The patient can be either female or male. In female patients, the hot flash may be a primary symptom resulting from menopausal or post menopausal hormonal variation. However, the hot flash can also be drug-induced by an anti-estrogen compound (e.g., tainoxifen, leuprolide acetate, etc.) or surgically induced by removal of estrogen-producing tissues (e.g., total abdominal hysterectomy, bilateral salpingo-oophorectomy, etc.). In male patients, the hot flashes typically occur as a side-effect of androgen-dependent therapy for metastatic prostate cancer. They can be either surgically induced (e.g., bilateral orchiectomy) or drug-induced (e.g., treatment with a gonadotrophin-releasing-hormone agonist, leuprolide acetate, etc.).

[0066] In the treatments described herein, including the treatinent of the symptoms of hormonal variation, e.g., hot flashes, the present invention encompasses either reducing the number of symptomatic events, reducing the severity of symptomatic events, or both.

[0067] The gabapentin can also act as an anti-pyretic agent, thereby moderating thermoregulation of a patient. Thus the present invention also provides a method of treating fever in a patient by administering a composition according to the invention to a patient experiencing a fever under conditions effective to treat the fever. By treating the fever, the present invention encompasses reducing or eliminating the fever, either completely or for a limited duration of time after each dose (e.g., up to about 24 hours).

[0068] The gabapentin can also act as anti-emetic agent for the treatment of nausea and emesis. Nausea and emesis are often induced by stimulation of either the chemoreceptor trigger zone or the emesis (or vomiting) centre in the central nervous system (CNS). Such stimulation can be caused by afferent stimulation (e.g., tactile pharyngeal impulses, labyrinthine disturbances, motion, increased intracranial pressure, pain, distension of viscera or psychological factors) or blood born emetic substances (e.g., as seen during pregnancy, cancer chemotherapy, uraemia, radiation therapy, electrolyte and endocrine disturbances, or the presence of chemical emetics).
Nausea and vomiting are also common post-operative side effects resulting from the use of anesthetics.

[0069] Thus a further aspect of the present invention relates to a method of treating nausea and emesis by administering a composition according to the invention to a patient experiencing nausea and/or emesis under conditions effective to treat the nausea andlor emesis. By treating the nausea and emesis, the present invention encompasses reducing or eliminating the feeling of nausea as well as reducing or eliminating the frequency of emesis, either completely or for a limited time after each dose (e.g., up to about 24 hours). Administration of the formulation can occur while a patient is experiencing nausea or emesis or in anticipation of the patient experiencing nausea or emesis.

[0070] U.S. Patent No. 6,310,098 mentions the use of gabapentin in the treatinent of hormonal variations, but very much emphasizes the use in post menopausal or menopausal women. We have now found that gabapentin can be used to treat dysmenorrhea and/or reduce or eliminate the unpleasant effects, e.g., premenstrual tension, mood swings, and pain, for example in the lower abdomen, which are caused by menstruation.

[0071] Thus according to a further feature of our invention, we provide the use of gabapentin to prevent or alleviate the side effects of menstruation. For this use, the gabapentin may be given before or at the first signs of menstruation or may be used to treat the adverse effects once the menstruation has started. The treatment may be continued for as long as the menstruation lasts.

[0072] According to a still further feature of the invention, we provide the treatment of the side effects of Hodgkin's disease, phaeochromcytoma, sleep apnea, allergic conditions, especially food allergies, diabetes and hyperthyroidism.

[0073] According to a yet further feature of the invention, we provide the use of gabapentin for the treatment of women, e.g., post menopausal women, who suffer from incontinence, e.g., urge incontinence; vaginal dryness; or dry eye syndrome.

[0074] The following examples illustrate the compositions and characteristics of the compositions of this invention regarding the dispersion of gabapentin or other active ingredients. Numerous improvements and further aspects of the invention are apparent to the skilled artisan upon consideration of the examples which follow.
Examples Example 1-Preparation of Batch A-Gabapentin With No CoatinJ4 [0075] Powdered gabapentin was blended with microcrystalline cellulose (Avicel pH101) in a high shear mixer-granulator. The powder mixture containing the desired amount of gabapentin was then granulated using a binder solution of polyvinylpyrrolidone (Kollidon K30 BASF). The binder solution was added to the powder mixture in the granulator in aliquots over a period of time (usually about 5 minutes, but depending on the batch size) until a suitable granulated mass was formed. The wet granules were then discharged from the granulator and dried in a hot-air oven (Gallenkamp Hotbox) to produce dry granules. The dry granules were screened through a sieve (1000 m Erweka), and blended with sodium starch glycolate super disintegrant (Explotab) and then further blended with magnesium stearate (BP
Thew Amott) as a lubricant and analyzed for drug content, before being fed to the hopper of a single punch (concentric cam) or rotary tablet press (F3 Manesty) fitted with 3.Omm deep concave punches to fomi tablets of ca 2.3mm thickness (Batch A
mini-tablets). These tablets have the following composition:

