(12) Patent Application Publication (10) Pub. No.: US 2006/0024365A1 Vaya Et Al

Home , Amesergide, Cefluprenam, Chloroxine, Cisatracurium besilate, Clazolam, Cloprednol

US 2006.0024.365A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0024365A1 Vaya et al. (43) Pub. Date: Feb. 2, 2006

(54) NOVEL DOSAGE FORM (30) Foreign Application Priority Data (76) Inventors: Navin Vaya, Gujarat (IN); Rajesh Aug. 5, 2002 (IN)...... 699/MUM/2002 Singh Karan, Gujarat (IN); Sunil Aug. 5, 2002 (IN). ... 697/MUM/2002 Sadanand, Gujarat (IN); Vinod Kumar Jan. 22, 2003 (IN)...... 80/MUM/2003 Gupta, Gujarat (IN) Jan. 22, 2003 (IN)...... 82/MUM/2003 Correspondence Address: Publication Classification HEDMAN & COSTIGAN P.C. (51) Int. Cl. 1185 AVENUE OF THE AMERICAS A6IK 9/22 (2006.01) NEW YORK, NY 10036 (US) (52) U.S. Cl...... 424/468

(22) Filed: May 19, 2005 A dosage form comprising of a high dose, high Solubility active ingredient as modified release and a low dose active ingredient as immediate release where the weight ratio of Related U.S. Application Data immediate release active ingredient and modified release active ingredient is from 1:10 to 1:15000 and the weight of (63) Continuation-in-part of application No. 10/630,446, modified release active ingredient per unit is from 500 mg to filed on Jul. 29, 2003. 1500 mg, a process for preparing the dosage form. Patent Application Publication Feb. 2, 2006 Sheet 1 of 10 US 2006/0024.365A1

FIGURE 1

FIGURE 2

FIGURE 3

Patent Application Publication Feb. 2, 2006 Sheet 2 of 10 US 2006/0024.365A1

FIGURE 4 (a)

FIGURE 4 (b)

Patent Application Publication Feb. 2, 2006 Sheet 3 of 10 US 2006/0024.365 A1

FIGURE 5

100

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C 2 4. 6. 8 O 2 4 8 20 22 24 26 Tire (hour Patent Application Publication Feb. 2, 2006 Sheet 4 of 10 US 2006/0024.365A1

FIGURE 6

120

O 2 4 6. 8 1 O 12 1 4 1 6 18 2C 22 24 26 Time (hour) Patent Application Publication Feb. 2, 2006 Sheet 5 of 10 US 2006/0024365A1

FIGURE 7

4 O

O ------O 2 4 6 8 O 12 4 6. 18 2O 22 24 26 Time (hour) Patent Application Publication Feb. 2, 2006 Sheet 6 of 10 US 2006/0024.365 A1

FIGURE 8

12. Tirne Hours) Patent Application Publication Feb. 2, 2006 Sheet 7 of 10 US 2006/0024.365 A1

FIGURE 9

12 Tine Hours) Patent Application Publication Feb. 2, 2006 Sheet 8 of 10 US 2006/0024365A1

FIGURE 10

O 2 4 6 8 O 12 l4 6 18 2C 22 24 Time Hours Patent Application Publication Feb. 2, 2006 Sheet 9 of 10 US 2006/0024.365A1

FIGURE

2 AO O

O 2 4 6 8 O 12 4 6 18 20 22 2 Time Hours Patent Application Publication Feb. 2, 2006 Sheet 10 of 10 US 2006/0024.365A1 FIGURE 12

2OO

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160

140

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O 4 8 12 6 2O 24 Tine Hours US 2006/0024365 A1 Feb. 2, 2006

NOVEL DOSAGE FORM 0010 Block Jurgen et. al. describes in PCT application No. WO 01/72286 A1 a formulation of vitamin composition 0001. This application is a continuation-in-part of Ser. whereas a beadlet comprises a slow release core coated by No. 10/630,446, filed Jul. 29, 2003. a controlled release coating. The Sustained release core is FIELD OF INVENTION coated with an immediate release layer. 0002 This invention relates to a dosage form comprising 0011 Richard Ting and Charles Hscao describes in U.S. of a high dose, high Solubility active ingredient as modified Pat. No. 6,372,254 B1 a press coated, pulsatile active release and a low dose active ingredient as immediate ingredient delivery System which comprises a core of imme release where the weight ratio of immediate release active diate release, enveloped by an extended release compart ingredient and modified release active ingredient is from 1:1 ment. to 1:15000 and the weight of modified release high dose high solubility active ingredient per unit is from 500 mg to 1500 0012. The need to use active ingredients with different mg and the weight of immediate release active ingredient is and complementary mechanisms of action frequently arises up to 500 mg, a proceSS for preparing the formulation. Low in treatment of diabetes. There are Several reasons to do this, dose active ingredient in present invention can optionally be namely, the disease itself is progressive, with deterioration also in a form of modified release. of glycemic control over time; mono-therapeutic attempts to achieve and maintain glycemic control often fail in the long BACKGROUND OF THE INVENTION run; multiple defects in the disease and consequently pri 0.003 Combining two active ingredients in one pharma mary drug failures (1,2,3). ceutical unit to improve patient compliance is known in 0013 Current guidelines for combination therapy advise literature. It can be either in the form of two or more active the use of agents with differing and complementary mecha ingredients in immediate release form or a combination of nisms of action in order to maximize therapeutic activity and immediate release and modified release form. There are reduce toxicity. Earlier introduction of combination therapy various techniques by which the combination of immediate is increasingly being recommended. The commonly com release and modified release is formulated in Single dosage bined active ingredients include biguanides (metformin)+ form. sulphonylureas, biguanides+PPAR agonists(thiazolidinedi 0004 Several examples of formulations having combi ones), Sulphonylureas--thiazolidinediones, non-Sulfonylurea nation of immediate release active ingredient and modified Secretagogues (repaglinide)+biguanides etc. Fixed dose release active ingredient are described below. combinations of many of the above mentioned co-administer active ingredients have also been approved by the FDA. 0005 Shoichi Higo and Kazuo Igusa describes in U.S. Most of these combinations are conventional formulations Pat. No. 5,985,843 various types of pharmaceutical formu combined together into a Single tablet. However, because of lations, which consists of a delayed release of Sucralfate and the disparity in the duration of action (half-life), these an immediate release fraction of another active ingredient. combinations are given twice or thrice a day. The pharmaceutical dosage forms are a tablet formulation containing immediate release and delayed release granules, 0014) To reduce this disparity in the duration of action, a a two or three layer tablet; a tablet with delayed release core novel Strategy would be to combine a Sustained release Surrounded by immediate release shell; a delayed release formulation of one active ingredient (shorter duration of tablet/granule coated with a film of immediate release active action) with conventional formulation (long duration of ingredient. action) of another active ingredient. This would make it possible to give the active ingredients in Same dosing 0006 Similarly Jurgen Zeidler et. al describes in U.S. frequency. Pat. No. 6,001,391 a process for producing solid combina tion tablets, which have at least two phases. The one of the 0015 This type of combination will give better compli two phases is processed by melt extrusion technique and ance and a relative freedom from mealtime drug adminis contains a water Soluble or Swellable binder. tration, thus, improving the quality of life. More importantly, because of prolonged duration of action, it shall produce a 0007. A compressed V-shaped center scored double layer Stricter control of blood glucose and consequently leSS tablet is disclosed by George M. Krause et. al in U.S. Pat. diabetic complications. No. 3,336,200, one layer of which contains immediate release Active Ingredient and the other layer contains SuS 0016. The techniques described above do not work well tained release Active Ingredient. The tablet is divisible in when the difference in the dose of active ingredients are high two equal halves. for example where the weight ratio of active ingredients is from 1:1 to 1: 15000 and the dose of modified release active 0008 Similarly Jacob A. Glassman described in U.S. Pat. ingredient per unit is from 500 mg to 1500 mg. The No. 4,503,031 a Super fast starting, slow release medicinal techniques described in the prior art do not give good results tablet, wherein the tablet is comprised of two layers of when the active ingredient is highly soluble. The weight of compressed matrix that are fused together by means of the dosage form becomes very high, or complicated process readily dissolvable adhesive Substance. for manufacturing is required, or accurate dosing of low 0009 Allan A. Rubin describes in U.S. Pat. No. 6,238, dose active ingredient is difficult when the techniques 699 B1 a pharmaceutical dosage form of carbidopa and reported in the prior art are utilized to make formulation with levodopa where both the Active Ingredients are present as high dose, high Solubility active ingredient in the form of immediate release and Sustained release. The formulation is modified release and low dose active ingredient into imme in the form of inlay tablet or bilayered tablet or a capsule diate release or modified release form where the weight ratio containing pellets. of low dose active ingredient and high dose, high Solubility US 2006/0024365 A1 Feb. 2, 2006 active ingredient is from 1:1 to 1:15000 and the weight of weight of modified release active ingredient per unit is from modified release active ingredient per unit is from 500 mg to 500 mg to 1500 mg. Low dose active ingredient in present 1500 mg and also it is inconvenient to Swallow due to large invention can optionally be also in a form of modified size. release. 0.017. Accordingly a need exists for a dosage form pro 0027. The present invention also provides solid oral Viding combination of immediate release and modified dosage form comprising a composition according to the release active ingredients and providing Solution to prob invention. lems associated with dosage forms described in prior art. 0028. The present invention also teaches the use of dual Further, the dosage form should be Simple and economical retard technique to effectively control the release rate of to produce. modified release active ingredient by using Small quantity of 0.018. Therefore an object of the present invention is a release controlling agents. This dual retard technique thus dosage form of combination of a high dose, high Solubility Sufficiently reduces the Size of the dosage form, which is active ingredient as modified release and a low dose active convenient for Swallowing. ingredient as immediate release where the weight ratio of immediate release active ingredient and modified release 0029. The present invention further teaches the use of active ingredient is from 1:1 to 1:15000 and the weight of hydrophobic release controlling agents, which do not hinder modified release active ingredient per unit is from 500 mg to the release of the low dose active ingredient. 1500 mg. 0030 The present invention further provides the dosage 0.019 Another object of the present invention is a dosage form that effectively prevents the problem of separation of form, which is Suitable for Swallowing for humans contain the layers of the multilayered tablets. ing two active ingredients one of which is in modified 0031. The present invention also provides a novel process release form and other in immediate release form. for preparing the novel formulations of the invention. 0020. Accordingly, an object of the present invention to 0032. The present invention further provides a method of provide a dosage form, which uses dual retard technique to treating an animal, particularly a human in need of treatment control the release of the high dose, high Solubility active utilizing the active agents, comprising administering a thera ingredient and Significantly reduce the amount of release peutically effective amount of composition or Solid oral controlling agents which are otherwise required in very high dosage form according to the invention to provide admin quantity and make the dosage form very bulky and therefore istration of two active ingredients one in immediate release pose difficulty in Swallowing. and other in modified release form.

0021. A further object of the present invention is to DETAILED DESCRIPTION OF THE provide a dosage form, containing one active ingredient in INVENTION an immediate release form and another active ingredient as modified release and the release or disintegration of the 0033. This invention relates to a novel dosage form of immediate release active ingredient is not hindered by the combination of high dose high Solubility active ingredient, modified release ingredient. as modified release and low dose active ingredient as immediate release, Suitable for Swallowing comprising dual 0022. Another object of the present invention is to pro retard technique to control the release of the high dose high vide a dosage form, which effectively avoids the problem of Solubility active ingredient, with Sufficient reduction in the Separation of layers of multilayered tablets. amount of release controlling agent, without interfering the 0023. A further object of the present invention is a release of each other. Low dose active ingredient in present formulation, which gives accurate dosing and is prepared by invention can optionally be also in a form of modified conventional and Simple processes. release. 0024. A further object of the present invention is to 0034. The term “modified release” as used herein in provide a dosage form, which can be given twice a day or relation to the composition according to the invention or a more preferably can be given once a day. rate controlling polymer or used in any other context means release, which is not immediate release and is taken to 0.025 A further object of the present invention is to encompass controlled release, Sustained release, prolonged provide a dosage form, wherein low dose active ingredient release, timed release, retarded release, extended release and can optionally be also in a form of modified release. delayed release. The term "modified release dosage form' as used herein can be described as dosage forms whose drug SUMMARY OF THE INVENTION release characteristics of time course and/or location are 0026. The above objects are realized by a dosage form, chosen to accomplish therapeutic or convenience objectives which is comprised of an inner portion and an outer portion. not offered by conventional dosage forms Such as a Solution The inner portion is Surrounded by the outer portion in Such or an immediate release dosage form. Modified release Solid a manner that only one Surface of the inner portion is oral dosage forms include both delayed and extended release exposed. The inner portion contains a low dose active drug products (as per US FDA guideline for "SUPAC-MR: ingredient in immediate release form and the outer portion Modified Release Solid Oral Dosage Forms). contains a high dose, high Solubility active ingredient as 0035. The term “immediate release” as used herein in modified release. The weight of the immediate release low relation to composition according to the invention or used in dose active ingredient and high dose, high Solubility modi any other context means release which is not modified fied release active ingredient is from 1:1 to 1:15000 and the release and releases more than 70% of the active ingredient US 2006/0024365 A1 Feb. 2, 2006

within 60 minutes. The term “immediate release dosage Succinates, palmoates, methaneSulfonates, benzoates, Sali form' as used herein can be described as dosage form which cylates, hydroxynaphthoates, benzenSulfonates, ascorbates, allows the drug to dissolve in the gastrointestinal contents, glycerophosphates, ketoglutarates and the like. with no intention of delaying or prolonging the dissolution 0044) Further, the low dose active ingredient, where or absorption of the drug (as per US FDA guideline for applicable, may be present either in the form of one Sub SUPAC-MR: Modified Release Solid Oral Dosage Forms). Stantially optically pure enantiomer or as a mixture of 0.036 The term “dosage form' denotes any form of the enantiomers or polymorphs thereof. formulation that contains an amount Sufficient to achieve a 0045. In the dosage form of the present invention, the therapeutic effect with a single administration. inner portion may optionally contain more than one low 0037. The term “active ingredient” refers to an agent, dose active ingredient. active ingredient compound or other Substance, or compo 0046. In the dosage form of the present invention, the Sitions and mixture thereof that provide Some pharmaco inner portion may optionally contain more than one low logical, often beneficial, effect. Reference to a specific active ingredient shall include where appropriate the active ingre dose antidiabetic active ingredient. dient and it's pharmaceutically acceptable Salts. 0047 The low dose active ingredient is in the form of 0.038. The term “high dose” as used herein refers to the immediate release and has dose of 500 mg or less. weight of active ingredient in unit dosage form according to 0048. The low dose active ingredient comprises of the the invention is from 500 mg to 1500 mg. following therapeutic classes but not limited to adrenergic agent, adrenocortical Steroid; adrenocortical Suppressant; 0039. The term “low dose” as used herein refers to the aldosterone antagonist; amino acid; anabolic; analeptic, weight of the active ingredient in unit dosage form accord analgesic, anesthetic; anorectic, anti-acne agent, anti-adren ing to the invention is less than or equal to 50 mg or may ergic, anti-allergic, anti-amebic, anti-anemic; anti-anginal; comprise up to but not including 500 mg or from more than anti-arthritic, anti-asthmatic, anti-atherosclerotic, antibacte 50 mg up to but no including 500 mg, preferably from 60 mg rial; anticholinergic, anticoagulant; anticonvulsant, antide up to 400 mg or more preferable from 75 mg to 350 mg. The preSSant; antidiabetic, antidiarrheal; antidiuretic, anti term “high solubility” as used herein in relation to high dose emetic, anti-epileptic, antifibrinolytic, antifungal; active ingredient means that from less than 1 part to 300 antihemorrhagic, antihistamine; antihyperlipidemia; antihy parts of water or less than 1 part to 30 parts of water will be pertensive; antihypotensive; anti-infective; anti-inflamma required to dissolve 1 part of active ingredient. tory; antimicrobial; antimigraine; antimitotic, antimycotic, 0040. The invention provides a novel dosage form of antinauseant, antineoplastic, antineutropenic, antiparasitic; high dose, high Solubility active ingredient as modified antiproliferative; antipsychotic, antirheumatic, antisebor release and a low dose active ingredient as immediate rheic, antisecretory; antispasmodic, antithrombotic, anti release where the weight ratio of immediate release active ulcerative, antiviral; appetite SuppreSSant; blood glucose ingredient and modified release active ingredient is from regulator, bone resorption inhibitor, bronchodilator, cardio 1:10 to 1:15000 or 1:1 to 1:15000 and the weight of modified Vascular agent, cholinergic, depressant, diagnostic aid; release antidiabetic active ingredient per unit is from 500 mg diuretic, dopaminergic agent, estrogen receptor agonist; to 1500 mg, a process for preparing the dosage form. fibrinolytic, fluorescent agent, free oxygen radical Scaven ger; gastric acid SupreSSant; gastrointestinal motility effec 0041) The dosage form comprises of two parts (i) inner tor; glucocorticoid; hair growth Stimulant; hemostatic; his portion as an immediate release and (ii) Outer portion as tamine H2 receptor antagonists, hormone; modified release. The two parts are compressed together in hypocholesterolemic, hypoglycemic, hypolipidemic, Such a way that one Surface of the inner portion remains hypotensive; imaging agent, immunizing agent; immuno exposed and the remaining Surfaces are covered by the outer modulator; immunoregulator; immunostimulant; immuno portion. SuppreSSant; keratolytic, LHRH agonist, mood regulator; mucolytic, mydriatic, nasal decongestant; neuromuscular 0.042 (i) Inner portion-Inner portion comprises of a low blocking agent; neuroprotective, NMDA antagonist; non dose active ingredient and includes one or more commonly hormonal Sterol derivative, plasminogen activator; platelet used excipients in oral immediate release pharmaceutical activating factor antagonist, platelet aggregation inhibitor; formulations. Low dose active ingredient in present inven psychotropic, radioactive agent; Scabicide, Sclerosing agent; tion can be either as an immediate release form or optionally Sedative, Sedative-hypnotic, Selective adenosine A1 antago as a modified release form. nist; Serotonin antagonist; Serotonin inhibitor, Serotonin 0043. The low dose active ingredient can be present in receptor antagonist; Steroid; thyroid hormone; thyroid the form of a free base or in the form of pharmaceutically inhibitor; thyromimetic, tranquilizer; amyotrophic lateral acceptable Salts. Pharmaceutically acceptable Salts forming Sclerosis agent; cerebral ischemia agent, Paget's disease part of this invention are intended to define but not limited agent; unstable angina agent; vasoconstrictor; vasodilator; to Salts of the carboxylic acid moiety Such as alkali metal wound healing agent; Xanthine oxidase inhibitor. Salts like Li, Na and K Salts, alkaline earth metal Salts like 0049. Examples of low dose active ingredient comprises Ca and Mg Salts, Salts of organic baseS Such as lysine, arginine, guanidine, diethanolamine, choline, and the like; of but not limited to ammonium or Substituted ammonium Salts and aluminium 0050) 16-alpha fluorocstradiol, 16alpha-gitoxin, 16-epi salts. Salts may be acid addition salts which defines but not estriol, 17 alpha dihydroequilenin, 17 alpha estradiol, 17 limited to Sulfates, nitrates, phosphates, perchlorates, beta estradiol, 17 hydroxy progesterone, 1alpha-hydrox borates, hydrohalides, acetates, tartrates, maleates, citrates, yvitamin D2,1-dodecpyrrolidinone, 20-epi-1.25 dihy US 2006/0024365 A1 Feb. 2, 2006

droxyvitamin D3, 22-oxacalcitriol, 2CVV, 2'-nor-cGMP, nucleotides, apadoline, apafant, Apalcillin Sodium, apaxi 3-isobutyl GABA, 5-ethynyluracil, 6-FUDCA, 7-methox fylline, ApaZone, aphidicolin glycinate, Apixifylline, ytacrine, Abamectin, abanoquil, abecarnil, abiraterone, Apomorphine Hydrochloride, apraclonidine, Apracloni Ablukast, Ablukast Sodium, Acadesine, acamproSate, dine Hydrochloride, Apramycin, Aprindine, Aprindine Acarbose, Acebutolol, Acecainide Hydrochloride, Acecli Hydrochloride, aproSulate Sodium, Aprotinin, Aptazapine dine, aceclofenae, AcedapSone, Aceglutamide Aluminum, Maleate, aptiganel, apurinic acid, apurinic acid, aranid Acemannan, Acetaminophen, Acetazolamide, Acetohexa ipine, Aranotin, Arbaprostil, arbekicin, arbidol, Arb mide, Acetohydroxamic Acid, acetomepregenol, utamine Hydrochloride, Arclofenin, Ardeparin Sodium, Acetophenazine Maleate, AcetoSulfone Sodium, Acetyl argatroban, Arginine, Argipressin Tannate, Arildone, arip choline Chloride, Acetylcysteine, acetyl-L-carnitine, iprazol, arotinolol, Arpinocid, Arteflene, Artilide Fuma acetylmethadol, Acifran, acipimoX, acitemate, Acitretin, rate, asimadoline, aspalatone, Asparaginase, Aspartic Acivicin, Aclarubicin, aclatonium, Acodazole Hydrochlo Acid, ASpartocin, asperfuran, Aspirin, aspoxicillin, ride, aconiazide, Acrisorcin, Acrivastine, Acronine, Acti Asprelin, Astemizole, Astromicin Sulfate, asulacrine, ata Somide, Actodigin, Acyclovir, acylfulvene, adafenoxate, meStane, Atenolol, ate Virdine, Atipamezole, AtiproSin adapalene, Adapalene, adatanserin, Adatanserin Hydro Maleate, Atolide, Atorvastatin Calcium, Atosiban, Atova chloride, adecypenol, adecypenol, Adefovir, adelmidrol, quone, atpenin B, Atracurium BeSylate, atrimustine, atri ademetionine, Adenosine, Adinazolam, Adipheinine nositol, Atropine, Auranofin, aureobasidin A, Aurothio Hydrochloride, adiposin, Adozelesin, adrafinil, Adrena glucose, Avilamycin, Avoparcin, Avridine, AXid, lone, airbutamine, alacepril, Alamecin, Alanine, Alapro axinastatin 1, axinastatin 2, axinastatin 3, AZabon, AZa clate, alaptide, Albendazole, albolabrin, Albuterol, Albu citidinie, AZaclorZine Hydrochloride, AZaconazole, aza toin, Alclofenae, AlclometaSone Dipropionate, Alcloxa, dirachtine, AZalanstat Dihydrochloride, AZaloxan Fuma aldecalmycin, Aldesleukin, Aldioxa, Alendronate rate, AZanator Maleate, AZanidazole, AZaperone, Sodium, alendronic acid, alentemol, Alentemol Hydro AZaribine, AZaserine, azasetron, AZatadine Maleate, AZa bromide, Aletamine Hydrochloride, Aleuronium Chlo thioprine, AZathioprine Sodium, azatoxin, azatyrosine, ride, Alexidine, alfacalcidol, Alfentanil Hydrochloride, aZelaic acid, azelastine, azelnidipine, AZepindole, alfuZosin, AlgeStone Acetonide, alglucerase, Aliflurane, AZetepa, azimilide, Azithromycin, AZlocillin, AZOlimine, alinastine, Alipamide, Allantoin, Allobarbital, Allopu AZOSemide, AZotomycin, Aztreonam, AZumolene rinol, ALL-TK antagonists, Alonimid, aloSetron, AloS Sodium, Bacampicillin Hydrochloride, baccatin III, Baci etron Hydrochloride, Alovudine, Alpertine, Alpha Amy tracin, Baclofen, bacoside A, bacoside B, bactobolamine, lase, alpha idoSone, Alpidem, Alprazolam, Alprenolol balanol, balaZipone, balhimycin, balofloxacin, bal Hydrochloride, Alprenoxime Hydrochloride, Alprostadil, Salazide, Bambermycins, bambuterol, Bamethan Sulfate, Alrestatin Sodium, Altanserin Tartrate, Alteplase, Althi Bamifylline Hydrochloride, Bamidazole, baohuoside 1, azide, Altretamine, altromycin B, Alverinc Citrate, Alvir Barmastine, barnidipine, Basifungin, Batanopride Hydro cept Sudotox, Amadinone Acetate, Amantadine Hydro chloride, batebulast, Batelapine Maleate, Batimastat, chloride, ambamustine, Ambomycin, Ambruticin, beauvericin, Becanthone Hydrochloride, becaplermin, Ambuphylline, AmbuSide, Amcinafal, Amcinonide, becliconazole, Beclomethasone Dipropionate, Amdinocillin, Amdinocillin Pivoxil, Amedalin Hydro befloxatone, Beinserazide, Belfosdil, Belladonna, chloride, amelometaSone, Ameltolide, AmeSergide, Amet Beloxamide, BemeSetron, Bemitradine, Bemoradan, antrone Acetate, ameZinium metilsulfate, amfebutamone, Benapryzine Hydrochloride, Benazepril Hydrochloride, Amfenac Sodium, Amflutizole, Amicycline, Amidephrine Benazeprilat, Bendacalol Mesylate, Bendazac, Bendrof MeSylate, amidox, Amifloxacin, amifostine, Amikacin, lumethiazide, benflumetol, benidipine, Benorterone, Amiloride Hydrochloride, Aminacrine Hydrochloride, Benoxaprofen, Benoxaprofen, Benoximate Hydrochlo Aminobenzoate Potassium, Aminobenzoate Sodium, ride, Benperidol, Bentazepam, Bentiromide, Benurestat, Aminocaproic Acid, Aminoglutethimide, Aminohippurate Benzbromarone, Benzethonium Chloride, Benzetimide Sodium, aminolevulinic acid, Aminophylline, Aminorex, Hydrochloride, Benzilonium Bromide, BenZindopyrine AminoSalicylate Sodium, AminoSalicylic acid, Amio Hydrochloride, benzisoxazole, Benzocaine, benzochlor darone, Amiprilose Hydrochloride, Amiquinsin Hydro ins, BenZoctamine Hydrochloride, BenZOdepa, benzoida chloride, amisulpride, Amitraz, Amitriptyline Hydrochlo ZOXan, BenZonatate, Benzoyl Peroxide, Benzoylpas Cal ride, AmlexanoX, amlodipine, Amobarbital Sodium, cium, benzoylstauroSporine, BenZquinamide, Amodiacquine, Amodiaquine Hydrochloride, Amorolfine, Benzthiazide, benztropine, Benztropine MeSylate, Benzy Amoxapine, Amoxicillin, Amphecloral, Amphetamine damine Hydrochloride, Benzylpenicilloyl Polylysine, Sulfate, Amphomycin, Amphotericin B, Ampicillin, bepridil, Bepridil Hydrochloride, Beractant, Beraprost, ampiroXicam, AmpyZine Sulfate, Amquinate, Amrinone, Berefrine, berlafenone, bertosamil, Berythromycin, amrinone, amrubicin, Amsacrine, amylin, amythiamicin, besipirdine, beta-alethine, betaclamycin B, Betametha AnageStone Acetate, anagrelide, Anakinra, ananain, Sone, betamipron, betaxolol, Betaxolol Hydrochloride, anaritide, Anaritide Acetate, AnastroZole, Anazolene Bethanechol Chloride, Bethanidine Sulfate, betulinic Sodium, Ancrod, andrographolide, Androstenedione, acid, bevantolol, Bevantolol Hydrochloride, Bezafibrate, angiogenesis inhibitors, Angiotensin Amide, Anidoxime, bFGF inhibitor, Bialamicol Hydrochloride, Biapenem, Anileridine, Anilopam Hydrochloride, Aniracetam, Bicalutamide, Biciifadine Hydrochloride, Biclodil Hydro Anirolac, Anisotropine Methylbromide, Anistreplase, chloride, Bidisomide, bifemelane, Bifonazole, AnitraZafen, anordrin, antagonist D, antagonist G, antar bimakalim, bimithil, Bindarit, Biniramycin, binoSpirone, elix, Antazoline Phosphate, Anthelmycin, Anthralin, bioxalomycin alpha2, Bipenamol Hydrochloride, Anthramycin, antiandrogen, AcedapSone, Felbamate, Biperiden, Biphenamine Hydrochloride, biriperone, antiestrogen, antineoplaston, Antipyrine, antisense oligo bisantrene, bisaramil, bisaziridinylspermine, bis-benzimi US 2006/0024365 A1 Feb. 2, 2006

