Alcohol-Resistant Formulations

Abstract

This disclosure relates to extended release oral dosage forms comprising a matrix containing a viscosity modifier (but no lipid) and coated granules containing a high water-soluble, high dose drug. The dosage forms have alcohol resistance and may also have crush resistance.

Claims

1. An extended release oral tablet dosage form consisting of: coated granules comprising a high water-soluble, high dose drug; and, a matrix that is external to the coated granules and that comprises a viscosity modifier in an amount from about 1 to about 60 percent by weight of the dosage form, wherein the matrix does not contain a lipid; wherein the coated granules are dispersed within the matrix and comprise: a granule comprising a high water-soluble, high dose drug in an amount from about 10 to about 90 percent by weight of the granule, a first strong film former in an amount from about 1 to about 90 percent by weight of the granule, and a second viscosity modifier in an amount from about 1 to about 90 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 5 to about 70 percent by weight of the coated granule, and wherein the coating comprises a second strong film former in an amount from about 1 to about 50 percent by weight of the coated granule, and an anti-adherent in an amount from about 0 to about 30 percent by weight of the coated granule. wherein the percent of said high water-soluble, high dose drug released after 2 hours in a solution of 0.1N hydrochloric acid and 40% alcohol is no more than 10 percentage points greater than the percent of said high water-soluble, high dose drug released in a solution of 0.1N hydrochloric acid in the absence of alcohol.

2. The oral dosage form according to claim 1 wherein the release of said high water-soluble, high dose drug from the dosage form 6 hours after testing is less than about 80 percent when tested in 500 ml of 0.1N hydrochloric acid solution using USP dissolution apparatus.

3. The dosage form of claim 1, wherein the viscosity modifier is a gelling polymer.

4. The dosage form of claim 3, wherein the gelling polymer is selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose.

5. The dosage form of claim 1, wherein the viscosity modifier is present in an amount from about 25 to about 45 percent by weight of the dosage form.

6. The dosage form of claim 1, wherein the coating is present in an amount from about 35 to about 55 percent by weight of the coated granule.

7. The dosage form of claim 1, wherein the first strong film former and the second strong film former are the same.

8. The dosage form of claim 1, wherein the first and second strong film formers are independently selected from the group consisting of: natural and synthetic starches, natural and synthetic celluloses, acrylics, vinylics, resins, methacrylate or shellac.

9. The dosage form of claim 1, wherein the first strong film former is present in an amount from about 10 to about 30 percent by weight of the granule.

10. The dosage form of claim 1, wherein the second viscosity modifier is selected from the group consisting of: sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked polyacrylic acid, gelatin, pectins, gums, polyethylene oxides, Konjac flour, carrageenan, xanthan gum, or mixtures thereof.

11. The dosage form of claim 1, wherein the second viscosity modifier is present in an amount from about 5 to about 40 percent by weight of the granule.

12. The dosage form of claim 1, wherein the coated granules comprise: a granule consisting essentially of a high water-soluble, high dose drug in an amount from about 10 to about 90 percent by weight of the granule, a first strong film former in an amount from about 1 to about 90 percent by weight of the granule, and a second viscosity modifier in an amount from about 1 to about 90 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 5 to about 70 percent by weight of the coated granule, and wherein the coating comprises a second strong film former in an amount from about 1 to about 50 percent by weight of the coated granule, and an anti-adherent in an amount from about 0 to about 30 percent by weight of the coated granule.

13. The dosage form of claim 1, wherein the high water-soluble, high dose drug is selected from quinapril, rabeprazole, dicyclomine, clindamycin, verapamil, lorsartan, trazodone, doxycycline, venlafaxine, amitriptyline, metformin, propranolol, sitagliptin, levetiracetam, levofloxacin, metoprolol, nitrofurantoin, gabapentin, promethazine, pravastatin, omeprazole, lisinopril, atomoxetine, tetracycline, oseltamivir, naproxen/sumatriptan, valacyclovir, diclofenac, bupropion, ranitidine, hydralzine and their pharmaceutically acceptable salts and solvates and mixtures thereof.

14. The dosage form of claim 1, wherein the high water-soluble, high dose drug is selected from acamprosate calcium, aceglutamide aluminum, acetazolamide sodium, acetohydroxamic acid, aliskiren fumarate, aminocaproic acid, aminophylline, amitriptyline HCl, amitriptyline HCl, balsalazide disodium dehydrate, benzphetamine HCl, buflomedil HCl, calcium acetate anhydrous, celiprolol HCl, chloroquine phosphate, diltiazem HCl, diphylline, disopyramide phosphate, divalproex sodium, dolasetron mesylate monohydrate, emtricitabine, eperisone HCl, estramustine sodium phosphate anhydrous, ethosuximide, etidronate disodium, famciclovir, flucloxacillin sodium hydrate, fudosteine, gabapentin, gemifloxacin mesylate, hydroxychloroquine sulfate, hydroxyurea, hydroxyzine HCl, levamisole HCl, levocamitine, losartan potassium, metformin HCl, methenamine hippurate, metoprolol succinate, mexiletine HCl, miglustat, milnacipran HCl, molindone HCl, naftidrofuryl oxalate, naltrexone HCl, orphenadrine HCl, oseltamivir phosphate, oseltamivir phosphate, oxprenolol HCl, pantoprazole sodium, penicillamine, phenelzine sulfate, piracetam, potassium bicarbonate, KCl, pregabalin, pseudoephedrine HCl, pyridostigmine bromide, quinapril HCl, rimantadine HCl, sotalol HCl, tacrine HCl, thioridazine HCl, ticlopidine HCl, ticlopidine HCl, tolmetin sodium anhydrous, tranexamic acid, trapidil, trientine HCl, tripelennamine HCl, venlafaxine, zinc acetate, abacavir sulfate, acebutolol HCl, bacampicillin HCl, benazepril HCl, beta-alanine, bupropion HBr, carbenicillin indanyl sodium chlordiazepoxide HCl, dantrolene sodium, desipramine HCl, desvenlafaxine succinate, dicyclomine HCl, flecamide acetate, hidrosmin, hydralazine HCl, labetalol HCl, lamivudine, 1-glutamine, lisdexamfetamine dimesylate, lisinopril dehydrate, loxapine succinate, miglitol, moracizine HCl, moxisylyte HCl, nortriptyline HCl, olsalazine sodium, ozagrel HCl, pentoxifylline, procarbazine, procarbazine HCl, raltegravir potassium, sitagliptin phosphate, sitaxsentan sodium, stavudine, strontium ranelate, tenofovir disoproxil fumarate, treosulfan, trimethobenzamide HCl, valacyclovir HCl, valganciclovir HCl, verapamil HCl, vildagliptin, aclatonium napadisilate, betaine, cevimeline HCl hydrate, chlorpromazine HCl, cysteamine bitartrate, didanosine, doxylamine succinate, fosfomycin trometamol, indinavir sulfate, itopride HCl, levetiracetam, lymecycline, maraviroc, mebeverine HCl, melperone HCl, meperidine HCl, meptazinol HCl, methenamine mandelate, metoprolol tartrate, paromomycin sulfate, procainamide HCl, ranitidine HCl, sodium oxybate, sodium valproate, tiapride HCl, venlafaxine HCl, vildagliptin, procaine HCl, sitaxsentan sodium and vigabatrin.