Table 2. Coinposition of Batch A mini-tablets Material %w/w mg /minitab Gabapentin 75 12.1 Avicel pH 101 20 3.22 Kollidon K30 2 0.32 Explotab 2 0.32 Mag. Stearate 1 0.16 The cumulative in vitro dissolution profile for these Batch A minitabs is shown in Example 5.

Example 2- Preparation of Batch B-Gabapentin Coated with pH Independent Soluble Polymer [0076] Another batch, Batch B, of mini-tablets was prepared in a similar manner to that described for Batch A, with the exception that Batch B was coated (Huttlin Microlab fluid bed coater) with a barrier coat of Methocel E5 (hydroxylpropylemethylcellulose - Colorcon), a pH independent soluble polymer, that protects the active ingredient from interaction with any subsequent coatings.
Batch B
forms the immediate release (first phase) component of the drug delivery system.
These tablets have the same composition as the Batch A tablets except that the hydroxypropylmethylcellulose forms 5% of the overall weight of the tablets, and they have an average tliickness of 2.5 mm. The resulting cumulative in vitro dissolution profile for these Batch B mini-tablets is shown in Example 5.
Example 3-Preparation of Batch C-Gabapentin Coated with pH Independent Insoluble Polymer [0077] Batch B mini-tablets from Example 2 were coated with a membrane of Eudragit polymers (Degussa AG) to achieve a timed release of the drug. The mini-tablets were placed in the coating machine, (bottom spray Wurster), and a mixture of Eudragit RL30D (a water-insoluble polyiner having high permeability and swelling that is pH independent insoluble polyiner, i.e., methacrylate copolymer with trimethyl-ammonioethyhnethacrylate functional groups) and Eudragit RS30D (a water-insoluble polymer having low permeability and swelling that is pH
independent- methacrylate copolymer with trimethyl-ammonioethylmethacrylate functional groups). Additionally talc (glidant) and triethyl citrate (plasticiser) were added to the polymer dispersed in water to produce the coating suspension. The coating suspension was sprayed onto the surface of the tablets as they were fluidized in the coater. Drying of the resulting membrane occurred in situ with a defined weight percent (10 or 15%) of coating material of (10:90 or 20:80 mixtures of RL30D/RS30D, respectively) around the mini-tablets.

Table 3. Composition of Batch 3 mini-tables Material % w/w mg/minitab Gabapentin 57.02 12.1 Avicel pH 101 15.17 3.22 Kollidon K30 1.51 0.32 Explotab 1.51 0.32 Mag. Stearate 0.75 0.16 HPMC 3.82 0.81 RL30D 1.12 0.25 RS30D 10.69 2.27 Talc 5.94 1.26 Triethyl Citrate 2.4 0.51 [0078] The products of this step form the modified or sustained release (second phase) portion of the formulation (Batch C).
The resulting cumulative in vitro dissolution profile for these Batch C
minitabs is shown in Example 5.
Example 4-Preparation of Batch D-Gabapentin Coated with pH DeUendent Soluble Polymer [0079] Further Batch B mini-tablets from Example 2 were coated with Eudragit L30D-55 (anionic polymer with methacrylic acid as a functional group) for dissolution above pH 5.5 or FS30D for dissolution above pH 7.0 (anionic polymer with methacrylic acid as a functional group from Degussa AG).

