CA2616204A1 - Sustained drug release composition - Google Patents

Sustained drug release composition Download PDF

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Publication number
CA2616204A1
CA2616204A1 CA002616204A CA2616204A CA2616204A1 CA 2616204 A1 CA2616204 A1 CA 2616204A1 CA 002616204 A CA002616204 A CA 002616204A CA 2616204 A CA2616204 A CA 2616204A CA 2616204 A1 CA2616204 A1 CA 2616204A1
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Prior art keywords
composition
agents
sustained release
active agent
dosage form
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CA002616204A
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CA2616204C (en
Inventor
Sonia Gervais
Damon Smith
Pauline Contamin
Rachid Ouzerourou
My Linh Ma
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Paladin Labs Inc
Endo Ventures Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications

Abstract

The invention relates to a sustained release formulation for delivering one or more pharmaceutically active agents The formulation comprises cross-linked high amylose starch and at least one pharmaceutically active agent, and, when subdivided into smaller dosage forms, the smaller dosage forms have substantially the same sustained release properties as the formulation from which they were derived The formulations can provide sustained release for up to at least 24 hours, and because of their divisability permits a recipient of the active agent or the person administering the active agent to titrate the dosage of the agent.

Description

SlUs'1'AINED DRUG YtELEASE COMPOSITION

TECWTIC.AL FIET..,Y) [0001] The present invention relates generally to a sustained release drug composition and more particularly to a sustained release drug conoposition, which when subdivided into smaller dosage forms, the smaller dosage forms display substantially the same drug release profile as the composition from which they were derived, ' A~tT
BACKGROUND
[0002] Typically, oral dosage forms for the delivery of pharmaceutically active agents or drugs release the agent during passage through the gastroiniestinal tract. Tho part of the gastrointes#.in.e.l tract to which the active agent is delivered depends in part on tb.e type of delivery system involved. Certain delivery systems release the active substance rapidly, leading to, for example, a rapid rise to a maximum concer.tration of drug in the blood usually followed by a rapid decrease in concentration as the drug is cleared from the body. If the drug concentration rises and/or decreases rapidly, this may create a narrow window of time during which the drug is therapeutically effective. As a result, sustained therapeutio efficacy may require admixaistration of multiple, sequential doses of the dtug.
In addition, if release of drug to the body is uncontrolled in tliis manner, adverse evexits associated with the drug may not be controllable and the drug may not be effecti-vexy delivered to the site requiring treatment, [0003] Various compositions and dosage forms have been used to control drug release and thereby provide sustained release of a.ctive agents to provide sustained efficaoy from one composition. For example, a well-known way of controlling the release of drug is to apply a coating to a solid core. For example, a polymer coating can produce a rate confixQlling film on the surface of the core. The release rate of the therapeutic agent can then be altered by factors including the thickness of the coating, the diffusivity of agent through the coating, and the rate of biodegradation of the coating. If the coated dosage form is brolcen, or damaged, during or after administration, the coating may no longer provide an effective rate coiArolling Blm resulting in the drug being rapidly xeleased from the core.

SUBSTITUTE SHEET (RULE 26) 100041 Drug dosing regimens, be they acute or chronic, may vary from patient to patient.
Different patients can have different therapeutic responses to a given dose of drug.
Further, pbysicians sometimes start with a smaller than recornmend.ed dose of a drug and titrate the dose upward over time to minitbi.ze, for the patient, the frequency and severity of adverse events associated with optimum blood concentrations of the drug.
Alternatively, for some patients and/or drug therapies, physicians start with a high, or loading dose of drug to achieve lnaximum and rapid therapeutic benefit and then reduce the dose administered to maintain efficacy, Such dosing regimens require precise control over the dosage administered, which, with the xight formulation, can be achieved using for exaixiple, a single tablet that may be sub-divided into subunits each having a smaller dose of the drug, wrliere each of the subunits delivers the drug in the same manner as tlhe tablet from which they were derived.

[0005] There is a need, therefore, for a formulation of a pharmaceutically aetive agent, which when sub-divided or broken into smaller dosage forms achieves substantxaIly the same sustained release profile as the original formulation, and wkd.ch conveniently permits modi.ficatioxX of dosing regimens, DISgLt)SU].~E OF THE INYE.14iTION

100061 The invention provides solid, sustained drug xelease dosage forms that ean: be subdivided into smaller dosage forms. The smaller dosage forms provide substantially the same drug release kinetics as the solid dosage forrn they were created from, The formuxa.tion.s provided herein permit a recipient, a trea.ting physician, or a person administering the drug, to conveniently create smaller dosage forms that can be used to more accurately and precisely deliver the appropriate amount of drug to the recipient.
[0007] In one aspect, the invention provides a solid, monolitbic sustained release pharrnaceutical composition comprising: (a) a sustained release matrix having a solvent accessible surface, wherein the matrix comprises cross-linked high arnylose starch; and (b) an effeotive amount of at least one phai:~maceutically aetivd agent disposed within the matrix. The composition has a hardness of greatex than about 100 N, for example, in the range from about 140N to about 350 N.

SUBSTITUTE SHEET (RULE 26) [00051 Such a compositio~,n when admifdstered to a mammal, for example, a human, achieves an effective plasma concentration, for example, a therapeutically effecti"ve plasma cor-eentration of the active agent from at least about 1 hout to at least about 24 ht+urs after initial administration. The composition comprises a solvent accessible surface that optiox-ally defuies a score or scores, which permits the composition to be sub-cUvided along the score to produce at least two subunits each having a new solvent accessible surface. At least one of the resulting subunits has substantially the same release kinetics of the active agent as the intact composition from which it was derived.
Furthermore, the dissolution profiles of at least one of the subunits and the composition from which it was derived have a similarity factor of at least 50%, at least 55 0, at least 60%, at least 65%, at least 70%, at least 75%, and at least 80%.

[0009I In =ther aspect, the invention provides a solid sustained release pk1armaceutical composition comprising: (a) a sustained release matrix having a solvent accessible surface, wherein the matrix comprises cross-linked high amylose starch; and (b) an effective amount of a pharmaceuiically active agent disposed within the matrix The composition (i) displays substantially the same release kinetics when the composition is broken or subdivided along a score, to create a new solvent accessible surface, and/or (ii) can be divided into at least two subunits where each subunit xeleases the active agent with substantially the same release profile as the composition from which they were derived..
[0010] The composition has a hardness of greater than about 1.00 N, and, for example, has a hardness in the range from about 100 N to about 350 N. Such a composition can be monolithic in nature. The new solvent accessible surface created by dividing or breaking the original dosage form, and like tho original solvent accessible, surface of the original intact form, can form a barrier having mernbrane-lilÃe properties when exposed to an aqtieous salvent.

[0011] The tlissolution profiles of at least one subunit and the composition from which it was derived have a similarity factor of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, and at least 80%. The subunits and the intact composition from which they are derived can be designed to be bioequivaleat, and each SUBSTITUTE SHEET (RULE 26) subunit can release the active agent for at least about 12 hours, about IS
hours, or at least 24 hours, [0012] The compositions described kierein cornprise from about 15% to about 60% by weight of the active ingredient and from about 15% to about 85% by vveight= of a controlled release excipient that defines the sustained release matrix, from about 20% to about 50% by weighi of the active ingredient and from about 20% to about 50%
by weight of the controlled release excipient, and from about 35% to about 50% by weight of the active ingredient and from about 20% to about 50% by weight of the controlled release excipient.

[0013] It is contemplated that a numbear of diiffexent controlled release excipients may be usefiil in tlie practice of the invention. The controlled release excipients comprise cross-linked high amylose starch. In certain embodiments, the cross-linked high amylose statch is cross linked with phosphorus oxychloride and/or comprises klydroxypropyl side chains. In certain other embodiments, the Gross-linlced high amylose starch comprises between about 65% and about 75% by weight of amylQse and is cross-li.nked with phosphorus oxychloride. One preferred cross-linked high amylose stttrch useful in the practice of the invention is known as CbNT.RAlVZIl7O cross-linked, high amylose starch, available ooiumercially from Labopharm, Inc., Laval, Canada.