dazole A, bis-benzimidazole B, bisnafide, Bisobrin Lac CefroXadine, cefSulodin, Ceftazidime, cefteram, ceftib tate, Bisoprolol, Bispyrithione Magsulfex, bistramide D, uten, Ceftizoxime Sodium, ceftriaxone, Cefuroxime, bistramide K, bistratene A, Bithionolate Sodium, celastrol, celikalim, celiprolol, cepacidine A, Ceph Bitolterol Mesylate, Bivalirudin, Bizelesin, Bleomycin acetrile Sodium, Cephalexin, Cephaloglycin, Cephalori Sulfate, Bolandiol Dipropionate, Bolasterone, Boldenone dine, Cephalothin Sodium, Cephapirin Sodium, Cephra Undecylenate, boldine, Bolenol, Bolmantalate, bopin dine, cericlamine, cerivastatin, Ceronapril, certoparin dolol, Bosentan, Boxidine, brefeldin, breflate, Brequinar Sodium, Ceruletide, Cetaben Sodium, Cetalkonium Chlo Sodium, Bretazenil, Bretylium Tosylate, Brifentanil ride, Cetamolol Hydrochloride, cetiedil, cetirizine, Hydrochloride, brimonidine, Brinolase, Brocresine, Bro Cetophenicol, Cetraxate Hydrochloride, cetrorelix, crinat, BrofoXine, Bromadoline Maleate, Bromazepam, Cetylpyridinium Chloride, Chenodiol, Chlophedianol Bromchlorenone, Bromelains, bromfenac, Brominidione, Hydrochloride, Chloral Betaine, Chlorambucil, Chloram Bromocriptine, Bromodiphenhydramine Hydrochloride, phenicol, Chlordantoin, Chlordiazepoxide, Chlorhexidine Bromoxamide, Bromperidol, Bromperidol Decanoate, Gluconate, chlorins, Chlormadinone Acetate, chloroori Brompheniramine Maleate, Broperamole, Bropirimine, enticin A, Chloroprocaine Hydrochloride, Chloropropa Brotizolam, Bucainide Maleate, bucindolol, Buclizine mide, Chloroquine, chloroquinoxaline Sulfonamide, Hydrochloride, Bucromarone, BudeSonide, budipine, Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxy budotitane, Buformin, Bumetamide, Bunaprolast, lenol, Chlorphenesin Carbamate, Chlorpheniramine bunazosin, Bunolol Hydrochloride, Bupicomide, Bupiv Maleate, Chlorpromazine, Chlorpropamide, Chlorpro acaine Hydrochloride, Buprenorphine Hydrochloride, thixene, Chlortetracycline Bisulfate, Chlorthalidone, Bupropion Hydrochloride, Buramate, BuSerelin Acetate, ChlorZOXaZone, Cholestyramine Resin, Chromonar Buspirone Hydrochloride, Busulfan, Butabarbital, Buta Hydrochloride, cibenzoline, cicaprost, Ciclafrine Hydro cetin, Butaclamol Hydrochloride, Butalbital, Butamben, chloride, CiclaZindol, ciclesonide, cicletanine, Ciclo Butamirate Citrate, Butaperazine, Butaprost, Butedronate piroX, Cicloprofen, cicloprolol, Cidofovir, Cidoxepin Tetrasodium, butenafine, Buterizine, buthionine Sulfox Hydrochloride, Cifenline, Ciglitazone, Ciladopa Hydro imine, Butikacin, Butilfenin, Butirosin Sulfate, Butix chloride, cilansetron, Cilastatin Sodium, CilaZapril, cilni irate, butiXocort propionate, Butoconazole Nitrate, Buto dipine, Cilobamine MeSylate, cilobradine, Cillofungin, nate, Butopamine, Butoprozine Hydrochloride, ciloStaZol, Cimaterol, Cimetidine, cimetropium bromide, Butorphanol, Butoxamine Hydrochloride, Butriptyline Cinalukast, Cinanserin Hydrochloride, Cinepazet Male Hydrochloride, Cactinomycin, Cadexomer Iodine, Caf ate, Cinflumide, Cingestol, cinitapride, Cinnamedrine, feine, calanolide A, Calcifediol, Calcipotriene, calcipot Cinnarizine, cinolazepam, Cinoxacin, Cinperene, Cinro riol, Calcitonin, Calcitriol, Calcium Undecylenate, mide, CintaZone, Cintriamide, Cioteronel, Cipamfylline, calphostin C, Calusterone, Cambendazole, camonagrel, Ciprefadol Succinate, Ciprocinonide, Ciprofibrate, Cipro camptothecin derivatives, canarypox IL-2, candesartan, floxacin, ciprostene, Ciramadol, Cirolemycin, cisapride, Candicidin, candoXatril, candoxatrilat, Caniglibose, Can cisatracurium besilate, Cisconazole, Cisplatin, cis-por renoate Potassium, Canrenone, capecitabine, Capobenate phyrin, cistinexine, citalopram, Citenamide, citicoline, Sodium, Capobenic Acid, Capreomycin Sulfate, capro citreamicin alpha, cladribine, Clamoxyquin Hydrochlo mab, capsaicin, Captopril, Capuride, Caracemide, Carba ride, Clarithromycin, clausenamide, Clavulanate Potas chol, Carbadox, Carbamazepine, Carbamide Peroxide, sium, Clazolam, Clazolimine, clebopride, Clemastine, Carbantel Lauryl Sulfate, Carbaspirin Calcium, Carbaz Clentiazem Maleate, Clidinium Bromide, clinafloxacin, eran, carbazomycin C, Carbenicillin Potassium, Car Clindamycin, Clioquinol, Clioxamide, Cliprofen, cloba benoXolone Sodium, Carbetimer, carbetocin, Carbidopa, Zam, Clobetasol Propionate, Clobetasone Butyrate, Clo Carbidopa-Levodopa, Carbinoxamine Maleate, Carbi cortolone Acetate, Clodanolene, ClodaZOn Hydrochlo phene Hydrochloride, Carbocloral, Carbocysteine, Car ride, clodronic acid, Clofazimine, Clofibrate, Clofilium bol-Fuchsin, Carboplatin, Carboprost, carbovir, carboxa Phosphate, Clogestone Acetate, Clomacran Phosphate, mide-amino-triaZO-le, carboxyamidotriazole, Clomegestone Acetate, Clometherone, clomethiazole, carboxymethylated beta-1,3-glucan, Carbuterol Hydro clomifene analogues, Clominorex, Clomiphene, Clomi chloride, CaRest M3, Carfentanil Citrate, Carisoprodol, pramine Hydrochloride, Clonazepam, Clonidine, Cloni Carmantadine, Carmustine, CARN 700, Camidazole, trate, Clonixeril, Clonixin, Clopamide, Clopenthixol, Clo CaroXaZone, carperitide, Carphenazine Maleate, Carpro peridone Hydrochloride, clopidogrel, Clopimozide, fen, CarSatrin Succinate, Cartazolate, carteolol, Carteolol Clopipazan MeSylate, Clopirac, Cloprednol, Cloprostenol Hydrochloride, cartilage derived inhibitor, Carubicin Sodium, CloraZepate Dipotassium, Clorethate, Clorex Hydrochloride, Carumonam Sodium, carvedilol, car olone, Cloroperone Hydrochloride, Clorprenaline Hydro Votroline, Carvotroline Hydrochloride, carZelesin, casein chloride, Clorsulon, Clortermine Hydrochloride, Closan kinase inhibitors (ICOS), castanospermine, cauru monam, tel, Closiramine Aceturate, Clothiapine, Clothixamide cebaracetam, cecropin B, Cedefingol, Cefaclor, Maleate Cloticasone Propionate, Clotrimazole, Cloxacil Cefadroxil, Cefamandole, Cefaparole, Cefatrizine, lin BenZathine, Cloxyquin, Clozapine, Cocaine, Coccid CefaZaflur Sodium, Cefazolin, CefbuperaZone, cefcapene ioidin, Codeine, Codoxime, Colchicine, colestimide, pivoxil, cefdaloxime pentexiltosilate, Cefdinir, cefditoren Colestipol Hydrochloride, Colestolone, Colforsin, Col pivoxil, Cefepime, cefetamet, Cefetecol, cefixime, ceflu fosceril Palmitate, Colistimethate Sodium, Colistin Sul prenam, CefinenoXime Hydrochloride, Cefinetazole, fate, collismycin A, collismycin B, Colterol Mesylate, cefminlox, cefodizime, Cefonicid Sodium, CefoperaZone combretastatin A4, combretastatin analogue, complesta Sodium, Ceforamide, cefoselis, Cefotaxime Sodium, tin, conagenin, Conorphone Hydrochloride, contignas Cefotetan, cefotiam, CefoXitin, cefoZopran, cefpimizole, terol, contortroStatin, Cormethasone Acetate, Corticorelin Cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil, Ovine Triflutate, Corticotropin, Cortisone Acetate, Corti US 2006/0024365 A1 Feb. 2, 2006

Vazol, Cortodoxone, coSalane, costatolide, CoSyntropin, Diflucortolone, Diflumidone Sodium, Diflunisal, Diflu cotinine, Coumadin, Coumermycin, crambescidin 816, prednate, Diftalone, Digitalis, Digitoxin, Digoxin, Dihex Crilvastatin, crisnatol, Cromitrile Sodium, Cromolyn yverine Hydrochloride, dihydrexidine, dihydro-5-azacy Sodium, Crotamiton, cryptophycin 8, cucumariosid, tidine, Dihydrocodeine Bitartrate, Dihydroergotamine Cuprimyxin, curacin A, curdlan Sulfate, curiosin, Cycla Mesylate, Dihydroestosterone, Dihydrostreptomycin Sul cillin, Cyclazocine, cyclazosin, cyclic HPMPC, Cyclin fate, Dihydrotachysterol, dihydrotaxol, 9-, Dilantin, Dil dole, Cycliramine Maleate, Cyclizine, Cyclobendazole, evalol Hydrochloride, Diltiazem Hydrochloride, Dime cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, fadane, Dimefline Hydrochloride, Dimenhydrinate, Cycloguanil Pamoate, Cycloheximide, cyclopentan Dimercaprol, Dimethadione, Dimethindene Maleate, thraquinones, Cyclopenthiazide, Cyclopentolate Hydro Dimethisterone, dimethyl prostaglandin A1, Dimethyl chloride, Cyclophenazine Hydrochloride, Cyclophospha Sulfoxide, dimethylhomospermine, dimiracetam, Dimox mide, cycloplatam, Cyclopropane, CycloSerine, cyclosin, amine Hydrochloride, Dinoprost, Dinoprostone, Dioxa CycloSporine, cyclothialidine, Cyclothiazide, cyclothia drol Hydrochloride, dioxamycin, Diphenhydramine Cit Zomycin, Cyheptamide, cypemycin, Cypenamine Hydro rate, Diphenidol, Diphenoxylate Hydrochloride, diphenyl chloride, Cyprazepam, Cyproheptadine Hydrochloride, spiromustine, Dipivefin Hydrochloride, Dipivefrin, Cyprolidol Hydrochloride, cyproterone, Cyproximide, dipliency prone, diprafenone, dipropylnorspermine, Dipy CySteamine, Cysteine Hydrochloride, Cystine, Cytara ridamole, Dipyrithione, Dipyrone, dirithromycin, disco bine, Cytarabine Hydrochloride, cytarabine ocfosfate, dermolide, Disobutamide, Disofenin, Disopyramide, Dis cytochalasin B, cytolytic factor, cytostatin, Dacarbazine, oxaril, disulfiram, Ditekiren, Divalproex Sodium, dacliximab, dactimicin, Dactinomycin, daidzein, Daleda Dizocilpine Maleate, Dobutamine, docarpamine, Doce lin Tosylate, dalfopristin, Dalteparin Sodium, Daltroban, benone, Docetaxel, Doconazole, docosanol, dofetilide, Dalvastatin, danaparoid, Danazol, Dantrolene, daphln dolasetron, Ebastine, ebiratide, elbrotidine, ebSelen, Odorin A, dapiprazole, dapitant, Dapoxetine Hydrochlo ecabapide, ecabet, ecadotril, ecdisteron, echicetin, ride, DapSone, Daptomycin, DarglitaZone Sodium, echistatin, Echothiophate Iodide, Eclanamine Maleate, darifenacin, darlucin A, Darodipine, darsidomine, Dauno EclaZolast, ecomustine, Econazole, ecteinascidin 722, rubicin Hydrochloride, Dazadrol Maleate, Dazepinil edaravone, Edatrexate, edelfosine, Edifolone Acetate, Hydrochloride, DaZmegrel, DaZopride Fumarate, DaZOXi edobacomab, Edoxudine, edrecolomab, Edrophonium ben Hydrochloride, Debrisoquin Sulfate, Decitabine, Chloride, edroxyprogesteone Acetate, efegatran, eflorni deferiprone, deflazacort, Dehydrocholic Acid, dehydrodi thine, efonidipine, egualcen, Elantrine, eleatonin, demnin B, Dehydroepiandrosterone, delapril, Delapril elemene, eletriptan, elgodipine, eliprodil, Elsamitrucin, Hydrochloride, Delavirdine Mesylate, deleguamine, del eltenae, Elucaine, emalkalim, emedastine, Emetine faprazine, Delmadinone Acetate, delmopinol, delphini Hydrochloride, emiglitate, Emilium Tosylate, emitefur, din, Demecarium Bromide, Demeclocycline, Demecy emoctakin, Enadoline Hydrochloride, enalapril, Enalap cline, DemoXepam, Denofungin, deoxypyridinoline, rilat, Enalkiren, enaZadrem, Encyprate, Endralazine Depakote, deprodone, Deprostil, depsidomycin, deramci MeSylate, EndrySone, Enflurane, englitaZone, Enilcona clane, dermatan Sulfate, DeSciclovir, Descinolone Zole, Enisoprost, Enlimomab, Enloplatin, Enofelast, Acetonide, Desflurane, Desipramine Hydrochloride, Enolicam Sodium, Enoxacin, enoxacin, enoxaparin desirudin, Deslanoside, deslorelin, desmopressin, Sodium, Enoxaparin Sodium, Enoximone, Enpiroline deSogeStrel, DeSonide, DeSoximetaSone, desOXoami Phosphate, Enprofylline, Enpromate, entacapone, odarone, DeSoxycorticosterone Acetate, detajmium bitar enterostatin, Enviradene, EnviroXime, Ephedrine, Epicil trate, Deterenol Hydrochloride, Detirelix Acetate, lin, Epimestrol, Epinephrine, Epinephryl Borate, Epipro DevaZepide, Dexamethasone, Dexamisole, Dexbromphe pidine, Epirizole, epirubicin, Epitetracycline Hydrochlo niramine Maleate, Dexchlorpheniramine Maleate, Dex ride, Epithiazide, Epoetin Alfa, Epoetin Beta, clamol Hydrochloride, Dexetimide, Dexfenfluramine Epoprostenol, Epoprostenol Sodium, epoxymeXrenone, Hydrochloride, dexifosfamide, Deximafen, Dexivacaine, epristeride, EproSartan, eptastigmine, equilenin, Equilin, deXketoprofen, dexloxiglumide, DeXmedetomidine, Dex Erbulozole, erdosteine, Ergoloid MeSylates, Ergonovine ormaplatin, DeXOXadrol Hydrochloride, Dexpanthenol, Maleate, Ergotamine Tartrate, erSentilide, ErSofermin, Dexpemedolac, Dexpropranolol Hydrochloride, Dexra erythritol, Erythrityl Tetranitrate, Erythromycin, Esmolol Zoxane, deXSotalol, dextrin 2-Sulphate, Dextroamphet Hydrochloride, Esorubicin Hydrochloride, Esprocquin amine, Dextromethorphan, Dextrorphan Hydrochloride, Hydrochloride, Estazolam, Estradiol, Estramustine, estra Dextrothyroxine Sodium, deXVerapamil, DeZaguanine, mustine analogue, EstraZinol Hydrobromide, Estriol, deZinamide, dezocine, Diacetolol Hydrochloride, Estrofurate, estrogen agonists, estrogen antagonists, Diamocaine Cyclamate, Diapamide, Diatrizoate Meglu Estrogens, Conjugated, Estrogens, Esterified, Estrone, mine, Diatrizoic Acid, Diaveridine, Diazepam, Diazi Estropipate, eSuprone, Etafedrine Hydrochloride, quone, Diazoxide, Dibenzepin Hydrochloride, Diben Etanidazole, etanterol, Etaroteine, EtaZolate Hydrochlo Zothiophene, Dibucaine, Dichliorvos, ride, Eterobarb, ethacizin, Ethacrynate Sodium, DichloralphenaZone, Dichlorphenamide, Dicirenone, Ethacrynic Acid, Ethambutol Hydrochloride, Ethamivan, Diclofenac Sodium, Dicloxacillin, dicranin, Dicumarol, Ethanolamine Oleate, Ethehlorvynol, Ether, Ethinyl estra Dicyclomine Hydrochloride, Didanosine, didemnin B, diol, Ethiodized Oil, Ethionamide, Ethonam Nitrate, didox, Dienestrol, dienogest, Diethylcarbamazine Citrate, Ethopropazine Hydrochloride, Ethosuximide, Ethotoin, diethylhomospermine, diethylnorspermine, Diethylpro Ethoxazene Hydrochloride, Ethybenztropine, Ethyl Chlo pion Hydrochloride, Diethylstilbestrol, Difenoximide ride, Ethyl Dibunate, Ethylestrenol, Ethyndiol, Ethyner Hydrochloride, Difenoxin, Diflorasone Diacetate, one, Ethynodiol Diacetate, Etibendazole, Etidocaine, Difloxacin Hydrochloride, Difluanine Hydrochloride, Etidronate Disodium, Etidronic Acid, Etifenin, Etintidine US 2006/0024365 A1 Feb. 2, 2006

Hydrochloride, etizolam, Etodolac, Etofenamate, Eto Galdansetron Hydrochloride, Gallamine Triethiodide, formin Hydrochloride, Etomidate, EtonogeStrel, Etoperi gallium nitrate, gallopamil, galocitabine, GamfeXine, done Hydrochloride, Etoposide, Etoprine, Etoxadrol gamolenic acid, Ganciclovir, ganirelix, gelatinase inhibi Hydrochloride, EtoZolin, etrabamine, Etretinate, tors, Gemcadiol, Gemcitabine, Gemeprost, Gemfibrozil, Etryptamine Acetate, Eucatropine Hydrochloride, Gentamicin Sulfate, Gentian Violet, gepirone, Gesta Eugenol, Euprocin Hydrochloride, eveninomicin, Exam clone, Gestodene, Gestonorone Caproate, Gestrinone, etazime, examorelin, Exaprolol Hydrochloride, exemes Gevotroline Hydrochloride, girisopam, glaspimod, glau tane, fadrozole, faerieflungin, Famciclovir, Famotidine, cocalyxin A, Glemanserin, Gliamilide, Glibornuride, Fampridine, fantofarone, Fantridone Hydrochloride, faro Glicetanile Sodium, Gliflumide, Glimepiride, Glipizide, penem, fasidotril, fasudil, faZarabine, fedotozine, felbam GloXimonam, Glucagon, glutapyrone, glutathione inhibi ate, Felbinac, Felodipine, Fely pressin, Fenalamide, Fen tors, Glutethimide, Glyburide, glycopine, glycopril, Gly amole, Fenbendazole, Fenbufen, Fencibutirol, copyrrolate, Glyhexamide, Glymidine Sodium, Glyocta Fenclofenac, Fenclonine, Fenclorac, Fendosal, FeneStrel, mide, Glyparamide, Gold Au 198, Gonadoctrinins, Fenethylline Hydrochloride, Fenfluramine Hydrochlo Gonadorelin, Gonadotropins, GoSerelin, Gramicidin, ride, Fengabine, Fenimide, Fenisorex, FenmetoZole Granisetron, grepafloxacin, Griseofulvin, Guaiapate, Hydrochloride, Fenmetramide, Fenobam, Fenoctimine Guaithylline, Guanabenz, Guanabenz. Acetate, Guanadrel Sulfate, fenofibrate, fenoldopam, Fenoprofen, Fenoterol, Sulfate, Guancydine, Guanethidine MonoSulfate, Guan Fenpipalone, Fenprinast Hydrochloride, Fenprostalene, facine Hydrochloride, Guanisoquin Sulfate, Guanoclor Fenguizone, fenretinide, fenspiride, Fentanyl Citrate, Sulfate, Guanoctine Hydrochloride, GuanoXabenz, Gua Fentiazac, Fenticlor, fenticonazole, Fenyripol Hydrochlo noxan Sulfate, Guanoxyfen Sulfate, Gusperimus Trihy ride, fepradinol, ferpifoSate Sodium, ferristene, ferrixan, drochloride, Halazepam, Halcinonide, halichondrin B, Ferrous Sulfate, Dried, Ferumoxides, ferumoxsil, Fetoxy Halobetasol Propionate, halofantrine, Halofantrine late Hydrochloride, fexofenadine, Fezolamine Fumarate, Hydrochloride, Halofenate, Halofuginone Hydrobromide, Fiacitabine, Fialuridine, Fibrinogen 1 125, filgrastim, halomon, Halopemide, Haloperidol, halopredone, Halo Filipin, finasteride, Flavodilol Maleate, flavopiridol, Fla progesterone, Haloprogin, Halothane, Halquinols, Hamy voxate Hydrochloride, Flazalone, flecainide, flerobuterol, cin, Han memopausal gonadotropins, hatomamicin, Fleroxacin, flesinoxan, Flestolol Sulfate, Fletazepam, fle hatomarubigin A, hatomarubigin B, hatomarubigin C, Zelastine, flobufen, Floctafenine, flomoxef, Flordipine, hatomarubigin D, Heparin Sodium, hepSulfam, heregulin, florfenicol, florifenine, flosatidil, Flosequinan, Floxacil Hetacillin, Heteronium Bromide, Hexachlorophene: lin, Floxuridine, fluasterone, Fluazacort, Flubanilate Hydrogen Peroxide, Hexafluorenium Bromide, hexam Hydrochloride, Flubendazole, Flucindole, Flucloronide, ethylene bisacetamide, Hexedine, Hexobendine, Hexo Fluconazole, Flucytosine, Fludalanine, Fludarabine Phos prenaline Sulfate, Hexylresorcinol, Histamine Phosphate, phate, Fludazonium Chloride, Fludeoxyglucose F 18, Histidine, Histoplasmin, Histrelin, Homatropine Hydro Fludorex, Fludrocortisone Acetate, Flufenamic Acid, bromide, Hoquizil Hydrochloride, Human chorionic Flufenisal, Flumazenil, flumecinol, Flumequine, Flumeri gonadotropin, Hycanthone, Hydralazine Hydrochloride, done, Flumethasone, Flumetramide, FlumeZapine, Flumi Hydralazine Polistirex, Hydrochlorothiazide, Hydroc norex, Flumizole, Flumoxonide, flunarizine, Flunidazole, odone Bitartrate, Hydrocortisone, Hydroflumethiazide, Flunisolide, Flunitrazepam, Flumixin, fluocalcitriol, Fluo Hydromorphone Hydrochloride, Hydroxyamphetamine cinolone Acetonide, Fluocinonide, Fluocortin Butyl, Hydrobromide, Hydroxychloroquine Sulfate, Hydrox Fluocortolone, Fluorescein, fluorodaunorunicin hydro yphenamate, Hydroxyprogesterone Caproate, Hydrox chloride, Fluorodopa F 18, Fluorometholone, Fluorou yurca, Hydroxy Zine Hydrochloride, Hymecromone, racil, Fluotracen Hydrochloride, Fluoxetine, Fluoxymes Hyoscyamine, hypericin, Ibafloxacin, ibandronic acid, terone, fluparoxan, Fluperamide, Fluperolone Acetate, ibogaine, Ibopamine, ibudilast, Ibufenac, Ibuprofen, Fluphenazine Decanoate, flupirtine, Fluprednisolone, Flu Ibutilide Fumarate, Icatibant Acetate, Ichthammol, Icoti produaZone, FluproStenol Sodium, FluguaZone, Flurado dine, idarubicin, idoxifene, Idoxuridine, idramantone, line Hydrochloride, Flurandrenolide, Flurazepam Hydro Iemefloxacin, IeSopitron, Ifetroban, Ifosfamide, Ilepeim chloride, Flurbiprofen, Fluretofen, flurithromycin, ide, illimaquinone, ilmofoSine, illomastat, Ilonidap, illo Flurocitabine, Flurofamide, Flurogestone Acetate, peridone, iloprost, Imafen Hydrochloride, ImaZodan Flurothyl, Fluroxene, Fluspiperone, Fluspirilene, Flutica Hydrochloride, imidapril, imidazenil, imidazoacridones, Some Propionate, flutrimazole, Flutroline, fluvastatin, Flu Imidecyl Iodine, Imidocarb Hydrochloride, Imidoline vastatin Sodium, fluvoxamine, Fluzinamide, Folic Acid, Hydrochloride, Imidurea, Imiloxan Hydrochloride, Imi Follicle regulatory protein, Folliculostatin, Fomepizole, penem, Imipramine Hydrochloride, imiquimod, immuno Fonazine MeSylate, forasartan, forfenimex, forfenirmex, Stimulant peptides, Impromidine Hydrochloride, Inda formeStane, Formocortal, formoterol, Fosarilate, Fos crinone, Indapamide, Indecainide Hydrochloride, azepam, Foscarnet Sodium, fosfomycin, Fosfonet Indeloxazine Hydrochloride, Indigotindisulfonate Sodium, fosinopril, Fosinoprilat, foSphenyloin, Fosqui Sodium, indinavir, Indocyanine Green, Indolapril Hydro done, Fostedil, fostriecin, fotemustine, Fuchsin, Basic, chloride, Indolidan, indometacin, Indomethacin Sodium, Fumoxicillin, Fungimycin, Furaprofen, Furazolidone, Indoprofen, indoramin, Indorenate Hydrochloride, Indox Furazolium Chloride, Furegrelate Sodium, Furobufen, ole, Indriline Hydrochloride, inocoterone, inogatran, ino Furodazole, Furosemide, Fusidate Sodium, Fusidic Acid, limomab, Inositol Niacinate, Insulin, interferons, interleu gabapentin, Gadobenate Dimeglumine, gadobenic acid, kins, Intrazole, Intriptyline Hydrochloride, iobenguane, gadobutrol, Gadodiamide, gadolinium texaphyrin, Gado Iobenzamic Acid, iobitridol, Iocarmate Meglumine, Iocar pentetate Dimeglumine, gadoteric acid, Gadoteridol, mic Acid, Iocetamic Acid, Iodamide, Iodine, Iodipamide GadoverSetamide, galantamine, galdansetron, Meglumine, Iodixanol, iodoamiloride, Iodoantipyrine I US 2006/0024365 A1 Feb. 2, 2006