[0080] Based upon 15% w/w polymer addition, these tablets have the following composition:
Table 4. Composition of Batch D mini-tablets Material %w/w mg /minitab Gabapentin 57.65 12.1 Avicel pH 101 15.34 3.22 Kollidon K30 1.52 0.32 Explotab 1.52 0.32 Mag. Stearate 0.76 0.16 HPMC 3.85 0.81 Eudragit L30 D-55 12.1 2.54 Talc 6.05 1.27 Triethyl Citrate 1.19 0.25 The resulting cumulative in vitro dissolution profile for these Batch D
Delayed Release (third phase) mini-tablets is shown in Example 5.
Example 5-Dissolution Characterization of Batches A, B, C, and D

[0081] In vitro dissolution characterization of Batches A, B, C and D mini-tablets was determined using the USP Dissolution Apparatus II (paddle) USP 28 2005 [711], used at 75 rpm. The dissolution media was a phosphate buffered solution at pH 7.6 (BP
2004 Phosphate Buffer pH 7.6) for the Batch B, C and D parts of the formulation.
The dissolution results for each of the individual components is shown in Tables 3 to in which t50 is the time to 50% release and t90 is the time to 90% release and the ratios are w/w.
Table 5. Dissolution of the Immediate Release Component (from Example 2).
Formulation t50 minutes t90 minutes Gapentin Core minitabs (A) in 0.1 m HCI 5 15 Gabapentin 5% HPMC Coat (B) in 0.1 m 8 15 HCI

Table 6. Dissolution of Sustained Release Components (from Example 3) Formulation t5o minutes t90 minutes 10% RL/RS (1:9) in pH 7.6 150 210 10% RL/RS (2:8) in pH 7.6 100 160 15% RL/RS (1:9) in pH 7.6 220 360 15% RL/RS (2:8) in pH 7.6 160 360 Table 7. Dissolution of Potential Delayed Release Components (from Example 4) Formulation t50 minutes t90 minutes 10% FS30D in pH 7.6 45 60 15% L30D-55 in pH 7.6 22 30 Example 6-Dissolution of Various Formuations of Batch B, C, and D

[0082] A formulation comprising 80 percent Batch B minitabs, 10 percent Batch C
(10% RL/RS (2:8)) minitabs and 10 percent Batch D (15% L30D-55) minitabs (the percentages being w/w) was filled into Size 00 hard gelatin capsules (Capsugel) to a total dose of 375 mg gabapentin. The dissolution test for this overall formulation was initially carried out at a pH of approximately 1.2 (0. 1M HCl) for 2 hours with a paddle speed of 75 rpm; samples were taken throughout the 2 hrs. Following sampling at 120 mins the dissolution pot was filtered and the remaining tablets were rinsed with de-ionized water. The remaining tablets were then added to 500 ml pH
6.8 phosphate buffer (BP 2004) (37 C) with a paddle speed of 75 rpm and sampled throughout a further 4 hr run (see Figure 1). The test was repeated three times.
Example 7-- Dissolution of Various Formuations of Batch B, C, and D

[0083] A formulation comprising 20 percent Batch B minitabs, 40 percent Batch C
(10% RL/RS (2:8) minitabs and 40 percent Batch D (15% L30D-55) minitabs (the percentages being w/w) was added to Size 00 gelatin capsules to a total dose of 375 mg gabapentin. The dissolution conditions used were as per Example 6. The test was repeated three times (see Figure 2) .
Example 8-In Vivo Pharmacological Properties of Formulations Containing Batch B, Batch C, and Batch D

[0084] The capsules of Example 6 and 7 can be predicted to have the properties shown in the following table when used in humans. The table also shows comparable properties for a 600 mg single dose of reference iunmediate-release (IR) gabapentin in humans. Delayed dissolution in laboratory experiments can be used to predict delayed dissolution in vivo. These simulated numbers reflect the physical properties demonstrated in dissolution studies shown in Example 5 and Figures 1 and 2.

Table 6. Pharmacokinetic Properties of Three Phase Sustained Release Fonnulation Percent Composition In Vitro Dissolution In Vivo IR SR DR Tim Time to Tmax Cmax* Tmax Material e to 80% -50% 50%