[0014) It is contemplated that a number of different pharmaceutically active agents can be incorporated into the compositions and dosage forms of the in.vention, Such active agents can include, for example, antidepressants, fox example, trazodone, and analgesics, for example, tramadol and acetaminophen or combinations thereof. It is contemplated that one, two, three or more active agents can be incorporated into the fozmulations described herein, [0015] In addition, the sustained release phatrn.aceutical composition optionally includes one or more pharmaceutical additives, Exemplary pharmaceutiGal additives include binding agmts (for example, hydroxypropylmethyleellulose), solubilizing agents (for exatAple, povidone or cetylpyridinium chloride), acidifying agents (for example, alginic acid), pore forming agents (for example, sucrose); lubricants (for example, sodium stearyl fumarate), and glidants (for example, colloidal silicon dioxide).
SUBSTITUTE SHEET (RULE 26) [00161 The sustained release pharmaceutical composition can qe tort.nulatect in.to a variety of shapes and forms such as tablets and caplets suitable for oral administration, In one eYnbodiment, the invention provides a caplet. Such tablets and caplets can be scored on one or both sides, and/or have multiple scores.

[0017] Also provided are methods ofnnalcing the formulations described herein as well as methods of using such fQrinulations.

&R.XEF DESgliIPTION OF To DRAWINGS

[0018] The invention is illustrated but is not limited by the annexed drawings, in which [0019] FIGURE 1 is a schematic representation of an exemplary formulation of the invention;

i00201 FIGURE 2 is a graph illustrating the in vitro dissolution profile of an intact tablet, (a) coinpared to a bisected tablet (o) of an exemplary 300 ing forrrAtxlation oftraxodone;
[00211 FIGURE 3 is a graph illustrating the in vitro dissolution profile of an intact tablet of an exemplary formulation containing 300 mg trwodone (+) wvith a bisect depth score of 23% of the tablet cup depth and a subdivided tablet (o) derived from an intact tablet with the same scoring;

[00221 FIGURE 4 is a graph illustrating the in vitro dissolution pro$le of an iu.tact tablet of an exemplary formlxl.ation containing 300 mg trazodone (i) with a bisect depth score of 9S fn of the tablet cup depth and a subdivided tablet (a) derived fi'om an intact tablet with the same scoring;

[0023] FIGURE 5 is a graph illustrating the test for uniformity of znass on an exemplary tablet formulation containing 150 mg trazodone where a hardness of 111 N is required to achieve a relative standard deviation (RSD) of less than 6% as required by the U.S.P.;
and [00241 FIGURE 6 is a graph illustrating the in vitro dissolution profile of an intact tablet (,&) compared to a bisected tablet (a) of an exemplary 150 mg formulation of tr=a2;odone;
[0025[ FIGURE 7 is a graph illustrating the in vitro dissolutian profile of an intact tablet (A,) compared to a bisected tablet (o) of an exemplary 300 mg formulation of tramadal.

SUBSTITUTE SHEET (RULE 26) DETAILED DESCRIPTION OF THE INVENTICEN

100261 The invention is based, in part, upon the discovery that it is possible to fornmu.late a sustained release composition, which when sub-divided, e,g., broken or separated into subunits or smaller dosage ,forms, at least one of the resulting subunits or smaller dosage forms has substantially the same dfug release profile as the original intact composition from which it was derived. Such a sustained release composition, whether sub-divided or intact, provides a rate of release of active agent that is controlled over a period of time up to about 12 hours, up to about 18 houxs, or up to about 24 hours, or more.
After admin.istration of such a sustained release composition, the drug plasma concentration of a patient may be corltrolled, e,g., up to 12 hours} up to 18 hours, and 24 hours. This discovery was surprising because if sub-divided (broken or separated into subunits), sustained or controlled release compositions can lose thexr sustained release properties, i.e., the subunits deliver the active agent in a rapid and uncontrolled fashion.

[0027] Accordingly, in one aspect the invention provides a solid, monolithic sustained release pharmaceutical composition comprising; (a) a sustained release matrix having a solvent accessible surfaoe, wherein the matrix eompxises cross-lin.ked high amylose starch; and (b) an effective amount of at least one pharmaceutically active agent disposed within the matrix, The composition has a hardness of greater than about 100 N, for example, in the xan.ge from about 1UO1+I to about 350 N.

[0028] As used hereirn, the term "effective atnount" can include therapeutically effective amounts and amounts suitable for titration regimens and the 1ike, where, for example, mu.ltiple tablets or subdivided tablets need to be administered to an individual to achieve amaxi.mv.zu therapeutic efficacy with tninimizing adverse effects.

10029] The term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substanGe, The term thus means any substance intended for use in the diagnosis, cure, unitigation, treatment or prev'ezition of disease or in the enhancemezxt of desirable physical or mental development and/oz' conditions in an animal or human. The phrase "there.peutically-effective amount" means that amount of such a SUBSTITUTE SHEET (RULE 26) substance that produces some desired local or systemic effect at a reasonabte ben.etrt/nsk ratio applicable to any treatment. The therapeutically effective atnount of such substance ,Aill vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of atlnainistration and the lilce, which can readily be determi.ned by one of ordinary skill in the art. p'or example, certain co7npositioxis of the present invention amay be administered in a sufficient amount to produce an amount at a reasonable benefit/risk ratio applicable to such treatment.

[00301 In another aspect, the invention provides a solid sustained release pharmaceutical composition comprising: (a) a sustained release matrix having a solvent accessible surface, wherein the matrix comprises cross-linlced high amylose starch; and (b) an effective amount of a pharmaceutically active agent tlisposed within the matrix The composition (i) displays substantially the same release kinetics when the compositxon is sub-divided by breaking or fracturing to oreate a new solvent accessible surfaoe, andior (ii) can be divided into at least two subunits where ea.c*b subunit releases tfxe active agent with substantially the same release profile as the composition i'xom which it was derived.
[0031) These formulations may be monolithic in nature. As used herein, the term "rnQnolithic is understood to mean a compositioti that releases an active agetlt in a substantially uniform fashion, with the composition dissolving or disintegrating substantially uniformly, rather than in layers, [0032) The foregoing compositions have hardness of greater than about 100 N.
The compositions typically have a hardness in the range from about 110 N to about Accordingly, the compositions opti.onally can have a hardness of 110 N, 120N, 140N or higher. Preferred hardnesses range from about 100 N to about 180N, or from 11 Ql4l' to about 140N, or about 140 N to about 180 N. For exarnple, the hardness may vary depending on the size of the tablet, e.g. a smaller tablet may have a hardness of about 100 N to about 140 N; a larger tablet may have a hardness of about 2201V' to 260 N. As used herein, the term "hard.ness" is used to describe the diametral breaking strength as measured by conventional pharmaceutical hardness testing equipment.
Preferably, such compression is performed in a single praeess, SUBSTITUTE SHEET (RULE 26) [0033] The sustained release matrices include a controlled release excipient.
The composition comprises from about 15% to about 60 % by weight pharmaceutically active agent, and from about 15% to about 85 fa by weight percent of a controlled release excipient. The controlled release excipient, when oxally administered to a tnammal, for example, a person, permits the pharmaceutically active agent to achieve and/or maixltain effective artd/or controlled plasma concentrations, for example, an effective plasma concentration for up to about 24 hours after initial administtation. Such release kinetics are substantially the same when an intact composition, e.g,, a tablet is broken, separated or sub-divided into subunits, [4034] As shown in Figure 1, an exemplary solid sustained release composition includes (i) a sustained release matrix having an interior or core 20 and a solvent accessible surface 30, and (xi) a pharmaceutically active agent 40 disposed therein. The sustained release matrix includes a controlled release excipient, such as cross-linked high amylose starch, When the composition, such as a solid dosage form, is fractured or divided, to produce subunits 60, eacki subunit contains a portion of the,original solvent accessible surface 30 and a uewly exposed solvent accessible surface 70.
Without wishing to be bound by theory, the controlled release excipient, e.g., cross-linked, high amylase starch, may form a membrane e.g, a senu-pezmeable men-brane, or barrier layer, which may be, for example, over, on, or constitute part of the solvent accessible surface .(30 and 70). Such a barrier may contribute to substantially stable release kinetics of the active agent in the sub-divided or intact forms, [00351 The i.utact solid sustained release co.inposition 10 optionally comprises one or moxe scores 50, shown in phantom in Figure 1. The scores can be used to guide the subdivision of the intact tablet. Although Figure 1 shows a tablet with two adjacent scores, however, it is contemplated that the tablet can contain more scores if more than two subunits are desired.