Description

DESCRIPTION OF DRAWINGS

[0051] FIG. 1 is a chart showing the comparative dissolution results for the formulation product of Example 1 in the absence and presence of 40% ethanol over a 12 hour period.

[0052] FIG. 2 is a chart showing the comparative dissolution results for the formulation product of Example 2 in the absence and presence of 40% ethanol over a 12 hour period.

[0053] FIG. 3 is a chart showing the comparative dissolution results for the marketed product Effexor XR in the absence and presence of 40% ethanol over a 6 hour period.

[0054] FIG. 4 is a chart showing the comparative dissolution results for the marketed product Toprol XL in the absence and presence of 40% ethanol over a 6 hour period.

DETAILED DESCRIPTION

[0055] Non-lipid matrix based alcohol-resistant extended release dosage forms of high water-soluble, high dose drugs are provided. A dosage form can include a matrix having a viscosity modifier and coated granules comprising a high water-soluble, high dose drug. In some cases, a dosage form, as described herein, has a release profile such that after 6 hours in 500 ml of 0.1N hydrochloric acid, less than about 80 percent of the high water-soluble, high dose drug is released. In addition, a dosage form may have crush resistance.

[0056] The term matrix refers to a monolithic system comprising active substance-containing particles (e.g., coated granules) dispersed and entrapped in a continuum of excipients, i.e., the matrix forming substances; see, for example, Colombo, P., Santi, P., Siepmann, J., Colombo, G., Sonvico, F., Rossi, A., Luca Strusi, O., 2008. Swellable and Rigid Matrices: Controlled Relelase Matrices with Cellulose Ethers. In: Pharmaceutical Dosage Forms: Tablets, Volume 2: Rational Design and Formulation. Third Edition, Augsburger, L. and Hoag, S. (eds.). Informa Healthcare, New York, London. As set forth further herein, coated granules comprising a high water-soluble, high dose drug are dispersed within a described matrix.

[0057] Provided herein is an extended release oral dosage form including a matrix, comprising a first viscosity modifier in an amount from about 5 to about 45 percent (e.g., about 25 to about 45 percent, including about 30 percent) by weight of the dosage form, and coated granules comprising a high water-soluble, high dose drug; and wherein the matrix does not comprise a lipid.

[0058] The dosage forms described herein can have a release profile such that the release of a high water-soluble, high dose drug from the dosage form after 6 hours is less than about 80 percent. In some embodiments, the release of a high water-soluble, high dose drug from the dosage form after 10 hours is less than about 85 percent. Release of a high water-soluble, high dose drug is measured using the USP dissolution apparatus number 2 and 500 ml of a 0.1 N hydrochloric acid solution as the dissolution medium.

[0059] The dosage form is alcohol resistant. Resistance to alcohol is measured using the USP dissolution apparatus number 2 and 500 ml of a 0.1 N hydrochloric acid solution (normal dissolution) or a 0.1N hydrochloric acid and 40% ethanolic solution (alcohol concentration is 40% v/v; dose dumping dissolution) as the dissolution medium. For an alcohol resistant formulation, as described herein, after 2 hours in a solution of 0.1N hydrochloric acid and 40% ethanol, the percent release of a high water-soluble, high dose drug is no more than 10 percentage points greater than the percent of a high water-soluble, high dose drug released in the 0.1N hydrochloric acid solution in the absence of alcohol. For example, if the dosage form releases 20% of the high water-soluble, high dose drug in the 0.1N hydrochloric acid solution in the absence of alcohol after 2 hours, then an alcohol resistant dosage form, as described herein, will not release any more than 30% of the high water-soluble, high dose drug in the solution having 0.1N hydrochloric acid and 40% ethanol.

[0060] In some embodiments, a dosage form, as described herein, may be crush resistant. Crush resistance is measured using techniques designed to simulate oral tampering. Such methods involve placing a tablet of the dosage form in a ceramic mortar (13 cm outer diameter). A pestle is then used to apply force vertically downward onto the tablet until it breaks. The broken tablet is further crushed using a 360 circular motion with downward force applied throughout. The circular crushing motion is repeated eleven times (twelve strokes total). The resulting powder is transferred to a dissolution vessel to measure in vitro drug release. The in vitro release profile of the crushed tablet samples is obtained in 500 ml of 0.1N hydrochloric acid dissolution medium. The samples are agitated at 50 rpm using USP apparatus 2 (paddles) at 37 C.