131, Iodocholesterol I 131, iododoxorubicin, Iodohippu Lofepramine Hydrochloride, Lofexidine Hydrochloride, rate Sodium I 131, Iodopyriacet I 125, Iodoquinol, Iodox lombricine, Lomefloxacin, lomerizine, Lometraline amate Meglumine, Iodoxamie Acid, Ioglicic Acid, Iofe Hydrochloride, lometrexol, Lomofungin, Lomoxicam, tamine Hydrochloride I 123, iofratol, Ioglucol, Lomustine, Lonapalene, lonazolac, lonidamine, Lopera Ioglucomide, Ioglycamic Acid, Iogulamide, Iohexol, mide Hydrochloride, loracarbef, Lorajmine Hydrochlo iomeprol, Iomethin I 125, Iopamidol, Iopanoic Acid, ride, loratadine, Lorazepam, Lorbamate, Lorcainide iopentol, Iophendylate, Ioprocemic Acid, iopromide, Hydrochloride, LorecleZole, Loreinadol, lorglumide, Iopronic Acid, Iopydol, Iopy done, iopyrol, Iosefamic Lorimetazepam, Lornoxicam, lornoxicam, Lortalamine, Acid, IoSeric Acid, IoSulamide Meglumine, IoSumetic LorZafone, loSartan, losigamone, loSOXantrone, LOSula Acid, IotaSul, Iotetric Acid, Iothalamate Sodium, Iotha Zine Hydrochloride, loteprednol, lovastatin, loviride, LOX lamic Acid, iotriside, Iotrolan, IotroXic Acid, Iotyrosine I apine, LOXoribine, lubeluzole, Lucanthone Hydrochlo 131, IoverSol, Ioxagiate Sodium, Ioxaglate Meglumine, ride, Lufironil, Lurosetron MeSylate, lurtotecan, Ioxaglic Acid, iOXilan, Ioxotrizoic Acid, ipazilide, ipenOX luteinizing hormone, lutetium, Lutrelin Acetate, luzin aZone, ipidacrine, Ipodate Calcium, ipomeanol, 4-, pra dole, Lyapolate Sodium, Lycetamine, lydicamycin, Lydi tropium Bromide, ipriflavone, Iprindole, profenin, mycin, Lynestrenol, Lypressin, Lysine, lySofylline, lySo Ipronidazole, I proplatin, Iproxamine Hydrochloride, ipsa Staphin, lytic peptides, Maduramicin, Mafenide, magainin pirone, irbesartan, irinotecan, irloxacin, iroplact, irSogla 2 amide, Magnesium Salicylate, Magnesium Sulfate, dine, Irtemazole, isalsteine, Isamoxole, isbogrel, Isepami magnolol, maitansine, Malethamer, mallotochromene, cin, isobengaZole, Isobutamben, ISOcarboxazid, mallotojaponin, Malotilate, malotilate, mangafodipir, ISOconazole, Isoetharine, isofloxythepin, Isoflupredone manidipine, maniwamycin A, Mannitol, mannostatin A, Acetate, Isoflurane, Isoflurophate, isohomohalicondrin B, manumycin E, manumycin F, mapinastine, Maprotiline, Isoleucine, Isomazole Hydrochloride, Isomylamine marimastat, Martek 8708, Martek 92211, Masoprocol, Hydrochloride, Isoniazid, Isopropamide Iodide, Isopropyl maspin, massetolide, matrilysin inhibitors, Maytansine, Alcohol, isopropyl unoprostone, Isoproterenol Hydro Mazapertine Succiniate, Mazindol, Mebendazole, chloride, Isosorbide, Isosorbide Mononitrate, Isotiquim Mebeverine Hydrochloride, Mebrofenin, Mebutamate, ide, Isotretinoin, ISOXepac, ISOXicam, ISOXSuprine Hydro Mecamylamine Hydrochloride, Mechlorethamine Hydro chloride, isradipine, itameline, itasetron, ItaZigrel, chloride, Meclocycline, Meclofenamate Sodium, Meclo itopride, Itraconazole, Ivermectin, jasplakinolide, Josa qualone, Meclorisone Dibutyrate, Medazepam Hydro mycin, kahalalide F, Kalafungin, Kanamycin Sulfate, chloride, Medorinone, Medrogestone, Medroxalol, Ketamine Hydrochloride, Ketanserin, Ketazocine, Keta Medroxyprogesterone, Medrysone, Meelizine Hydro Zolam, Kethoxal, Ketipramine Fumarate, Ketoconazole, chloride, Mefenamic Acid, Mefenidil, Mefenorex Hydro Ketoprofen, Ketorfanol, ketorolac, Ketotifen Fumarate, chloride, Mefexamide, Mefloquine Hydrochloride, Kitasamycin, Labetalol Hydrochloride, Lacidipine, laci Mefruside, Megalomicin Potassium Phosphate, Mege dipine, lactitol, lactivicin, laennec, lafutidine, lamel Strol Acetate, Meglumine, Meglutol, Melengestrol larin-N triacetate, lamifiban, Lamivudine, Lamotrigine, Acetate, Melitracen Hydrochloride, Melphalan, Memo lanoconazole, Lanoxin, lanperisone, lanreotide, Lanso tine Hydrochloride, Menabitan Hydrochloride, Menoc prazole, latanoprost, lateritin, laurocapram, Lauryl ISO tone, menogaril, Menotropins, Meobentine Sulfate, quinolinium Bromide, LaVoltidine Succinate, lazabemide, Mepartricin, Mepenzolate Bromide, Meperidine Hydro Lecimibide, leinamycin, lemildipine, leminoprazole, chloride, Mephentermine Sulfate, Mephenyloin, lenercept, Leniquinsin, lenograstim, Lemperone, lentinan Mephobarbital, Mepivacaine Hydrochloride, Meprobam Sulfate, leptin, leptolstatin, lercanidipine, Lergotrile, ate, Meptazinol Hydrochloride, Mequidox, Meralein lerisetron, Letimide Hydrochloride, letraZuril, letrozole, Sodium, merbarone, Mercaptopurine, Mercufenol Chlo Leucine, leucomyzin, Leuprolide Acetate, leuprolide-- ride, Mercury, Ammoniated, Merisoprol Hg 197, Mero estrogen-progesterone, leuprorelin, Levamfetamine Suc penem, MeSalamine, MeSeclaZone, MeSoridazine, Mes cinate, levamisole, Levdobutamine Lactobionate, Levero terolone, Mestranol, Mesuprine Hydrochloride, Metalol makalim, levetiracetam, Levey closerine, leVobetaxolol, Hydrochloride, Metaproterenol Polistirex, Metaraminol levobunolol, levobupivacaine, levocabastine, levocar Bitartrate, Metaxalone, Meteneprost, meterelin, Met nitine, Levodopa, levodropropizine, levofloxacin, Levo formin, Methacholine Chloride, Methacycline, Metha furaltadone, Levoleucovorin Calcium, Levomethadyl done Hydrochloride, Methadyl Acetate, Methalthiazide, Acetate, Levomethadyl Acetate Hydrochloride, levo Methamphetamine Hydrochloride, Methaqualone, Meth moprolol, Levonantradol Hydrochloride, Levonordefrin, azolamide, Methdilazine, Methenamine, Methenolone Levonorgestrel, Levopropoxyphene NapSylate, Levopro Acetate, Methetoin, Methicillin Sodium, Methimazole, pylcillin Potassium, levormeloxifene, Levorphanol Tar methioninase, Methionine, Methisazone, Methixene trate, levosimendan, leVOSulpiride, Levothyroxine Hydrochloride, Methocarbamol, Methohexital Sodium, Sodium, Levoxadrol Hydrochloride, Lexipafant, Methopholine, Methotrexate, Methotrimeprazine, meth Lexithromycin, liarozole, Libenzapril, Lidamidine oxatone, Methoxyflurane, MethSuximide, Methyclothiaz Hydrochloride, Lidocaine, Lidofenin, Lidoflazine, ide, Methyl Palmoxirate, Methylatropine Nitrate, Meth Lifarizine, Lifibrate, Lifibrol, Linarotene, Lincomycin, ylbenzethonium Chloride, Methyldopa, Methyldopate linear polyamine analogue, Linogliride, Linopirdine, Hydrochloride, Methylene Blue, Methylergonovine linotroban, linsidomine, lintitript, lintopride, Liothyro Maleate, methylhistamine, R-alpha, methylinosine mono nine I 125, liothyronine Sodium, Liotrix, lirexapride, phosphate, Methylphenidate Hydrochloride, Methylpred lisinopril, lisSoclinamide 7, Lixazinone Sulfate, lobapl nisolone, Methyltestosterone, Methynodiol Diacelate, atin, Lobenzarit Sodium, Lobucavir, Lodelaben, Iodoxa Methysergide, Methysergide Maleate, Metiamide, mide, Lofemizole Hydrochloride, Lofentanil Oxalate, Metiapine, Metioprim, metipamide, Metipranolol, Meti US 2006/0024365 A1 Feb. 2, 2006

Zoline Hydrochloride, Metkephamid Acetate, metoclopra nitaZOXamide, nitecapone, Nitrafudam Hydrochloride, mide, Metocurine Iodide, Metogest, Metolazone, Metopi Nitralamine Hydrochloride, Nitramisole Hydrochloride, mazine, Metoprine, Metoprolol, Metoquizine, Nitrazepam, Nitrendipine, Nitrocycline, Nitrodan, Nitro metrifonate, Metrizamide, Metrizoate Sodium, Metron furantoin, Nitrofurazone, Nitroglycerin, Nitromersol, idazole, Meturedepa, Metyrapone, Metyrosine, Mexilet Nitromide, Nitromifene Citrate, Nitrous Oxide, nitroxide ine Hydrochloride, Mexrenoate Potassium, Mezlocillin, antioxidant, nitrullyn, Nivazol, Nivinnedone Sodium, mfonelic Acid, Mianserin Hydrochloride, mibefradil, Nizatidine, Noberastine, Nocodazole, Nogalamycin, Mibefradil Dihydrochloride, Mibolerone, michellamine Nolinium Bromide, Nomifensine Maleate, Noracymeth B, Miconazole, microcolin A, Midaflur, Midazolam adol Hydrochloride, Norbolethone, Norepinephrine Bitar Hydrochloride, midodrine, mifepristone, Mifobate, migli trate, Norethindrone, Norethynodrel, Norfloxacin, Nor tol, millacemide, milameline, mildronate, Milenperone, flurane, Norgestimate, Norgestomet, Norgestrel, Milipertine, milnacipran, Milrinone, miltefosine, Mim Nortriptyline Hydrochloride, NoScapine, Novobiocin bane Hydrochloride, minaprine, Minaxolone, Minocro Sodium, N-Substituted benzaimides, Nufenoxole, mil, Minocycline, Minoxidil, Mioflazine Hydrochloride, Nylestriol, Nystatin, O6-benzylguanine, Obidoxime miokamycin, mipragoside, mirfentanil, mirimoStim, Mir Chloride, Ocaperidone, Ocfentanil Hydrochloride, Ocina incamycin Hydrochloride, Mirisetron Maleate, Mirtazap plon, Octanoic Acid, OctaZamide, Octenidine Hydrochlo ine, mismatched double stranded RNA, Misonidazole, ride, Octodrine, Octreotide, Octriptyline Phosphate, Misoprostol, Mitindomide, Mitocarcin, Mitocromin, Ofloxacin, Oformine, okicenone, Olanzapine, oligonucle Mitogillin, mitoguaZone, mitolactol, Mitomalcin, Mito otides, olopatadine, olprinone, olSalazine, Olsalazine mycin, mitonafide, Mitosper, Mitotane, mitoxantrone, Sodium, Olvanil, omeprazole, onapristone, ondansetron, mivacurium chloride, mivaZerol, mixanpril, Mixidine, OntaZolast, Oocyte maturation inhibitor, Opipramol mizolastine, mizoribine, Moclobemide, modafinil, Moda Hydrochloride, oracin, Orconazole Nitrate, Orgotein, Orl line Sulfate, Modecainide, moexipril, mofarotene, Mofe islat, Ormaplatin, Ormetoprim, Ornidazole, Orpanoxin, giline Hydrochloride, mofeZolac, molgramoStim, Molina Orphenadrine Citrate, OSaterone, otenZepad, Oxacillin Zone, Molindone Hydrochloride, Molsidomine, Sodium, OXagrelate, Oxaliplatin, OXamarin Hydrochlo mometasone, Monatepil Maleate, Monensin, Monoc ride, oxamisole, Oxamniquine, Oxandrolone, Oxantel tanoin, Montelukast Sodium, montirelin, mopidamol, Pamoate, Oxaprotiline Hydrochloride, Oxaprozin, Oxar moracizine, Morantel Tartrate, Moricizine, Morniflumate, bazole, Oxatomide, oxaunomycin, Oxazepam, oxcarba Morphine Sulfate, Morrhuate Sodium, mosapramine, Zepine, Oxendolone, Oxethazaine, Oxetorone Fumarate, moSapride, motilide, Motretinide, Moxalactam Disodium, Oxfendazole, Oxfenicine, Oxibendazole, oxiconazole, Moxazocine, moxiraprine, Moxinidazole, moxonidine, Oxidopamine, Oxidronic Acid, Oxifungin Hydrochloride, MumpS Skin Test Antigen, mustard anticancer agent, Oxilorphan, Oximonam, Oximonam Sodium, Oxipero Muzolimine, mycaperoxide B, Mycophenolic Acid, myri mide, OXiracetam, OXiramide, OXisuran, OXmetidine aporone, Nabazenil, Nabilone, Nabitan Hydrochloride, Hydrochloride, Oxodipine, OxogeStone Phenpropionate, Naboctate Hydrochloride, Nabumetone, N-acetyldina Oxolinic Acid, Oxprenolol Hydrochloride, Oxtriphylline, line, Nadide, nadifloxacin, Nadolol, nadroparin calcium, Oxybutynin Chloride, Oxychlorosene, Oxycodone, nafadotride, nafamoStat, nafarelin, Nafcillin Sodium, Oxymetazoline Hydrochloride, Oxymetholone, Oxymor Nafenopin, Nafimidone Hydrochloride, Naflocort, Nafo phone Hydrochloride, Oxypertine, OxyphenbutaZone, mine Malate, Nafoxidine Hydrochloride, Nafronyl Oxypurinol, Oxytetracycline, Oxytocin, OZagrel, Ozoli Oxalate, Naftifine Hydrochloride, naftopidil, naglivan, none, Paclitaxel, palauamine, Paldimycin, palinavir, nagrestip, Nalbuphine Hydrochloride, Nalidixate Sodium, palmitoylrhizoxin, Palmoxirate Sodium, pamaqueside, Nalidixic Acid, nalmefene, Nalmexone Hydrochloride, Pamatolol Sulfate, pamicogrel, Pamidronate Disodium, naloxone-pentazocine, Naltrexone, Namoxyrate, Nan pamidronic acid, Panadiplon, panamesine, panaxytriol, drolone Phenpropionate, Nantradol Hydrochloride, Pancopride, Pancuronium Bromide, panipenem, pan Napacitadine Hydrochloride, napadisilate, NapameZole norin, panomifene, pantethine, pantoprazole, Papaverine Hydrochloride, napavin, Naphazoline Hydrochloride, Hydrochloride, parabactin, Parachlorophenol, Paralde naphterpin, Naproxen, NaproXol, napSagatran, Naranol hyde, Paramethasone Acetate, Paranyline Hydrochloride, Hydrochloride, Narasin, naratriptan, nartograstim, Parapenzolate Bromide, Pararosaniline Pamoate, Par nasaruplase, Natamycin, nateplase, Naxagolide Hydro bendazole, Parconazole Hydrochloride, Paregoric, Parep chloride, Nebivolol, Nebramycin, medaplatin, Nedocro tide Sulfate, Pargyline Hydrochloride, parnaparin Sodium, mil, Nefazodone Hydrochloride, Neflumozide Hydro Paromomycin Sulfate, Paroxetine, parthenolide, Partricin, chloride, Nefopam Hydrochloride, NeleZaprine Maleate, Paulomycin, paZelliptine, PaZinaclone, PaZOxide, paZu Nemazoline Hydrochloride, nemorubicin, Neomycin floxacin, pefloxacin, pegaspargase, Pegorgotein, Pel Palmitate, NeoStigmine Bromide, neridronic acid, anserin Hydrochloride, peldesine, Peliomycin, Pelretin, Netilmicin Sulfate, neutral endopeptidase, Neutramycin, Pelrinone Hydrochloride, Pemedolac, Pemerid Nitrate, Nevirapine, Nexeridine Hydrochloride, Niacin, Nibrox pemirolast, Pemoline, Penamecillin, Penbutolol Sulfate, ane, Nicardipine Hydrochloride, Nicergoline, Niclosa Penciclovir, Penfluridol, Penicillin G BenZathine, Peni mide, Nicorandil, Nicotinyl Alcohol, Nifedipine, Nifirm cillin G Potassium, Penicillin G Procaine, Penicillin G erone, Nifluridide, Nifuradene, Nifuraldezone, Nifuratel, Sodium, Penicillin V, Penicillin V BenZathine, Penicillin Nifuratrone, Nifurdazil, Nifurimide, Nifurpirinol, V Hydrabamine, Penicillin V Potassium, Pentabamate, Nifurcquinazol, Nifurthiazole, nilutamide, Nilvadipine, Pentaerythritol Tetranitrate, pentafuside, pentamidine, NimaZone, Nimodipine, niperotidine, niravoline, Nirida pentamorphone, Pentamustine, Pentapiperium Methylsul Zole, nisamycin, Nisbuterol MeSylate, nisin, Nisobamate, fate, Pentazocine, Pentetic Acid, Pentiapine Maleate, pen Nisoldipine, Nisoxetine, Nisterime Acetate, Nitarsone, tigetide, Pentisomicin, Pentizidone Sodium, Pentobar US 2006/0024365 A1 Feb. 2, 2006 10

bital, Pentomone, Pentopril, pentosan, pentostatin, Hydrochloride, Propafenone Hydrochloride, propagerma Pentoxifylline, Pentrinitrol, pentrozole, Peplomycin Sul nium, Propanidid, Propantheline Bromide, Proparacaine fate, Pepstatin, perflubron, perfofamide, Perfosfamide, Hydrochloride, Propatyl Nitrate, propentofylline, Propen pergolide, Perhexiline Maleate, perillyl alcohol, Perin Zolate Hydrochloride, Propikacin, Propiomazine, Propi dopril, perindoprilat, Perlapine, Permethrin, peroSpirone, onic Acid, propionylcarnitine, L-, propiram, propiram-- Perphenazine, Phenacemide, phenaridine, phenazinomy paracetamol, propiverine, Propofol, Propoxycaine cin, Phenazopyridine Hydrochloride, Phenbutazone Hydrochloride, Propoxyphene Hydrochloride, Propra Sodium Glycerate, Phencarbamide, Phencyclidine nolol Hydrochloride, Propulsid, propyl bis-acridone, Pro Hydrochloride, Phendimetrazine Tartrate, Phenelzine Sul pylhexedrine, Propyliodone, Propylthiouracil, Proqua fate, Phenmetrazine Hydrochloride, Phenobarbital, Phe Zone, Prorenoate Potassium, Proroxan Hydrochloride, noxybenzamine Hydrochloride, Phenprocoumon, Proscillaridin, Prostalene, prostratin, Protamine Sulfate, phenSerine, phensuccinal, PhenSuximide, Phentermine, protegrin, Protirelin, protoSufloxacin, Protriptyline Phentermine Hydrochloride, phentolamine mesilate, Hydrochloride, Proxazole, Proxazole Citrate, Proxicro Phentoxifylline, Phenyl Aminosalicylate, phenylacetate, mil, Proxorphan Tartrate, prulifloxacin, Pseudoephedrine Phenylalanine, phenylalanyl ketoconazole, Phenylbuta Hydrochloride, Puromycin, purpurins, Pyrabrom, Pyran Zone, Phenylephrine Hydrochloride, Phenylpropanola tel Pamoate, PyraZinamide, Pyrazofurin, pyrazoloacri mine Hydrochloride, Phenylpropanolamine Polistirex, dine, Pyridostigmine Bromide, Pyrilamine Maleate, Phenyramidol Hydrochloride, Phenyloin, phosphatase Pyrimethamine, Pyrinoline, Pyrithione Sodium, inhibitors, PhySoStigmine, picenadol, picibanil, Picotrin Pyrithione Zinc, Pyrovalerone Hydrochloride, Pyroxam Diolamine, picroliv, picumeterol, pidotimod, Pifamine, ine Maleate, Pyrrocaine, Pyrroliphene Hydrochloride, Pilocarpine, pilsicainide, pimagedine, Pimetine Hydro Pyrrolnitrin, Pyrvinium Pamoate, Quadazocine Mesylate, chloride, pimilprost, Pimobendan, Pimozide, Pinacidil, Quazepam, Quazinone, QuaZodine, QuaZolast, quetiap Pinadoline, Pindolol, pinnenol, pinocebrin, Pinoxepin ine, quiflapon, quinagolide, Quinaldine Blue, quinapril, Hydrochloride, pioglitaZone, Pipamperone, PipaZethate, Quinaprilat, QuinaZOsin Hydrochloride, Quinbolone, pipecuronium bromide, Piperacetazine, Piperacillin Quinctolate, Quindecamine Acetate, Quindonium Bro Sodium, Piperamide Maleate, piperazine, Pipobroman, mide, Quinelorane Hydrochloride, Quinestrol, Quinfa Piposulfan, Pipotiazine Palmitate, Pipoxolan Hydrochlo mide, Quingestanol Acetate, Quingestrone, Quinidine ride, Piprozolin, Piquindone Hydrochloride, Piquizil Gluconate, Quinielorane Hydrochloride, Quinine Sulfate, Hydrochloride, Piracetam, Pirandamine Hydrochloride, Quinpirole Hydrochloride, Quinterenol Sulfate, Quinuc pirarubicin, Pirazmonam Sodium, Pirazolac, Pirbenicillin lium Bromide, Quinupristin, Quipazine Maleate, Sodium, Pirbuterol Acetate, Pirenperone, Pirenzepine Rabeprazole Sodium, Racephenicol, Racepinephrine, raf Hydrochloride, piretamide, Pirfenidone, Piridicillin antagonists, Rafoxamide, Ralitoline, raloxifene, raltitr Sodium, Piridironate Sodium, Piriprost, piritrexim, Pirli exed, ramatroban, Ramipril, Ramoplanin, ramosetron, mycin Hydrochloride, pirlindole, pirmagrel, Pirmenol ranelic acid, Ranimycin, Ranitidine, ranolazine, Rauwol Hydrochloride, Pirnabine, Piroctone, Pirodavir, piro fia Serpentina, recainam, Recainam Hydrochloride, domast, Pirogliride Tartrate, Pirolate, Pirolazamide, Reclazepam, regaVirumab, RegramoStim, Relaxin, Relo Piroxantrone Hydrochloride, Piroxicam, Piroximone, Pir mycin, Remacemide Hydrochloride, Remifentanil Hydro profen, Pirquinozol, Pirsidomine, Prenylamine, Pituitary, chloride, Remiprostol, Remoxipride, Repirinast, Repro Posterior, Pivampicillin Hydrochloride, Pivopril, Pizoty micin, Reproterol Hydrochloride, Reserpine, line, placetin A, platinum compounds, platinum-triamine resinferatoxin, Resorcinol, retelliptine demethylated, complex, Plicamycin, Plomestane, Pobilukast Edamine, reticulon, reviparin Sodium, revizinone, rhenium Re 186 Podofilox, Poisonoak Extract, Poldine Methylsulfate, etidronate, rhizoxin, Ribaminol, Ribavirin, Riboprine, Poliglusam, Polignate Sodium, Polymyxin B Sulfate, ribozymes, ricasetron, Ridogrel, Rifabutin, Rifametane, Polythiazide, Ponalrestat, Porfimer Sodium, Porfiromy Rifamexil, Rifamide, Rifampin, Rifapentine, Rifaximin, cin, Potassium Chloride, Potassium Iodide, Potassium RII retinamide, rilopiroX, Riluzole, rimantadine, Rimca Permanganate, Povidone-Iodine, Practolol, Pralidoxime Zole Hydrochloride, Rimexolone, Rimiterol Hydrobro Chloride, Pramiracetam Hydrochloride, Pramoxine mide, rimoprogin, riodipine, Rioprostil, Ripazepam, rip Hydrochloride, Pranolium Chloride, Pravadoline Male isartan, Risedronate Sodium, risedronic acid, Risocaine, ate, Pravastatin (Pravachol), Prazepam, Prazosin, Pra Risotilide Hydrochloride, rispenzepine, Risperdal, Ris Zosin Hydrochloride, Prednazate, Prednicarbate, Predni peridone, Ritanserin, ritipenem, Ritodrine, Ritolukast, mustine, Prednisolone, Prednisone, Prednival, ritonavir, rizatriptan benzoate, Rocastine Hydrochloride, Pregnenolone Succiniate, Prenalterol Hydrochloride, Rocuronium Bromide, Rodocaine, Roflurane, Rogletim Pridefine Hydrochloride, Prifelone, Prilocalne Hydro ide, rohitukine, rokitamycin, Roletamicide, Rolgamidine, chloride, Prilosec, Primaquine Phosphate, Primidolol, Rolicyprine, Rolipram, Rolitetracycline, Rolodine, Primidone, Prinivil, Prinomide Tromethamine, Prinox RomaZarit, romurtide, Ronidazole, ropinirole, Ropitoin Odan, Prizidilol Hydrochloride, Proadifen Hydrochloride, Hydrochloride, ropivacaine, Ropizine, roquinimex, Rosa Probenecid, Probicromil Calcium, Probucol, Procaina ramicin, RoSoxacin, Rotoxamine, roXaitidine, RoxarSone, mide Hydrochloride, Procaine Hydrochloride, Procarba roXindole, roXithromycin, rubiginone B1, ruboxyl, zine Hydrochloride, Procaterol Hydrochloride, Prochlor rufloxacin, rupatidine, Rutamycin, ruzadolane, Sabelu perazine, Procinonide, Proclonol, Procyclidine Zole, Safingol, Safironil, Saintopin, Salbutamol, R-Sal Hydrochloride, Prodilidine Hydrochloride, Prodolic Acid, colex, Salethamide Maleate, Salicyl Alcohol, Salicyla Profadol Hydrochloride, Progabide, Progesterone, Pro mide, Salicylate Meglumine, Salicylic Acid, Salmeterol, glumide, Proinsulin Human, Proline, Prolintane Hydro Salnacedin, Salsalate, Sameridine, Sampatrilat, Sancyc chloride, Promazine Hydrochloride, Promethazine line, Sanfeltrinem, Sanguinarium Chloride, Saperconazole, US 2006/0024365 A1 Feb. 2, 2006 11

Saprisartan, Sapropterin, Saquinavir, Sarafloxacin Hydro olene Succinate, taZanolast, tazarotene, Tazifylline chloride, Saralasin Acetate, SarCNU, Sarcophytol A, Sar Hydrochloride, Tazobactam, Tazofelone, Tazolol Hydro gramoStim, Sarmoxicillin, Sarpicillin, Sarpogrelate, Saru chloride, Tebufelone, Tebuguine, Technetium Tc 99 m plase, Saterinone, Satigrel, Satumomab pendetide, Schick Bicisate, Teclozan, Tecogalan Sodium, Teecleukin, Teflu Test Control, Scopafungin, Scopolamine Hydrobromide, rane, Tegafur, Tegretol, Teicoplanin, telenzepine, tellu Scrazaipine Hydrochloride, Sdi 1 mimetics, Secalciferol, rapyrylium, telmeSteine, telmisartan, telomerase inhibi Secobarbital, Seelzone, Seglitide Acetate, Selegiline, Sel torS, Teloxantrone Hydrochloride, Teludipine egiline Hydrochloride, Selenium Sulfide, Selenomethion Hydrochloride, Temafloxacin Hydrochloride, Tematro ine Se 75, Selfotel, Sematilide, Semduramicin, Semotiadil, pium Methyl Sulfate, Temazepam, Temelastine, temoca Semustine, Sense oligonucleotides, Sepazonium Chloride, pril, Temocillin, temoporfin, temozolomide, Tenidap, Seperidol Hydrochloride, Seprilose, Seproxetine Hydro Teniposide, tenosal, tenoxicam, tepirindole, Tepoxalin, chloride, Seractide Acetate, Sergolexole Maleate, Serine, Teprotide, terazosin, Terbinafine, Terbutaline Sulfate, Ter Sermetacin, Sermorelin Acetate, Sertaconazole, Sertin conazole, terfenadine, terflavoxate, terguride, Teriparatide dole, Sertraline, Setiptiline, Setoperone, Sevirumab, Sevof Acetate, terlakiren, terlipressin, terodiline, Teroxalene lurane, Sezolamide, Sibopirdine, Sibutramine Hydrochlo Hydrochloride, Teroxirone, tertatolol, Tesicam, Tesimide, ride, Signal transduction inhibitors, Silandrone, Silipide, TeStolactone, Testosterone, Tetracaine, tetrachlorodeca Silteplase, Silver Nitrate, Simendan, SimtraZene, Simvas oxide, Tetracycline, Tetrahydrozoline Hydrochloride, Tet tatin, Sincalide, Sinefungin, Sinitrodil, Sinnabidol, ramisole Hydrochloride, Tetrazolast Meglumine, tetra Sipatrigine, Sirolimus, Sisomicin, Sitogluside, Sizofiran, Zomine, TetrofoSmin, Tetroquinone, TetroXoprim, Sobuzoxane, Sodium Amylosulfate, Sodium Iodide I 123, Tetrydamine, thaliblastine, Thalidomide, Theofibrate, Sodium Nitroprusside, Sodium Oxybate, sodium pheny Theophylline, Thiabendazole, Thiamiprine, Thiampheni lacetate, Sodium Salicylate, Solverol, Solypertine Tar col, Thiamylal, Thiazesim Hydrochloride, Thiazinamium trate, Somalapor, Somantadine Hydrochloride, Chloride, Thiethylperazine, Thimerfonate Sodium, Somatomedin B, Somatomedin C, Somatrem, Somatropin, Thimerosal, thiocoraline, thiofedrine, Thioguanine, thi Somenopor, Somidobove, Sonermin, Sorbinil, Sorivu Omarinol, Thiopental Sodium, thioperamide, Thior dine, Sotalol, Soterenol Hydrochloride, Sparfloxacin, idazine, Thiotepa, Thiothixene, Thiphenamil Hydrochlo Sparfosate Sodium, Sparfosic acid, SparSomycin, ride, Thiphencillin Potassium, Thiram, Thozalinone, Sparteine Sulfate, Spectinomycin Hydrochloride, Spica Threonine, Thrombin, thrombopoietin, thrombopoietin mycin D, Spiperone, Spiradoline Mesylate, Spiramycin, mimetic, thymalfasin, thymopoietin receptor agonist, thy Spirapril Hydrochloride, Spiraprilat, Spirogermanium motrinan, Thyromedan Hydrochloride, Thyroxine 1 125, Hydrochloride, Spiromustine, Spironolactone, Spiropl Thyroxine 1131, Tiacrilast, Tiacrilast Sodium, tiagabine, atin, SpiroXasone, Splenopentin, Spongistatin 1, Sprodia Tiamenidine, tianeptine, tiapafant, Tiapamil Hydrochlo mide, Squalamine, Stallimycin Hydrochloride, Stannous ride, Tiaramide Hydrochloride, Tiazofurin, Tibenelast Pyrophosphate, Stannous Sulfur Colloid, Stanozolol, Sta Sodium, Tibolone, Tibric Acid, Ticabesone Propionate, tolon, Staurosporine, Stavudine, Steffimycin, Stenbolone Ticarbodine, Ticarcillin Cresyl Sodium, Ticlatone, ticlo Acetate, Stepronin, Stilbazium Iodide, Stilonium Iodide, pidine, Ticrynafen, tienoXolol, Tifurac Sodium, Tige Stipiamide, Stiripentol, Stobadine, Streptomycin Sulfate, monam Dicholine, Tigestol, Tiletamine Hydrochloride, StreptonicOZid, Streptonigrin, Streptozocin, Stromely Sin Tilidine Hydrochloride, tilisolol, tilnoprofen arbamel, inhibitors, Strontium Chloride Sr 89, Succibun, Succimer, Tilorone Hydrochloride, Tiluldronate Disodium, tiludronic Succinylcholine Chloride, Sucralfate, Sucrosofate Potas acid, Timefurone, Timobesone Acetate, Timolol, tin ethyl sium, Sudoxicam, Sufentanil, Sufotidine, Sulazepam, etiopurpurin, Tinabinol, Timidazole, Tinzaparin Sodium, Sulbactam Pivoxil, Sulconazole Nitrate, Sulfabenz, Sul Tioconazole, Tiodazosin, Tiodonium Chloride, Tioperi fabenzamide, Sulfacetamide, Sulfacytine, Sulfadiazine, done Hydrochloride, Tiopinac, Tiospirone Hydrochloride, Sulfadoxine, Sulfalene, Sulfamerazine, Sulfameter, Sul Tiotidine, tiotropium bromide, Tioxidazole, Tipentosin famethazine, Sulfamethizole, Sulfamethoxazole, Sulfa Hydrochloride, Tipredane, Tiprenolol Hydrochloride, monomethoxine, Sulfamoxole, Sulfanilate Zinc, Sulfani Tiprinast Meglumine, Tipropidil Hydrochloride, Tique tran, SulfaSalazine, SulfaSomizole, Sulfazamet, Sulfinalol Side, Tiquinamide Hydrochloride, tirandaly digin, Tira Hydrochloride, sulfinosine, Sulfinpyrazone, Sulfisox paZamine, tirilazad, tirofiban, tiropramide, titanocene azole, Sulfomyxin, Sulfonterol Hydrochloride, Sulfoxam dichloride, Tixanox, Tixocortol Pivalate, Tizanidine ine, Sulinldac, Sulmarin, Sulnidazole, Suloctidil, Hydrochloride, Tobramycin, Tocainide, Tocamphyl, Sulofenur, Sulopenem, Suloxifen Oxalate, Sulpiride, Sul Tofenacin Hydrochloride, Tolamolol, Tolazamide, Tola prostone, Sultamicillin, Sulthiame, Sultopride, Sulukast, Zoline Hydrochloride, Tolbutamide, Tolcapone, Tolci Sumaroteine, Sumatriptan, Suncillin Sodium, Suproclone, clate, Tolfamide, Tolgabide, lamotrigine, Tolimidone, Suprofen, Suradista, Suramin, Surfomer, Suricainide Tolindate, Tolimetin, Tolnaftate, Tolpovidone 1 131, Maleate, Suritozole, Suronacrine Maleate, Suxemerid Tolpyrramide, Tolrestat, Tomelukast, Tomoxetine Hydro Sulfate, Swainsonine, Symakalim, Symclosene, Symetine chloride, Tonazocine MeSylate, Topiramate, topotecan, Hydrochloride, Synthetic glycosaminoglycans, Taciamine Topotecan Hydrochloride, topSentin, Topterone, Hydrochloride, Tacrine Hydrochloride, Tacrolimus, Toquizine, toraSemide, toremifene, Torsemide, ToSifen, Talampicillin Hydrochloride, Taleranol, Talisomycin, tal ToSufloxacin, totipotent Stem cell factor, Tracazolate, tra limustine, Talmetacin, Talniflumate, Talopram Hydro fermin, Tralonide, Tramadol Hydrochloride, Tramazoline chloride, Talosalate, Tametraline Hydrochloride, Tamox Hydrochloride, trandolapril, Tranexamic Acid, Tranilast, ifen, Tampramine Fumarate, Tamsulosin Hydrochloride, Transcainide, translation inhibitors, traXanox, Trazodone Tandamine Hydrochloride, tandoSpirone, tapgen, taproS Hydrochloride, Trazodone-HCL, Trebenzomine Hydro tene, Tasosartan, tauromustine, Taxane, Taxoid, Tazad chloride, Trefentanil Hydrochloride, Treloxinate, Trepi US 2006/0024365 A1 Feb. 2, 2006 12