[0036] Accordingly, the invention provides a sustained release solid dosage form comprising cross-linked high amylose starch and a pharmaceutically active agent, wherein the solid dosage form can be separated into subunits, with each subunit having substantially the same sustained release properties as the intact or unbroken solid dosage SUBSTITUTE SHEET (RULE 26) form. Dosage fortns may be bisected, e.g., divided into two suos-canua.iiy equal pieces, or may be divided into other fractional sections, e.g., tlxitds or faurths.
1]osage forms may also be divided into unequal sections, e.g., one-thXrd/two-thirds.

[00371 In vitro dissolution profiles of intact and separated sustained formulations as described herein may be compared using fit factors or other mathematical comparisons.
Such fit factors are known to those slCilled in the art and are used to predict bioequivalency of different dosage fornxs, The fit factor f 1 represents relative error between two curves, or in other words, the mean relative difference on aIl measured points. Fit factor f 1 is sometimes referred to as the difference factor, 7he mean relative difference for each sample point should be between about 0 to about 15% for bxQequivalence. In some embodiments, compositions and/or formulations may have a similarity factors between an intact dosage fbrm and subunits of the intact dosage fortn of less than about 15%, less than about 10%, or less than about 7%. The fit factor f2 is a logarithmic transformation of the mean of squaxes differences between two curves. Fit factor fz is sometimes referred to as the similarity factor. The similarity factor should be between about 50% and about 100% for bioequivalence, e.g., between the suburiit foms and intact dosage forms. In some embodiments, compositions and/or formulations can have similarity factors between an intact dosage form and the su buzaits derived from the intact dosage form of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, and at least 80%.

[00381 The formu.lations described herein can provide rise in plasma concontrations of the active ingredient, which thereafter remain relatively and substan.tially stable for at least 10, at least 12, at least 18, or at least 24 hours or more, regardless of whether the dosage form is separated into subunits or is in an intact foxm. The plasma concentration between one hour and 24 hours may remain within 'about 45% of the mean plasma concentration, more preferably betuveen about 30% of the mean, and most preferably, betweeti about 15% of the mean plasma concentration, In certain formulations, after an initial rapid release of the active agent, within an hour of ingestzon the active agent is released in -vivo with approximately zero order kinetics for at least about 24 hours, leading to plateau plasma concentrations.

SUBSTITUTE SHEET (RULE 26) t00:39] Dosages in a particular sustained release formulation catl vary to a large extent depending on required needs of the patient, and the specific requirements of the treating physician. For example, the dosage of any compositions of the present invention will 'vary depending on the symptoms, age and body weight of the patient, the natuxe and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Dosages for the conapositions of the present iuveintion niay be readily determined by techniques known to those of skill in the art or as taught herein. The precise time of adsniiaistration and amount 'of any particular subject composition that wi11 yield the most effective treatment in a given patient will depend upon the activity, pharma.coltineties, and bioavailability of a subject cot'u.positiora, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of inedication), route of administration, aDd the lilte. The guidelines presented herein may be used to optimize the treatrnent, e,g., determining the optimum time and/or amount of ad.ministration, which vvlll require no more than routine experimentation consisting of monitoring the subject and atljusting the dosage and/or timing.

[00401 Specific sustained dosages can be tailored using the dosage forms by breaking tlie dosage f4rms disclosed herein into substantially similar but smaller doses having substantially similar sustained release profiles. For example, smaller doses may be useful -for patients lighter in weight and/or for paediatric use. Alteernatively, one dosage may be provided, but in a szn.aller form that inay be more acceptable to a patient, For example, a patient may be able to divide a dosage into easier-to-swallow components while still niaintaining the sustained release properties of the dosage form. The ability to alter dosage on a patient by patient basis with one dosage form may also be convenient for, e.g., D. physician or a pharmacist.

[00411 For some patients, a typical recommended dose may be larger than what is needed, increasing the chance of adverse effects. For example, patients taking txamadol, reported adverse reactions include dizziness, z)attsea and constipation.
Reported adverse effects for trazodone forxnulations include dizziness, dry-mouth, nervousness and fatigue.
Patients taking betahistidine have reported gastdc upset, nausea azxd headache.

l0 SUBSTITUTE SHEET (RULE 26) [0042] One approach for decreasing adverse effects is dose titration. For example, for patients that do not require an immediate response, a dose that is about one-fottrth to one-half the recommended dose may be initially administered and over a course of a time, e.g., two to four weeks, the dose may be titrated or increased until the desired effect is obtained. For acute conditions, titration can occur over the course of days, rather than weeks, The disclosed dosage forms may used in such dose titration regimens, for example, by dividing an intact form into sub-sections that can be taken individually for smaller doses and then taken in larger sub-sections or intact forms for larger doses. Dose titration is often used, for example, in the admiuaxstration of analgesics such as opioids to achieve pain relief while maantainitrg an acoeptable level of adverse side effects, [0043] The disclosed dosage forms may be used in such dosage regimens that start with, e.g., the recommended do.se, and subsequently have reduced dosages according to the patient's needs. For example, such a regimen may be accomplished by administering an iiitaet dosage form as disclosed herein and then dividing an intact form into subunits, each of which can be taken individually for smaller doses.

[00441 The composition according to the invention is normally prepared in the form of a tablet. Although tJre tablet can adopt a wide variety of shapes as is well known to those skilled fii the art, the preferred shape is a caplet. Such caplets may be formed, for example, with composition including a controlled release excipient and at least one active agent and using upper atid lower pu.nches set in a tableting machine as is lcnown in the art. In some etnbodimeatss, tablets may include a coating, such as, for example, an inert coating containing a colorant. Suitable coatings include, for example, aqueous film coating polymers such as polyvinyl alcohol, talc, macrogel and the lilce, and mixtuses thereof; Suitable colorants include, for example, iron oxides, lakes, natural colorants and other colorants known to those skilled in the art. Preferably, such a coating does not affect the release kinetics, e.g. dissolution performance of a dosage form when intact or when sub-divided.

[00451 In soane embodinients, tlie dosage forms, e.g., tablets may be scored.
Preferably, scored tablets or un-scored tablets are broken with high breaking accuracy thereby ensuring matching or proporti.onal release profiles from each resultant sub-division.

SUBSTITUTE SHEET (RULE 26) BrealÃing accuracy may determined for example, by evaluating the mass uniformity of sepa.rated, e.gõ bisected; parts of the same tablet. The mass tuxiformity of a tablet may be determined in tezyns of relative standard deviation (RSD) from the mean mass of tablet sections using the U.S.P. test limit of uuifor:mity (RSL7 below 6%), Figure 5 indicates, for the exemplary forxnulatioa as described in Example 2, hereinbelow, that for sucll a formulation, the minimum tablet hardness needed for mass uniformity with an RSD
below 6% is about 110 N.