[0061] A viscosity modifier, as described herein, is a material, which upon dissolution or dispersion in an aqueous solution or dispersion (e.g., water) at a concentration of 2% w/w (based on the dry material), creates a solution/dispersion with a viscosity of from about 100 to about 200,000 mPa.Math.s (e.g., 4,000 to 175,000 mPa.Math.s, and 75,000 to 140,000 mPa.Math.s) as measured at 20 C. (0.2 C.) using the analysis method described in the USP 33 monograph for hypromellose (incorporated herein by reference). Examples of viscosity modifiers include sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, crosslinked polyacrylic acid (e.g., carbomers), gelatin, pectins, gums (e.g., gum arabic, gum tragacanth, xanthan gums, and guar gums), polyethylene oxides, Konjac flour, carrageenan, or mixtures thereof. In some embodiments, the viscosity modifier is a natural or synthetic cellulose such as hydroxypropylmethylcellulose. In some embodiments, the viscosity modifier is a gelling polymer. Gelling polymers can include natural and synthetic starches, natural and synthetic celluloses, acrylates, and polyalkylene oxides. Examples include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose. In some embodiments, the gelling polymer is hydroxypropylmethylcellulose (HPMC).

[0062] When HPMC is used in the dosage form, the HPMC can have different methyl to hydroxypropyl substitution percent ratios ranging from 30:0 in the A-type, 29:8.5 for the E-type, 28:5 in the F-type, 22:8 for the K-type all available from DOW Chemical Company, Midland, Mich. or any other HPMC polymers available from other suppliers such as Aqualon.

[0063] Coated granules of the dosage forms described herein include a granule comprising a high water-soluble, high dose drug and a coating on the granule. In some embodiments, a coated granule can include a granule comprising a high water-soluble, high dose drug in an amount from about 10 to about 90 percent by weight of the granule, a first strong film former in an amount from about 1 to about 90 percent by weight of the granule, a second viscosity modifier in an amount from about 1 to about 90 percent by weight of the granule, and a fat/wax in an amount from about 0 to about 40 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 5 to about 70 percent by weight of the coated granule, and wherein the coating comprises a second strong film former in an amount from about 1 to about 50 percent by weight of the coated granule, and an anti-adherent in an amount from about 0 to about 30 percent by weight of the coated granule.

[0064] As used herein, references to a high water-soluble, high dose drug means a drug with aqueous solubility of 33 mg,/ml or higher and which is generally administered at a maximum daily dose of 80 mg or more, where the maximum daily dose is calculated as the number of dosage forms allowed/day multiplied by the strength of the dosage form administered.

[0065] Examples of high water-soluble, high dose drugs according to the present invention include Quinapril, Rabeprazole, Dicyclomine, Clindamycin, Verapamil, Lorsartan, Trazodone, Doxycycline, Venlafaxine, Amitriptyline, Metformin, Propranolol, Sitagliptin, Levetiracetam, Levofloxacin, Metoprolol, Nitrofurantoin, Gabapentin, Promethazine, Pravastatin, Omeprazole, Lisinopril, Atomoxetine, Tetracycline, Oseltamivir, Naproxen/Sumatriptan, Valacyclovir, Diclofenac, Bupropion, Ranitidine, and their pharmaceutically acceptable salts and solvates.

[0066] Further examples include acamprosate calcium, aceglutamide aluminum, acetazolamide sodium, acetohydroxamic acid, aliskiren fumarate, aminocaproic acid, aminophylline, amitriptyline hydrochloride, amitriptyline hydrochloride, balsalazide disodium dehydrate, benzphetamine hydrochloride, buflomedil hydrochloride, calcium acetate anhydrous, celiprolol hydrochloride, chloroquine phosphate, diltiazem hydrochloride, diphylline, disopyramide phosphate, divalproex sodium, dolasetron mesylate monohydrate, emtricitabine, eperisone hydrochloride, estramustine sodium phosphate anhydrous, ethosuximide, etidronate disodium, famciclovir, flucloxacillin sodium hydrate, fudosteine, gabapentin, gemifloxacin mesylate, hydroxychloroquine sulfate, hydroxyurea, hydroxyzine hydrochloride, levamisole hydrochloride, levocarnitine, losartan potassium, metformin hydrochloride, methenamine hippurate, metoprolol succinate, mexiletine hydrochloride, miglustat, milnacipran hydrochloride, molindone hydrochloride, naftidrofuryl oxalate, naltrexone hydrochloride, orphenadrine hydrochloride, oseltamivir phosphate, oseltamivir phosphate, oxprenolol hydrochloride, pantoprazole sodium, penicillamine, phenelzine sulfate, piracetam, potassium bicarbonate, potassium chloride, pregabalin, pseudoephedrine hydrochloride, pyridostigmine bromide, quinapril hydrochloride, rimantadine hydrochloride, sotalol hydrochloride, tacrine hydrochloride, thioridazine hydrochloride, ticlopidine hydrochloride, ticlopidine hydrochloride, tolmetin sodium anhydrous, tranexamic acid, trapidil, trientine hydrochloride, tripelennamine hydrochloride, venlafaxine, zinc acetate, abacavir sulfate, acebutolol hydrochloride, bacampicillin hydrochloride, benazepril hydrochloride, beta-alanine, bupropion hydrobromide, carbenicillin indanyl sodium chlordiazepoxide hydrochloride, dantrolene sodium, desipramine hydrochloride, desvenlafaxine succinate, dicyclomine hydrochloride, flecamide acetate, hidrosmin, hydralazine hydrochloride, labetalol hydrochloride, lamivudine, 1-glutamine, lisdexamfetamine dimesylate, lisinopril dehydrate, loxapine succinate, miglitol, moracizine hydrochloride, moxisylyte hydrochloride, nortriptyline hydrochloride, olsalazine sodium, ozagrel hydrochloride, pentoxifylline, procarbazine, procarbazine hydrochloride, raltegravir potassium, sitagliptin phosphate, sitaxsentan sodium, stavudine, strontium ranelate, tenofovir disoproxil fumarate, treosulfan, trimethobenzamide hydrochloride, valacyclovir hydrochloride, valganciclovir hydrochloride, verapamil hydrochloride, vildagliptin, aclatonium napadisilate, betaine, cevimeline hydrochloride hydrate, chlorpromazine hydrochloride, cysteamine bitartrate, didanosine, doxylamine succinate, fosfomycin trometamol, indinavir sulfate, itopride hydrochloride, levetiracetam, lymecycline, maraviroc, mebeverine hydrochloride, melperone hydrochloride, meperidine hydrochloride, meptazinol hydrochloride, methenamine mandelate, metoprolol tartrate, paromomycin sulfate, procainamide hydrochloride, ranitidine hydrochloride, sodium oxybate, sodium valproate, tiapride hydrochloride, venlafaxine hydrochloride, vildagliptin, procaine hydrochloride, sitaxsentan sodium and vigabatrin

[0067] One particular example of a high water-soluble, high dose drug is Venlafaxine and its pharmaceutically acceptable salts, such as the hydrochloride.