pam Maleate, Trestolone Acetate, tretinoin, Triacetin, 182716) (Reglitazar), AR-HO39242, MCC-555 (Netoglita triacetyluridine, Triafungin, Triamcinolone, Triampy Zine Zone), AR-HO49020 Tesaglitazar), CS-011 (CI-1037), Sulfate, Triamterene, Triazolam, Tribenoside, tricaprilin, GW-409544X, KRP-297, RG-12525, BM-15.2054, CLX Tricetamide, Trichlormethiazide, trichohyalin, triciribine, O940, CLX-0921, DRF-2189, GW-1929, GW-9820, LR-90, Tricitrates, Triclofenol piperazine, Triclofos Sodium, Tri LY-510929, NIP-221, NIP-223, JTP-20993, LY 29311 Na, clonide, trientine, Trifenagrel, triflavin, Triflocin, Tri FK 614, BMS 298585, R 483, TAK 559, DRF 2725 flubazam, Triflumidate, Trifluoperazine Hydrochloride, (Ragaglitazar), L-686398, L-168049, L-805645, L-054852, Trifluperidol, Triflu promazine, Triflu promazine Hydro Demethyl asteriquinone B1 (L-783281), L-363586, KRP chloride, Trifluridine, Trihexyphenidyl Hydrochloride, 297, P32/98, CRE-16336 and EML-16257. TriloStane, TrimaZOsin Hydrochloride, trimegestone, Tri meprazine Tartrate, Trimethadione, Trimethaphan Cam 0052 AS indicated above the inner portion of the present Sylate, Trimethobenzamide Hydrochloride, Trimethop invention may comprise auxiliary excipients Such as for rim, Trimetozine, Trimetrexate, Trimipramine, example diluents, binders, lubricants, Surfactants, disinte Trimoprostil, Trimoxamine Hydrochloride, Triolein 1 grants, plasticisers, anti-tack agents, opacifying agents, pig 125, Triolein 1 131, Trioxifene Mesylate, Tripamide, ments, and Such like. AS will be appreciated by those skilled Tripelennamine Hydrochloride, Triprolidine Hydrochlo in the art, the exact choice of excipient and their relative ride, Triptorelin, Trisulfapyrimidines, Troclosene Potas amounts will depend to Some extent on the final oral dosage sium, troglitaZone, Trolamine, Troleandomycin, trombo form. dipine, trometamol, Tropanserin Hydrochloride, 0053 Suitable diluents include for example pharmaceu Tropicamide, tropine ester, tropisetron, trospectomycin, tically acceptable inert fillerS Such as microcrystalline cel trovafloxacin, trovirdine, Tryptophan, Tuberculin, Tub lulose, lactose, Starch, dibasic calcium phosphate, Saccha ocurarine Chloride, Tubulozole Hydrochloride, tucarcsol, rides, and/or mixtures of the foregoing. Examples of diluents tulobuterol, turosteride, Tybamate, tylogenin, Tyro include microcrystalline celluloses Such as those Sold under panoate Sodium, Tyrosine, Tyrothricin, tyrphostins, ube the Trade Mark Avicel PH 101, Avicel PH 102, Avicel PH nimex, Uldazepam, Undecylenic Acid, Uracil Mustard, 112, Avicel PH 200, Avicel PH301 and Avicel PH 302; urapidil, Urea, Uredepa, uridine triphosphate, Urofol lactose Such as lactose monohydrate, lactose anhydrous and litropin, Urokinase, Ursodiol, Valaciclovir, Valine, Val Pharmatose DCL21 (Pharmatose is a Trade Mark), including noctamide, Valproate Sodium, Valproic Acid, Valsartan, anhydrous, monohydrate and Spray dried forms, dibasic Vamicamide, Vanadeine, Vancomycin, Vaninolol, calcium phosphate Such as Emcompress (Emcompress is a Vapi.prost Hydrochloride, Vapreotide, variolin B, Vaso Trade Mark); mannitol; Pearlitol SD 200 (Pearlitol SD 200 pressin, Vecuronium Bromide, VelareSol, Velnacrine is a trade mark); Starch, Sorbitol; Sucrose; and glucose. Maleate, venlafaxine, Veradoline Hydrochloride, veram ine, Verapamil Hydrochloride, verdins, Verilopam Hydro 0054 Suitable binders include for example starch, povi chloride, Verlukast, Verofylline, Veroxan, verteporfin, done, hydroxypropylmethylcellulose, pregelatinised Starch, Vesnarinone, vexibinol, Vidarabine, vigabatrin, Vilox hydroxypropylcellulose and/or mixtures of the foregoing. azine Hydrochloride, Vinblastine Sulfate, vinburnine cit Suitable lubricants, including agents that act on the flowabil rate, VincofoS, Vinconate, Vincristine Sulfate, Vindesline, ity of the powder to be compressed are, for example, Vindesine Sulfate, Vinepidine Sulfate, Vinglycinate Sul colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a fate, Vinleurosine Sulfate, Vinorelbine, Vinpocetine, Vin Trade Mark), talc, Stearic acid, magnesium Stearate, calcium toperol, vinxaltine, Vinzolidine Sulfate, Viprostol, Virgin Stearate and Sodium Stearyl fumarate. iamycin, Viridofulvin, Viroxime, vitaxin, Volazocine, 0055 Suitable disintegrants include for example lightly Voriconazole, Vorozole, VOXergolide, Warfarin Sodium, crosslinked polyvinyl pyrrollidone, corn Starch, potato Xamoterol, Xanomeline, XanoXate Sodium, Xanthinol Starch, maize Starch and modified Starches, croScarmellose Niacinate, Xemilofiban, Xenalipin, Xenbucin, Xilobam, Sodium, croSS-povidone, Sodium Starch glycolate and com Ximoprofen, Xipamide, Xorphanol MeSylate, Xylamidine binations and mixtures thereof. Tosylate, Xylazine Hydrochloride, Xylometazoline Hydrochloride, Xylose, yangamblin, Zabicipril, Zacopride, 0056 The amount of release controlling agent(s) to be Zafirlukast, Zalcitabine, Zaleplon, ZaloSpirone, Zaltidine used in will be determined based on drug release rate etc. Hydrochloride, Zaltoprofen, Zanamivir, Zankiren, Zanot 0057 The release controlling agents(s) are selected from erone, Zantac, Zarirlukast, Zatebradine, Zatosetron, alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, Zatosetron Maleate, Zenarestat, Zenazocine MeSylate, cellulose esters, nitro celluloses, polymers of acrylic and Zeniplatin, Zeranol, Zidometacin, Zidovudine, Zifrosi methacrylic acids and esters thereof, polyamides, polycar lone, Zilantel, Zilascorb, Zileuton, Zimeldine Hydrochlo bonates, polyalkylenes, polyalkylene glycols, polyalkylene ride, Zinc Undecylenate, Zindotrine, Zinoconazole terephthalates, polyvinyl esters, polyvinylpyrrolidone, Hydrochloride, Zinostatin, Zinterol Hydrochloride, Zin polyglycolides, polysiloxanes and polyurethanes and co ViroXime, Ziprasidone, Zobolt, Zofenopril Calcium, Zofenoprilat, Zolamine Hydrochloride, Zolazepam polymers thereof. Hydrochloride, Zoledronie acid, Zolertine Hydrochloride, 0058. The high water soluble/permeable release control Zolmitriptan, Zolpidem, Zomepirac Sodium, Zometapine, ling agents is Suitably polyvinyl alcohol, polyvinylpyrroli ZonicleZole Hydrochloride, Zonisamide, Zopiclone, done, methylcellulose, hydroxypropylcellulose, hydrox Zopolrestat, Zorbamycin, Zorubicin Hydrochloride, ypropylmethyl cellulose or polyethylene glycol, alginates, Zotepine, Zucapsaicin. polyacrylic acids, Xanthun gum or a mixture thereof. 0051. Further examples of low dose, antidiabetic active 0059. The low water soluble/permeable release control ingredients comprises of but not limited to JTT-501 (PNU ling agents is Suitably ethylcellulose, cellulose acetate, cel US 2006/0024365 A1 Feb. 2, 2006 lulose propionate (lower, medium or higher molecular 0063. Further advantages of present invention include the weight), cellulose acetate propionate, cellulose acetate disintegration of inner portion is not hindered as non butyrate, cellulose acetate phthalate, cellulose triacetate, Swellable release controlling agents are used which do not poly(methyl methacrylate), poly(ethyl methacrylate), poly Swell and maintain the shape during operation and it effec (butyl methacrylate), poly(isobutyl methacrylate), and poly tively prevents the Separation of the layers of the multilay (hexyl methacrylate). Poly(isodecyl methacrylate), poly ered tablets which is normally associated with normal mul (lauryl methacrylate), poly(phenyl methacrylate), poly tilayered tablets. (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl 0064. The high dose, high solubility active ingredient can actylate), poly (octadecyl acrylate), waxes Such as beeswax, be present in the form of a free base or in the form of carnauba wax, microcrystalline wax, and OZokerite; fatty pharmaceutically acceptable Salts. Pharmaceutically accept alcohols Such as cetoStearyl alcohol, Stearyl alcohol, cetyl able Salts forming part of this invention are intended to alcohol and myristyl alcohol, and fatty acid esterS Such as define but not limited to salts of the carboxylic acid moiety glyceryl monoStearate, glyceryl distearate, glycerol Such as alkali metal Salts like Li, Na and K Salts, alkaline monooleate, acetylated monoglycerides, tristearin, tripalm earth metal Salts like Ca and Mg Salts, Salts of organic bases itin, cetyl esters wax, glyceryl palmitostearate, glyceryl Such as lysine, arginine, guanidine, diethanolamine, choline, behenate, and hydrogenated castor oil or a mixture thereof. and the like; ammonium or Substituted ammonium Salts and The non-biodegradable materials are Selected from but are aluminium Salts. Salts may be acid addition Salts which not limited to Ammonio methacrylate copolymers type A defines but not limited to Sulfates, nitrates, phosphates, and B as described in USP, Polyacrylate dispersion 30% as perchlorates, borates, hydrohalides, acetates, tartrates, male described in Ph. Eur, Polyvinyl acetate dispersion, cellulose ates, citrates, Succinates, palmoates, methaneSulfonates, derivatives Such as ethylcellulose, cellulose acetate waxes benzoates, Salicylates, hydroxynaphthoates, benzensul Such as beeswax, carnauba wax, microcrystalline wax, and fonates, ascorbates, glycerophosphates, ketoglutarates and oZokerite; fatty alcohols Such as cetoStearyl alcohol, Stearyl the like. Further, the high dose, high Solubility active ingre alcohol, cetyl alcohol and myristyl alcohol; and fatty acid dient, where applicable, may be present either in the form of esterS Such as glyceryl monoStearate, glyceryl distearate, one Substantially optically pure enantiomer or as a mixture glycerol monooleate, acetylated monoglycerides, triStearin, of enantiomers or polymorphs thereof. tripalmitin, cetyl esters wax, glyceryl palmitoStearate, glyc eryl behenate, and hydrogenated castor oil. 0065. The high dose, high solubility active ingredient is in the form of modified release and has dose from 500 mg 0060. The mucoadhesive release controlling agents are to 1500 mg. The high dose, high solubility active ingredient Selected from but are not limited to carbopol, Sodium comprises of the following therapeutic classes but not lim carboxymethyl cellulose, hydroxypropyl cellulose, hydrox ited to adrenergic agent, adrenocortical Steroid; adrenocor ypropylmethyl cellulose, hydroxyethyl cellulose, methyl tical Suppressant, aldosterone antagonist, amino acid; ana cellulose, Sodium hyaluronate, gaur gum, Sodium alginate, bolic; analeptic; analgesic, anesthetic; anorectic, anti-acne polycabophil, Starch, dextran or chitosan. agent, anti-adrenergic, anti-allergic, anti-amebic; anti-ane mic, anti-anginal; anti-arthritic, anti-asthmatic, anti-athero 0061 Active ingredients especially the poorly soluble Sclerotic, antibacterial; anticholinergic, anticoagulant; anti active ingredients mentioned above can be micronized to convulsant, antidepressant, antidiabetic, antidiarrheal; increase solubility and/or bioavialability. antidiuretic, anti-emetic, anti-epileptic, antifibrinolytic, 0062 (ii) Outer Portion: The outer portion comprises of antifungal, antihemorrhagic, antihistamine; antihyperlipi a) Micro matrix particles containing high dose, high Solu demia; antihypertensive, antihypotensive; anti-infective; bility active ingredient and one or more hydrophobic release anti-inflammatory; antimicrobial; antimigraine; antimitotic, controlling agent, b) Coating of Micro matrix particles with antimycotic, antinauseant, antineoplastic, antineutropenic, one or more hydrophobic release controlling agents. The antiparasitic, antiproliferative, antipsychotic, antirheumatic; outer portion may also include one or more commonly used antiseborrheic, antisecretory; antispasmodic, antithrom excipients in oral pharmaceutical formulations. The release botic, anti-ulcerative; antiviral; appetite SuppreSSant; blood of the high dose, high Solubility active ingredient is con glucose regulator, bone resorption inhibitor, bronchodilator; trolled through dual retard technique. The dual retard tech cardiovascular agent, cholinergic, depressant; diagnostic nique is a combination of matrix formulations and reservoir aid; diuretic, dopaminergic agent, estrogen receptor agonist; formulations. First the micro matrix particles of high dose, fibrinolytic, fluorescent agent, free oxygen radical Scaven high Solubility dose active ingredient and one or more ger; gastric acid SupreSSant; gastrointestinal motility effec hydrophobic release controlling agents are formed and then tor; glucocorticoid; hair growth Stimulant; hemostatic; his these are further coated with one or more release controlling tamine H2 receptor antagonists, hormone; agents. Thus the dual retard release technique presents the hypocholesterolemic, hypoglycemic, hypolipidemic, double barriers and effectively controls the diffusion of the hypotensive; imaging agent, immunizing agent; immuno high dose, high Solubility active ingredients from the present modulator; immunoregulator; immunostimulant; immuno invention in predictable manner and also significantly SuppreSSant; keratolytic, LHRH agonist, mood regulator; reduces the amount of release controlling agents which are mucolytic, mydriatic, nasal decongestant; neuromuscular otherwise required in very high quantity and make the blocking agent; neuroprotective, NMDA antagonist; non dosage form very bulky and therefore pose difficulty in hormonal Sterol derivative, plasminogen activator; platelet Swallowing. The other advantages of the present invention activating factor antagonist, platelet aggregation inhibitor; are Such as it reduces the chances of dose dumping, unnec psychotropic, radioactive agent; Scabicide, Sclerosing agent; essary burst effects and failure of the System, which are Sedative, Sedative-hypnotic, Selective adenosine Al antago otherwise usually associated with Simple matrix or reservoir nist; Serotonin antagonist; Serotonin inhibitor, Serotonin Systems. receptor antagonist; Steroid; thyroid hormone; thyroid US 2006/0024365 A1 Feb. 2, 2006 inhibitor; thyromimetic, tranquilizer; amyotrophic lateral (butyl methacrylate), poly(isobutyl methacrylate), and poly Sclerosis agent; cerebral ischemia agent, Paget's disease (hexyl methacrylate). Poly(isodecyl methacrylate), poly agent; unstable angina agent; vasoconstrictor; vasodilator; (lauryl methacrylate), poly(phenyl methacrylate), poly wound healing agent; Xanthine oxidase inhibitor. (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl 0.066 Examples of high dose, high solubility active actylate), poly (octadecyl acrylate), waxes Such as beeswax, ingredients comprise of but not limited to potassium chlo carnauba wax, microcrystalline wax, and OZokerite; fatty ride, metformin hydrochloride, phenformin, buformin, clin alcohols Such as cetoStearyl alcohol, Stearyl alcohol, cetyl damycin, hydroxyurea, eprosartan; erythromycin, lactobion alcohol and myristyl alcohol, and fatty acid esterS Such as ate, Vancomycin hydrochloride, balsalazide disodium, glyceryl monoStearate, glycerol distearate, glycerol Sodium Valproate, niacin, aminocaproic acid, acetami monooleate, acetylated monoglycerides, tristearin, tripalm nophen, Ciprofloxacin, quetiapine. Other drugs Suitable for itin, cetyl esters wax, glyceryl palmitoStearate, glyceryl use and meeting the Solubility and dose criteria described behenate, and hydrogenated castor oil. above will be apparent to those skilled in the art. 0076 According to an especially preferred embodiment the release controlling agents contains ammonio methacry 0067. In the dosage form of the present invention, the late co-polymers and fatty acid esters as hereinafter outer portion may optionally contain more than one high described. The Suitable hydrophobic agents are polymers dose high Solubility active ingredient. sold under the Trade Mark Eudragit RS (Ammonio Meth 0068. In the dosage form of the present invention, the acrylate Copolymer type B USP), (Eudragit NE 30D (Poly outer portion may optionally contain more than one high acrylate dispersion 30% Ph. Eur), Eudragit RL (Ammonio dose high Solubility antidiabetic active ingredient. Methacrylate Copolymer type A USP) and Kollicoat SR 30 D and fatty acid esterS Such as glyceryl behenate, glycerol 0069. As indicated above the outer portion of the present distearate and hydrogenated castor oil. Eudragit polymers invention may comprise auxiliary excipients Such as for are polymeric lacquer Substances based on acrylate and/or example lubricants, plasticisers, anti-tack agents, opacifying methacrylates. agents, pigments, and Such like. AS will be appreciated by those skilled in the art, the exact choice of excipient and their 0077. The outer portion can also include one or more relative amounts will depend to Some extent on the final oral commonly used excipients in oral pharmaceutical formula dosage form. tions. 0070 Suitable lubricants, including agents that act on the 0078 Representative commonly used excipients in oral flowability of the powder to be compressed are, for example, pharmaceutical formulations include talc, fumed Silica, colloidal silicon dioxide such as Aerosil 200 (Aerosil is a glyceryl monoStearate, magnesium Stearate, calcium Stear Trade Mark), talc, Stearic acid, magnesium Stearate, calcium ate, kaolin, colloidal Silica, gypsum, Tween 80, Geleol Stearate and Sodium Stearyl fumarate. pastiles (trade mark), micronised silica and magnesium trisilicate. The quantity of commonly used excipients in oral 0071. In micro matrix particles, the active ingredient and pharmaceutical formulations used is from about 0.5% to one or more hydrophobic release controlling agents are about 200% by weight, preferably from 2 to 100% more preferably present in a ratio of from 100:1 to 100:75, more particularly 10 to 60% based on the total dry weight of the particularly from 100:2.5 to 100:50, still more preferably polymer. from 100:2.5 to 100:30 and most preferably from 100:2.5 to 100:2O. 0079 The outer portion can also include a material that improves the processing of the release controlling agents. 0.072 In outer portion, micro matrix particles and coating Such materials are generally referred to as "plasticisers' and of one or more hydrophobic release controlling agents are include, for example, adipates, azelates, benzoates, citrates, preferably present in a ratio of from 100:0.5 to 100:75, more isoebucaes, phthalates, Sebacates, Stearates, tartrates, poly particularly from 100:2.5 to 100:50, still more preferably hydric alcohols and glycols. from 100:2.5 to 100:30 and most preferably from 100:2.5 to 100:2O. 0080 Representative plasticisers include acetylated monoglycerides, butyl phthalylbutyl gylcolate, dibutyl tar 0073. According to one embodiment the release control trate; diethyl phthalate; dimethyl phthalate, ethyl phthalyl ling agents are pharmaceutically excipients, which are ethyl glycolate, glycerin; ethylene glycol, propylene glycol, hydrophobic in nature. Triethyl citrate, triacetin; tripropinoin, diacetin, dibutyl phthalate; acetyl monoglyceride; polyethylene glycols, cas 0.074 The polymers that can be used to form the rate tor oil; triethyl citrate; polyhydric alcohols, acetate esters, controlling membrane or micromatrix are described in glycerol triacetate, acetyl triethylcitrate, dibenzyl phthalate, greater detail herein below. dihexyl phthalate, butyl octyl phthalate, disononyl phtha 0075. The hydrophobic release controlling agents are late, butyloctyl phthalate, dioctyl azelate, epoxidised tallate, Selected from but are not limited to Ammonio methacrylate triisoctyl trimellitate, diethyleXyl phthalate, di-n-octyl copolymers type A and B as described in USP, methacrylic phthalate, di-I-Octyl phthalate, di-I-decyl phthalate, di-n- acid copolymer type A, B and C as described in USP undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethyleXyl Polyacrylate dispersion 30% as described in Ph. Eur, Poly trimelitate, di-2-ethyleXyl adipate, di-2-ethylhexyl Seba Vinyl acetate dispersion, ethylcellulose, cellulose acetate, cate, di-2-ethylhexyl azelate, dibutyl Sebacate, glyceryl cellulose propionate (lower, medium or higher molecular monocaprylate, glycerol distearate and glyceryl monoca weight), cellulose acetate propionate, cellulose acetate prate. The amount of plasticiser to be used is from about 1% butyrate, cellulose acetate phthalate, cellulose triacetate, to 50% based on the weight of the dry release controlling poly(methyl methacrylate), poly(ethyl methacrylate), poly agent(s). The amount of release controlling agent(s) to be US 2006/0024365 A1 Feb. 2, 2006 used in forming the outer portion will be determined based portion and oblong shaped flat bottom beveled edges on various parameterS Such as the desired delivery proper punches for the compression of the Outer portion. ties, including the amount of active ingredient to be deliv ered, the active ingredient release rate desired, and the size BRIEF DESCRIPTION OF THE DRAWINGS of the micro matrix particles. 0086 FIG. 1 is a plan view of the dosage form described 0081. The novel dosage form of the present invention can in the present invention; be manufactured by the following procedure: 0087 FIG. 2 is an edge view of the dosage form 0082 Inner Portion described in the present invention; 0.083. The granules of the inner portion can be manufac 0088 FIG. 3 is a transverse section view as seen along tured in accordance with usual techniques in which the the line 3-3 of FIG. 1; active ingredient and other excipients are mixed and granu 0089 FIG. 4 (a) is a cross section of coated micro matrix lated by adding Solution of binder in a low or high Shear particles prepared by Spheronization and coating for the mixer or by fluidized bed granulation. The granulate is dried, purpose of illustration only. preferably in a fluidized bed dryer. The dried granulate is Sieved and mixed with lubricants and disintegrants. Alter 0090 FIG. 4 (b) is a cross section of coated micro matrix natively the manufacture of granules of inner portion can be particles prepared by granulation and coating for the purpose made by direct mixing of the directly compressible excipi of illustration only. ents or by roller compaction. 0091 FIG. 5 is a plot of% active ingredient versus time for immediate release and modified release active agent; B) Outer Portion 0092 FIG. 6 is a plot of% active ingredient versus time 0084. The micro matrix particles of the outer portion can for modified release active agent prepared using dual retard be manufactured in accordance with usual techniques in technique as described in the present invention and prepared which the active ingredient and one or more hydrophobic without retard release technique as per examples 1 and 3; release controlling agents are mixed and granulated by adding Solvent in a low or high shear mixer or by fluidized 0093 FIG. 7 is a plot of% active ingredient versus time bed granulator. The granulate is dried, preferably in a for modified release active agent prepared using dual retard fluidized bed dryer. The dried granulate is sized. The sizing technique as described in the present invention and prepared of the micromatrix particles can be done using oscillating without retard release technique as per examples 2 and 4. granulator, comminuting mill or any other conventional 0094 FIG. 8 is a plot of metformin plasma concentration method. The Sieve used for the Sizing can have openings versus time for test (a) and reference (b) formulation; from 0.25 mm to 5 mm. Alternatively the micro matrix particles can be made by extrusion, Spheronization or by 0095 FIG. 9 is a plot of rosiglitazone plasma concen roller compaction. The micro matrix particles can be coated tration versus time for test (a) and reference (b) formulation; by a Solution of one or more hydrophobic release controlling 0096 FIG. 10 is a plot of metformin plasma concentra agents by any known method, including Spray application. tion versus time for test (a and b) and reference (c) formu Spraying can be carried out using a fluidized bed coated lation; (preferably Wurster coating), or in a pan coating System. Alternatively the coating of the micro matrix particles with 0097 FIG. 11 is a plot of metformin plasma concentra one or more rate controlling agents can be done by hot melt tion versus time for test (a) and reference (b) formulation; process using a granulator or fluidized bed coated (prefer 0098 FIG. 12 is a plot of rosiglitazone plasma concen ably Wurster coating), or in a pan coating System. tration versus time for test (a) and reference (b) formulation; Tablet Compression 0099 Referring to FIGS. 1 to 3, a dosage form 4 as described in the present invention having an inner portion 1 0085. The compression of tablets is carried out on usual containing low dose active ingredient as immediate release press coaters (e.g. machines of the Manesty, Cadmach or and outer portion 2 containing high dose, high Solubility Kilian) with slight modification. The device such as feed active ingredient as modified release. FIG. 4(a)& 4(b) frame and hopperS making top layer are eliminated. The shows the croSS Section of the coated micro matrix particles granules of the inner layer are charged in the hopper of the 5 and having 6 a high dose, high Solubility active ingredient, machine compressing first layer and the granules of the outer 7 hydrophobic release controlling agent and 8 a coating of layer are charged in the hopper of the machine compressing hydrophobic release controlling agent. FIG. 5 shows the release profile of a low dose active ingredient as immediate the coating. On operation only the bottom layer of the release 9 and the release profile of a high solubility active coating (outer portion) is deposited into the die and the first ingredient as modified release 10. FIGS. 6 and 7 shows layer is placed on it. The compression wheels then embed release of high dose, high Solubility active agent 11 & 12 and the first layer in the granules of the outer layer, displacing 15 & 16 as per example 1 & 2 respectively from a dosage Some of latter to form Sides, and finally press the whole into form prepared using dual retard technique as described in the tablet. The resultant tablet has inner portion covered by the present invention and release of high dose, high Solu the Outer portion from all the Sides except top Surface that bility active agent 13 & 14 and 17 & 18 as per example 3 & remains uncovered and the level of the inner portion and the 4 respectively from a dosage form prepared without using outer portion is Same. The tablets can be made of various dual retard release technique. The total quantity of the sizes and shapes. The present invention uses round punch hydrophobic release controlling agent is Same in all the tooling with upper flat bottom punches and lower flat bottom dosage forms inspite of that the figures clearly shows that beveled edges lower punches for the compression of inner dual retard technology significantly reduces the burst effect US 2006/0024365 A1 Feb. 2, 2006 and effectively controls the release rate of the high dose, 0103) The dissolution of high dose high solubility ingre high Solubility active ingredient for prolonged period. dient of the formulation of the present invention is achieved not more than 45% in 1 hour and from 25 to 90% in six DESCRIPTION OF THE PREFERRED hours. EMBODIMENTS 0104. The dissolution of metformin hydrochloride is 0100. The following examples further illustrate but by no achieved not more than 50% in 1 hour, and from 30 to 90% means limit the present invention. is in four hours and not less than 65% in 12 hours. 0101 The dissolution of novel dosage form of the present 0105. After oral administration of a dosage form of the invention was determined by following method. present invention the maximum plasma concentration can be achieved between 700 ng/ml and 2500 ng/ml, preferably from 900 ng/ml to 2400 ng/ml and more preferably from For sodium valproate 1000 ng/ml to 2350 ng/ml. The in vivo mean dissolution time (MDT) of the dosage form of the present invention is Instrument Apparatus I, USP (basket) Revolution 60/min. 4 to 6 hours. The minimum plasma concentration (at 24 Temperature 37 - O.5. C. hours) of the said dosage form ranges between 0 to 450 Dissolution medium 1000 ml pH 6.8 buffer ng/ml after oral administration. For niacin Instrument Apparatus I, USP (Basket) EXAMPLES Revolution 100/min. Temperature 37 - O.5. C. Dissolution medium 900 m O.1 NHCI Example 1 For lamotrigine 0106 Production of Inner Portion Instrument Apparatus II, USP (Paddle) Revolution 100/min. 0107 11.71% w/w of pravastatin sodium is mixed with Temperature 37 - O.5. C. 52.62% w/w of lactose monohydrate and 22.22% w/w starch Dissolution medium 1OOO in O.OO1 NHCI and the mixture is granulated in a binder of 2.22 V povidone For pravastatin sodium in water and then dried. The granules are Sieved and mixed Instrument Apparatus II, USP (Paddle) with 1.11% W/w magnesium Stearate, 9.0 g Sodium Starch Revolution 100/min. Temperature 37 - O.5. C. glycolate, 0.11% w/w lake of Sunset yellow. This mixture is Dissolution medium 900 ml pH 6.8 buffer compressed to 90 mg weight tablets having a diameter of For metformin hydrochloride 6.35 mm. Instrument Apparatus II, USP (Paddle) Revolution 50/min. 2) Production of Outer Portion Temperature 37 - O.5. C. Dissolution medium 900 m O.1 NHCI 0108) A) Micro matrix particles-90.91% w/w of niacin is For rosiglitazone maleate mixed with 9.09% w/w of Eudragit RSPO (Ammonio Meth acrylate Copolymer type B USP) and the mixture is granu Instrument Apparatus II, USP (Paddle) Revolution 100/min. lated with a Solvent mixture of acetone and methylene Temperature 37 - O.5. C. chloride and then dried. The granules are sized. Dissolution medium SOO in O.O1 NHCI For glimepiride 0109 B) Coating of Micro matrix particles-85.84% W/w of micro matrix particles is charged in fluidized bed Instrument Apparatus II, USP (Paddle) Revolution 75/min. processor. 13.61% w/w of hydrogenated castor oil is dis Temperature 37 - O.5. C. Solved in acetone and this coating Solution is sprayed to coat Dissolution medium 500 ml 0.5% sodium lauryl the micro matrix particles. The coated micro matrix particles sulfate in water are sieved and mixed with 0.86% w/w magnesium Stearate. 3) Compression of Tablets 0102) The composition of outer portion in the dosage form comprising high dose high Solubility antidiabetic 0110 Tablet (A)-90 mg granules of inner portion are active ingredient is as follows pressed to tablets (equal to 10 mg pravastatin) using 6.35 mm round punches and 643 mg granules of Outer portion (equal to 500 mg niacin) are compressed using 14.95x8.35 mm oblong punches. Tablet (B)-90 mg granules of inner Micro matrix particles portion are pressed to tablets (equal to 10 mg pravastatin) Metformin hydrochloride 75% w/w to 99% w/w using 6.35 mm round punches and 1286 mg granules of Eudragit RS 1% w/w to 25% w/w outer portion (equal to 1000 mg niacin) are compressed Coated micro matrix particles using 20.3x9.8 mm oblong punches. The compression is Micro matrix particles done on press coater machine in Such a manner that the Hydrogenated castor oil resultant tablet has inner portion covered by the outer Magnesium stearate portion from all the Sides except top Surface that remains uncovered and the level of the inner portion and the outer portion is on the same Surface. US 2006/0024365 A1 Feb. 2, 2006 17