[00461 Scoring may have varying depths, e.g., from about 0% (e.g., no scoring) to about 95% of the tablet eup depth. Each tablet may have one, two, or multiple scores, and/or scoring on one or both sides of the tablet. As can be seen in Example 1, hereinbelow, scoring does not substantially affect the release profiles of the tablets when intact or when broken along the score.

10047] The fon-aulations may have in Wtro profiles as described in the Examples hereinbelow. The in vitro rel.ease profiles oan be measured using the U.S,I'.
laadclle method (apparatus type II as described in U.S.P. XXVI) at 150 revolutions fier minute, at 37-+0.6 C, in 900 mL of hydrochloride/sQdium chloride pH 1.2 solution (acid stage) followed after one hour by 900 mI, of sodium phosphate monobasic buffer p116.0 (buffer stage). In some embodiments, foxmulations may have release kinetics, whereby, when tested by the foregoing method, not more than about 30% of the active ingredient is released by 1 hour after initxation of the experiment, about 35% to 55% of the a.ctxve ingredient is released by 6 hours, not more than about 80% of the active ingredient is released by 12 hours, and/or not less thm about 80% of the active ingredient is released by 24 hours.

[0048] Foimulatiazas contemplated herein may reach steady-state, for example, on-average, wvithin a normal population, after about the fourth administratiQn.
The peak-ta-tYou~gh ratio produced by s-ach formulations at steady-state may be about 60%
to 'about 100%.

[0049] The formulations described herein are particularly useful in the deliveiy of pharw.aceutically active agents a.t~d theix derivatives. Derivatives include phannacoutically acceptable pro drugs, metabolites, salts and esters, or the like. For SUBSTITUTE SHEET (RULE 26) example, the term "pharmaceutically-acceptable salts" is art-recognized and refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention.

[0050] The term. "phatxnaceutically active agent ' refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substauce that acts locally or systemically in a subject. Examples of pharmaceutically active agents, also xeferred to herein as. "dru.gs,?" axe described in well-known literature references such as the Merck Index, the Physicians DesXc Reference, and The pharmacological Basis of Therapeutics, and they include, without limitation, medicaments; vitamins; mineral supplements;
substances used for the treatament, prevention, diagnosis, cure or mitigation of a disease or illness; substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active,after they have been placed i-a a physiological eriviranment.

600511 Compositions and formulations contemplated herein may include one or more pharmacentically active agents, For example, a composition may include two, three or more different phannaceutically active agents.