[0068] Another particular example of a high water-soluble, high dose drug is Metoprolol and its pharmaceutically acceptable salts, such as the tartrate, fumarate and succinate.

[0069] In some embodiments, the high water-soluble, high dose drug is present in an amount from about 30 to about 90 percent by weight of the granule. In some embodiments, the high water-soluble, high dose drug is present in an amount from about 40 to about 80 percent by weight of the granule. In some embodiments, Venlafaxine hydrochloride is present in an amount from about 40 to about 50 percent by weight of the granule. In some embodiments, Metoprolol succinate is present in an amount from about 70 to about 80 percent by weight of the granule.

[0070] A strong film former is a polymer, which is at least slightly soluble, preferably, soluble in alcohol and at most slightly soluble in water and forms a dry 3-mil film with tensile strength not less than 1000 lb/in.sup.2 when measured by the appropriate tensile strength measuring equipment such as the texture analyzer manufactured by Texture Technologies, Brookfield, Lloyd Instruments, and the like. For example, a strong film former can be selected from natural and synthetic starches, natural and synthetic celluloses, acrylics, vinylics and resins. In some embodiments, a strong film former is selected from ethylcellulose; polyvinyl acetate; (meth)acrylate copolymers such as Ammonio Methacrylate Copolymer, Type B (Eudragit RS); Ammonia Methacrylate Copolymer, Type A (Eudragit RL); Amino Methacrylate Copolymer (Eudragit E); Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion (Eudragit NE); Methacrylic Acid Copolymer, Type A (Eudragit L); Methacrylic Acid Copolymer, Type B (Eudragit S); and shellac. In some cases, the first and second strong film formers are the same.

[0071] In some embodiments, a strong film former is a natural or synthetic cellulose such as ethylcellulose (EC). Ethylcellulose is an inert, hydrophobic polymer and is essentially tasteless, odorless, colorless, non-caloric, and physiologically inert. There are many types of ethylcellulose which can be used, as long as they meet the other requirements, such as alcohol solubility, discussed herein. The ethylcellulose used can have different ethoxy content such as 48.0-49.5% described as N-type; 49.6-51.5% described as T-type; 50.5-52.5% described as X-type; all available from Aqualon, Hercules Research Center, Wilmington, Del.

[0072] The ethylcellulose used can have different molecular weights such as including EC polymers of the N-type that form 5% w/w solution in toluene:ethanol (80:20) that have viscosity ranges of 5.6-8.0 centipoise (cps) described as N7; 8.0-11 cps described as N10; 12-16 cps described as N14; 18-24 cps described as N22; 40-52 cps described as N50; 80-105 cps described as N100. The ethylcellulose used can also include different degrees of substitution of ethoxy groups per anhydroglucose unit, such as 2.65-2.81 for the X-type. N-type has values of 2.46-2.58.

[0073] In some embodiments, the first strong film former is present in an amount from about 1 to about 90 percent by weight of the granule. For example, the first strong film former can be present in an amount from about 5 to about 40 percent by weight of the granule (e.g. from about 10 to about 30 percent by weight of the granule). In some cases, the second strong film former is present in an amount from about 10 to about 50 percent by weight of the coated granule. In some cases, the second strong film former can be present in an amount from about 10 to about 40 percent by weight of the coated granule.

[0074] In some embodiments, a second viscosity modifier is the same as the viscosity modifier used in the matrix of the dosage form. In some cases, the second viscosity modifier is hydroxypropylmethylcellulose. In some embodiments, the second viscosity modifier is present in an amount from about 1 to about 90 percent by weight of the granule. In some embodiments, the second viscosity modifier is present in an amount from about 1 to about 60 percent by weight of the granule, for example about 5 to about 40 percent by weight of the granule.

[0075] The lipid or fat/wax, as described herein, references to hydrophobic compounds generally having a hydrophilic/lipophilic balance (HLB) of about 6 or less and also having a melting point which is 30 C. or more. The term can be used interchangeably with fat or wax if they meet the same specifications. Lipids can be fatty acids, fatty alcohol, fatty esters or waxes. The fatty acids can be substituted or unsubstituted, saturated or unsaturated. However, generally they have a chain length of at least about 14. The fatty esters may include fatty acid bound to alcohols, glycols or glycerol to form mono-, di-, and tri-fatty substituted esters. Examples include, glycerol fatty esters, fatty glyceride derivatives, and fatty alcohols such as glycerol behenate (COMPRITOL), glycerol palmitostearate (PRECIROL), stearoyl macroglycerides (GELUCIRE), insect and animal waxes, vegetable waxes, mineral waxes, petroleum waxes, and synthetic waxes.

[0076] The fat/wax, as used herein in the granules, can be independently selected from the group of lipids that have melting point well above room temperature and typical storage condition (15-30 C.). Most preferably, the fat/wax can be selected from the group of lipids that has melting point above 60 C. Lipids with high melting point have improved stability and less susceptibility to gastric lipases which allows them to circumvent the disadvantage of using lipids described above. For example, the fat/wax can be independently selected from the group consisting of: glycerol behenate, carnauba wax and bees wax. In some embodiments, the fat/wax are glycerol behenate

[0077] In some cases, the fat/wax may be present in an amount from about 0 to about 30 percent by weight of the granule.

[0078] The coat may include anti-adherent which is used to prevent particle growth through agglomeration during coating. Anti-adherent can be selected from a fat/wax as defined hereinabove or a group of materials including stearic acid salts, talc, and starches. In some embodiment, the anti-adherent is magnesium stearate. In some embodiments, the anti-adherent is present in an amount from about 10 to about 25 percent by weight of the coated granule.