0111. The dissolution rate of the novel dosage form was 0116 Compression of Tablets determined (Table 1 and 2) 0117 Tablet (A)-65 mg granules of inner portion are pressed to tablets (equal to 25 mg lamotrigine) using 5.55 TABLE 1. mm round punches and 643 mg granules of Outer portion (equal to 500 mg Sodium valproate) are compressed using Dissolution profile of tablet (A 14.95x8.35 mm oblong punches. Niacin Pravastatin sodium 0118 Tablet (B)-65 mg granules of inner portion are pressed to tablets (equal to 25 mg lamotrigine) using 5.55 Time Time mm round punches and 1286 mg granules of Outer portion (hour) % Released (min) % Released (equal to 1000 mg Sodium valproate) are compressed using 1. 12.4 45 83.8 20.3x9.8 mm oblong punches. The compression procedure 2 19.1 60 84.1 4 29.4 is Same as Example 1. The dissolution rate of the novel 6 37.4 dosage form was determined (Table 3 and 4) 8 41.9 1O 47.1 TABLE 3 12 50.6 14 54.6 Dissolution profile of tablet (A 24 67.7 Sodium valproate Lamotrigine Time Time 0112 (hour) % Released (min) % Released TABLE 2 1. 23.3 15 83.5 2 36.3 3O 88.6 Dissolution profile of tablet (B 4 55.1 45 91.6 6 67.5 60 92.8 Niacin Pravastatin sodium 8 77.0 1O 83.8 Time Time 12 88.9 (hour) % Released (min) % Released 14 92.5 24 104.6 1. 9.8 45 84.1 2 15.3 60 85.6 4 24.7 6 28.7 0119) 8 31.4 1O 35.7 TABLE 4 12 39.1 14 41.9 Dissolution profile of tablet (B 24 515 Sodium valproate Lamotrigine Time Time Example 2 (hour) % Released (min) % Released 1) Production of Inner Portion 1. 19.O 15 90.3 2 29.5 3O 95.6 0113 38.47% w/w of lamotrigine is mixed with 2.71% 4 45.2 45 98.3 w/w of crosspovidone and 0.18% w/w colloidal silicon 6 55.9 dioxide and the mixture is granulated in a binder of 0.71% 8 65.O 1O 71.9 W/w povidone in water and then dried. The granules are 12 77.8 sieved and mixed with 28.70% w/w of Mannitol (Pearlitol 14 82.4 SD 200 R.T.M.), 12.31% w/w of crosspovidone, 2.31% w/w 24 95.8 of magnesium stearate, 6.15% w/w aspartame, 2.31% w/w talc, 5.0% w/w flavour and 1.15% w/w of colloidal silicon dioxide. This mixture is compressed to 65 mg weight tablets 0120 Dosage forms described in the examples 3 and 4 having a diameter of 5.55 mm. are prepared by not coating the micro matrix particles of the outer portion but the hydrophobic release controlling agent 2) Production of Outer Portion is mixed with the micro matrix particles. The Sole purpose 0114 A) Micro matrix particles-90.91% w/w of sodium of these examples is to demonstrate the usefulness of the valproate is mixed with 9.09% w/w of Eudragit RSPO present invention as described earlier. The examples clearly (Ammonio Methacrylate Copolymer type B USP) and the show that the rate of release of the modified release active mixture is granulated with a Solvent mixture of acetone and ingredient is significantly faster than the present invention. methylene chloride and then dried. The granules are sized. Example 3 0115 B) Coating of Micro matrix particles-85.84% 0121 Production of Inner Portion W/w of micro matrix particles is charged in fluidized bed Same as for Example 1 processor. 13.61% w/w of hydrogenated castor oil is dis Solved in acetone and this coating Solution is sprayed to coat 0122) Production of Outer Portion the micro matrix particles. The coated micro matrix particles 0123) 77.76% w/w of niacin is mixed with 7.78% w/w of are sieved and mixed with 0.86% w/w magnesium Stearate. Eudragit RSPO (Ammonio Methacrylate Copolymer type B US 2006/0024365 A1 Feb. 2, 2006

USP) and the mixture is granulated with a solvent mixture 0131 The dissolution rate of the novel dosage form was of acetone and methylene chloride and then dried. The determined (Table 7 and 8) granules are sized and mixed with 13.61% w/w of hydro genated castor oil and 0.86% W/w of magnesium Stearate. TABLE 7 Compression of Tablets Dissolution profile of tablet (A 0124 Tablet (A)-Same as for Example 1 Sodium valproate Lamotrigine 0125 Tablet (B)-Same as for Example 1 Time Time 0.126 The dissolution rate of the novel dosage form was (hour) % Released (min) % Released determined (Table 5 and 6) 1. 58.3 15 81.8 2 79.9 3O 89.8 4 98.5 45 91.7 TABLE 5 6 101.6 60 97.4 Dissolution profile of tablet (A Niacin Pravastatin sodium 0132) Time Time (hour) % Released (min) % Released TABLE 8 1. 30.1 45 75.9 Dissolution profile of tablet (B 2 43.6 60 80.9 4 61.6 Sodium valproate Lamotrigine 6 74.1 8 83.9 Time Time 1O 92.1 (hour) % Released (min) % Released 12 99.4 24 102.6 1. 50.2 15 86.1 2 69.1 3O 87.3 4 91.O 45 92.6 6 101.3 60 98.3 O127) TABLE 6 Example 5 Dissolution profile of tablet (B 0133) 1) Production of Inner Portion 5.89% w/w of rosiglitazone maleate is mixed with 55.89% w/w of lactose Niacin Pravastatin sodium monohydrate and 22.22% w/w starch and the mixture is Time Time granulated in a binder of 2.78% w/w povidone and 2.78% (hour) % Released (min) % Released W/w Starch in water and then dried. The granules are Sieved 1. 29.9 45 89.6 and mixed with 0.28% w/w magnesium stearate, 10.00% 2 36.3 60 90.0 w/w sodium starch glycolate, 0.17% w/w ferric oxide yel 4 52.8 low. This mixture is compressed to 90 mg weight tablets 6 63.4 8 73.5 having a diameter of 6.35 mm. 1O 77.8 12 84.5 2) Production of Outer Portion 24 90.5 0134) A) Micro matrix particles-90.91% w/w of met formin hydrochloride is mixed with 9.09% w/w of Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and the mixture is granulated with a Solvent mixture of acetone Example 4 and methylene chloride and then dried. The granules are 1) Production of Inner Portion sized. 0135 B) Coating of Micro matrix particles-85.54% w/w Same as for Example 2 of micro matrix particles is charged in fluidized bed pro 2) Production of Outer Portion cessor. 13.61% w/w of hydrogenated castor oil is dissolved in acetone and this coating Solution is sprayed to coat the 0128) 77.76% w/w of sodium valproate is mixed with micro matrix particles. The coated micro matrix particles are 7.78% w/w of Eudragit RSPO (Ammonio Methacrylate Copolymer type B USP) and the mixture is granulated with sieved and mixed with 0.86% w/w magnesium stearate. a Solvent mixture of acetone and methylene chloride and 3) Compression of Tablets then dried. The granules are sized and mixed with 13.61% 0136 Tablet (A)-90 mg granules of inner portion are w/w of hydrogenated castor oil and 0.86% w/w of magne pressed to tablets (equal to 4 mg rosiglitazone) using 6.35 sium Stearate. mm round punches and 643 mg granules of Outer portion 3) Compression of Tablets (equal to 500 mg metformin hydrochloride) are compressed using 14.95x8.35 mm oblong punches. 0129. Tablet (A)-Same as for Example 2 0137 Tablet (B)-90 mg granules of inner portion are 0130 Tablet (B)-Same as for Example 2 pressed to tablets (equal to 4 mg rosiglitazone) using 6.35 US 2006/0024365 A1 Feb. 2, 2006 mm round punches and 1286 mg granules of outer portion chloride) are compressed using 20.3x9.8 mm oval punches. (equal to 1000 mg metformin hydrochloride) are com The compression procedure is Same as Example 5. pressed using 20.3x9.8 mm oblong punches. 0146 The dissolution rate of the novel dosage form was 0.138. The compression is done on press coater machine determined (Table 11) in Such a manner that the resultant tablet has inner portion covered by the outer portion from all the Sides except top TABLE 11 Surface that remains uncovered and the level of the inner portion and the outer portion is on the Same Surface. Dissolution profile 0.139. The dissolution rate of the novel dosage form was Metformin Rosiglitazone determined (Table 9 and 10) Hydrochloride Maleate Time Time TABLE 9 (hour) % Released (min) % Released Dissolution profile of tablet (A 1. 32.10 15 75.63 2 41.65 3O 88.35 Metformin hydrochloride Rosiglitazone 4 59.05 45 103.49 6 63.90 60 105.7O Time (hour) % Released Time (min) % Released 8 73.63 1O 79.35 1. 42.5 15 8488 12 84.21 2 58.0 3O 99.02 24 94.91 4 74.09 45 101.26 6 86.1 60 104.4 8 97.8 1O 101.9 12 103.7 Example 7 0147 Production of Inner Portion 0140 Same as for Example 5 TABLE 10 0148 Production of Outer Portion 0149 Micro Matrix Particles Dissolution profile of tablet (B 0150 Same as for Example 5 Metformin hydrochloride Rosiglitazone 0151 B) Coating of Micro matrix particles-89.36% w/w Time (hour) % Released Time (min) % Released of micro matrix particles is charged in fluidized bed pro 38.2 45 96.79 cessor. 10.15% w/w of glycerol distearate type 1 Ph. Eur. 53.4 60 99.32 (Precirol ATO 5 R.T.M.) is dissolved in acetone and this 69.5 coating Solution is sprayed to coat the micro matrix particles. 78.1 The coated micro matrix particles are Sieved and mixed with 86.8 0.49% w/w magnesium stearate. 93.6 97.65 0152 Compression of Tablets 0153 90 mg granule of inner portion are pressed to tablets (equal to 4 mg rosiglitazone maleate) using 6.35 mm Example 6 round punches and 1231 mg granules of outer portion (equal to 1000 mg metformin hydrochloride) are compressed using 0141 Production of Inner Portion 20.3x9.8 mm oval punches. The compression procedure is Same as for Example 5 Same as Example 5. The dissolution rate of the novel dosage 0142 Production of Outer Portion form was determined (Table 12) 0143 A) Micro matrix particles-86.96% w/w of met TABLE 12 formin hydrochloride is mixed with 13.07% w/w of Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and Dissolution profile the mixture is granulated with a Solvent mixture of acetone Metformin Rosiglitazone and methylene chloride and then dried. The granules are Hydrochloride Maleate sized. Time Time 0144 B) Coating of Micro matrix particles-86.40% (hour) % Released (min) % Released W/w of micro matrix particles is charged in fluidized bed 1. 39.9 15 78.32 processor. 13.15% w/w of hydrogenated castor oil is dis 2 51.7 3O 89.15 Solved in acetone and this coating Solution is sprayed to coat 4 69.2 45 97.13 the micro matrix particles. The coated micro matrix particles 6 82.5 60 100.57 are sieved and mixed with 0.45% w/w magnesium Stearate. 8 83.8 1O 91.2 0145 Compression of tablets 90 mg granule of inner 12 94.9 portion are pressed to tablets (equivalent to 4 mg roSiglita 24 99.8 Zone) using 6.35 mm round punches and 1331 mg granules of outer portion (equivalent to 1000 mg metformin hydro US 2006/0024365 A1 Feb. 2, 2006

Example 8 0164. 12.61% w/w of hydrogenated castor oil is dis Solved in acetone and this coating Solution is sprayed to coat 0154) Production of Inner Portion the micro matrix particles. The coated micro matrix particles O155 2.94% w/w of rosiglitazone maleate is mixed with are sieved and mixed with 0.91% w/w magnesium Stearate. 87.80% w/w of Mannitol (Pearlitol SD 200 R.T.M.), 6.67% W/w of crosspoVidone, 2.0% W/w of magnesium Stearate, Compression of Tablets 0.56% w/w of colloidal Silicon dioxide and 0.03% w/w 0.165 90 mg granule of inner portion are pressed to ferric oxide red. This mixture is compressed to 90 mg weight tablets (equal to 1 mg glimepiride) using 6.35 mm round tablets having a diameter of 6.35 mm. punches and 694 mg granules of outer portion (equal to 500 Production of Outer Portion mg metformin hydrochloride) are compressed using 14.95x 8.35 mm oblong punches. The compression procedure is 0156 Same as of Example 5. Same as Example 5. O157 Compression of tablets 90 mg granule of inner 0166 The dissolution rate of the novel dosage form was portion are pressed to tablets (equal to 2 mg rosiglitaZone determined maleate) using 6.35 mm round punches and 1281 mg granule of outer portion (equal to 1000 mg metformin TABLE 1.4 hydrochoride) are compressed using 20.3x9.8 mm oval punches. The compression procedure is Same as Example 5. Dissolution profile Metformin 0158. The dissolution rate of the novel dosage form was Hydrochloride Glimepiride determined Time Time TABLE 13 (hour) % Released (min) % Released 1. 28.0 15 69.4 Dissolution profile 2 40.5 3O 91.87 Metformin Rosiglitazone 4 57.8 45 99.64 Hydrochloride Maleate 6 65.8 60 103.87 8 73.2 Time Time 1O 80.3 (hour) % Released (min) % Released 12 85.O 24 101.8 1. 38.29 15 80.2 2 53.40 3O 96.1 4 69.51 45 103.4 6 78.11 8 86.86 Example 10 1O 93.60 12 97.65 1) Production of Inner Portion 24 100.17 Same as for Example 5 2) Production of Outer Portion Example 9 0167 Micro Matrix Particles 0159) Production of Inner Portion 0168 Same as for Example 5 0160) 1.11% w/w of glimepiride is mixed with 63.28% w/w of lactose monohydrate and 22.22% w/w starch and the 0169 B) Coating of Micro matrix particles-91.21% mixture is granulated in a binder of 2.22% w/w povidone in w/w of micro matrix particles and 8.29% w/w of hydroge water and then dried. The granules are Sieved and mixed nated castor oil is mixed and charged in planetary mixer with 1.11% w/w magnesium stearate, 10.0% w/w sodium which is heated from outside to maintain the temperature starch glycolate, 0.06% w/w lake of brilliant blue. This approximately 80 C. with the help of a water bath. The mixture is compressed to 90 mg weight tablets having a above blend is mixed by running the planetary mixer for 1 diameter of 6.35 mm. hour to coat the micro matrix particles. The coated micro matrix particles are sieved and mixed with 0.50% w/w 0161 Production of Outer Portion magnesium Stearate. 0162 A) Micro matrix particle-83.33% w/w of met formin hydrochloride is mixed with 16.67% w/w of Eudragit 3) Compression of Tablets RS (Ammonio Methacrylate Copolymer type B USP) and 0170 90 mg granule of inner portion are pressed to the mixture is granulated with a Solvent mixture of acetone tablets (equal to 4 mg rosiglitazone maleate) using 6.35 mm and methylene chloride and then dried. The granules are round punches and 1206 mg granules of outer portion (equal sized. to 1000 mg metformin hydrochloride) are compressed using 0163 Coating of Micro matrix particles-86.46% w/w of 20.3x9.8 mm oval punches. The compression procedure is micro matrix particles is charged in fluidized bed processor. Same as Example 5. US 2006/0024365 A1 Feb. 2, 2006

0171 The dissolution rate of the novel dosage form was 0175) determined TABLE 1.7 TABLE 1.5 Dissolution profile of tablet (B Dissolution profile Metformin Metformin Rosiglitazone hydrochloride Rosiglitazone Hydrochloride Maleate Time Time Time Time (hour) % Released (min) % Released (hour) % Released (min) % Released 1. 50.3 15 99.22 1. 25.7 3O 85.9 2 70.5 3O 105.26 2 36.6 45 100.3 4 88.0 45 107.53 4 49.1 60 104.9 6 100.9 60 107.53 6 57.5 8 66.5 1O 71.3 12 76.O Example 12 14 90.7 0176) Production of Inner Portion 0172 Dosage forms described in the example 11 are Same as for Example 7. prepared by not coating the micro matrix particles of the outer portion but the hydrophobic release controlling agent 0177 Production of Outer Portion is mixed with the micro matrix particles. The Sole purpose 0.178 A) Micro matrix particles-93.02% w/w of met of these examples is to demonstrate the usefulness of the formin hydrochloride is mixed with 6.98% w/w of Eudragit present invention as described earlier. The examples clearly RS (Ammonio Methacrylate Copolymer type B USP) and show that the rate of release of the modified release active the mixture is granulated with a Solvent mixutre of acetone ingredient is significantly faster than the present invention. and methylene chloride and then dried. The granules are sized. Example 11 0179 B) Coating of Micro matrix particles-85.18% 1) Production of Inner Portion W/w of micro matrix particles is charged in fluidized bed processor. 13.87% w/w of hydrogenated castor oil is dis Same as for Example 5 Solved in acetone and this coating Solution is sprayed to coat 2) Production of Outer Portion the micro matrix particles. The coated micro matrix particles are sieved and mixed with 0.95% w/w magnesium Stearate. 0173) 77.76% w/w of metformin hydrochloride is mixed with 7.780% w/w of Eudragit RS (Ammonio Methacrylate 3) Compression of Tablets Copolymer type B USP) and the mixture is granulated with a Solvent mixture of acetone and methylene chloride and 0180 90 mg granule of inner portion are pressed to then dried. The granules are sized and mixed with 13.61% tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round w/w of hydrogenated castor oil and 0.86% w/w of magne punches and 1262 mg granules of outer portion (equal to sium Stearate. 1000 mg metformin hydrochloride) are compressed using 20.3x9.8 mm oblong punches. The compression procedure 3) Compression of Tablets is Same as Example 5. Tablet (A)-Same as for Example 5 0181. The dissolution rate of the novel dosage form was Tablet (B)-Same as for Example 5 determined 0.174. The dissolution rate of the novel dosage form was TABLE 1.8 determined (Table 16 and 17) Dissolution profile TABLE 16 Metformin Hydrochloride Rosiglitazone Dissolution profile of tablet (A Time Time Metformin (hour) % Released (min) % Released hydrochloride Rosiglitazone 1. 40.9 45 89.68 Time Time 2 52.2 60 91.42 (hour) % Released (min) % Released 4 68.4 6 79.2 1. 63.9 15 100.08 8 88.6 2 85.5 3O 106.41 1O 99.9 4 102.1 45 109.77 12 101.5 US 2006/0024365 A1 Feb. 2, 2006 22

Example 13 0193 The dissolution rate of the novel dosage form was determined (Table 20) 0182 Production of Inner Portion Same as for Example 7. TABLE 2.0 0183 Production of Outer Portion Dissolution profile A) Micro matrix particles-Same as for Example 12. Metformin Hydrochloride RosiglitaZOne Time Time 0184 B) Coating of Micro matrix particles-88.70% w/w (hour) % Released (min) % Released of micro matrix particles is charged in fluidized bed pro 1. 42.40 45 86.05 cessor. 10.31% w/w of hydrogenated castor oil is dissolved 2 58.1 60 90.73 in acetone and this coating Solution is sprayed to coat the 4 75.9 micro matrix particles. The coated micro matrix particles are 6 86.5 8 94.5 sieved and mixed with 0.99% w/w magnesium stearate. 1O 99.0 Compression of Tablets 0185. 90 mg granule of inner portion are pressed to tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round Example 15 punches and 1212 mg granules of outer portion (equal to 1000 mg metformin hydrochloride) are compressed using 0194 Production of Inner Portion 20.3x9.8 mm oblong punches. The compression procedure Same as for Example 7. is Same as Example 5. 0195 Production of Outer Portion 0186 The dissolution rate of the novel dosage form was 0196) A) Micro matrix particles-90.91% w/w of met determined (Table 19) formin hydrochloride is mixed with 4.55% w/w of Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and TABLE 1.9 4.55% w/w of Eudragit RL (Ammonio Methacrylate Dissolution profile Copolymer type A USP) and the mixture is granulated with a Solvent mixture of acetone and methylene chloride and Metformin Hydrochloride Rosiglitazone then dried. The granules are sized. Time Time 0.197 B) Coating of Micro matrix particles-85.47% (hour) % Released (min) % Released W/w of micro matrix particles is charged in fluidized bed 1. 44.50 15 79.9 processor. 13.60% w/w of hydrogenated castor oil is dis 2 58.90 3O 89.9 Solved in acetone and this coating Solution is sprayed to coat 4 76.90 45 95.8 6 91.40 60 100.6 the micro matrix particles. The coated micro matrix particles 8 102.40 are sieved and mixed with 0.93% w/w magnesium Stearate. 0198 Compression of Tablets 0199 90 mg granule of inner portion are pressed to Example 14 tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round 0187 Production of Inner Portion punches and 1287 mg granules of outer portion (equal to 1000 mg metformin hydrochloride) are compressed using Same as for Example 11. 20.3x9.8 mm oblong punches. The compression procedure is Same as Example 5. 0188 Production of Outer Portion 0189 A) Micro matrix particles-Same as for Example 0200. The dissolution rate of the novel dosage form was 12. determined (Table 21) 0190 B) Coating of Micro matrix particles-90.56% w/w TABLE 21 of micro matrix particles is charged in fluidized bed pro Dissolution profile cessor. 8.42% w/w of hydrogenated castor oil is dissolved in acetone and this coating Solution is sprayed to coat the micro Metformin Hydrochloride Rosiglitazone matrix particles. The coated micro matrix particles are Time Time sieved and mixed with 1.01% w/w magnesium stearate. (hour) % Released (min) % Released 0191 Compression of Tablets 1. 34.8 45 92.65 2 48.3 60 97.02 0.192 90 mg granule of inner portion are pressed to 4 66.2 tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round 6 79.3 8 85.9 punches and 1187 mg granules of Outer portion (equal to 1O 92.6 1000 mg metformin hydrochloride) are compressed using 12 97.6 20.3x9.8 mm oblong punches. The compression procedure is Same as Example 5. US 2006/0024365 A1 Feb. 2, 2006 23

Example 16 0211 The dissolution rate of the novel dosage form was 0201 Production of Inner Portion determined (Table 23) Same as for Example 7. TABLE 23 0202) Production of Outer Portion Dissolution profile 0203 A) Micro matrix particles-Same as for Example Metformin Hydrochloride Rosiglitazone 15. Time Time 0204 B) Coating of Micro matrix particles-94.66% w/w (hour) % Released (min) % Released of micro matrix particles is charged in fluidized bed pro 1. 35.O 15 69.2 cessor. 4.30% w/w of hydrogenated castor oil is dissolved in 2 47.3 3O 79.5 acetone and this coating Solution is sprayed to coat the micro 4 60.8 45 85.7 matrix particles. The coated micro matrix particles are 6 72.5 60 90.4 sieved and mixed with 1.03% w/w magnesium stearate. 8 81.8 1O 89.2 0205 Compression of Tablets 12 94.1 24 98.2 0206 90 mg granule of inner portion are pressed to tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round punches and 1162 mg granules of Outer portion (equal to 1000 mg metformin hydrochloride) are compressed using Example 18 20.3x9.8 mm oblong punches. The compression procedure is Same as Example 5. 1) Production of Inner Portion 0207. The dissolution rate of the novel dosage form was Same as for Example 7. determined (Table 22) 2) Production of Outer Portion TABLE 22 0212 A) Micro matrix particles-Same as for Example Dissolution profile 5. Metformin Hydrochloride Rosiglitazone 0213 B) Coating of Micro matrix particles-87.09% w/w of micro matrix particles is charged in fluidized bed pro Time Time (hour) % Released (min) % Released cessor. 11.88% w/w of hydrogenated castor oil is dissolved in acetone and this coating Solution is sprayed to coat the 1. 47.56 45 92.94 2 61.93 60 96.70 micro matrix particles. The coated micro matrix particles are 4 82.42 sieved and mixed with 1.03% w/w magnesium stearate. 6 96.O 8 1OO.O 3) Compression of Tablets 0214) 90 mg granule of inner portion are pressed to tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round Example 17 punches and 1263 mg granules of outer portion (equal to 1) Production of Inner Portion 1000 mg metformin hydrochloride) are compressed using 20.3x9.8 mm oblong punches. The compression procedure Same as for Example 7. is Same as Example 5. 2) Production of Outer Portion 0215. The dissolution rate of the novel dosage form was 0208 A) Micro matrix particles-Same as for Example determined (Table 24) 5. 0209 B) Coating of Micro matrix particles-88.92% w/w TABLE 24 of micro matrix particles is charged in fluidized bed pro Dissolution profile cessor. 10.11% w/w of hydrogenated castor oil is dissolved in acetone and this coating Solution is sprayed to coat the Metformin Hydrochloride Rosiglitazone micro matrix particles. The coated micro matrix particles are Time Time sieved and mixed with 0.97% w/w magnesium stearate. (hour) % Released (min) % Released 3) Compression of Tablets 1. 38.7 3O 78.66 2 52.9 45 8347 0210 90 mg granule of inner portion are pressed to 4 71.6 60 88.06 tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round 6 82.3 8 91.3 punches and 1237 mg granules of outer portion (equal to 1O 97.3 1000 mg metformin hydrochloride) are compressed using 12 101.1 20.3x9.8 mm oblong punches. The compression procedure is Same as Example 5. US 2006/0024365 A1 Feb. 2, 2006 24