(0052] The pharmaceutically active substance of the invention can vary widely with the purpose for the composition. It is contemplated that one or a plurality of different phaxmacetttically active agents are included in the formulations described herein. Norn-linliting examples of broad categories of useful pharmaceutically active agents include the following therapeu.tic categories: azzabolic agents, antacids, anti-asthmatic agents, anti-ch.olesterolemic and anti-lipid agents, .anti-coagulazits, antx-convulsants, .anti-diarrheals, anti-emetics, anti-infective agents, anti-inflammatory agents, auti-manic agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic 'agents, anti-spasmodic agents, anti-ftombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussi.ves, appetite suppressants, biologicals, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietlc agents, expectoratits, gastrointestinal sedatives, h.yperglycemic agents, hypnotics, hypoglycernic agents, ion exchange resins, laxatives, miiieral supplements, SUBSTITUTE SHEET (RULE 26) mucolytic agents, neuromuscular drugs, peripheral vasoclilrztors, psychotropics, sedatives, stizn.ulants, thyroid and anti-thyroid agents, uterine relaxants, vitamins, and pro-drugs.
[0053] More specifically, non-limiting examples of useful phannaceutically active sszbstances include the following therapeutic categories: analgesics, such as nonsteroidal anti-infla.nmmatory drugs, opiate agonists and salicylates; antihistamines, such as Hl -blockers and Hz -blockers; anti-infactive agents, such as anthelxn.in.tics, antianaerobics, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, niacrolide antibiotics, miseellaneous R-iactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials, antituberculosis antim.ycobacterials, antiprotozoals, antimalarial antiprotozoals, antiviral agents, antiretroviral agents, scabicides, and urinary anti-izafectives;
an.tineoplastic agents, such as alkylatixl.g agents, nitrogen mustard aklylating agents, nitrosourea alkylating agents, antimeta.bolites, purine analog antimetaboiites, pyrirnidxn.e analog antimetabolites, hormonal antineoplastiGs, natural antineoplastics, antibiotic natural, antineoplastics, and vinca alkaloid natural antineoplastics; autonomic agents, such as anticholinergics, antimuscarinic anticholinergics, ergot alkaloids, parasympathamimetics, cholinergic agonist parasynmpathomimeties, cholinesterase inhibitor parasyrnpa.thomimeties, syrnpathol.ytics, cx-blocker sy.tnpatholytics, 0-blocker sympatholytics, sympathomirnet:ics, and adrenergic agonist sympathomimetics; cardiovascular agents, such as antianginals, (3-bloclcer antianginals, calcium-channel blocker antianginals, nitrate antianghXals, antiarrhythmxcs, cardiac glycoside ae.tiarrhythxnics, class I
antiarrhythnaics, class II.
antiarrhythnlics, class IIT antiarxhythrnics, class IV antiarrhythmics, antihypertensive agents, a-blocker antihypertensives, angiotensin-converting enzyme inhibitor (ACp inhibitor) antihypertensives, 0 =blocker antihypertensives, calcitun-channel blocker antihypertensives, central-acting adrenergic antihypertensives, diuretic antihypertensive agents, peripheral vasodilator antihypertensives, antilipetnics, bile acid sequestrant antilipemxGs, HMG-COA reductase inldbitors, antilipemics, inotropes, cardiac glycoside inotropes, and thrombolytic agents; dermatological agents, such as antahistarnines, anti-inflarnza.atory agents, corticosteroid anti-inflammatory agents; electrolyeie and renal agents, such as acidifying agents, alkalinizing agents, diuretics, carbonic anhydrase inhibitor diuretics, loop diureties, osmotic diuretics, potassium-sparing diuretics, thiazide SUBSTITUTE SHEET (RULE 26) dituretics, electrolyte xeplacements, and uricosuric agents; enzymes, sucli as pancreatic enzymes and tbrombolytic enzymes; gastrointestinal agents, such as antidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents, salicylate gasteoint.esti,nal anti-infiasnmatory agents, antacid anti-ulcer agents, gastrio acid-pump iu.hibitor anti-ulcer agents, gastric mucosal anti-ulcer agents, HZ -blocker anti-ulcer agents, cholelitholytic agents, digestants, emetics, laxatives and stool softeners, and prokinetic agents;
hematological agents, such as antianemia agents, hematopoietic antianemia agents, coagulatioa1 agents, anticoagulants, hemostatic coagulation agents, platelet inhibitor coagulation agents, thrombolytie enzyme coagulation agents, and plasma volume expanders; hormones and hormone modifiers, such as aboxtifaeieuts, adrenal agents, corticosteroid adrenal agents, androgens, anti-androgens, antidiabetic agents, sulfonylurea antidiabetic agents, antihypoglycemic agents, oral contraceptives, progestin contraceptives, estrogens, fertility agents, oxytocics, parathyroid agents, pituitary hormones, pr4gestins, antithyroid agents, thyroid hormones, and toGolytics;
immunobiologic agents, such as immtznoglobulins, immrxriosuppxessives, toxoids, and vaccines; local anesthetics, such as amide local anesthetics and ester local anesthetics;
musculoskeletal agents, such as anti-gout anti-inflammatory agents, corticosteroid anti-inflammatory agents, gold compound anti-inflammatory agents, immuno-suppressive anti-inflammatory agents, nonsteroidal anti-unflammatory drugs (NSAXUs), salicylate anti-inflammatory agents, skeletal muscle relaxants, neuromuscular blocker skeletal muscle relaxants, and reverse neuromuscular blocker skeletal muscle relaxants;
neurological a'gents, such as anticozivulsants, barbiturate anticonvulsan.ts, benzodiazepine anticon'vulsfants, anti-misraine agents, anti-pai.'kinsonian agents, anti-vertigo agents, opiate agonists, and opiate antagonists; sychotropic agents, such as antidepressants, hetexocyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants, ' antiman.ics, antipsychotics, phenothia.zine antipsychotics, anxiolytics, sedatives, and hypnotics, barbiturate sedatives and hypndtics, benzodiazepine anxiolytics, sedatives, and hypnotics, and psychostimulants; respiratory agents, such as antitussives, bronchodila_tQrs, adrenergic agonist bronchodilators, antimusca.rinic bronchodilators, expectorants, mucolytic agents, respiratoxy antx-inflammatory agents, and respiratory cotticosteroid a,n.ti-inflanlmatory SUBSTITUTE SHEET (RULE 26) agents; toxicology agents, such as antidotes, heavy metal antagQnists/chelating agents, substance abuse agents, deterrent substance abvse agents, axid withdrawal substance abuse agents; minerals; and vitamins, such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin F, and vitamin K, 111054] Preferred classes of useful pharmaceutically active agents from the above categories include: (1) nonsteroidal anti-infil,ammatory drugs (N'SAIDs) analgesics, such as diclofeuac, ibuprofen, ketoprofen, and naproxen; (2) opiate agonist analgesics, such as codeine, fentanyl, tramadol, liydrom,orphone, and rnorplii.ne; (3) salicylate analgesics, such as aspirin; (4) Hl-blocker antihistamines, such as clemastine and terfenadine; (5) 112 -blocker an.tihistamines, such as cimetid.ine, famotidine, nizadine, and ranitidine; (6) anti-infective agents, such as mupirocin; (7) aJntianaexobic anti-infectives, such as chloramphenicol and clindaxnycia; (8) antifu.ngal antibiotic anti-infectives, such as amphotericin b, clotrimazole, fl.uconazole, and ketoconazole; (9) xnacrol.ide aatibiotic a.n.ti-infectives, such as azithromycin and e*rthromycin; (10) misceIlazieous P-lactam antibiotic anti-infectives, such as aztreonam and hnipenem; (11) penicillin an.tibiotxc anti-infectives, such as nafoillin, oxaciIlitl, penicillin. Gr, and penicillin V;
(12) quinolone antibiotic anti-infectives, such as ciprofloxacin and norflQxacin; (13) tetracycline antibiotic anti-infectives, such as doxyopcline, xninocycline, and tetracycline; (14) antituberculosis antimycobacterial anti-infect'sves such as isoniazid (IlO), and rifampin;
(15) antiprotozQal anti-infectives, such as atovaquone and dapsone; (16) antimalarial antiprotozoal aiiti-infectives, such as chloroquine and pyrimetham.ine; (17) anti-retroviral anti-infectives, such as zitonavir and zxdovudine; (18) antiviral anti-infeotive agents, such as acyolovir, ganeiolovir, interferon alfa, and riniantadxne; (19) alkylating antineoplastic agents, such as carboplatin and cisplatin; (20) nitrosourea alkylating antineopldstic agents, suah as cat'mustine (.QCNIJ); (21) antimetabolite antineoplastic agellts, such as methotrexate; (22) pyrimidine analog antimetabolite antineoplastic agents, such as lluorouracil (5-FU) and gemcitabine; (23) hormo17a3= antineoplastics, such as goser'e1in, leuprolide, and ta.moxi.fen; (24) natural antineoplastics, such as aldesleukin, interleulCin-2, docetaxel, etoposide (VP-16), xnterferon alfa, paclitaxel, and tretixioin (ATRA); (25) antibiotic natural antineoplastios, such as bleomycin, dactinomycin, da.Yanorubicin, doxorubicin, and mitomycin; (26) vinca alkaloid natural antineoplastics, such as SUBSTITUTE SHEET (RULE 26) vinblastinE and vincristine; (27) autonomic agents, such as nicot.ine; (28) anticholinergic autonomic agents, such as benztropine and trihexyphenidyl; (29) an.timuscarinic anticholinergic autonomic agents, such as atropine and oxybutynin; (30) ergot alkaloid autonomic agents, such as bromocriptine; (31) cholinergic agonist pa.rasympathomiin.etics, such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetics, such as pyridostigmine; (33) a-blocker syiupatholytics, such as pra,zosin; (34) 9-blocker sytnpatholytics, such as atenolol; (35) adrenergic agonist syinpathomimet,ics, such as albuterol and dobutamine; (36) cardiovascular agents, such as aspirin; (37) i-blocker aritia.nginals, such as atenolol and propranolol; (38) calcium-cktanuel blocker antian.ginals, such as nifedipine and verapamil; (39) nitrate antianginals, such as isosorbide dinitrate (ISDN); (40) cardiac glycoside mttiarrhykhmics, such as di.goxin; (41) class X antiarxhythmics, such as lidocaine, mexiletane, phenytoin, procainamide, and quxnidine; (42) class Ii antiarrhythmics, such as atenolol, metoprolol, propranolol, and timoiol; (43) class XSI antiar,rhytlimics, such as amiadarone; (44) class IV
antiarrhythmics, such as d.iltiazern and verapamil; (45) a blocker antihypertensives, such as prazosin; (46) a.ngiotensin-convertin.g enzyme inhibitor (ACE inhibitor) antihypertensives, such as captopril and enalapril; (47) P-blocker antiIiypertensives, such as atenolol, metoprolol, nadolol, and propanolol; (48) calcium-chamel blocker antihypertensive agents, such as diltiazem and uifedipine; (49) central-acting adrenergic antahypertensives, such as clonidine and nlethyldopa; (50) diurectic antihypertensive agents, such as arailoride, furosemide, hydrochlorothiazide (FICTZ), and spironolactone;
(51) peripheral vasodilatcar andhypertensives, such as hydralazine and minoxidil; (52) antilipemics, such as gemfibrozil and probucol; (53) bile acid sequestrant andlipemics, such as cholestyrarnine; (54) T-IMO-CoA reductase inhibitor antilipemics, such as lovastatin and pravastatin; (55) inotropes, such as amrinone, dobutamine, and dopamin,e;
(56) cardiac glycoside inotropes, such as digoxin; (57) thrombolytic agents, such as alteplase (TPA), anistreplase, streptokinase, and urolCinase; (58) dermatological agents, such as colchicine, isotreCin.oin, methotrexate, minoxidil, tretinoin (ATRA);
(59) detmatological corticosteroid anti-inflamtxxatory agents, such as betamethasone and dexarn.ethasone; (60) antifungal anti-iufectives, such as amphotericin B, clotriniazole, miconazole, and nystatin; (61) antiviral anti-infectives, such as acyelovir;
(62) SUBSTITUTE SHEET (RULE 26) aiitineoplastics, such as fluorouracil (5-FU); (63) electrolytic and renal agents, such as lactulose; (64) loop diuretics, such as furosexnide; (65) potassium-sparing diuretics, such as ttzamterene; (66) thia,zide diuretics, such as hydrochlorothiazide (UCTZ);
(67) uricosiYrio agents, such as probenecid; (68) enzymes such as RNase and DNase;
(69) throrn.bolytic enzymes, such as alteplase, anistreplase, streptokinase and urokinase; (70) antiemetios, such as proclilQrperazine; (71) salicylate gastxointestinal anti-irxammatory agents, such as sulfasalazitie; (72) gastric acid-pump inhibitor anti-ulcer agents, such as omepxazole; (73) H2 -blocleer anti-ulcer agents, such as cimetidine, faniotidine, ni2atidine, and ranitidine;.(74) digestants, such as pancrelipase; (75) prokinetic agents, such as erythronmyein; (76) fentanyl; (77) hematopoi.etic a.ntianemia agents, such as exythropoietin, filgrastiin (G-CSp), and sargraruostim (GM-CSp'); (78) coagulation agents, such as antihe:mophilic factors 1-10 (AM 1-10); (79) anticoagulants, such as warfarin; (80) tluom.bolytic enzyme coagulation agents, such as alt,eplase, anistreplase, streptokinase and urokinase; (81) hormones and hormone modifiers, such as bromocziptine; (82) abortifacients, such as methotrexate; (83) antidiabetic agents, such as insulin; (84) oral contraceptives, such as estrogen and progestin; (85) progestin contraceptives, stich as levonorgestrel and norgestrel; (86) estrogens such as conjugated estrogens, diethylstilbestrol (DES), estrogen (estradiol, estrone, and estropipate); (87) fertility agents, such as clomiphene, human chorionic gonacia.tropin (HCG), and znenotropins; (8$) parathyroid agents such as calcitonin; (89) pituitary hormones, such as desmopressin, goserelhi, oxytocin, and vasopressin (ADJT); (90) progestins, such as medroxyprogesterorie, norethindrone, and progesterone; (91) thyroid hormones, such as levothyroxine; (92) ixrnmunobiologic agents, such as interferon beta-lb and inter'feron garcuna-lb; (93) immunoglobulins, such as irnmttne globu.iin IM, I1ViIG, ICrIIVI and immune globulin IV, IVIG, ICxIV; (94) amide local anesthetics, such as lidoca.ine; (95) ester local anesthetics, such as benzocai.rle and procaite; (96) muscuioskeletal corticosteroid anti-infl=matory agents, such as becloxnethasone, betamethasone, cortisone, dexamethasone, hydroGortisone, and prednisone; (97) musculoskelefal anti-inflarnmatory immunosuppressives, such as azathioprin.e, cyclophosphamide, and methotrexate; (98) museuloskeletal nonsteroidal anti-inflammatory drags (NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorlac, and naproxen; (99) skeletal muscle 1s SUBSTITUTE SHEET (RULE 26) relaxants, such as baclofen, cyclobenza.pxine, and d:tazepam; (100) reverse neuromusoular blooker skeletaX muscle relaxants, such as pyridostigmine; (101) neurological agents, such as nimodipine, rilu.zole, tacrine, trazodone, and ticlopidine; (102) anticonvrtlsants, such as carbamazepine, gabapentin, lamotrigine, phenytoin, and valpxoic acid;
(103) basbiturate anticonvulsants, stich as phenobarbital and primidoxle; (104) benzodiazcpino anticonvulsants, such as clonazepam, diazepam, and lorazepam; (105) auti-parkisonian agents, such as bromocriptine, levodopa, carbidopa, and pergolide; (106) anti-vertigo agents, such as maclxzine; (107) opiate agonists, such as codeine, fentanyl, hydromorphone, methadone, trfratnadol, and morphine; (108) opiate antagonists, such as naloxone; (109) (3 -blocker anti-glaucoma agents, such as timolol; (110) miotic anti-glaueoma agents, such as pilocarpine; (111) ophthalmic aminoglycoside antiinfectives, such as gentamicin, neomycin, and tobrasuycin; (112) ophthalmic quinolone anti-ipfectives, such as ciprofloxacin, norfloxacin, and ofloxacin.; (113) ophthalmio corticosteroid anti-inflam.matory agents, such as dexamethasone and prednisolore; (114) ophtbalmic nonsteroidal anti-inflammatory dru.gs (NSAIDs), such as diclofenac;
(115) antipsychotics, such as clozapine, haloperidol, and risperidone; (116) benzodia2epine anxiolytics, sedatives and hypnotics, such as clonazepam, diazepam, lorazepam, oxazepam, and prazepam; (117) psychostimulants, such as methylphenidate an1.
petnoline; (118) antitussives, such as codeine; (119) bronchodilators, such as theophylline; (120) adrenErgic agonist bronchodilators, such as albuterol;
(121) respiratory corticosteroid anti-intlammatory agents, such as dexamethasone;
(122) antidotes, such as flumazenil and naloxozie; (123) heavy metal antagonists/chelating agents, such as psxliaillamine; (124) deterrent substance abuse agents, such as disulfirm-n, naltrexone, and nicotine; (125) withdrawal substance abuse agents, such as bromocriptine; (126) minerals, such as iron, calcium, and magnesxum; (127) vitamin B
compounds, such as cyanocobalamin (vitamin B12) and niacin (vitamin B3); (128) vitamin C cornlrounds, such as ascorbic acid; (129) vitatnizi D compounds, such as caloitriol, aaad (130) histiamine type drugs such as betahistine hydrochloride.