Tmax Control 100 0 0 . < 15 min. 2-5 4-5 6 hr.
(reference IR 7.5 hr. incg/ml product; 600 min.
mg) Example 6 80 10 10 - 7.5 - 4 hr. 2-5 1.5 - 2 >61ir (2:8 (L30D55) min. hr. incg/ml RL/RS) Example 7 20 40 40 -5 hr. >2 -5 0.375 - >6hr.
(2:8 (L30D55) -2.5 hr. 0.5 RL/RS) hr. mcg/ml *Contribution to Cmax from IR component.
Control data are actual data from clinical observations; other data are predicted (simulated) values, and are composites for the designated mixtures of IR, SR
and DR
in each case; simulations are for a 375 mg dose.
Example 9-Capsules of Formulations Comprising Batch B, Batch C, and Batch D to Human [0085] Capsules of Batch B minitabs from Example 2, Batch C minitabs from Example 3, Batch D minitabs from Example 4, and the capsules of Examples 6 and are administered to healthy human volunteers at a dose of 375 mg gabapentin and blood samples taken at appropriate time intervals. These samples are then analyzed to provide the pharmacokinetic profile for the batch or capsule under examination.
Example 10-Analysis of Gabapentin UsinI4 Reversed Phase Gradients [0086] Analysis of gabapentin dissolution samples is by reversed phase gradient HPLC using varying proportions of pH 7.8 phosphate buffer and methanol as mobile phase. Gabapentin is derivatized with orthophthalaldehyde-(OPA) to improve its UV

absorption and phenylalanine is employed as an internal standard. The derivatization reaction takes place in the autosampler. Separation is performed on a Zorbax Eclipse AAA 4.6 x 150 mm, 5 m particle size HPLC column (Agilent part no. 994400-902) and detection is by UV absorbance at 338 mn. Quantification of gabapentin in samples is on the basis of peak area measurements, with calibration against standards of known gabapentin concentration.
Example 11-Treatment of Hot Flashes usinlz Gabapentin Formulations [0087] To treat, for example, hot flashes with 900 mg of gabapentin, the following formulation is used. Around 360 mg of gabapentin is coated by a suitable pH
independent soluble polymer, for example, hydroxypropylmethylcellulose. Next, mg of gabapentin is coated by different two water insoluble polymers, one having high permeability and the other having low permeability, both, however, having swelling that is pH independent. For the purpose of this experiment, Eudragit (high permeability) and Eudragit RS30D (low permeability) satisfy these requirements. Lastly, 270 mg of gabapentin is coated with both Eudragit L30D-and Eudragit FS30D. The coated gabapentin tablets above are dried and then packaged into a single unit dosage form for oral administration. Ingestion results in (1) an immediate release of the hydroxypropylmethylcellulose-coated gabapentin in the stomach, (2) a sustained released dose of the water insoluble-coated gabapentin in the stomach and upper small intestine, and (3) a delayed release of gabapentin into the upper and lower small intestine due to the dissolution properties of Eudragit (dissolution above pH 5.5) and Eudragit FS30D (dissolution above pH 7.0).
Example 12-In Vitro and In Vivo Dissolution Rates of Pregabalin and Formulations Thereof [0088] To study the in vitro and in vivo dissolution rates of preabalin, the active ingredient pregabalin can be substituted for gabapentin in Batches B, C, and D
as described in Examples 2-4. The in vitro studies of pregabalin can be conducted similarly as in Example 5. In vivo studies can be conducted by using a 900 mg of pregabalin formulation. Around 360 mg of pregabalin is coated by a suitable pH
independent soluble polymer, for example, hydroxypropylmethylcellulose. Next, mg of pregabalin is coated by different two water insoluble polymers, one having high permeability and the other having low permeability, both, however, having swelling that is pH independent. For the purpose of this experiment, Eudragit RL30D
(high permeability) and Eudragit RS30D (low permeability) satisfy these requirements.
Lastly, 270 mg of pregabalin is coated with both Eudragit L30D-55 and Eudragit FS30D. The coated pregabalin tablets above are dried and then packaged into a single unit dosage form for oral administration. Ingestion results in (1) an immediate release of the hydroxypropylmethylcellulose-coated pregabalin in the stomach, (2) a sustained released dose of the water insoluble-coated pregabalin in the stomach and upper small intestine, and (3) a delayed release of pregabalin into the upper and lower small intestine due to the dissolution properties of Eudragit L30D-55 (dissolution above pH 5.5) and Eudragit FS30D (dissolution above pH 7.0).

Claims (27)

1. A composition comprising:
(a) an active ingredient selected from the group consisting of gabapentin and pregabalin coated by a pH independent soluble polymer excipient;
(b) an active ingredient selected from the group consisting of gabapentin and pregabalin coated by a pH independent insoluble polymer excipient; and (c) an active ingredient selected from the group consisting of gabapentin and pregabalin coated by a pH dependent soluble polymer excipient.