Example 19 Criteria for Inclusion: 0216) Production of Inner Portion 0224 Healthy male volunteers aged between 18 to 45 0217 2.22% w/w of glimepiride is mixed with 62.17% yearS. w/w of lactose monohydrate and 22.22% w/w starch and the mixture is granulated in a binder of 2.22% w/w povidone in Test Formulation, Dose and Mode of Administration: water and then dried. The granules are Sieved and mixed 0225 Test Formulation: 4 mg/1000 mg Rosiglitazone/ with 0.56% w/w magnesium stearate, 10.0% w/w sodium Metformin SR prepared as per the invention disclosed in the starch glycolate, 0.06% w/w lake of erythrocine and 0.56% examples. w/w colloidal silicon dioxide. This mixture is compressed to 90 mg weight tablets having a diameter of 6.35 mm. 0226 Volunteers received a single oral dose of above Production of outer portion-Same as for example 18. products with 200 ml of water following high calorie diet Compression of tablets 90 mg granule of inner portion are (-800 Kcal). pressed to tablets (equal to 2 mg glimepiride) using 6.35 mm round punches and 1263 mg granules of outer portion (equal Reference Product, Dose and Mode of Administration: to 1000 mg metformin hydrochloride) are compressed using 0227 Reference: Immediate release 4 mg Enselin plus 20.3x9.8 mm oblong punches. The compression procedure Glycomate' (2x500 mg) is same as Example 5. The dissolution rate of the novel 0228 Volunteers received a single oral dose of above dosage form was determined (Table 25) products with 200 ml of water following high calorie diet TABLE 25 (-800 Kcal). Pharmacokinetics: Dissolution profile 0229. The following Pharmacokinetic parameters were Metformin Hydrochloride Glimepiride calculated using non compartments methods: the area under Time Time the drug plasma concentration curve from time of dosing to (hour) % Released (min) % Released the time of last sampling point (AUCo.); the area under the 1. 38.79 45 1OO.7 drug plasma concentration verSuS time curve extrapolated to 2 54.12 60 102.2 infinity (AUC of ); the maximum measured concentra 4 69.54 tion of the drug in the plasma (C) and the time at which 6 82.04 this concentration was measured (ts); the concentration at 8 89.78 24 hours (C); the time taken for drug plasma concentra 1O 95.06 tion to decrease by 50% (t); and the terminal first-order 12 100.48 elimination rate constant (K). 0230 Area Under the curve (AUC) is the integral part of Example 20 drug blood level over time from zero to infinity and is a 0218 Determination of relative bioavailability of Met measure of quantity of drug absorbed and in the body. formin Sustained release formulation with respect to met 0231 AUC (0-t) represents area under the curve from formin immediate release tablet. Zero to time t, where t represents the time at which last blood 0219. The study was carried out to demonstrate the Sample was taken. Sustained release characteristic of metformin in the combi 0232 AUC (0-) represents area under the curve from nation formulation and to evaluate the relative bioavailabil Zero to infinity. ity of combination formulation of Sustained release Met formin hydrochloride and RosiglitaZone maleate verSuS 0233 Elimination half life of a drug is the time in hours metformin immediate release tablet 2x500 mg (marketed as necessary to reduce the drug concentration in the blood, Glycomet? by USV Ltd.; India.) and rosiglitazone immedi plasma or Serum to /2 after equilibrium is reached. ate release tablets 4 mg (marketed as Enselin'? by Torrent pharma Ltd., India.). 0234 C is the peak plasma concentration achieved Methodology: after the administration of the drug. 0235 T is the time to reach peak plasma concentra 0220. The biostudy had an open label, randomized two tion. period, two treatment, two way Single dose croSSOver Study with 7 days washout period between treatment days. Statistical Methods: 0221 Non-compartmental Pharmacokinetic assessment 0236. Descriptive statistics of relevant Pharmacokinetic was based on the plasma levels of Metformin and Rosigli parameters were performed. An analysis of variance taZone measured by blood Sampling. Blood Samples were obtained before dosing and at the following times after (ANOVA) was used to assess treatment differences. administration of test and reference formulations, 0237 Methods used for analysis of Metformin and RosiglitaZone in plasma Samples: 0222 Pre-dose, 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 15.0, 18.0, and 24.0 hours. Analysis of Metformin Number of Subjects and Study Population: 0238 Estimation of Metformin in plasma samples was 0223 Twelve (12) volunteers were enrolled and all of carried out by High Performance Liquid Chromatography them completed the study. All 12 volunteers were included and UV detection at 234 nm. Briefly 0.5 ml of plasma in the Pharmacokinetic and Safety analyses. Sample was precipitated with 2.0 ml acetonitrile. Samples US 2006/0024365 A1 Feb. 2, 2006 25 were centrifuged and Supernatant aliquot was washed with 0245 Non-compartmental Pharmacokinetic assessment dichloromethane. After centrifugation, aqueous layer was was based on the plasma levels of metformin measured by injected on HPLC. blood Sampling. Blood Samples were obtained before dosing Analysis of RosiglitaZone: and at the following times after administration of test and reference formulations, 0239 Estimation of Rosiglitazone in plasma samples was carried out by LC-MS/MS. Briefly 0.1 ml of plasma sample 0246 Pre-dose, 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, was precipitated with 0.25 ml acetonitrile. Samples were 6.0, 8.0, 10.0, 12.0, 15.0, and 24.0 hours. centrifuged and Supernatant aliquot was analyzed by LC Number of Subjects and Study Population: MS/MS. 0247 Twelve (12) volunteers were enrolled and 11 of Pharmacokinetic Results: them completed the study. All 12 volunteers were included 0240 The summary of the statistical analysis and confi in the Pharmacokinetic and Safety analyses. dence intervals of the Pharmacokinetic parameters is con Criteria for Inclusion: tained in Tables 26 & 27. The mean plasma concentration versus time curve is depicted in FIG. 8 (metformin) & FIG. 0248 Healthy male volunteers aged between 18 to 45 9 (rosiglitazone) wherein curve a represents Test Formula yearS. tion and curve b represents Reference Formulation. Test product, Dose and Mode of Administration: TABLE 26 0249 Formulation A: 4 mg/1000 mg Rosiglitazone/Met formin dosage form prepared as per the invention disclosed Bioavailability Summary and Analysis - Metformin SR in the examples. Formulation B: 4 mg/1000 mg Rosiglita AUCo if ng hr 15980 - 3456 19551 - 4265 Zone/Metformin SR dosage form prepared as per the inven AUCo ng hr 1.4983 - 2930 19091 - 42OO tion disclosed in the examples. Cmax ng/ml 1737.61 - 249.09 2558.37 - 623.05 C24h ng/ml 113.87 - 91.05 56.44 + 37.94 0250 In the morning, volunteers received a single oral Tmax hir 5.42 + 0.68 4.42 + 0.88 dose of above products with 200 ml of water following high T12 hir 4.71 - 1.36 4.26 + 1.14 calorie diet (-800 Kcal). Reference Product, Dose and Mode of Administration: 0241) 0251) Formulation C: Immediate release 4 mg Enselin' TABLE 27 plus Glycomate' (2x500 mg) Bioavailability Summary and Analysis - 0252) In the morning, volunteers received a single oral dose of above products with 200 ml of water following high AUCo. if ng hr/ml 1851 + 414 1730 - 465 AUCo ng * hr/ml 1795 - 4O1 1676 - 438 calorie diet (-800 Kcal) Cmax ng/ml 243.48 - 40.78 247.48 + 45.38 Pharmacokinetics: C24h ng/ml 6.36 + 5.19 3.37 - 4.36 Tmax hir 3.75 - 1.03 3.25 + 1.66 0253) Same as for example 20. t1/2 hir 3.73 - 0.60 3.63 - 0.79 Statistical Methods: Conclusion: 0254 Same as for example 20. 0242 Metformin in test formulation has shown sustained Methods used for analysis of Metformin and Rosiglitazone release characteristics with lower C and prolonged ta. in plasma Samples: (Figure 8). The relative bioavailability of both the compo nents was Studied. Same as for example 20. Example 21 Pharmacokinetic Results: Determination of Relative Bioavailability of Two Formula 0255 The summary of the statistical analysis and confi tions with Different Release Profiles: dence intervals of the Pharmacokinetic parameters is con 0243 A biostudy was carried out with the preliminary tained in objective of comparing the relative bioavailability of the 1000 mg metformin sustained release formulations (A & B) TABLE 28 relative to immediate release metformin tablets 2x500 mg The mean plasma concentration versus time curve is (marketed as Glycomet' by USV Ltd.; India.). A secondary depicted in FIG. 10. wherein curve a represents Formulation A, objective was to characterize the plasma concentration pro curve b represents Formulation B and curve c represents the file of metformin in the Sustained release formulation rela Formulation C. tive to immediate release formulation i.e. Glycomet' 2x500 AUC if ng hr/m 16508+ 17762- 15985 mg tablets. AUCo. ng * hr/m 15899+ 14989- 15558 Cmax ng/ml 1801.72- 1551.01-- 2121.96 Methodology: C24h ng/ml 79.58- 2O4.96- 45.48+ Tmax Hr 5.36 + 0.51 5.46 + 0.78 4.00 + 0.74 0244. The biostudy had an open label, randomized, three T12 Hr 4.08 + 1.32 7.23 + 3.45 4.61 + 1.54 periods, three treatment, three way, Single dose croSSOver design with 7 days washout period between treatment dayS. US 2006/0024365 A1 Feb. 2, 2006 26

Conclusion: Both the formulations according to the inven Statistical Methods: tion tested had reduced C. compared to that of the 0264. Descriptive statistics of relevant Pharmacokinetic reference product (Glycomet tablets), with Formulation B parameters were performed. An analysis of variance being Significantly reduced. The t of both the formula tions according to invention were prolonged relative to that (ANOVA) was used to assess treatment differences. of Glycomet” tablets. The concentration at 24 hours (Cal.) 0265 Westlake's 90% confidence interval for the ratio of of Formulation B was almost 4.5 times higher than Gly two formulations for log transformed data were calculated, comet tablets and almost 2.6 times higher than Formulation and to test that the difference between two formulations are A. within the (80 to 125%) limits. Methods used for analysis of Metformin and Rosiglitazone Example 22 in plasma Samples: Determination of Relative Bioavailability of Metformin Same as for example 20. Sustained Release Formulations Pharmacokinetic Results: 0256 The study was carried out to assess the effect of 0266 The summary of the statistical analysis and confi night time administration and to evaluate the relative bio dence intervals of the Pharmacokinetic parameters is con availability of combination formulation of Sustained release tained in Table 29 & 30. The mean plasma concentration Metformin and RosiglitaZone (prepared as per the invention versus time curve is depicted in FIG. 11 (Metformin) & 12 disclosed in the examples) versus metformin Sustained (RosiglitaZone) wherein curve a represents Test Formulation release tablet (marketed as Glucophage XR" by Bristol and curve b represents Reference Formulation. Myers Squibb, USA.) and rosiglitazone immediate release tablet (marketed as Avandia' by Glaxo Smithkline; United TABLE 29 Kingdom.). Bioavailability Summary and Analysis - Metformin SR Methodology: AUC if nghr/m 16939+ 16396- 83.84 11.6.16 AUC nghr/m 16107+ 15951- 87.33 112.67 0257 The biostudy had an open label, randomized two Cmax ng/ml 1515.29- 1558.78 90.89 109.11 period, two treatment, two way Single dose croSSOver Study C24 h ng/ml 120.10- 79.63 with 7 days washout period between treatment days. Tmax hir 7.64 8.86+ 0258 Non-compartmental Pharmacokinetic assessment T12 hir 4.12+ 3.36 was based on the plasma levels of Metformin and Rosigli taZone measured by blood Sampling. Blood Samples were 0267 obtained before dosing and at the following times after administration of test and reference formulations, TABLE 30 0259 Pre-dose, 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, Bioavailability Summary and Analysis - Rosiglitazone (4 mg) 6.0, 8.0, 10.0, 12.0, 15.0, 18.0, and 24.0 hours. AUC if nghr?m 1308- 1258 + 331 85.73 114.27 Number of Subjects and Study Population: AUCo. nghr?m 1266- 1234 - 324 86.61 11339 Cmax ng/ml 145.70+ 161.83- 80.88 11912 C24 h ng/ml 6.O7- 1.80 + 3.11 0260 Sixteen (16) volunteers were enrolled and 15 of Tmax hir 5.07. 4.13 + 1.91 them completed the study. All 15 volunteers were included T12 hir 3.59- 3.32 + 0.59 in the Pharmacokinetic and Safety analyses. Criteria for Inclusion: Conclusion: 0261 Healthy male volunteers aged between 18 to 45 0268. The relative bioavailability study shown that yearS. bioeduivalance was achieved between the 4 mg/1000 mg combination formulation and the respective components, for Test Product, Dose and Mode of Administration: both AUC and C, parameters (Table 29 & 30). Moreover, 0262 Test Formulation: 4 mg/1000 mg Rosiglitazone/ in the test formulation, the concentration of Metformin at 24 Metformin Sustained release dosage form prepared as per the hrs was almost 1.5 times more than Glucophage XR (FIG. invention disclosed in the examples. Volunteers received a 11) wherein curve a represents Test formulation and b single oral dose of above products with 200 ml of water represents Reference formulation (Table 29). Similarly following high calorie dinner (~1400 KCal). RosiglitaZone component of the test formulation also shown higher concentration at 24 hrs as that of Avandia' (FIG. 12; Reference Product, Dose and Mode of Administration: wherein curve a represents Test Formulation and curve b 0263. Reference: 4 mg. Avandia'? plus Glucophage XR2 represents Reference Formulation and Table 30). (2x500 mg) Volunteers received a single oral dose of above Example 23 products with 200 ml of water following calorie dinner (-1400 Kcal). 0269) 1) Production of Inner Portion Pharmacokinetics: 0270) 69.61% w/w of Aspirin coated granules (Aspirin 96% w/w, 2.0% w/w hydrogenated castor oil & 2.0% w/w Same as for example 20. citric acid anhydrous coated) mixed with the mixture of US 2006/0024365 A1 Feb. 2, 2006 27

11.56% w/w of microcrystalline cellulose (PH112, dried), type A and B as described in USP, methacrylic acid copoly 7.17% w/w sodium starch Glycolate (dried), 2.24% w/w mer type A, B and C as described in USP, polyacrylate citric acid anhydrous, 4.48% w/w talc, 1.79% w/w colloidal dispersion 30% as described in Ph. Eur., polyvinyl acetate silicon dioxide, 1.79% w/w Stearic acid and 1.35% w/w dispersion, ethylcellulose, cellulose acetate, cellulose pro hydrogenated vegetable oil. pionate (lower, medium or higher molecular weight), cellu lose acetate propionate, cellulose acetate butyrate, cellulose 0271 Production of Outer Portion acetate phthalate, cellulose triacetate, poly(methyl meth 0272 A) Micro matrix particles-93.02% w/w of nico acrylate), poly(ethyl methacrylate), poly(butyl methacry tinic acid is mixed with 6.98% w/w of Eudragit RS PO late), poly(isobutyl methacrylate), poly (hexyl methacry (Ammonio Methacrylate Copolymer type B USP) and the late), poly(isodecyl methacrylate), poly (lauryl mixture is granulated with a Solvent mixture of acetone and methacrylate), poly(phenyl methacrylate), poly (methyl methylene chloride and then dried. The granules are sized acrylate), poly (isopropyl acrylate), poly (isobutyl actylate), through 11.0 mm Screen. poly (octadecyl acrylate), waxes Such as beeswax, carnauba wax, microcrystalline wax, and OZokerite; fatty alcohols 0273 B) Coating of Micro matrix particles-92.67% w/w Such as cetoStearyl alcohol, Stearyl alcohol, cetyl alcohol of micro matrix particles is charged in fluidized bed pro and myristyl alcohol; and fatty acid esterS Such as glyceryl cessor. 6.47% w/w of hydrogenated castor oil is dissolved in monoStearate, glycerol distearate, glycerol monooleate, acetone and this coating Solution is sprayed to coat the micro acetylated monoglycerides, tristearin, tripalmitin, cetyl matrix particles. The coated micro matrix particles are esters wax, glyceryl palmitoStearate, glyceryl behenate and sieved and mixed with 0.86% w/w magnesium stearate. hydrogenated castor oil. 0274 Compression of Tablets 6. A dosage form according to claim 5, wherein the 0275 Tablet (A)-483.17 mg granules of inner portion hydrophobic release controlling agent(s) is selected prefer are pressed to tablets (equal to 325.0 mg aspirin) using ably from ammonio methacrylate co-polymers. 15.0x6.35 mm plain, capsule shape punches with one side 7. A dosage form according to claim 6, wherein the break line and 1160 mg granules of outer portion (equal to preferred ammonio methacrylate co-polymers are Selected 1000 mg nicotinic acid) are compressed using 20.3x9.8 mm from Eudragit RSPO (Ammonio Methacrylate Copolymer plain, capsule shape punches. type B USP), Eudragit RL (Ammonio Methacrylate Copoly mer type A USP) and Eudragit NE30D (Polyacrylate dis 0276 Tablet (B)-223.0 mg granules of inner portion are persion 30% Ph. Eur). pressed to tablets (equal to 150.0 mg aspirin) using 13.5x 8. A dosage form according to claim 1, wherein in micro 6.35 mm plain, capsule shape punches with one side break matrix particles, the active ingredient and one or more line and 1160 mg granules of outer portion (equal to 1000 hydrophobic release controlling agents are present in a ratio mg nicotinic acid) are compressed using 20.3x9.8 mm plain, of from 100:1 to 100:75. capsule shape punches. The compression is done on press 9. A dosage form according to claim 8, wherein in micro coater machine in Such a manner that the resultant tablet has matrix particles, the active ingredient and one or more inner portion covered by the Outer portion from all the sides hydrophobic release controlling agents are present prefer except top Surface that remains uncovered and the level of ably in ratio of from 100:2.5 to 100:50. the inner portion and the outer portion is on the same 10. A dosage form according to claim 8, wherein in micro Surface. matrix particles, the active ingredient and one or more What is claimed is: hydrophobic release controlling agents are present more 1. A dosage form of combination of high dose high preferably in ratio of from 100:2.5 to 100:30 Solubility active ingredient, as modified release and low 11. A dosage form according to claim 8, wherein in micro dose active ingredient as immediate release Suitable for matrix particles, the active ingredient and one or more Swallowing, comprising of dual retard technique to control hydrophobic release controlling agents are present most the release of high dose, high Solubility active ingredient, preferably in ratio of from 100:2.5 to 100:20. wherein Said dosage form comprising of an inner portion 12. A dosage form according to claim 1, coating of micro having a low dose active ingredient as immediate release matrix particles comprises one or more hydrophobic release and an outer portion having a high dose, high Solubility controlling agents. active ingredient as modified release, in which the outer 13. A dosage form according to claim 12, wherein the portion comprises a) micro matrix particles and b) coating hydrophobic release controlling agents are Selected from the on micro matrix particles. group comprising of ammonio methacrylate copolymers 2. A dosage form according to claim 1, in the form of a type A and B as described in USP, methacrylic acid copoly tablet, wherein Said inner portion is covered by the outer mer type A, B and C as described in USP, polyacrylate portion from all the Sides except top Surface that remains dispersion 30% as described in Ph. Eur., polyvinyl acetate uncovered. dispersion, ethylcellulose, cellulose acetate, cellulose pro 3. A dosage form according to claim 1, wherein the dosage pionate (lower, medium or higher molecular weight), cellu form is with Sufficient reduction in the amount of release lose acetate propionate, cellulose acetate butyrate, cellulose controlling agent. acetate phthalate, cellulose triacetate, poly(methyl meth 4. A dosage form according to claim 1, wherein the micro acrylate), poly(ethyl methacrylate), poly(butyl methacry matrix particles comprises one or more hydrophobic release late), poly(isobutyl methacrylate), poly (hexyl methacry controlling agents. late), poly(isodecyl methacrylate), poly (lauryl 5. A dosage form according to claim 4, wherein the methacrylate), poly(phenyl methacrylate), poly (methyl hydrophobic release controlling agents are Selected from the acrylate), poly (isopropyl acrylate), poly (isobutyl actylate), group comprising of ammonio methacrylate copolymers poly (octadecyl acrylate), waxes Such as beeswax, carnauba US 2006/0024365 A1 Feb. 2, 2006 28 wax, microcrystalline wax, and OZokerite; fatty alcohols blocking agent; neuroprotective, NMDA antagonist; non Such as cetoStearyl alcohol, Stearyl alcohol, cetyl alcohol hormonal Sterol derivative, plasminogen activator; platelet and myristyl alcohol; and fatty acid esterS Such as glyceryl activating factor antagonist, platelet aggregation inhibitor; monoStearate, glycerol distearate, glycerol monooleate, psychotropic, radioactive agent; Scabicide, Sclerosing agent; acetylated monoglycerides, tristearin, tripalmitin, cetyl Sedative, Sedative-hypnotic, Selective adenosine Al antago esters wax, glyceryl palmitostearate, glyceryl behenate glyc nist; Serotonin antagonist; Serotonin inhibitor, Serotonin erol distearate, and hydrogenated castor oil. receptor antagonist; Steroid; thyroid hormone; thyroid 14. A dosage form according to claim 13, wherein the inhibitor; thyromimetic, tranquilizer; amyotrophic lateral hydrophobic release controlling agent(s) is selected from Sclerosis agent; cerebral ischemia agent, Paget's disease fatty acid esters. agent; unstable angina agent; vasoconstrictor; vasodilator; 15. A dosage form according to claim 14, wherein the wound healing agent, Xanthine oxidase inhibitor and the hydrophobic release controlling agents is Selected from the like. group comprising of hydrogenated castor oil and glycerol 23. A dosage form according to claim 22, wherein the low distearate. dose active ingredient is Selected from the group comprising 16. A dosage form according to claim 1, wherein in outer of 16-alpha fluorocStradiol, 16alpha-gitoxin, 16-epieStriol, portion, micro matrix particles and coating of one or more 17alpha dihydroequilenin, 17 alpha estradiol, 17 beta estra hydrophobic release controlling agents are present in a ratio diol, 17 hydroxy progesterone, 1alpha-hydroxyvitamin D2, of from 100:0.5 to 100:75. 1-dodecpyrrolidinone, 20-epi-1.25 dihydroxyvitamin D3, 17. A dosage form according to claim 16, wherein in outer 22-oxacalcitriol, 2CW, 2-nor-cGMP, 3-isobutyl GABA, portion, micro matrix particles and coating of one or more 5-ethynyluracil, 6-FUDCA, 7-methoxytacrine, Abamectin, hydrophobic release controlling agents are present prefer abanoquil, abecarnil, abiraterone, Ablukast, Ablukast ably in a ratio of from 100:1 to 100:50. Sodium, Acadesine, acamprosate, Acarbose, Acebutolol, 18. A dosage form according to claim 16, wherein in outer Acecainide Hydrochloride, Aceclidine, aceclofenae, portion, micro matrix particles and coating of one or more AcedapSone, Aceglutamide Aluminum, Acemannan, hydrophobic release controlling agents are more preferably Acetaminophen, Acetazolamide, Acetohexamide, Acetohy present in a ratio of from 100:2.5 to 100:20. droxamic Acid, acetomepregenol, Acetophenazine Maleate, 19. A dosage form according to claim 1, wherein the AcetoSulfone Sodium, Acetylcholine Chloride, Acetylcys weight ratio of immediate release active ingredient and teine, acetyl-L-carnitine, acetylmethadol, Acifran, acipimox, modified release active ingredient is from 1:1 to 1:15000. acitemate, Acitretin, Acivicin, Aclarubicin, aclatonium, 20. A dosage form according to claim 1, wherein the low Acodazole Hydrochloride, aconiazide, Acrisorcin, Acrivas dose active ingredient can optionally be also in a form of tine, Acronine, Actisomide, Actodigin, Acyclovir, acylful modified release. Vene, adafenoxate, adapalene, Adapalene, adatanserin, Ada 21. A dosage form according to claim 1, wherein the low tanserin Hydrochloride, adecypenol, adecypenol, Adefovir, dose active ingredient comprises dose less than or equal to adelmidrol, ademetionine, Adenosine, Adinazolam, 500 mg. Adipheinine Hydrochloride, adiposin, Adozelesin, adrafinil, 22. A dosage form according to claim 1, wherein the low Adrenalone, airbutamine, alacepril, Alamecin, Alanine, Ala dose active ingredient is Selected from the group comprising proclate, alaptide, Albendazole, albolabrin, Albuterol, Albu of adrenergic agent; adrenocortical Steroid; adrenocortical toin, Alclofenae, Alclometasone Dipropionate, Alcloxa, SuppreSSant; aldosterone antagonist, amino acid; anabolic; aldecalmycin, Aldesleukin, Aldioxa, Alendronate Sodium, analeptic, analgesic, anesthetic; anorectic, anti-acne agent, alendronic acid, alentemol, Alentemol Hydrobromide, Ale anti-adrenergic, anti-allergic, anti-amebic, anti-anemic, tamine Hydrochloride, Aleuronium Chloride, Alexidine, anti-anginal; anti-arthritic, anti-asthmatic, anti-atheroscle alfacalcidol, Alfentanil Hydrochloride, alfuZosin, AlgeStone rotic, antibacterial; anticholinergic, anticoagulant; anticon Acetonide, alglucerase, Aliflurane, alinastine, Alipamide, Vulsant, antidepressant, antidiabetic, antidiarrheal; antidi Allantoin, Allobarbital, Allopurinol, ALL-TK antagonists, uretic, anti-emetic, anti-epileptic, antifibrinolytic; Alonimid, aloSetron, Alosetron Hydrochloride, Alovudine, antifungal, antihemorrhagic, antihistamine; antihyperlipi Alpertine, Alpha Amylase, alpha idoSone, Alpidem, Alpra demia; antihypertensive, antihypotensive; anti-infective; Zolam, Alprenolol Hydrochloride, Alprenoxime Hydrochlo anti-inflammatory; antimicrobial; antimigraine; antimitotic, ride, Alprostadil, Alrestatin Sodium, Altanserin Tartrate, antimycotic, antinauseant, antineoplastic, antineutropenic, Alteplase, Althiazide, Altretamine, altromycin B, Alverinc antiparasitic, antiproliferative; antipsychotic, antirheumatic; Citrate, Alvircept Sudotox, Amadinone Acetate, Amantadine antiseborrheic, antisecretory; antispasmodic, antithrom Hydrochloride, ambamustine, Ambomycin, Ambruticin, botic, anti-ulcerative; antiviral; appetite SuppreSSant; blood Ambuphylline, AmbuSide, Amcinafal, Amcinonide, Amdi glucose regulator, bone resorption inhibitor, bronchodilator; nocillin, Amdinocillin Pivoxil, Amedalin Hydrochloride, cardiovascular agent, cholinergic, depressant, diagnostic amelometasone, Ameltolide, AmeSergide, Ametantrone aid; diuretic, dopaminergic agent; estrogen receptor agonist, Acetate, ameZinium metilsulfate, amfebutamone, Amfenac fibrinolytic, fluorescent agent, free oxygen radical Scaven Sodium, Amflutizole, Amicycline, Amidephrine MeSylate, ger; gastric acid SupreSSant; gastrointestinal motility effec amidox, Amifloxacin, amifostine, Amikacin, Amiloride tor; glucocorticoid; hair growth Stimulant; hemostatic; his Hydrochloride, Aminacrine Hydrochloride, Aminobenzoate tamine H2 receptor antagonists, hormone; Potassium, Aminobenzoate Sodium, Aminocaproic Acid, hypocholesterolemic, hypoglycemic, hypolipidemic, Aminoglutethimide, Aminohippurate Sodium, aminole hypotensive; imaging agent, immunizing agent; immuno Vulinic acid, Aminophylline, A minorex, AminoSalicylate modulator; immunoregulator; immunostimulant; immuno Sodium, AminoSalicylic acid, Amiodarone, Amiprilose SuppreSSant; keratolytic, LHRH agonist, mood regulator; Hydrochloride, Amiquinsin Hydrochloride, amisulpride, mucolytic, mydriatic, nasal decongestant; neuromuscular Amitraz, Amitriptyline Hydrochloride, AmlexanoX, amlo US 2006/0024365 A1 Feb. 2, 2006 29 dipine, Amobarbital Sodium, Amodiaquine, Amodiaquine berlafenone, bertosamil, Berythromycin, besipirdine, beta Hydrochloride, Amorolfine, Amoxapine, Amoxicillin, alethine, betaclamycin B, Betamethasone, betamipron, Amphecloral, Amphetamine Sulfate, Amphomycin, Ampho betaxolol, Betaxolol Hydrochloride, Bethanechol Chloride, tericin B, Ampicillin, ampiroXicam, AmpyZine Sulfate, Bethanidine Sulfate, betulinic acid, bevantolol, Bevantolol Amguinate, Amrinone, amrinone, amrubicin, Amsacrine, Hydrochloride, Bezafibrate, bFGF inhibitor, Bialamicol amylin, amythiamicin, AnageStone Acetate, anagrelide, Hydrochloride, Biapenem, Bicalutamide, Biciifadine Hydro Anakinra, ananain, anaritide, Anaritide Acetate, Anastro chloride, Biclodil Hydrochloride, Bidisomide, bifemelane, Zole, Anazolene Sodium, Ancrod, andrographolide, Andros Bifonazole, bimakalim, bimithil, Bindarit, Biniramycin, tenedione, angiogenesis inhibitors, Angiotensin Amide, Ani binoSpirone, bioxalomycin alpha2, Bipenamol Hydrochlo doXime, Anileridine, Anilopam Hydrochloride, Aniracetam, ride, Biperiden, Biphenamine Hydrochloride, biriperone, Anirolac, Anisotropine Methylbromide, Anistreplase, Ani bisantrene, bisaramil, bisaZiridinylspermine, bis-benzimida traZafen, anordrin, antagonist D, antagonist G, antarelix, Zole A, bis-benzimidazole B, bisnafide, Bisobrin Lactate, Antazoline Phosphate, Anthelmycin, Anthralin, Anthramy Bisoprolol, Bispyrithione Magsulfex, bistramide D, bistra cin, antiandrogen, AcedapSone, Felbamate, antiestrogen, mide K, bistratene A, Bithionolate Sodium, Bitolterol Mesy antineoplaston, Antipyrine, antisense oligonucleotides, apa late, Bivalirudin, Bizelesin, Bleomycin Sulfate, Bolandiol doline, apafant, Apalcillin Sodium, apaxifylline, ApaZone, Dipropionate, Bolasterone, Boldenone Undecylenate, bol aphidicolin glycinate, Apixifylline, Apomorphine Hydro dine, Bolenol, Bolmantalate, bopindolol, Bosentan, Boxi chloride, apraclonidine, Apraclonidine Hydrochloride, dine, brefeldin, breflate, Brequinar Sodium, Bretazenil, Apramycin, Aprindine, Aprindine Hydrochloride, aproSulate Bretylium Tosylate, Brifentanil Hydrochloride, brimoni Sodium, Aprotinin, Aptazapine Maleate, aptiganel, apurinic dine, Brinolase, Brocresine, Brocrinat, Brofoxine, Broma acid, apurinic acid, aranidipine, Aranotin, Arbaprostil, doline Maleate, Bromazepam, Bromchlorenone, Brome arbekicin, arbidol, Arbutamine Hydrochloride, Arclofenin, lains, bromfenac, Brominidione, Bromocriptine, Ardeparin Sodium, argatroban, Arginine, Argipressin Tan Bromodiphenhydramine Hydrochloride, Bromoxamide, nate, Arildone, aripiprazol, arotinolol, Arpinocid, Arteflene, Bromperidol, Bromperidol Decanoate, Brompheniramine Artilide Fumarate, asimadoline, aspalatone, Asparaginase, Maleate, Broperamole, Bropirimine, Brotizolam, Bucainide ASpartic Acid, ASpartocin, asperfuran, Aspirin, aspoxicillin, Maleate, bucindolol, Buclizine Hydrochloride, Bucromar Asprelin, Astemizole, Astromicin Sulfate, asulacrine, ata one, BudeSonide, budipine, budotitane, Buformin, Bumeta meStane, Atenolol, ateVirdine, Atipamezole, AtiproSin Male mide, Bunaprolast, bunaZosin, Bunolol Hydrochloride, ate, Atolide, Atorvastatin Calcium, Atosiban, Atovaquone, Bupicomide, Bupivacaine Hydrochloride, Buprenorphine atpenin B, Atracurium BeSylate, atrimustine, atrinositol, Hydrochloride, Bupropion Hydrochloride, Buramate, Atropine, Auranofin, aureobasidin A, Aurothioglucose, Buserelin Acetate, Buspirone Hydrochloride, BuSulfan, But Avilamycin, Avoparcin, Avridine, AXid, axinastatin 1, axin abarbital, Butacetin, Butaclamol Hydrochloride, Butalbital, astatin 2, axinastatin 3, AZabon, AZacitidinie, AZaclorzine Butamben, Butamirate Citrate, Butaperazine, Butaprost, Hydrochloride, AZaconazole, azadirachtine, AZalanstat Butedronate Tetrasodium, butenafine, Buterizine, buthion Dihydrochloride, AZaloxan Fumarate, AZanator Maleate, ine Sulfoximine, Butikacin, Butilfenin, Butirosin Sulfate, AZanidazole, AZaperone, AZaribine, AZaserine, azasetron, Butixirate, butiXocort propionate, Butoconazole Nitrate, AZatadine Maleate, AZathioprine, AZathioprine Sodium, Butonate, Butopamine, Butoprozine Hydrochloride, Butor aZatoxin, azatyrosine, azelaic acid, azelastine, azelnidipine, phanol, Butoxamine Hydrochloride, Butriptyline Hydro AZepindole, AZetepa, azimilide, Azithromycin, AZlocillin, chloride, Cactinomycin, CadeXomer Iodine, Caffeine, cal AZOlimine, AZOSemide, AZotomycin, Aztreonam, anolide A, Calcifediol, Calcipotriene, calcipotriol, AZumolene Sodium, Bacampicillin Hydrochloride, baccatin Calcitonin, Calcitriol, Calcium Undecylenate, calphostin C, III, Bacitracin, Baclofen, bacoside A, bacoside B, bactobo Calusterone, Cambendazole, camonagrel, camptothecin lamine, balanol, balaZipone, balhimycin, balofloxacin, bal derivatives, canarypox IL-2, candesartan, Candicidin, can Salazide, Bambermycins, bambuterol, Bamethan Sulfate, doXatril, candoxatrilat, Caniglibose, Canrenoate Potassium, Bamifylline Hydrochloride, Bamidazole, baohuoside 1, Bar Canrenone, capecitabine, Capobenate Sodium, Capobenic mastine, barnidipine, Basifungin, Batanopride Hydrochlo Acid, Capreomycin Sulfate, capromab, capsaicin, Captopril, ride, batebulast, Batelapine Maleate, BatimaStat, beauveri Capuride, Caracemide, Carbachol, Carbadox, Carbam cin, Becanthone Hydrochloride, becaplermin, azepine, Carbamide Peroxide, Carbantel Lauryl Sulfate, becliconazole, Beclomethasone Dipropionate, befloxatone, Carbaspirin Calcium, CarbaZeran, carbazomycin C, Carbe Beinserazide, Belfosdil, Belladonna, Beloxamide, nicillin Potassium, Carbenoxolone Sodium, Carbetimer, car BemeSetron, Bemitradine, Bemoradan, Benapry Zine Hydro betocin, Carbidopa, Carbidopa-Levodopa, Carbinoxamine chloride, Benazepril Hydrochloride, Benazeprilat, Benda Maleate, Carbiphene Hydrochloride, Carbocloral, Car calol Mesylate, Bendazac, Bendroflumethiazide, benflume bocysteine, Carbol-Fuchsin, Carboplatin, Carboprost, car tol, benidipine, Benorterone, Benoxaprofen, Benoxaprofen, bovir, carboxamide-amino-triaZO-le, carboxyamidotriazole, Benoximate Hydrochloride, Benperidol, Bentazepam, Ben carboxymethylated beta-1,3-glucan, Carbuterol Hydrochlo tiromide, Benurestat, Benzbromarone, Benzethonium Chlo ride, CaRest M3, Carfentanil Citrate, Carisoprodol, Carman ride, Benzetimide Hydrochloride, Benzilonium Bromide, tadine, Carmustine, CARN 700, Camidazole, Caroxazone, BenZindopyrine Hydrochloride, benzisoxazole, Benzocaine, carperitide, Carphenazine Maleate, Carprofen, CarSatrin benzochlorins, BenZoctamine Hydrochloride, BenZOdepa, Succinate, CartaZolate, carteolol, Carteolol Hydrochloride, benzoidaZOXan, BenZonatate, Benzoyl Peroxide, Ben cartilage derived inhibitor, Carubicin Hydrochloride, Caru Zoylpas Calcium, benzoylstauroSporine, BenZquinamide, monam Sodium, carvedilol, carvotroline, Carvotroline Benzthiazide, benztropine, Benztropine MeSylate, Benzy Hydrochloride, carzelesin, casein kinase inhibitors (ICOS), damine Hydrochloride, Benzylpenicilloyl Polylysine, bepri castanospermine, caurumonam, cebaracetam, cecropin B, dil, Bepridil Hydrochloride, Beractant, Beraprost, Berefrine, Cedefingol, Cefaclor, Cefadroxil, Cefamandole, Cefaparole, US 2006/0024365 A1 Feb. 2, 2006 30