[0055) In sotn.E embodiments, compositions disclosed hereiiL include more than about 15% pharmaceutically active ingredient by weight, for example betweeri about 15% and about 60%, or between about 20% and about 60%, or between about 20% and about 55 /a SUBSTITUTE SHEET (RULE 26) by weight. In other embotliments, compositions contempla.ted herexn may ixlclude nxore than about 15% weight controlled release excipient such as cross-linked high amylose starch, for example, be'Cween about, 15% and about 85%, or about 20% and about 85%, or about 20% and about 60%, or about 20% aud about 50%, or about 30% and about 50%
by weight. The composition according to the invention preferably comprise from about 15% to about 50% by weight, more preferably, from about 25% to about 50%
active ingredient and from about 20% to 60% by weight, more p;referably from about 25% to about 50% by weight of contirolled release excipient. In a paxticular eznbodino.ent, this invention is directed to a composition comprising about 5% to about 50% by weight of active ingredient and about 30% to about 50% by weight of oross-linked high =ylose starch, [0056] Controlled release excipients cQntemplated herein may vary to a]arge extent as is well known to one skilled in the art, provided that a formulation including an excipient llas the disclosed release properties and/4r therapeutic action. Controlled release excipients may include cross-linked starches, hydrogels, celluloses, and/or polymers, and other controlled release excipients known to those skiIled in the art, 10057] In one embodiment, the controlled release excipient preferably comprises a cross-linked high amylose starch, for example, where the cross-linked high amylose starch-is cross-linked with phosphorus oxychloride and/or comprises hydroxypropyl side chains.
A suitable excipient has been developed by and is available commercxally from Labopharm, Inc., Laval, Canada, under the trademark CQNTRALvZ10'. The synthesis of the CONT,1tAMIDO excipient is described, for example, in U.S. Patent No, 6,607,748, hereby incorporated by reference in its entirety for all purposes, Compositions contemplated herein may include cross-linked high amylose starch together with one or more additional controlled release excipients.

[0058] Cross-linking of starch represents a power.ful method for modifying starch.
Usually, starch granules are cross-linked to increase resistance of the paste to shear or heat, Suc.h chemically cross-linked starches provide a desirable smooth texture and possess viscosity stability throughout processing operations and normal shelf life. In some embodimeu.ts, cross-linked high ainylose starch as contemplated herein may be SUBSTITUTE SHEET (RULE 26) gelatinized after cross-linking. In a preferred embodiment, cjross-luitdng hxgh amylose starch may include additionaX chemical modification (e.g., hydroxypropylation) prior to gelatiniaation, [0059] The cross-linking of high amylose starch may be realized according to procedures described in the aat, For example, cross-linking of amylose calx be carried out in the inamer described in 141ateescu [8IOC.'I-IEMIE 60: 535-537 (1978)] by reacting amylose with epichloroh.ydrin in an alkaline medium. In the same manner, starch can also be cross-linked with a reagent selected from the group consisting of epichloxohydrin, adipic acid anhydride, sodium ttzmetaphosphate and phosphorous oxychlorid.e or other cross-lirxldng agents including, but not limited to, 2,3-dibromopropanol, linear mixed anhydrides of acetic and di- Qr tribasic carboxylic acids, vinyl sulfone, diepoxides, cyanuric chloride, hexahydxo-1,3,5-trisacryloyl-s-triazine, hexamethylene diisocyanate, toluene 2,4-diisocyanate, .I+I,N-methylenebisacrylanxide, N,N'-bis (hydroxymethyl) elliyleneurea, mixed aarbonic-carboxylic acid anhydrides, imidazolides of carbonic atid polybasic carboxylic acids, iruXdazoliiun salts of polybasic carboxylic acids, and guanidine derivatives of polycarboxylic acids.. The reaction conditions employed will vary with the type and amount of the cross-linking agent that is used, as well as the base concentration, amount and type of starch.