2. The composition of claim 1, wherein the pH independent soluble polymer excipient is hydroxypropylmethyl cellulose.

3. The composition of claim 1, wherein the pH independent insoluble polymer excipient is selected from the group consisting of Eudragit RL30D, Eudragit RS30D, and a combination thereof.

4. The composition of claim 3, wherein the pH independent insoluble polymer excipient has a thickness of 25 to 150 microns.

5. The composition of claim 1, wherein the pH dependent excipient is selected from the group consisting of Eudragit L30D-55, Eudragit FS30D, and a combination thereof.

6. The composition of claim 5, wherein the pH dependent excipient has a thickness of 25 to 150 microns.

7. The composition of claim 1, wherein 20-60% of the active ingredient is released by the pH independent soluble polymer excipient within a period of up to 3 hours after dosing.

8. The composition of claim 7, wherein 20-60% of the active ingredient is released by the pH independent insoluble polymer excipient within a period of up to 12 hours after dosing.

9. The composition of claim 8, wherein 15-50% of the active ingredient is released by the pH dependent soluble polymer excipient after a delay of 3 to

10 hours after dosing.

10. The composition of claim 1, wherein 250 mg of gabapentin is in a solid unit dosage form.

11. The composition of claim 1, wherein 375 mg of gabapentin is in a solid unit of dosage form.

12. The composition of claim 1, wherein the active ingredient is released at a C max and AUC (absolute bioavailability of active ingredient) 50% proportional to dosage strength of the active ingredient.

13. The composition of claim 12, wherein the active ingredient is release from a C max to 50% of C max within 2 to 24 hours.

14. The composition of claim 1, wherein the active ingredient is coated in the form of mini-tablets.

15. The composition of claim 1, further coinprising a disintegrant, a flavor component, a colorizer, a sweetener, a binder, a filler, a lubricant, a plasticizer or a combination thereof.

16. A composition comprising (a) gabapentin coated by hydroxypropylmethyl cellulose;
(b) gabapentin coated by a pH independent insoluble polymer release agent selected from the group consisting of Eudragit RL30D, Eudragit RS30D, and a combination thereof;
(c) gabapentin coated by a pH dependent soluble polymer release agent selected from the group consisting of Eudragit L30D-55, Eudragit FS30D, and a combination thereof.

17. The composition of claim 16, wherein the pH independent insoluble polymer excipient has a thickness of 25 to 150 microns.

18. The composition of claim 16, wherein the pH dependent excipient has a thickness of 25 to 150 microns.

19. A composition produced by a process comprising the steps of:
(a) separately mixing an active ingredient with a pH independent soluble polymer;
(b) separately mixing an active ingredient with a pH independent insoluble polymer;
(c) separately mixing an active ingredient with a pH dependent soluble polymer;

(d) forming the resulting mixture of steps (a)-(c) into mini-tablets; and (e) filling the mixture of mini-tablets from step (d) into a single unit dosage form suitable for oral administration.

20. A composition produced by the process comprising the steps of:
(a) mixing an active ingredient with a filler;
(b) 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) coating the mini-tablets of step (d) with excipients from the group consisting of:
(i) a pH independent soluble polymer;
(ii) a pH independent insoluble polymer; and (iii) a pH dependent soluble polymer;
(f) drying the coated mini-tablets of step (e); and (g) formulating the mixture of coated mini-tablets into a single unit dosage form suitable for oral administration.

21. The composition of claim. 16 for the treatment of a neurological disease or injury selected from the group consisting of epilepsy, seizures secondary to stroke, and head/brain trauma.

22. The composition of claim 16 for the treatment of chronic pain associated with the group consisting of neuropathic, muscular and skeletal pain, tardive dyskinesia or migraines, reflect sympathetic dystrophy syndrome (RSD), and fibromyalgia.

23. The composition of claim 16 for the treatment of a psychiatric disorders selected from the group consisting of bi-polar disease, panic, anxiety, depression, alcoholism, and manic behavior.

24. The composition of claim 16 for the treatment of menstrual related symptoms selected from the group consisting of premenstrual tension, mood swings, hot flashes and pain.

25. The composition of claim 16 for the treatment of post menopausal related symptoms selected from the group consisting of urge incontinence, vaginal dryness, and dry eye syndrome.

26. The composition of claim 1, wherein the composition is administered once or twice daily.

27. The composition of claim 16, wherein the composition is administered once or twice daily.