Cefatrizine, Cefazaflur Sodium, Cefazolin, Cefbuperazone, tin Sulfate, collismycin A, collismycin B, Colterol Mesylate, cefcapene pivoxil, cefdaloXime penteXil tosilate, Cefdinir, combretastatin A4, combretastatin analogue, complestatin, cefditoren pivoxil, Cefepime, cefetamet, Cefetecol, conagenin, Conorphone Hydrochloride, contignasterol, con cefixime, cefluprenam, CefinenoXime Hydrochloride, Cefin tortrostatin, Cormethasone Acetate, Corticorelin Ovine Tri etazole, cefminlox, cefodizime, Cefonicid Sodium, Cefop flutate, Corticotropin, Cortisone Acetate, CortivaZol, Corto eraZone Sodium, Ceforamide, cefoSelis, Cefotaxime doxone, coSalane, costatolide, CoSyntropin, cotinine, Sodium, Cefotetan, cefotiam, CefoXitin, cefoZopran, cefpi Coumadin, Coumermycin, crambescidin 816, Crilvastatin, mizole, Cefpiramide, cefpirome, cefpodoxime proxetil, cef crisinatol, Cromitrile Sodium, Cromolyn Sodium, Crotami prozil, CefroXadine, cefSulodin, Ceftazidime, cefteram, cef ton, cryptophycin 8, cucumariosid, Cuprimyxin, curacin A, tibuten, Ceftizoxime Sodium, ceftriaxone, Cefuroxime, curdlan Sulfate, curiosin, Cyclacillin, Cyclazocine, cycla celastrol, celikalim, celiprolol, cepacidine A, Cephacetrile Zosin, cyclic HPMPC, Cyclindole, Cycliramine Maleate, Sodium, Cephalexin, Cephaloglycin, Cephaloridine, Cepha Cyclizine, Cyclobendazole, cyclobenzaprine, cyclobut A, lothin Sodium, Cephapirin Sodium, Cephradine, cer cyclobut G, cyclocapron, Cycloguanil Pamoate, Cyclohex iclamine, cerivastatin, Ceronapril, certoparin Sodium, Ceru imide, cyclopentanthraquinones, Cyclopenthiazide, Cyclo letide, Cetaben Sodium, Cetalkonium Chloride, Cetamolol pentolate Hydrochloride, Cyclophenazine Hydrochloride, Hydrochloride, cetiedil, cetirizine, Cetophenicol, Cetraxate Cyclophosphamide, cycloplatam, Cyclopropane, CycloS Hydrochloride, cetrorelix, Cetylpyridinium Chloride, erine, cycloSin, Cyclosporine, cyclothialidine, Cyclothiaz Chenodiol, Chlophedianol Hydrochloride, Chloral Betaine, ide, cyclothiazomycin, Cyheptamide, cypemycin, Cype Chlorambucil, Chloramphenicol, Chlordantoin, Chlordiaz namine Hydrochloride, Cyprazepam, Cyproheptadine epoxide, Chlorhexidine Gluconate, chlorins, Chlormadinone Hydrochloride, Cyprolidol Hydrochloride, cyproterone, Acetate, chloroorienticin A, Chloroprocaine Hydrochloride, Cyproximide, CySteamine, Cysteine Hydrochloride, Cys Chloropropamide, Chloroquine, chloroquinoxaline Sulfona tine, Cytarabine, Cytarabine Hydrochloride, cytarabine mide, Chlorothiazide, Chlorotrianisene, Chloroxine, Ocfosfate, cytochalasin B, cytolytic factor, cytostatin, Dac Chloroxylenol, Chlorphenesin Carbamate, chlorphe arbazine, dacliximab, dactimicin, Dactinomycin, daidzein, niramine Maleate, Chlorpromazine, Chlorpropamide, Chlo Daledalin Tosylate, dalfopristin, Dalteparin Sodium, Dal rprothixene, Chlortetracycline Bisulfate, Chlorthalidone, troban, Dalvastatin, danaparoid, Danazol, Dantrolene, ChlorZoxazone, Cholestyramine Resin, Chromonar Hydro daphlnodorin A, dapiprazole, dapitant, Dapoxetine Hydro chloride, cibenzoline, cicaprost, Ciclafrine Hydrochloride, chloride, DapSone, Daptomycin, DarglitaZone Sodium, Ciclazindol, ciclesonide, cicletanine, Ciclopirox, Ciclopro darifenacin, darlucin A, Darodipine, darsidomine, Daunoru fen, cicloprolol, Cidofovir, Cidoxepin Hydrochloride, bicin Hydrochloride, Dazadrol Maleate, Dazepinil Hydro Cifenline, CiglitaZone, Ciladopa Hydrochloride, cilansetron, chloride, DaZmegrel, DaZopride Fumarate, DaZOXiben Cilastatin Sodium, CilaZapril, cilnidipine, Cilobamine Hydrochloride, Debrisoquin Sulfate, Decitabine, defer MeSylate, cilobradine, Cillofungin, ciloStaZol, Cimaterol, iprone, deflazacort, Dehydrocholic Acid, dehydrodidemnin Cimetidine, cimetropium bromide, Cinalukast, Cinanserin B, Dehydroepiandrosterone, delapril, Delapril Hydrochlo Hydrochloride, Cinepazet Maleate, Cinflumide, Cingestol, ride, Delavirdine MeSylate, deleguamine, delfaprazine, Del cinitapride, Cinnamedrine, Cinnarizine, cinolazepam, Cino madinone Acetate, delmopinol, delphinidin, Demecarium Xacin, Cinperene, Cinromide, CintaZone, Cintriamide, Ciot Bromide, Demeclocycline, Demecycline, Demoxepam, eronel, Cipamfylline, Ciprefadol Succinate, Ciprocinonide, Denofungin, deoxypyridinoline, Depakote, deprodone, Ciprofibrate, Ciprofloxacin, ciprostene, Ciramadol, Cirole Deprostil, depSidomycin, deramciclane, dermatan Sulfate, mycin, cisapride, cisatracurium besilate, Cisconazole, Cis Desciclovir, Descinolone Acetonide, Desflurane, platin, cis-porphyrin, cistinexine, citalopram, Citenamide, Desipramine Hydrochloride, desirudin, Deslanoside, citicoline, citreamicin alpha, cladribine, Clamoxyquin deslorelin, desmopressin, desogestrel, DeSonide, DeS Hydrochloride, Clarithromycin, clausenamide, Clavulanate Oximetasone, desoxoamiodarone, DeSoxycorticosterone Potassium, Clazolam, Clazolimine, clebopride, Clemastine, Acetate, detajmium bit artrate, Deterenol Hydrochloride, Clentiazem Maleate, Clidinium Bromide, clinafloxacin, Detirelix Acetate, DevaZepide, Dexamethasone, Dexami Clindamycin, Clioquinol, Clioxamide, Cliprofen, clobazam, Sole, Dexbrompheniramine Maleate, DeXchlorpheniramine Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Maleate, Dexclamol Hydrochloride, Dexetimide, Dexfen Acetate, Clodanolene, Clodazon Hydrochloride, clodronic fluramine Hydrochloride, dexifosfamide, Deximafen, Dexi acid, Clofazimine, Clofibrate, Clofilium Phosphate, Cloge vacaine, dexketoprofen, dexloxiglumide, DeXmedetomi Stone Acetate, Clomacran Phosphate, Clomegestone dine, DeXormaplatin, Dexoxadrol Hydrochloride, Acetate, Clometherone, clomethiazole, clomifene ana Dexpanthenol, Dexpemedolac, Dexpropranolol Hydrochlo logues, Clominorex, Clomiphene, Clomipramine Hydro ride, DeXraZOxane, deXSotalol, dextrin 2-Sulphate, Dextro chloride, Clonazepam, Clonidine, Clonitrate, Clonixeril, amphetamine, Dextromethorphan, Dextrorphan Hydrochlo Clonixin, Clopamide, Clopenthixol, Cloperidone Hydro ride, Dextrothyroxine Sodium, deXVerapamil, DeZaguanine, chloride, clopidogrel, Clopimozide, Clopipazan MeSylate, dezinamide, deZOcine, Diacetolol Hydrochloride, Clopirac, Cloprednol, Cloprostenol Sodium, CloraZepate Diamocaine Cyclamate, Diapamide, Diatrizoate Meglu Dipotassium, Clorethate, Clorexolone, Cloroperone Hydro mine, Diatrizoic Acid, Diaveridine, Diazepam, Diaziquone, chloride, Clorprenaline Hydrochloride, Clorsulon, Clorter Diazoxide, Dibenzepin Hydrochloride, Dibenzothiophene, mine Hydrochloride, CloSantel, Closiramine Aceturate, Dibucaine, Dichliorvos, Dichloralphenazone, Dichlorphe Clothiapine, Clothixamide Maleate CloticaSone Propionate, namide, Dicirenone, Diclofenac Sodium, Dicloxacillin, dic Clotrimazole, Cloxacillin BenZathine, Cloxyquin, CloZap ranin, Dicumarol, Dicyclomine Hydrochloride, Didanosine, ine, Cocaine, Coccidioidin, Codeine, Codoxime, Colchicine, didemnin B, didox, Dienestrol, dienogest, Diethylcarbam colestimide, Colestipol Hydrochloride, Colestolone, Col azine Citrate, diethylhomospermine, diethylnorspermine, forsin, Colfosceril Palmitate, Colistimethate Sodium, Colis Diethylpropion Hydrochloride, Diethylstilbestrol, Difenox US 2006/0024365 A1 Feb. 2, 2006 imide Hydrochloride, Difenoxin, Diflorasone Diacetate, poside, Etoprine, Etoxadrol Hydrochloride, EtoZolin, etra Difloxacin Hydrochloride, Difluanine Hydrochloride, Diflu bamine, Etretinate, Etryptamine Acetate, Eucatropine cortolone, Diflumidone Sodium, Diflunisal, Difluprednate, Hydrochloride, Eugenol, Euprocin Hydrochloride, eveni Diftalone, Digitalis, Digitoxin, Digoxin, Dihexyverine nomicin, Exametazime, examorelin, Exaprolol Hydrochlo Hydrochloride, dihydrexidine, dihydro-5-azacytidine, Dihy ride, exemestane, fadrozole, faerieflungin, Famciclovir, drocodeine Bitartrate, Dihydroergotamine Mesylate, Dihy Famotidine, Fampridine, fantofarone, Fantridone Hydro droestosterone, Dihydrostreptomycin Sulfate, Dihydrotach chloride, faropenem, fasidotril, fasudil, faZarabine, fedot ysterol, dihydrotaxol, 9-, Dilantin, Dilevalol Hydrochloride, Ozine, felbamate, Felbinac, Felodipine, Fely pressin, Fenala Diltiazem Hydrochloride, Dimefadane, Dimefline Hydro mide, Fenamole, Fenbendazole, Fenbufen, Fencibutirol, chloride, Dimenhydrinate, Dimercaprol, Dimethadione, Fenclofenac, Fenclonine, Fenclorac, Fendosal, FeneStrel, Dimethindene Maleate, Dimethisterone, dimethyl prostag Fenethylline Hydrochloride, Fenfluramine Hydrochloride, landin Al, Dimethyl Sulfoxide, dimethylhomospermine, Fengabine, Fenimide, Fenisorex, Fenmetozole Hydrochlo dimiracetam, Dimoxamine Hydrochloride, Dinoprost, Dino ride, Fenmetramide, Fenobam, Fenoctimine Sulfate, fenofi prostone, Dioxadrol Hydrochloride, dioxamycin, Diphenhy brate, fenoldopam, Fenoprofen, Fenoterol, Fenpipalone, dramine Citrate, Diphenidol, Diphenoxylate Hydrochloride, Fenprinast Hydrochloride, Fenprostalene, Fenguizone, fen diphenyl spiromustine, Dipivefin Hydrochloride, Dipivefrin, retinide, fenspiride, Fentanyl Citrate, Fentiazac, Fenticlor, dipliencyprone, diprafenone, dipropylnorspermine, Dipy fenticonazole, Fenyripol Hydrochloride, fepradinol, ferpifo ridamole, Dipyrithione, Dipyrone, dirithromycin, discoder Sate Sodium, ferristene, ferriXan, Ferrous Sulfate, Dried, mollide, Disobutamide, Disofenin, Disopyramide, Disoxaril, Ferumoxides, ferumoxsil, Fetoxylate Hydrochloride, fex disulfiram, Ditekiren, Divalproex Sodium, Dizocilpine ofenadine, FeZolamine Fumarate, Fiacitabine, Fialuridine, Maleate, Dobutamine, docarpamine, Docebenone, Doc Fibrinogen 1125, filgrastim, Filipin, finasteride, Flavodilol etaxel, Doconazole, docOSanol, dolfetilide, dolasetron, Ebas Maleate, flavopiridol, Flavoxate Hydrochloride, Flazalone, tine, ebiratide, ebrotidine, ebSelen, ecabapide, ecabet, eca flecainide, flerobuterol, Fleroxacin, flesinoxan, Flestolol dotril, ecdisteron, echicetin, echistatin, Echothiophate Sulfate, Fletazepam, flezelastine, flobufen, Floctafenine, flo Iodide, Eclanamine Maleate, EclaZolast, ecomustine, Econa moxef, Flordipine, florfenicol, florifenine, flosatidil, Flose Zole, ecteinascidin 722, edaravone, Edatrexate, edelfosine, quinan, Floxacillin, Floxuridine, fluiasterone, Fluazacort, Edifolone Acetate, edobacomab, Edoxudine, edrecolomab, Flubanilate Hydrochloride, Flubendazole, Flucindole, Flu Edrophonium Chloride, edroxyprogesteone Acetate, efegat cloronide, Fluconazole, Flucytosine, Fludalanine, Fludara ran, efornithine, efonidipine, egualcen, Elantrine, eleatonin, bine Phosphate, Fludazonium Chloride, Fludeoxyglucose F elemene, eletriptan, elgodipine, eliprodil, Elsamitrucin, elte 18, Fludorex, Fludrocortisone Acetate, Flufenamic Acid, nae, Elucaine, emalkalim, emedastine, Emetine Hydrochlo Flufenisal, Flumazenil, flumecinol, Flumequine, Flumeri ride, emiglitate, Emilium Tosylate, emitefur, emoctakin, done, Flumethasone, Flumetramide, FlumeZapine, Flumi Enadoline Hydrochloride, enalapril, Enalaprilat, Enalkiren, norex, Flumizole, Flumoxonide, flunarizine, Flunidazole, enaZadrem, Encyprate, Endralazine MeSylate, EndrySone, Flunisolide, Flunitrazepam, Flunixin, fluocalcitriol, Fluoci Enflurane, englitaZone, Enilconazole, Enisoprost, Enlimo nolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocor mab, Enloplatin, Enofelast, Enolicam Sodium, Enoxacin, tolone, Fluorescein, fluorodaunorunicin hydrochloride, enoxacin, enoxaparin Sodium, Enoxaparin Sodium, Enoxi Fluorodopa F 18, Fluorometholone, Fluorouracil, Flu mone, Enpiroline Phosphate, Enprofylline, Enpromate, enta otracen Hydrochloride, Fluoxetine, Fluoxymesterone, flup capone, enterostatin, Enviradene, EnviroXime, Ephedrine, aroXan, Fluperamide, Fluperolone Acetate, Fluphenazine Epicillin, Epimestrol, Epinephrine, Epinephryl Borate, Decanoate, flupirtine, Fluprednisolone, FluproduaZone, Flu Epipropidine, Epirizole, epirubicin, Epitetracycline Hydro prostenol Sodium, FluguaZone, Fluradoline Hydrochloride, chloride, Epithiazide, Epoetin Alfa, Epoetin Beta, EpoproS Flurandrenolide, Flurazepam Hydrochloride, Flurbiprofen, tenol, Epoprostenol Sodium, epoxymeXrenone, epristeride, Fluretofen, flurithromycin, Flurocitabine, Flurofamide, EproSartan, eptastigmine, equilenin, Equilin, Erbulozole, Flurogestone Acetate, Flurothyl, Fluroxene, Fluspiperone, erdosteine, Ergoloid MeSylates, Ergonovine Maleate, Fluspirilene, Fluticasone Propionate, flutrimazole, Flutro Ergotamine Tartrate, erSentilide, ErSofermin, erythritol, line, fluvastatin, Fluvastatin Sodium, fluvoxamine, FluZina Erythrityl Tetranitrate, Erythromycin, Esmolol Hydrochlo mide, Folic Acid, Follicle regulatory protein, Folliculostatin, ride, Esorubicin Hydrochloride, Esprocquin Hydrochloride, Fomepizole, Fonazine MeSylate, forasartan, forfenimex, for Estazolam, Estradiol, Estramustine, estramustine analogue, fenirmex, formeStane, Formocortal, formoterol, Fosarilate, EstraZinol Hydrobromide, Estriol, Estrofurate, estrogen ago FoSazepam, Foscarnet Sodium, fosfomycin, Fosfonet nists, estrogen antagonists, Estrogens, Conjugated, Estro Sodium, foSinopril, Fosinoprilat, foSphenyloin, Fosquidone, gens, Esterified, Estrone, Estropipate, eSuprone, Etafedrine Fostedil, fostriecin, fotemustine, Fuchsin, Basic, Fumoxicil Hydrochloride, Etanidazole, etanterol, Etarotene, EtaZolate lin, Fungimycin, Furaprofen, Furazolidone, Furazolium Hydrochloride, Eterobarb, ethacizin, Ethacrynate Sodium, Chloride, Furegrelate Sodium, Furobufen, Furodazole, Ethacrynic Acid, Ethambutol Hydrochloride, Ethamivan, Furosemide, Fusidate Sodium, Fusidic Acid, gabapentin, Ethanolamine Oleate, Ethehlorvynol, Ether, Ethinyl estra Gadobenate Dimeglumine, gadobenic acid, gadobutrol, diol, Ethiodized Oil, Ethionamide, Ethonam Nitrate, Etho Gadodiamide, gadolinium teXaphyrin, Gadopentetate propazine Hydrochloride, EthosuXimide, Ethotoin, Ethoxa Dimeglumine, gadoteric acid, Gadoteridol, Gadoverseta Zene Hydrochloride, Ethybenztropine, Ethyl Chloride, Ethyl mide, galantamine, galdansetron, Galdansetron Hydrochlo Dibunate, Ethylestrenol, Ethyndiol, Ethynerone, Ethynodiol ride, Gallamine Triethiodide, gallium nitrate, gallopamil, Diacetate, Etibendazole, Etidocaine, Etidronate Disodium, galocitabine, Gamfexine, gamolenic acid, Ganciclovir, Etidronic Acid, Etifenin, Etintidine Hydrochloride, eti ganirelix, gelatinase inhibitors, Gemcadiol, Gemcitabine, Zolam, Etodolac, Etofenamate, Etoformin Hydrochloride, Gemeprost, Gemfibrozil, Gentamicin Sulfate, Gentian Vio Etomidate, EtonogeStrel, Etoperidone Hydrochloride, Eto let, gepirone, Gestaclone, Gestodene, GeStonorone US 2006/0024365 A1 Feb. 2, 2006 32