[0079] The term coating is meant to encompass a material which substantially surrounds the granules and provides some additional function, such as, without limitation, taste masking, storage stability, reduced reactivity, controlled release, and/or abuse resistance. In some embodiments, the coating is present in an amount from about 30 to about 70 percent by weight of the coated granule. For example, the coating can be present in an amount of about 30 to about 55 percent by weight of the coated granule, including about 35 to about 50 percent, e.g. about 40 to about 50 percent.

[0080] In some embodiments, the extended release oral dosage form described herein comprises a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount from about 5 to about 45 percent by weight of the dosage form, for example, from about 25 to about 45 percent by weight, including about 30 percent by weight, of the dosage form; and coated granules, wherein the coated granules comprise a granule comprising a high water-soluble, high dose drug in an amount from about 30 to about 90 percent by weight of the granule, for example, from about 40 to about 80 percent by weight of the granule, ethylcellulose in an amount from about 5 to about 40 percent by weight of the granule, for example, from about 10 to about 30 percent by weight of the granule, hydroxypropylmethylcellulose in an amount from about 1 to about 60 percent by weight of the granule, for example, from about 5 to about 40 percent by weight of the granule, and a fat/wax (e.g. glycerol behenate) in an amount from about 0 to about 20 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 5 to about 70 percent by weight of the coated granule, for example, in an amount of about 30 to about 70 percent by weight of the coated granule, including about 30 to about 55 percent, e.g. about 40 percent, and wherein the coating comprises ethylcellulose in an amount from about 1 to about 50 percent by weight of the coated granule or from about 10 to about 40 percent by weight of the coated granule, and magnesium stearate in an amount from about 10 to about 25 percent by weight of the coated granule; and wherein the matrix does not comprise a lipid.

[0081] In some embodiments, the extended release oral dosage form described herein comprises a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount from about 5 to about 45 percent by weight of the dosage form, for example, from about 25 to about 45 percent by weight, including about 30 percent by weight, of the dosage form; and coated granules, wherein the coated granules comprises a granule consisting essentially of a high water-soluble, high dose drug in an amount from about 30 to about 90 percent by weight of the granule, for example, from about 40 to about 80 percent by weight of the granule, ethylcellulose in an amount from about 5 to about 40 percent by weight of the granule, for example, from about 10 to about 30 percent by weight of the granule, hydroxypropylmethylcellulose in an amount from about 1 to about 60 percent by weight of the granule, for example, from about 5 to about 40 percent by weight of the granule, and a fat/wax (e.g. glycerol behenate) in an amount from about 0 to about 20 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 5 to about 70 percent by weight of the coated granule, for example, in an amount of about 30 to about 70 percent by weight of the coated granule, including about 30 to about 55 percent, e.g. about 40 percent, and wherein the coating comprises ethylcellulose in an amount from about 1 to about 50 percent by weight of the coated granule or from about 10 to about 40 percent by weight of the coated granule, and magnesium stearate in an amount from about 10 to about 25 percent by weight of the coated granule; and the matrix does not comprise a lipid.

[0082] In some embodiments, the extended release oral dosage form described herein comprises a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount from about 5 to about 45 percent by weight of the dosage for in, for example, from about 25 to about 45 percent by weight, including about 30 percent by weight, of the dosage form; and coated granules, wherein the coated granules comprise a granule consisting essentially of a high water-soluble, high dose drug in an amount from about 30 to about 90 percent by weight of the granule, for example, from about 40 to about 80 percent by weight of the granule, ethylcellulose in an amount from about 5 to about 40 percent by weight of the granule, for example, from about 10 to about 30 percent by weight of the granule, hydroxypropylmethylcellulose in an amount from about 1 to about 60 percent by weight of the granule, for example, from about 5 to about 40 percent by weight of the granule, and a fat/wax (e.g. glycerol behenate) in an amount from about 0 to about 20 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 5 to about 70 percent by weight of the coated granule, for example, in an amount of about 30 to about 70 percent by weight of the coated granule, including about 30 to about 55 percent, e.g. about 40 percent, and wherein the coating consists essentially of ethylcellulose in an amount from about 1 to about 50 percent by weight of the coated granule or from about 10 to about 40 percent by weight of the coated granule, and magnesium stearate in an amount from about 10 to about 25 percent by weight of the coated granule; and the matrix does not comprise a lipid.

[0083] In some embodiments, the extended release oral dosage form described herein comprises a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount from about 30 percent by weight of the dosage form; and coated granules, wherein the coated granules comprise a granule consisting essentially of Venlafaxine hydrochloride in an amount from about 40 to about 50 percent by weight of the granule, ethylcellulose in an amount from about 10 to about 20 percent by weight of the granule, hydroxypropylmethylcellulose in an amount from about 30 to about 40 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 30 to about 55 percent, e.g. about 50 percent, and wherein the coating consists essentially of ethylcellulose in an amount from about 10 to about 40 percent by weight of the coated granule, and magnesium stearate in an amount from about 10 to about 25 percent by weight of the coated granule; and the matrix does not comprise a lipid.

[0084] In some embodiments, the extended release oral dosage form described herein comprises a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount from about 30 percent by weight of the dosage form; and coated granules, wherein the coated granules comprise a granule consisting essentially of Metoprolol succinate in an amount from about 70 to about 80 percent by weight of the granule, ethylcellulose in an amount from about 10 to about 20 percent by weight of the granule, hydroxypropylmethylcellulose in an amount from about 5 to about 15 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 30 to about 55 percent, e.g. about 40 percent, and wherein the coating consists essentially of ethylcellulose in an amount from about 10 to about 40 percent by weight of the coated granule, and magnesium stearate in an amount from about 10 to about 25 percent by weight of the coated granule; and the matrix does not comprise a lipid.

[0085] The coated granules and dosage forms as described herein can be prepared using methods known to those in the art, see, for example, U.S. Publication No. 2008/0311205, incorporated herein by reference. In general, the high water-soluble high dose drug is formulated into polymer-rich granules onto which a polymeric coat is applied. The coated granules are subsequently mixed with a viscosity modifier.