[0060] It is contemplated that starches containing more than about 40 l4 wlw amylose can be used to form cross-iinked high amylose starch, e.g., pea and wxirikled pea sta.ech, bean starch, hybrids or genetically modified tapioca or potato starch, or any other root, tuber or cereal starch. Preferably, high amylose starch containing about 70% wfw amylose is used as the base material. For example, high amylose staxch, Cerestar Axn.ylo .Ciel 03003 (Cerestar U.S.A. Inc.), may be used. In certain formulations, the excipient comprises cross-linked high amylose starch comprising between about 65% and about 75% by weight amylose cross-linked with phosphorus oxychloride.

[0061] The pharmaceutical composition according to the invention optionally can also comprise pbarmaeeutically acceptable additives. Such additives can include, for exa.mple, sugars, such as lacto-se, glucose and sucrose; other starches, such as corn: starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, SUBSTITUTE SHEET (RULE 26) ethyl cellulose and cellulose acetate; powdered ixagacanth; malt; gelatin;
talc; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as rniagnesium hydroxide and aluminum hydroxide; alginic acid; and other non-toxic compatible substances employed in pbarm.aceutical foxmulatiom. Such additives may also include colorants and/or taste-masking additives.

[0067.] For example, the compositions disclosed herein nxay include any one of a mixture of a binding agent, a solubilizing agent, an acidifying agent, a pore forming:
agent, a lubricant, a glidant, as is well known to those skilled in the art. Prefezred pharmaceutical additives that are used in providing a composition according to the invention may include, for example, binding agents that include hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, metliylcellulose, dicalcium phosphate, calcium phosphate, rxticrocrystalline cellulose, start or the like, solubilizing agents such as povidone, cetylpyridinium chloride, or the like, acidifying agents such as alginic acid, citric acid, succinic acid, bxle acid or the like, a pore forming agent such as sucrose, lactose, mannitol or the like, lubricants such as sodium stearyl fumarate, magnesium stearate, calcium stearate, steaxic acid, hydrogentated vegetable oils or the like and/or glidants such as colloidal silicon dioxide, talc or the like. Other additives well known to thQse skilled in the art may of course be included in the composition according to the invention without d.eparting from the scope and spirit of the present invention.

[00631 For example, in one embodiment, the eomposition may comprise about 10%
to 50 !o by weight active ingredient, for example, tramadol, acetatninophen, betahistine, about 20% to 60% by weight cross-linked high amylase staxch (for example, CONTRAMID cross-linked high amylose starch), about 10% to 25% by weight hydxoxypropylmethylcellulose, about 1% to 5% by weight sodium stearyl'fumarate, and up to about 1 weight percent colloidal silicon dioxide.

100641 In an exemplary formulation protocol for producing a 5 kg batch of an exemplary sustained release formula.tion containing trazodQxie, CON'T'RAMIDO exGipient, hydroxypropylmethyl cellulose, trazodone IIC1 and sodiurn , stearyl fuznarate are individually weighed and sifted through a 30 mesh filter. Collodial silicon dioxide is SUBSTITUTE SHEET (RULE 26) weighed and pre-blended with CON'T'12.taMID o, sifted through a 30 mesh filter, and blended for 10-30 seconds, for example, 15 seconds to produce a pre-blend.
Fiydroxypropylm.ethylcellulose, trazodone and the CQntrsznid(D-collodial silicon dioxide pre-blend, are combxned and blended for 5-10 minutes, for example, 7 rnirrutes, to produce a bulk blend, A small portion of the resulting bulk blend is aombined with the sodium stearyl fiunarate and blended for 20-60 seconds, for example, 30 seconds. The resulting sodium stearyl fwmarate blend is combined with the residual bulk blend, and the resulting znixture blended for about 2-6 minutes, for example, 4 minutes. The final blend is cozzipressed into tablets using a compression pressure of 27 W. Caplets m formed using a caplet standard concave punch.

[0065) The i-avention will now be illustrated by means of the following examples wbich are given for the purpose of illustration only and without any intention to limit the scope of the present itivention.
IEXA,I1X'LES
]Example 1_ [0066] A sustained release 300 mg trazodone containing formulation (denoted Formulation 1) was prepared having the composition set forth in TA.BLE 1.

TABLE 1- Formulation 1.

Ingredients Tablet Tablet mg %
COh(T1t~1ID excipien t 200 32.1 Trazodone I-ICI 300 48.2 Idydz'oxypropylmethylcellttlose K100M 100 16.1 Colloidal silicon dioxide 3 0.5 Sodium stearyl fuxnarate 9 1.4 Opadry II, Pink 83F94306 10.4 1.7 Total 622.4 100 10067] Formulation 1was compressed into tablets and analyzed, The in vitro release lcinetics of the intact dosage form and subdivided (bisected) dosage forms created by breaking the intact dosage form into two weYe measured as follows.

SUBSTITUTE SHEET (RULE 26) C0068] Briefly, the in vitro release kinetics of Formulatxon 1 were measured using the U,S,P. paddle method (apparatus type Il as described in U.S.P. XKV'I) at 150 revolutions.
per minute, at 37zW.5 C, in 900 mL of hydroohloride/sodiu.m chloride pH 1.2 solution (acid stage) followed after one hour by 900 mL of sodio.m phosphate ,mon.obasic buffer pH 6.0 (buffer sta.ge), The in vitro dissolution profiles, as shown in Figure 2, show that in this formulation, #xe release profiles of both the intact and bisected tablet have a similarity factor of 73.9 and a difference factor of 6.1, [0069] In addition, the e~fect of different score depths on release ldneties were measured.
The in vitro release kinetics of two forms of the tablet having 23% scoring and 95%
scoring are shown in Figures 3 and 4, respectively. Figures 3 and 4 demonstrate that the in vitro release profile of this formulation (either of the intact tablet or the subdivided tablet created by breakizxg the intact tablet along the score) is not substantially affected by scoring depth.

Example [0070] A sustained release 150 tu,g trazodone containing formulation (denoted Fornrn~..ulation 2) was prepared having the composition set forfih in TABLE 2.

TABLE 2 - Formulation 2 Ingredients Tablet Tablet 111 %
CONTRAMW excxpient 252 46,8 Trazodone HC1 150 27,8 Hydroxypropylmethy1cellulose 'K.100M 126 23.4 Colloidal silicon dioxide 3 0.5 Sodium stearyI f-umarate $ 1,5 Total 540 100 [00711 Formulation 2 was compressed into tablets. Mass utaiformity testing on this formulation using the U.S.P,test limit of uniformity to achieve an RSD below 6%
indicates that the tuinimum tablet hardness needed to achieve mass uniformity is about 11 ON (see, Figure 5).

SUBSTITUTE SHEET (RULE 26) 10072] The in vitro release kinetics of the intact dosage form and subdivided (bisected) dosage forrns created by breeking the intact dosage foxm into two were measured as described in Exainple 1. The in vitro dissolution pxof'iles, as shown in Figure 6, show that in this formtxlation, the release profiles for both the intact and bisected tablet have a similarity factor of 73,4 and a difference factor of 6.4.

Example 3 [0073] A sustained release 300 mg tramadol containing formulation (denoted FormuXation 3) was prepaared having the composition set forth in TABLE 3.