[0086] In some embodiments, the dosage form may also include at least one other ingredient or excipient in addition to the coated particle and viscosity modifier in the matrix. The other ingredient or excipient may include, but is not limited to, taste masking agents, binders, fillers, sugars, artificial sweeteners, polymers, flavoring agents, coloring agents, lubricants, glidants, bio- or muco-adhesives, surfactants, buffers, and disintegrants. The amount of any one or more of these ingredients will vary with the amount of coating, granule size, shape of the dosage form, form of the dosage form, number of ingredients used, the particular mixture of ingredients used, the number of dosage forms that will formulate a dose, the amount of drug per dose and the like. Any combination or amounts are contemplated sufficient to produce a dosage form having the described release profile and/or tamper-resistance provided.

[0087] Taste masking agent(s) include anything known to be used as a taste masking agents in this art. Examples include Eudragit E-100, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose, Hydroxyethylcellulose, carboxymethylcellulose, shellac, zein, carbomers, poloxamers, modified chitosans, carrageenans, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymers including Eudragit L 100, S 100, L30D-55, polyvinylacetate phthalate (PVAP). Taste masking agents can be used in conventional amounts, for example, in an amount of about 0 to about 50 percent by weight of the total dosage form (e.g., about 5 to about 40 percent by weight of the total dosage form; about 10 to about 30 percent by weight of the total dosage form).

[0088] Binders can be used to add cohesiveness to powders and provide the necessary bonding to form granules that can be compressed into hard tablets that have acceptable mechanical strength to withstand subsequent processing or shipping and handling. Examples of binders include acacia, tragacanth, gelatin, starch (both modified or unmodified), cellulose materials such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and sodium carboxy methylcellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars, invert sugars, and the like, polyvinylpyrrolidone, polymethacrylate and other acrylic and vinyl-based polymers. Binders can be used in conventional amounts, for example, in an amount of about 0 to about 50 percent by weight of the total dosage form (e.g., about 2 to about 10 percent by weight of the total dosage form).

[0089] Fillers can include mannitol, dextrose, sorbitol, lactose, sucrose, and calcium carbonate. Fillers can be used in conventional amounts, for example, in an amount of about 0 to about 90 percent by weight of the total dosage form (e.g., from about 10 to about 50 percent by weight of the total dosage form). In some embodiments, a filler can be a sugar. For example, sugar, sugar alcohols, ketoses, saccharides, polysaccharides, oligosaccharides and the like, as well as celluloses and modified celluloses.

[0090] Sugars may also include direct compression and/or non-direct compression sugars. Non-direct compression sugars include, without limitation, dextrose, mannitol, sorbitol, trehalose, lactose and sucrose. These sugars generally exist as either a direct compression sugar, i.e., a sugar which has been modified to increase its compressibility and/or flow, or a non-direct compression sugar which does not have sufficient flowability and/or compressibility to allow it to be used in high speed processing and multi-tablet presses without some sort of augmentation such as, without limitation, a glidant to increase flow, granulation to increase flow and/or compressibility and the like. While not definitive, sometimes a non-direct compression sugar will have at least about 90% of its particles smaller than about 200 microns, and more preferably 80% smaller than about 150 microns.

[0091] The amount of total sugar can range from about 0 to about 90 (e.g., about 5 to about 75; about 10 and 50) by weight of the total dosage form. Other non-carbohydrate diluents and fillers which may be used include, for example, dihydrated or anhydrous dibasic calcium phosphate, tricalcium phosphate, calcium carbonate, anhydrous or hydrated calcium sulphate, and calcium lactate trihydrate. Non-carbohydrate diluents and fillers may be used in an amount of from about 0 to about 90 percent (e.g., from about 5 to about 75 percent; from about 10 to about 50 percent) by weight of the total dosage form.

[0092] Artificial sweeteners can include saccharin, aspartame, sucralose, neotame, and acesulfame potassium. Artificial sweeteners may be used in conventional amounts, for example, in an amount ranging from about 0.1 to about 2 percent by weight of the total dosage form.

[0093] Flavoring agents can include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. For example, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Also useful as flavoring agents are vanilla, citrus oil, including lemon, orange, banana, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.

[0094] Flavoring agents may be used in conventional amounts, for example, in an amount ranging from about 0.01 to about 3 percent by weight of the dosage form (e.g., from about 0.1 to about 2.5 percent by weight of the dosage form; from about 0.25 to about 2 percent by weight of the dosage form).

[0095] Coloring agents can include titanium dioxide, iron oxides such as red or yellow iron oxide, and dyes suitable for food such as those known as FD&C dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, and paprika. Coloring agents may be used in conventional amounts, for example, in an amount ranging from about 0.001 to about 1% by weight of the total dosage form.

[0096] Lubricants can include intrinsic or extrinsic lubricants. Intrinsic lubricants may include magnesium, calcium, zinc salts of stearic acid, hydrogenated and partially hydrogenated vegetable oils, animal fats, polyethylene glycol, polyoxyethylene monostearate, talc, light mineral oils, sodium benzoate, sodium lauryl sulphate, magnesium oxide and the like. Lubricants may be used in conventional amounts, for example, in an amount from about 0.1 to about 5 percent by weight of the dosage form (e.g., from about 0.25 to about 2.5 percent; from about 0.5 to about 2 percent).

[0097] Surfactants can include, without limitation, various grades of the following commercial products: Arlacel, Tween, Capmul, Centrophase, Cremophor, Labrafac, Labrafil, Labrasol, Myverol, Tagat, and any non-toxic short and medium chain alcohols. Surfactants can be used in conventional amounts, for example, in an amount of about 0.01 to about 5 percent by weight of the dosage form (e.g., in an amount of about 0.1 to about 2 percent).

[0098] Buffers can include any weak acid or weak base or, preferably, any buffer system that is not harmful to the gastrointestinal mucosa. These include, but are not limited to, sodium carbonate, potassium carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salts. Buffers can be used in conventional amounts, for example, in an amount of about 0.1 to about 10 percent by weight of the dosage form (e.g., from about 1 to about 5 percent).

[0099] The dosage form may also contain minor amounts of nontoxic substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters.

[0100] A dosage form, as used herein, is a tablet, capsule, caplet, sachet, powder or other solid known for the administration of medicines orally. It is generally made from a mixture as defined herein and is generally formed (as in a tablet) into a form for use by a doctor or patient for administration.

[0101] Dosage forms may be provided in a range of shapes and sizes. In some embodiments, the dosage form is in a size capable of oral administration and provides a therapeutic amount of drug. Generally, such dosage forms will be less than 1.5 inches in any one direction, more preferably less than 1 inch and most preferably less than 0.75 inch. Shapes include but not limited to round with both flat or convex face, capsule shape (caplets), diamond shape, triangular, rectangular, hexagonal, pentagonal, heart-shaped, animal shaped tablets like rabbits, elephants etc. Dosage forms can be any size and shape, but preferable of a size and shape to maximize alcohol resistance.

[0102] Dosage forms, especially tablets, may also be coated to improve the appearance of the dosage form, and also to maximize alcohol resistance.

[0103] Dosage forms are formulated to be suitable generally for once-a-day or twice-a-day administration. The amount of drug present in the dosage form can vary from about 20 mg to 1.5 g, more preferably 40 mg to 1 g and most preferably 80 mg to 800 mg.

[0104] Tablets can either be manufactured by direct compression, wet granulation, dry granulation followed by coating and tablet compression or any other tablet manufacturing technique. See, e.g., U.S. Pat. Nos. 5,178,878, 5,223,264 and 6,024,981 which are incorporated by reference herein.

EXAMPLES

Example 1

85 mg Venlafaxine Hydrochloride Formulation (Equivalent to 75 mg Venlafaxine Base)

[0105]

TABLE-US-00001 TABLE 1 Material % w/w Uncoated Granules Venlafaxine hydrochloride 46.3 hydroxypropylmethylcellulose 37.0 (K100M) ethylcellulose 16.7 Coated Granules uncoated granules 50.0 ethylcellulose 33.3 magnesium stearate 16.7 Dosage Form coated granules 43.1 lactose monohydrate 26.5 hydroxypropylmethylcellulose (K100M) 30.0 magnesium stearate 0.5

[0106] Granules were manufactured in a high shear granulator where Venlafaxine hydrochloride, hydroxypropylmethylcellulose, and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, a 10% hydro-ethanolic (30:70) solution of the remaining ethylcellulose was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.

[0107] The uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/magnesium stearate mixture to provide a coat of 50% by weight of the coated granules. Coated granules were mixed with lactose monohydrate and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of Venlafaxine hydrochloride; it is not based on the theoretical content. The blended mixture was then compressed in a rotary tablet press to form tablets. The 0.31250.5625 capsule shaped tablets weighed 850 mg and had an average hardness of about 100N.

Example 2

190 mg Metoprolol Succinate Formulation (Equivalent to 200 mg Metoprolol Tartrate)

[0108]

TABLE-US-00002 TABLE 2 Material % w/w Uncoated Granules Metoprolol succinate 76.8 hydroxypropylmethylcellulose 9.6 (K100M) ethylcellulose 13.6 Coated Granules uncoated granules 60.00 ethylcellulose 26.7 magnesium stearate 13.3 Dosage Form coated granules 48.5 lactose monohydrate 21.0 hydroxypropylmethylcellulose 30.0 (K100M) magnesium stearate 0.5

[0109] Granules were manufactured in a high shear granulator where Metoprolol succinate, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, a 10% hydro-ethanolic (30:70) solution of the remaining ethylcellulose was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.

[0110] The uncoated granules were then coated in a bottom spray fluid bed using a 15% acetone suspension of a 2:1 ethylcellulose/magnesium stearate mixture to provide a coat of 40% by weight of the coated granules. Coated granules were mixed with lactose monohydrate and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of Metoprolol succinate; it is not based on the theoretical content. The blended mixture was then compressed in a rotary tablet press to form tablets. The 0.31250.5625 inch capsule shaped tablets weighed 850 mg and had an average hardness of about 111 N.

[0111] In a similar manner to Examples 1 and 2, non-lipid matrix based alcohol-resistant extended release dosage forms of the following high water-soluble, high dose drugs may be prepared:

Example 3

100 mg Desvenlafaxine (Example of Anti-Depressant)

[0112]

TABLE-US-00003 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w desvenlafaxine 70.0 uncoated granules 60.0 coated granules 50.0 hydroxypropylmethyl- 15.0 ethylcellulose 26.7 lactose monohydrate 24.5 cellulose (K100M) magnesium 13.3 hydroxypropylmethyl- 25.0 ethylcellulose 15.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 478

Example 4

150 mg Pregabalin (Example of Anti-Epilepsy and Pain Drug)

[0113]

TABLE-US-00004 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Pregabalin 75.0 uncoated granules 50.0 coated granules 50.0 hydroxypropylmethyl- 10.0 ethylcellulose 33.3 lactose monohydrate 24.5 cellulose (K100M) magnesium 16.7 hydroxypropylmethyl- 25.0 ethylcellulose 15.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 800

Example 5

400 mg Gabapentin (Example of Anti-Epilepsy Drug)

[0114]

TABLE-US-00005 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Gabapentin 90.0 uncoated granules 85.0 coated granules 65.0 hydroxypropylmethyl- 5.0 ethylcellulose 10.0 lactose monohydrate 14.5 cellulose (K100M) magnesium 5.0 hydroxypropylmethyl- 20.0 ethylcellulose 5.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 805

Example 6

100 mg Miglustat (Example of Anti-Gaucher Drug)

[0115]

TABLE-US-00006 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Miglustat 65.0 uncoated granules 60.0 coated granules 50.0 hydroxypropylmethyl- 15.0 ethylcellulose 26.7 lactose monohydrate 29.5 cellulose (K100M) magnesium 13.3 hydroxypropylmethyl- 20.0 ethylcellulose 20.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 513

Example 7

200 mg Chlorpromazine HCl (Example of Antipsychotic Drugs)

[0116]