TA.BILE 3 - Formulation 3 Ingredients Tablet Tablet (mg) /v CfJNTRA1VrTr? excipient 200 32.7 Tramradol HC1 300 49.0 Hydroxylpropylmethyl 'cellulose K14t1M 100 16.3 Colloidal silicon dioxide 3 0.5 Sodium stearyl fumarate 9 1.5 Total 612 100 [0074] The above formulation was compressed into tablets. The in vitro release kinetics of the intact dosage form atd subdivided (bisected) dosage forms created by breaking the intact dosage form into two were measured as follows. Briefly, the in vitro release kinetics of the in.tact and bisected tablets were measured using the U.S.P.
basket method (apparatus type I as described in US.P. XX'Vl) at 100 revalutions per minute, at 3710.5 C, in 900 mL of sodium phosphate monobasic buffer pH 6.8. The in vitNC-dissolution proflle$, as shown in Figure 7, show that in ti'ii,s forrnulation, the release profiles frrr both the intact and bisected tablet have a similarity factor of 58.3 and a difference factor of 14.2.

Example 4 (0075] A sustained release 300 mg acetamiuaophen containing formulation (denoted p'ormulation 4) can be prepued baving the composition set forth in TABLE 4.

SUBSTITUTE SHEET (RULE 26) TABLE 4 - Fornnalation 4 Ingredients Tablet Tablet mg~ 0/0 CONTR." excipient 200 32.1 Acetanmirwphen 300 4$,2 Fiydroxylpropylmethyl cellulose K10DM 100 16.1 Colloidal silicon dioxide 3 0.5 Sodium stearyl fiunarate 9' 1.4 Total 612 100 [0476] Xt is contemplated that with this fotxnulation, when compressed into tablets, the intact and bisected dosage forms will display substantittlly similar in viti-o release kinetics, Exmple 5 [0077] A sustained release 48 mg betahistine containing fonnulation (clenoted Formulation 5) can be prepared having the composition set forth in TABLE 5, TA.ULE 5 - Formulation 5 Ingzedients Tablet Tablet m } lo CONTRAMPexcipient 168 54.90 Betahistine bICI 48 15.69 HydxQxylpropylmethyl cellulose K100M 84 27.45 Colloidal silicon dioxide 1.5 0.49 Sodium stearyl funrnarate 4.5 1,47 Total 306 100.00 [0078] It is contemplated that with this formulation, when compressed into tablets, the intact and bisected dosage forms wil1 display substantially similar in vitro release lsineti.cs.

SUBSTITUTE SHEET (RULE 26) [0079] Although the present invention has been illustrated by means of preferred embodiments thereof, it i5 understood that the invention intends to cover broad aspects thereof without departing from the spirit and scope of the invention as defined irl the apponded claims.

SUBSTITUTE SHEET (RULE 26)

Claims (42)

1. A solid, monolithic sustained release pharmaceutical composition, the composition comprising:
a. a sustained release matrix having a solvent accessible surface, wherein the matrix comprises cross-linked high amylose starch; and b. an effective amount of at least one pharmaceutically active agent disposed within the matrix, wherein the composition has a hardness of greater than about 100 N.
2. The composition of claim 1, wherein the hardness is in the range of about 100N to about 350 N.
3. The composition of claim 1 or 2, wherein the composition, when administered to a mammal, achieves an effective plasma concentration of the active agent from at least about 1 hour to at least about 24 hours after initial administration.
4. The composition of any one of claims 1-3, wherein the solvent accessible surface defines a score that permits the composition to be fractured along the score to produce at least two subunits each having a new solvent accessible surface.
5. The composition of claim 4, wherein at least one of the subunits has substantially the same release kinetics of the active agent as the intact composition from which it was derived,
6. The composition of claim 4 or 5, wherein the dissolution profiles of at least one of the subunits and the composition from which it was derived have a similarity factor of at least 50%.
7. The composition of claim 6, wherein the similarity factor is at least 55%.
8. A solid sustained release pharmaceutical composition comprising:
a. a sustained release matrix having a solvent accessible surface, wherein the matrix comprises cross-linked high amylose starch; and b. an effective amount of a pharmaceutically active agent disposed within the matrix, wherein the composition displays substantially the same release kinetics when the composition is broken to create a new solvent accessible surface.
9. A solid sustained release pharmaceutical composition comprising:
a. a sustained release matrix comprising cross-linked high amylose starch;
and b. an effective amount of a pharmaceutically active agent disposed within the matrix, wherein the composition can be divided into at least two subunits where each subunit releases the active agent with substantially the same release profile as the composition from which it was derived.
10. The composition of claim 8 of 9, wherein the composition has a hardness of greater than about 100 N.
11. The composition of claim 10, wherein the composition has a hardness in the range of from about 100 N to about 180 N.
12. The composition of claim any one of claims 8-11, wherein the composition is monolithic.
13. The composition of any one of claims 9-12, wherein the dissolution profiles of at least one subunit and the composition from which it was derived have a similarity factor of at least 50%.
14. The composition of claim 13, wherein the similarity factor is at least 55%.
15. The composition of any one of claims 4-8, wherein the new solvent accessible surface is capable of forming a barrier upon contact with a solvent.
16. The composition of claims 4-8, wherein the subunits and the intact composition from which they are derived are bioequivalent.
17. A sustained release solid dosage form comprising cross-linked high amylose starch and at least one pharmaceutically active agent disposed within the starch, wherein the solid dosage form can be subdivided into subunits and each subunit has substantially the same sustained release properties as the intact solid dosage form.
18. The sustained release solid dosage form of claim 17, wherein each subunit releases the active agent for at least about 12 hours.
19. The sustained release solid dosage form of claim 18, wherein each subunit releases the active agent for at least about 18 hours.
20. The sustained release solid dosage form of claim 18, wherein each subunit releases the active agent for at least about 24 hours.
21. The sustained release solid dosage form of any one of claims 17-20, wherein the solid dosage form has a hardness of greater than about 100 N.
22. The sustained release solid dosage form of any one of claims 17-21, wherein each subunit is bioequivalent to the intact solid dosage form.
23. The composition of any one of claims 1-22 comprising from about 15% to about 60% by weight of the active ingredient and from about 15% to about 85% by weight of the starch.
24. The composition of claim 23 comprising from about 20% to about 50% by weight of the active ingredient and from about 20% to about 50% by weight of the starch.
25. The composition of claim 24 comprising from about 35% to about 50% by weight of the active ingredient and from about 20% to about 50% by weight of the starch.
26. The composition of any one of claims 1-25, wherein the starch is crosslinked with phosphorus oxychloride.
27. The composition of any one of claims 1-26, wherein the starch comprises hydroxypropyl side chains.
28. The composition of any one of claims 1-27, wherein the active agent is selected from the group consisting of an antidepressant or an analgesic,
29. The composition of claim 28, wherein the antidepressant is trazodone.
30. The composition of claim 28, wherein the analgesic is tramadol, acetaminophen or a combination thereof.
31. The composition of any one of claims 1-30 further comprising a pharmaceutical additive.
32. The composition of claim 31, wherein the pharmaceutical additive is selected from the group consisting of a binding agent, a solubilizing agent, an acidifying agent, a pore forming agents, a lubricant, and a glidant.
33. The composition of claim 32, wherein the binding agent is hydroxypropylmethylcellulose.
34. The composition of claim 32, wherein the lubricant is sodium stearyl fumarate.
35. The composition of claim 32, wherein the glidant is colloidal silicon dioxide.
36. The composition of any one of claims 1-35, wherein the composition is in the form of a tablet.
37. The composition of claim 36, wherein the tablet has a score.
38. The composition of any one of claims 1-35, wherein the composition is in the form of a caplet.
39. The composition of claim 38, wherein the caplet has a score.
40. The composition of claim 37 or 39, wherein the composition, when fractured along the score creates a new solvent accessible surface.
41. A method producing the composition of any one of claims 1-40.
42. A method of treating a mammal, the method comprising administering to the mammal the composition of any one of claims 1-40.
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