TABLE-US-00007 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Chlorpromazine HCl 70.0 uncoated granules 70.0 coated granules 50.0 hydroxypropylmethyl- 10.0 ethylcellulose 20.0 lactose monohydrate 29.5 cellulose (K100M) magnesium 10.0 Carbomer Homopolymer 20.0 ethylcellulose 20.0 stearate Type A (Carbopol 971P) magnesium stearate 0.5 Tablet weight (mg) 817

Example 8

80 mg Propranolol HCl (Example of Anti-Hypertension Drug, Anti-Angina)

[0117]

TABLE-US-00008 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Propranolol HCl 60.0 uncoated granules 50.0 coated granules 45.0 hydroxypropylmethyl- 15.0 ethylcellulose 33.3 lactose monohydrate 24.5 cellulose (K100M) magnesium 16.7 hydroxypropylmethyl- 30.0 ethylcellulose 25.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 593

Example 9

750 mg Levetiracetam (Example of Anti-Epileptic)

[0118]

TABLE-US-00009 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Levetiracetam 90.0 uncoated granules 90.0 coated granules 70.0 hydroxypropylmethyl- 5.0 ethylcellulose 6.7 lactose monohydrate 9.5 cellulose (K100M) magnesium 3.3 hydroxypropylmethyl- 20.0 ethylcellulose 5.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 1323

Example 10

174 mg Bupropion HBr (Example of Anti-Depressant)

[0119]

TABLE-US-00010 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Bupropion HBr 80.0 uncoated granules 65.0 coated granules 50.0 hydroxypropylmethyl- 10.0 ethylcellulose 23.3 lactose monohydrate 29.5 cellulose (K100M) magnesium 11.7 hydroxypropylmethyl- 20.0 ethylcellulose 10.0 stearate cellulose (K 4M) magnesium stearate 0.5 Tablet weight (mg) 670

Example 11

500 mg Tetracycline HCl (Example of Antibiotic)

[0120]

TABLE-US-00011 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Tetracycline HCl, 90.0 uncoated granules 85.0 coated granules 68.0 hydroxypropylmethyl- 5.0 ethylcellulose 10.0 lactose monohydrate 16.5 cellulose (K100M) magnesium 5.0 hydroxypropylmethyl- 15.0 ethylcellulose 5.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 962

Example 12

100 mg Diclofenac Sodium (Example of Anti-Inflammatory)

[0121]

TABLE-US-00012 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Diclofenac sodium 60.0 uncoated granules 85.0 coated granules 40.0 hydroxypropylmethyl- 20.0 ethylcellulose 10.0 lactose monohydrate 39.5 cellulose (K100M) magnesium 5.0 hydroxypropylmethyl- 10.0 ethylcellulose 20.0 stearate cellulose (K100M) Carbomer Homopolymer 10.0 Type A (Carbopol 971P) magnesium stearate 0.5 Tablet weight (mg) 491

Example 13

336 mg Ranitidine HCl Equivalent to 300 mg Ranitidine Base (Example of Anti-Ulcer Agent)

[0122]

TABLE-US-00013 Uncoated granules Coated granules Dosage Form Material % w/w Material % w/w Material % w/w Ranitidine HCl 80.0 uncoated granules 85.0 coated granules 60.0 hydroxypropylmethyl- 10.0 ethylcellulose 10.0 lactose monohydrate 29.5 cellulose (K100M) magnesium 5.0 hydroxypropylmethyl- 10.0 ethylcellulose 10.0 stearate cellulose (K100M) magnesium stearate 0.5 Tablet weight (mg) 824

Example 14

Dissolution and Tamper Testing

[0123] The products of Examples 1 and 2 were subjected to dissolution experiments in 0.1N hydrochloric acid and 0.1N hydrochloric acid and 40% v/v alcohol. Tablets were tested using the USP dissolution apparatus number 2 using 500 ml of 0.1 N hydrochloric acid (normal dissolution) or 40% ethanolic solution (dose dumping dissolution) as the dissolution medium. Unless otherwise specified, aliquots were removed after 15, 30, 45, 60, 120, 180, 240, 480, 720 minutes of stirring in the normal dissolution test and the dose dumping dissolution. Samples were analyzed for drug using HPLC.

[0124] Results of the above experiments are detailed in FIGS. 1 and 2. Tablets were considered to be alcohol-resistant if the percent of drug released after 2 hours in 0.1N hydrochloric acid/40% v/v alcohol was no more than 10 percentage points greater than the percent of drug released after 2 hours from a solution of 0.1N hydrochloric acid in the absence of alcohol.

[0125] As seen in FIGS. 1 and 2, the formulated dosage forms met the criteria for alcohol resistance. Specifically, for the venlafaxine HCl formulated product, the percent of drug released after 2 hours in absence of alcohol was 23% compared to 18% in presence of alcohol. For the metoprolol succinate formulated product, the percent of drug released after 2 hours in absence of alcohol was 8% compared to 16% in presence of alcohol. For both formulated products, the drug release in alcohol was extended over 12 hours reflecting protection against alcohol is extended well beyond the 2 hours described above. The results are in contrast to the commercially available venlafaxine HCl and metoprolol succinate products known as Effexor XR and Toprol XL respectively. The results for these products are shown in FIGS. 3 and 4. As seen in the figures both products were very susceptible to alcohol with 90% of the dose released in the presence of alcohol compared to 15-21% released in absence of alcohol after 2 hours.

[0126] Simulated oral tampering testing is conducted by crushing tablets using ceramic mortars and pestles. A tablet is placed in a ceramic mortar (13 cm outer diameter). A pestle is used to apply force vertically downward onto the tablet until it breaks. The broken tablet is further crushed using a 360 circular motion with downward force applied throughout. The circular crushing motion is repeated eleven times (twelve strokes total). The resulting powder is transferred to a dissolution vessel for in vitro drug release. The in vitro release profile of the crushed tablet samples is obtained in 500 mL of 0.1 N hydrochloric acid dissolution medium. The samples are agitated at 50 rpm with USP apparatus 2 (paddles) at 37 C. These are the same in vitro conditions as those employed in the in vitro dissolution test described above. Aliquots are removed after 15, 30, 45, 60. and 120 minutes of stirring and are analyzed for drug using HPLC.

[0127] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.