Caproate, Gestrinone, GeVotroline Hydrochloride, giriso mine, IoSumetic Acid, IotaSul, Iotetric Acid, Iothalamate pam, glaspimod, glaucocalyxin A, Glemanserin, Gliamilide, Sodium, Iothalamic Acid, iotriside, Iotrolan, IotroXic Acid, Glibornuride, Glicetanile Sodium, Gliflumide, Glimepiride, Iotyrosine 1 131, IoverSol, Ioxagiate Sodium, Ioxaglate Glipizide, Gloximonam, Glucagon, glutapyrone, glutathione Meglumine, Ioxaglic Acid, ioxilan, Ioxotrizoic Acid, ipazil inhibitors, Glutethimide, Glyburide, glycopine, glycopril, ide, ipenoxazone, ipidacrine, Ipodate Calcium, ipomeanol, Glycopyrrolate, Glyhexamide, Glymidine Sodium, Glyoc 4-, pratropium Bromide, ipriflavone, Iprindole, Iprofenin, tamide, Glyparamide, Gold Au 198, Gonadoctrinins, Gona Ipronidazole, proplatin, Iproxamine Hydrochloride, ipsa dorelin, Gonadotropins, Goserelin, Gramicidin, Granisetron, pirone, irbesartan, irinotecan, irloxacin, iroplact, irSoglad grepafloxacin, Griseofulvin, Guaiapate, Guaithylline, Gua ine, Irtemazole, isalsteine, Isamoxole, isbogrel, Isepamicin, nabenz, Guanabenz, Acetate, Guanadrel Sulfate, Guancy isobengaZole, Isobutamben, Isocarboxazid, ISOconazole, dine, Guanethidine Monosulfate, Guanfacine Hydrochlo Isoetharine, isofloxythepin, Isoflupredone Acetate, Isoflu ride, Guanisoquin Sulfate, Guanoclor Sulfate, Guanoctine rane, Isoflurophate, isohomohalicondrin B, Isoleucine, Iso Hydrochloride, GuanoXabenz, Guanoxan Sulfate, Guanoxy mazole Hydrochloride, Isomylamine Hydrochloride, Iso fen Sulfate, Gusperimus Trihydrochloride, Halazepam, Hal niazid, Isopropamide Iodide, Isopropyl Alcohol, isopropyl cinonide, halichondrin B, Halobetasol Propionate, halofan unoprostone, Isoproterenol Hydrochloride, ISOSorbide, ISOS trine, Halofantrine Hydrochloride, Halofenate, orbide Mononitrate, Isotiquimide, Isotretinoin, ISOXepac, Halofuginone Hydrobromide, halomon, Halopemide, Halo ISOXicam, ISOXSuprine Hydrochloride, isradipine, itameline, peridol, halopredone, Haloprogesterone, Haloprogin, Hal itasetron, ItaZigrel, itopride, Itraconazole, Ivermectin, jas othane, Halquinols, Hamycin, Han memopausal gonadotro plakinolide, Josamycin, kahalalide F, Kalafungin, Kanamy pins, hatomamicin, hatomarubigin A, hatomarubigin B, cin Sulfate, Ketamine Hydrochloride, Ketanserin, Ketazo hatomarubigin C, hatomarubigin D, Heparin Sodium, hep cine, Ketazolam, Kethoxal, Ketipramine Fumarate, Sulfam, heregulin, Hetacillin, Heteronium Bromide, Ketoconazole, Ketoprofen, Ketorfanol, ketorolac, Ketotifen Hexachlorophene:Hydrogen Peroxide, Hexafluorenium Fumarate, Kitasamycin, Labetalol Hydrochloride, Lacid Bromide, hexamethylene bisacetamide, Hexedine, Hex ipine, lacidipine, lactitol, lactivicin, laennec, lafutidine, obendine, Hexoprenaline Sulfate, Hexylresorcinol, Hista lamellarin-N triacetate, lamifiban, Lamivudine, Lamot mine Phosphate, Histidine, Histoplasmin, Histrelin, Homa rigine, lanoconazole, Lanoxin, lanperisone, lanreotide, Lan tropine Hydrobromide, Hoquizil Hydrochloride, Human Soprazole, latanoprost, lateritin, laurocapram, Lauryl Iso chorionic gonadotropin, Hycanthone, Hydralazine Hydro quinolinium Bromide, LaVoltidine Succinate, lazabemide, chloride, Hydralazine Polistirex, Hydrochlorothiazide, Lecimibide, leinamycin, lemildipine, leminoprazole, lener Hydrocodone Bitartrate, Hydrocortisone, Hydroflumethiaz cept, Leniquinsin, lenograstim, Lenperone, lentinan Sulfate, ide, Hydromorphone Hydrochloride, Hydroxyamphetamine leptin, leptolstatin, lercanidipine, Lergotrile, lerisetron, Hydrobromide, Hydroxychloroquine Sulfate, Hydroxyphe Letimide Hydrochloride, letraZuril, letrozole, Leucine, leu namate, Hydroxyprogesterone Caproate, Hydroxyurca, comyzin, Leuprolide Acetate, leuprolide--estrogen-proges Hydroxyzine Hydrochloride, Hymecromone, Hyoscyamine, terone, leuprorelin, Levamfetamine Succinate, levamisole, hypericin, Ibafloxacin, ibandronic acid, ibogaine, Ibopam Levdobutamine Lactobionate, Leveromakalim, levetirac ine, ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icati etam, Levey closerine, leVobetaxolol, levobunolol, levobupi bant Acetate, Ichthammol, Icotidine, idarubicin, idoxifene, vacaine, levocabastine, levocarnitine, Levodopa, levodro Idoxuridine, idramantone, Iemefloxacin, IeSopitron, propizine, levofloxacin, Levofuraltadone, Levoleucovorin Ifetroban, Ifosfamide, Ilepeimide, illimaquinone, ilmofoS Calcium, Levomethadyl Acetate, Levomethadyl Acetate ine, ilomastat, Ilonidap, illoperidone, iloprost, Imafen Hydro Hydrochloride, levomoprolol, Levonantradol Hydrochlo chloride, ImaZodan Hydrochloride, imidapril, imidazenil, ride, Levonordefrin, Levonorgestrel, Levopropoxyphene imidazoacridones, Imidecyl Iodine, Imidocarb Hydrochlo NapSylate, Levopropylcillin Potassium, leVormeloxifene, ride, Imidoline Hydrochloride, Imidurea, Imiloxan Hydro Levorphanol Tartrate, levosimendan, levOSulpiride, chloride, Imipenem, Imipramine Hydrochloride, imiqui Levothyroxine Sodium, Levoxadrol Hydrochloride, Lexi mod, immunostimulant peptides, Impromidine pafant, Lexithromycin, liarozole, Libenzapril, Lidamidine Hydrochloride, Indacrinone, Indapamide, Indecainide Hydrochloride, Lidocaine, Lidofenin, Lidoflazine, Lifariz Hydrochloride, Indeloxazine Hydrochloride, Indigotindisul ine, Lifibrate, Lifibrol, Linarotene, Lincomycin, linear fonate Sodium, indinavir, Indocyanine Green, Indolapril polyamine analogue, Linogliride, Linopirdine, linotroban, Hydrochloride, Indolidan, indometacin, Indomethacin linsidomine, lintitript, lintopride, Liothyronine I 125, liothy Sodium, Indoprofen, indoramin, Indorenate Hydrochloride, ronine Sodium, Liotrix, lirexapride, lisinopril, lisSoclinamide Indoxole, Indriline Hydrochloride, inocoterone, inogatran, 7, Lixazinone Sulfate, lobaplatin, Lobenzarit Sodium, Lobu inolimomab, InoSitol Niacinate, Insulin, interferons, inter cavir, Lodelaben, Iodoxamide, Lofemizole Hydrochloride, leukins, Intrazole, Intriptyline Hydrochloride, iobenguane, Lofentanil Oxalate, Lofepramine Hydrochloride, Lofexidine Iobenzamic Acid, iobitridol, Iocarmate Meglumine, Iocar Hydrochloride, lombricine, Lomefloxacin, lomerizine, mic Acid, Iocetamic Acid, Iodamide, Iodine, Iodipamide Lometraline Hydrochloride, lometrexol, Lomofungin, Meglumine, Iodixanol, iodoamiloride, Iodoantipyrine I 131, Lomoxicam, Lomustine, Lonapalene, lonazolac, Iodocholesterol I 131, iododoxorubicin, Iodohippurate lonidamine, Loperamide Hydrochloride, loracarbef, Sodium I 131, Iodopyracet I 125, Iodoquinol, Iodoxamate Lorajmine Hydrochloride, loratadine, Lorazepam, Lorbam Meglumine, Iodoxamie Acid, Ioglicic Acid, Iofetamine ate, Lorcainide Hydrochloride, LorecleZole, Loreinadol, lor Hydrochloride I 123, iofratol, Ioglucol, Ioglucomide, Iogly glumide, Lormetazepam, Lornoxicam, lornoxicam, Lorta camic Acid, Iogulamide, Iohexol, iomeprol, Iomethin I 125, lamine, LorZafone, losartan, losigamone, loSOXantrone, Iopamidol, Iopanoic Acid, iopentol, Iophendylate, Ioproce LOSulazine Hydrochloride, loteprednol, lovastatin, loviride, mic Acid, iopromide, Iopronic Acid, Iopydol, Iopy done, Loxapine, Loxoribine, lubeluzole, Lucanthone Hydrochlo iopyrol, Iosefamic Acid, IoSeric Acid, IoSulamide Meglu ride, Lufironil, Lurosetron MeSylate, lurtotecan, luteinizing US 2006/0024365 A1 Feb. 2, 2006 33 hormone, lutetium, Lutrelin Acetate, luZindole, Lyapolate cin Hydrochloride, Mirisetron Maleate, Mirtazapine, mis Sodium, Lycetamine, lydicamycin, Lydimycin, Lynestrenol, matched double stranded RNA, Misonidazole, Misoprostol, Lypressin, Lysine, lySofylline, lysostaphin, lytic peptides, Mitindomide, Mitocarcin, Mitocromin, Mitogillin, mitogua Maduramicin, Mafenide, magainin 2 amide, Magnesium Zone, mitolactol, Mitomalcin, Mitomycin, mitonafide, Mito Salicylate, Magnesium Sulfate, magnolol, maitansine, Male Sper, Mitotane, mitoxantrone, mivacurium chloride, mivaZ thamer, mallotochromene, mallotojaponin, Malotilate, erol, mixanpril, Mixidine, mizolastine, mizoribine, malotilate, mangafodipir, manidipine, maniwamycin A, Moclobemide, modafinil, Modaline Sulfate, Modecainide, Mannitol, mannostatin A, manumycin E, manumycin F, moexipril, mofarotene, Mofegiline Hydrochloride, mof mapinastine, Maprotiline, marimastat, Martek 158708, Mar eZolac, molgramoStim, MolinaZone, Molindone Hydrochlo tek 92211, Masoprocol, maspin, massetolide, matrily Sin ride, Molsidomine, mometasone, Monatepil Maleate, Mon inhibitors, Maytansine, Mazapertine Succiniate, Mazindol, ensin, Monoctanoin, Montelukast Sodium, montirelin, Mebendazole, Mebeverine Hydrochloride, Mebrofenin, mopidamol, moracizine, Morantel Tartrate, Moricizine, Mebutamate, Mecamylamine Hydrochloride, Mechlore Morniflumate, Morphine Sulfate, Morrhuate Sodium, thamine Hydrochloride, Meclocycline, Meclofenamate mosapramine, mosapride, motilide, Motretinide, Moxalac Sodium, Mecloqualone, Meclorisone Dibutyrate, tam Disodium, Moxazocine, moxiraprine, Moxinidazole, Medazepam Hydrochloride, Medorinone, Medrogestone, moxonidine, Mumps Skin Test Antigen, mustard anticancer Medroxalol, Medroxyprogesterone, Medrysone, Meelizine agent, Muzolimine, mycaperoxide B, Mycophenolic Acid, Hydrochloride, Mefenamic Acid, Mefenidil, Mefenorex myriaporone, Nabazenil, Nabilone, Nabitan Hydrochloride, Hydrochloride, Mefexamide, Mefloquine Hydrochloride, Naboctate Hydrochloride, Nabumetone, N-acetyldinaline, Mefruside, Megalomicin Potassium Phosphate, Megestrol Nadide, nadifloxacin, Nadolol, nadroparin calcium, nafadot Acetate, Meglumine, Meglutol, Melengestrol Acetate, Meli ride, nafamoStat, nafarelin, Nafcillin Sodium, Nafenopin, tracen Hydrochloride, Melphalan, Memotine Hydrochlo Nafimidone Hydrochloride, Naflocort, Nafomine Malate, ride, Menabitan Hydrochloride, Menoctone, menogaril, Nafoxidine Hydrochloride, Nafronyl Oxalate, Naftifine Menotropins, Meobentine Sulfate, Mepartricin, Mepen Hydrochloride, naftopidil, naglivan, nagreStip, Nalbuphine Zolate Bromide, Meperidine Hydrochloride, Mephentermine Hydrochloride, Nalidixate Sodium, Nalidixic Acid, Sulfate, Mephenyloin, Mephobarbital, Mepivacaine Hydro nalmefene, NalmeXOne Hydrochloride, naloxone-pentazo chloride, Meprobamate, Meptazinol Hydrochloride, Mequi cine, Naltrexone, NamoXyrate, Nandrolone Phenpropionate, dox, Meralein Sodium, merbarone, Mercaptopurine, Mer Nantradol Hydrochloride, Napacitadine Hydrochloride, cufenol Chloride, Mercury, Ammoniated, Merisoprol Hg napadisilate, Napamezole Hydrochloride, napavin, Nap 197, Meropenem, Mesalamine, Meseclazone, Mesoridazine, hazoline Hydrochloride, naphterpin, Naproxen, NaproXol, Mesterolone, Mestranol, Mesuprine Hydrochloride, Metalol napsagatran, Naranol Hydrochloride, Narasin, naratriptan, Hydrochloride, Metaproterenol Polistirex, Metaraminol nartograstim, nasaruplase, Natamycin, nateplase, Nax Bitartrate, Metaxalone, Meteneprost, meterelin, Metformin, agolide Hydrochloride, Nebivolol, Nebramycin, nedaplatin, Methacholine Chloride, Methacycline, Methadone Hydro Nedocromil, Nefazodone Hydrochloride, Neflumozide chloride, Methadyl Acetate, Methalthiazide, Methamphet Hydrochloride, Nefopam Hydrochloride, NeleZaprine Male amine Hydrochloride, Methaqualone, Methazolamide, ate, Nemazoline Hydrochloride, nemorubicin, Neomycin Methdilazine, Methenamine, Methenolone Acetate, Meth Palmitate, Neostigmine Bromide, neridronic acid, Netilmi etoin, Methicillin Sodium, Methimazole, methioninase, cin Sulfate, neutral endopeptidase, Neutramycin, Nevirap Methionine, Methisazone, Methixene Hydrochloride, ine, Nexeridine Hydrochloride, Niacin, Nibroxane, Nicar Methocarbamol, Methohexital Sodium, Methopholine, dipine Hydrochloride, Nicergoline, Niclosamide, Methotrexate, Methotrimeprazine, methoxatone, Methoxy Nicorandil, Nicotinyl Alcohol, Nifedipine, Nifirmerone, flurane, MethSuximide, Methyclothiazide, Methyl 10 Pal Nifluridide, Nifuradene, Nifuraldezone, Nifuratel, Nifura moxirate, Methylatropine Nitrate, Methylbenzethonium trone, Nifurdazil, Nifurimide, Nifurpirinol, Nifurcquinazol, Chloride, Methyldopa, Methyldopate Hydrochloride, Meth Nifurthiazole, nilutamide, Nilvadipine, Nimazone, Nimo ylene Blue, Methylergonovine Maleate, methylhistamine, dipine, niperotidine, niravoline, Niridazole, nisamycin, Nis R-alpha, methylinosine monophosphate, Methylphenidate buterol Mesylate, nisin, Nisobamate, Nisoldipine, Nisoxet Hydrochloride, Methylprednisolone, Methyltestosterone, ine, Nisterime Acetate, NitarSone, nitaZOXamide, Methynodiol Diacelate, Methysergide, Methysergide Male nitecapone, Nitrafudam Hydrochloride, Nitralamine Hydro ate, Metiamide, Metiapine, Metioprim, metipamide, chloride, Nitramisole Hydrochloride, Nitrazepam, Nitren Metipranolol, Metizoline Hydrochloride, Metkephamid dipine, Nitrocycline, Nitrodan, Nitrofurantoin, Nitrofura Acetate, metoclopramide, Metocurine Iodide, Metogest, Zone, Nitroglycerin, Nitromersol, Nitromide, Nitromifene Metolazone, Metopimazine, Metoprine, Metoprolol, Meto Citrate, Nitrous Oxide, nitroxide antioxidant, nitrullyn, quizine, metrifonate, Metrizamide, Metrizoate Sodium, Nivazol, Nivinmedone Sodium, Nizatidine, Noberastine, Metronidazole, Meturedepa, Metyrapone, Metyrosine, Nocodazole, Nogalamycin, Nolinium Bromide, Mexiletine Hydrochloride, Mexrenoate Potassium, Nomifensine Maleate, Noracymethadol Hydrochloride, Mezlocillin, mfonelic Acid, Mianserin Hydrochloride, Norbolethone, Norepinephrine Bitartrate, Norethindrone, mibefradil, Mibefradil Dihydrochloride, Mibolerone, mich Norethynodrel, Norfloxacin, Norflurane, Norgestimate, ellamine B, Miconazole, microcolin A, Midaflur, Mida Norgestomet, Norgestrel, Nortriptyline Hydrochloride, Nos Zolam Hydrochloride, midodrine, mifepristone, Mifobate, capine, Novobiocin Sodium, N-substituted benzaimides, miglitol, millacemide, milameline, mildronate, Milenperone, Nufenoxole, Nylestriol, Nystatin, O6-benzylguanine, Obi Milipertine, milnacipran, Milrinone, miltefosine, Mimbane doxime Chloride, Ocaperidone, Ocfentanil Hydrochloride, Hydrochloride, minaprine, Minaxolone, Minocromil, Ocinaplon, Octanoic Acid, OctaZamide, Octenidine Hydro Minocycline, Minoxidil, Mioflazine Hydrochloride, mioka chloride, Octodrine, Octreotide, Octriptyline Phosphate, mycin, mipragoside, mirfentanil, mirimoStim, Mirincamy Ofloxacin, Oformine, okicenone, Olanzapine, oligonucle US 2006/0024365 A1 Feb. 2, 2006 34 otides, olopatadine, olprinone, olSalazine, Olsalazine pimilprost, Pimobendan, Pimozide, Pinacidil, Pinadoline, Sodium, Olvanil, omeprazole, onapristone, ondansetron, Pindolol, pinnenol, pinocebrin, Pinoxepin Hydrochloride, Ontazolast, Oocyte maturation inhibitor, Opipramol Hydro pioglitaZone, Pipamperone, Pipazethate, pipecuronium bro chloride, oracin, Orconazole Nitrate, Orgotein, Orlislat, mide, Piperacetazine, Piperacillin Sodium, Piperamide Ormaplatin, Ormetoprim, Ornidazole, Orpanoxin, Maleate, piperazine, Pipobroman, Piposulfan, Pipotiazine Orphenadrine Citrate, OSaterone, otenZepad, Oxacillin Palmitate, Pipoxolan Hydrochloride, Piprozolin, Piquindone Sodium, OXagrelate, Oxaliplatin, OXamarin Hydrochloride, Hydrochloride, Piquizil Hydrochloride, Piracetam, Piran oxamisole, Oxamniquine, Oxandrolone, Oxantel Pamoate, damine Hydrochloride, pirarubicin, Pirazmonam Sodium, Oxaprotiline Hydrochloride, Oxaprozin, Oxarbazole, Pirazolac, Pirbenicillin Sodium, Pirbuterol Acetate, Piren Oxatomide, oxaunomycin, Oxazepam, Oxcarbazepine, perone, Pirenzepine Hydrochloride, piretamide, Pirfeni Oxendolone, Oxethazaine, Oxetorone Fumarate, Oxfenda done, Piridicillin Sodium, Piridronate Sodium, Piriprost, Zole, Oxfenicine, Oxibendazole, oxiconazole, Oxidopamine, piritrexim, Pirlimycin Hydrochloride, pirlindole, pirmagrel, Oxidronic Acid, Oxifungin Hydrochloride, Oxilorphan, Pirmenol Hydrochloride, Pirnabine, Piroctone, Pirodavir, OXimonam, OXimonam Sodium, OXiperomide, OXiracetam, pirodomast, Pirogliride Tartrate, Pirolate, Pirolazamide, Oxiramide, Oxisuran, Oxmetidine Hydrochloride, oxo Piroxantrone Hydrochloride, Piroxicam, Piroximone, Pir dipine, Oxogestone Phenpropionate, OXolinic Acid, Oxpre profen, Pirquinozol, Pirsidomine, Prenylamine, Pituitary, nolol Hydrochloride, Oxtriphylline, Oxybutynin Chloride, Posterior, Pivampicillin Hydrochloride, Pivopril, Pizotyline, Oxychlorosene, Oxycodone, Oxymetazoline Hydrochloride, placetin A, platinum compounds, platinum-triamine com Oxymetholone, Oxymorphone Hydrochloride, Oxypertine, plex, Plicamycin, Plomestane, Pobilukast Edamine, Podo OxyphenbutaZone, Oxypurinol, Oxytetracycline, Oxytocin, filox, Poisonoak Extract, Poldine Methylsulfate, Poliglusam, OZagrel, Ozolinone, Paclitaxel, palauamine, Paldimycin, Polignate Sodium, Polymyxin B Sulfate, Polythiazide, palinavir, palmitoylrhizoxin, Palmoxirate Sodium, pam Ponalrestat, Porfimer Sodium, Porfiromycin, Potassium aqueside, Pamatolol Sulfate, pamicogrel, Pamidronate Diso Chloride, Potassium Iodide, Potassium Permanganate, Povi dium, pamidronic acid, Panadiplon, panamesine, panax done-Iodine, Practolol, Pralidoxime Chloride, Pramiracetam ytriol, Pancopride, Pancuronium Bromide, panipenem, Hydrochloride, Pramoxine Hydrochloride, Pranolium Chlo pannorin, panomifene, pantethine, pantoprazole, Papaverine ride, Pravadoline Maleate, Pravastatin (Pravachol), Hydrochloride, parabactin, Parachlorophenol, Paraldehyde, Prazepam, Prazosin, Prazosin Hydrochloride, Prednazate, Paramethasone Acetate, Paranyline Hydrochloride, Parap Prednicarbate, Prednimustine, Prednisolone, Prednisone, enzolate Bromide, Pararosaniline Pamoate, Parbendazole, Prednival, Pregnenolone Succiniate, Prenalterol Hydrochlo Parconazole Hydrochloride, Paregoric, Pareptide Sulfate, ride, Pridefine Hydrochloride, Prifelone, Prilocalne Hydro Pargyline Hydrochloride, parnaparin Sodium, Paromomycin chloride, Prilosec, Primaquine Phosphate, Primidolol, Sulfate, Paroxetine, parthenolide, Partricin, Paulomycin, Primidone, Prinivil, prinomide Tromethamine, Prinoxodan, paZelliptine, PaZinaclone, PaZOxide, paZufloxacin, pefloxa Prizidilol Hydrochloride, Proadifen Hydrochloride, cin, pegaspargase, Pegorgotein, Pelanserin Hydrochloride, Probenecid, Probicromil Calcium, Probucol, Procainamide peldesine, Peliomycin, Pelretin, Pelrinone Hydrochloride, Hydrochloride, Procaine Hydrochloride, Procarbazine Pemedolac, Pemerid Nitrate, pemirolast, Pemoline, Pena Hydrochloride, Procaterol Hydrochloride, Prochlorperazine, mecillin, Penbutolol Sulfate, Penciclovir, Penfluridol, Peni Procinonide, Proclonol, Procyclidine Hydrochloride, Prodi cillin G BenZathine, Penicillin G Potassium, Penicillin G lidine Hydrochloride, Prodolic Acid, Profadol Hydrochlo Procaine, Penicillin G Sodium, Penicillin V, Penicillin V ride, Progabide, Progesterone, Proglumide, Proinsulin Benzathine, Penicillin V Hydrabamine, Penicillin V Potas Human, Proline, Prolintane Hydrochloride, Promazine sium, Pentabamate, Pentaerythritol Tetranitrate, pentafuside, Hydrochloride, Promethazine Hydrochloride, Propafenone pentamidine, pentamorphone, Pentamustine, Pentapiperium Hydrochloride, propagermanium, Propanidid, Propantheline Methylsulfate, Pentazocine, Pentetic Acid, Pentiapine Male Bromide, Proparacaine Hydrochloride, Propatyl Nitrate, ate, pentigetide, Pentisomicin, Pentizidone Sodium, Pento propentofylline, Propenzolate Hydrochloride, Propikacin, barbital, Pentomone, Pentopril, pentosan, pentostatin, Pen Propiomazine, Propionic Acid, propionylcarnitine, L-, toxifylline, Pentrinitrol, pentrozole, Peplomycin Sulfate, propiram, propiram-paracetamol, propiverine, Propofol, Pepstatin, perflubron, perfofamide, Perfosfamide, pergolide, Propoxycaine Hydrochloride, Propoxyphene Hydrochlo Perhexiline Maleate, perillyl alcohol, Perindopril, perindop ride, Propranolol Hydrochloride, Propulsid, propyl bis-ac rilat, Perlapine, Permethrin, peroSpirone, Perphenazine, ridone, Propylhexedrine, Propyliodone, Propylthiouracil, Phenacemide, phenaridine, phenazinomycin, PhenaZopyri ProquaZone, Prorenoate Potassium, Proroxan Hydrochlo dine Hydrochloride, Phenbutazone Sodium Glycerate, Phen ride, Proscillaridin, Prostalene, prostratin, Protamine Sul carbamide, Phencyclidine Hydrochloride, Phendimetrazine fate, protegrin, Protirelin, protoSufloxacin, Protriptyline Tartrate, Phenelzine Sulfate, Phenmetrazine Hydrochloride, Hydrochloride, Proxazole, Proxazole Citrate, ProXicromil, Phenobarbital, Phenoxybenzamine Hydrochloride, Phen Proxorphan Tartrate, prulifloxacin, Pseudoephedrine Hydro procoumon, phenserine, phensuccinal, PhenSuximide, Phen chloride, Puromycin, purpurins, Pyrabrom, Pyrantel, Pamo termine, Phentermine Hydrochloride, phentolamine mesi ate, Pyrazinamide, Pyrazofurin, pyrazoloacridine, Pyri late, Phentoxifylline, Phenyl AminoSalicylate, dostigmine Bromide, Pyrilamine Maleate, Pyrimethamine, phenylacetate, Phenylalanine, phenylalanyl ketoconazole, Pyrinoline, Pyrithione Sodium, Pyrithione Zinc, Pyrovale Phenylbutazone, Phenylephrine Hydrochloride, Phenylpro rone Hydrochloride, Pyroxamine Maleate, Pyrrocaine, Pyr panolamine Hydrochloride, Phenylpropanolamine Polis roliphene Hydrochloride, Pyrrolnitrin, Pyrvinium Pamoate, tirex, Phenyramidol Hydrochloride, Phenyloin, phosphatase Quadazocine MeSylate, Quazepam, Quazinone, QuaZodine, inhibitors, PhySoStigmine, picenadol, picibanil, Picotrin QuaZolast, quetiapine, quiflapon, quinagolide, Quinaldine Diolamine, picroliv, picumeterol, pidotimod, Pifamine, Pilo Blue, quinapril, Quinaprilat, QuinaZOsin Hydrochloride, carpine, pilsicainide, pimagedine, Pimetine Hydrochloride, Quinbolone, Quinctolate, Quindecamine Acetate, Quindo US 2006/0024365 A1 Feb. 2, 2006 35 nium Bromide, Quinelorane Hydrochloride, Quinestrol, Sulfate, Spectinomycin Hydrochloride, Spicamycin D, Spip Quinfamide, QuingeStanol Acetate, Quingestrone, Quini erone, Spiradoline MeSylate, Spiramycin, Spirapril Hydro dine Gluconate, Quinielorane Hydrochloride, Quinine Sul chloride, Spiraprilat, Spirogermanium Hydrochloride, fate, Quinpirole Hydrochloride, Quinterenol Sulfate, Qui Spiromustine, Spironolactone, Spiroplatin, SpiroXasone, nuclium Bromide, Quinupristin, Quipazine Maleate, Splenopentin, Spongistatin 1, Sprodiamide, Squalamine, Stal Rabeprazole Sodium, Racephenicol, Racepinephrine, raf limycin Hydrochloride, Stannous Pyrophosphate, Stannous antagonists, RafoXamide, Ralitoline, raloxifene, raltitrexed, Sulfur Colloid, Stanozolol, Statolon, stauroSporine, Stavu ramatroban, Ramipril, Ramoplanin, ramosetron, ranelic dine, Steffimycin, Stenbolone Acetate, Stepronin, Stilbazium acid, Ranimycin, Ranitidine, ranolazine, Rauwolfia Serpen Iodide, Stilonium Iodide, Stipiamide, Stiripentol, Stobadine, tina, recainam, Recainam Hydrochloride, Reclazepam, Streptomycin Sulfate, StreptonicOZid, Streptonigrin, Strep regaVirumab, RegramoStim, Relaxin, Relomycin, Remace tozocin, stromelysin inhibitors, Strontium Chloride Sr 89, mide Hydrochloride, Remifentanil Hydrochloride, Remi Succibun, Succimer, Succinylcholine Chloride, Sucralfate, prostol, Remoxipride, Repirinast, Repromicin, Reproterol Sucrosofate Potassium, Sudoxicam, Sufentanil, Sufotidine, Hydrochloride, Reserpine, resinferatoxin, Resorcinol, retel Sulazepam, Sulbactam Pivoxil, Sulconazole Nitrate, Sulfa liptine demethylated, reticulon, reviparin Sodium, reviz benz, Sulfabenzamide, Sulfacetamide, Sulfacytine, Sulfadi inone, rhenium Re 186 etidronate, rhizoxin, Ribaminol, azine, Sulfadoxine, Sulfalene, Sulfamerazine, Sulfameter, Ribavirin, Riboprine, ribozymes, ricasetron, Ridogrel, Sulfamethazine, Sulfamethizole, Sulfamethoxazole, Sulfa Rifabutin, Rifametane, Rifamexil, Rifamide, Rifampin, monomethoxine, Sulfamoxole, Sulfanilate Zinc, Sulfanit Rifapentine, Rifaximin, R11 retinamide, rilopirox, Riluzole, ran, SulfaSalazine, SulfaSomizole, Sulfazamet, Sulfinalol rimantadine, Rimcazole Hydrochloride, Rimexolone, Rim Hydrochloride, Sulfinosine, Sulfinpyrazone, Sulfisoxazole, iterol Hydrobromide, rimoprogin, riodipine, Rioprostil, Sulfomyxin, Sulfonterol Hydrochloride, Sulfoxamine, Ripazepam, ripisartan, Risedronate Sodium, risedronic acid, Sulinldac, Sulmarin, Sulnidazole, Suloctidil, Sulofenur, Risocaine, Risotilide Hydrochloride, rispenzepine, Risper Sulopenem, Suloxifen Oxalate, Sulpiride, Sulprostone, Sul dal, Risperidone, Ritanserin, ritipenem, Ritodrine, tamicillin, Sulthiame, Sultopride, Sulukast, Sumaroteine, Ritolukast, ritonavir, rizatriptan benzoate, Rocastine Hydro Sumatriptan, Suncillin Sodium, Suproclone, Suprofen, Sura chloride, Rocuronium Bromide, Rodocaine, Roflurane, dista, Suramin, Surfomer, Suricainide Maleate, SuritoZole, Rogletimide, rohitukine, rokitamycin, Roletamicide, Rolga Suronacrine Maleate, Suxemerid Sulfate, Swainsonine, midine, Rolicyprine, Rolipram, Rolitetracycline, Rolodine, Symakalim, Symclosene, Symetine Hydrochloride, Synthetic Romazarit, romurtide, Ronidazole, ropinirole, Ropitoin glycosaminoglycans, Taciamine Hydrochloride, Tacrine Hydrochloride, ropivacaine, Ropizine, roquinimex, Rosa Hydrochloride, Tacrolimus, Talampicillin Hydrochloride, ramicin, RoSoxacin, Rotoxamine, roXaitidine, RoxarSone, Taleranol, Talisomycin, tallimustine, Talmetacin, Talniflu roXindole, roXithromycin, rubiginone Bi, ruboxyl, rufloxa mate, Talopram Hydrochloride, Talosalate, Tametraline cin, rupatidine, Rutamycin, ruzadolane, Sabeluzole, Safin Hydrochloride, Tamoxifen, Tampramine Fumarate, Tamsu gol, Safironil, Saintopin, Salbutamol, R-, Salcolex, Saletha losin Hydrochloride, Tandamine Hydrochloride, tan mide Maleate, Salicyl Alcohol, Salicylamide, Salicylate doSpirone, tapgen, taprostene, TaSOSartan, tauromustine, Meglumine, Salicylic Acid, Salmeterol, Salnacedin, Sal Taxane, Taxoid, Tazadolene Succinate, taZanolast, tazaro Salate, Sameridine, Sampatrilat, Sancycline, Sanfetrinem, tene, Tazifylline Hydrochloride, Tazobactam, Tazofelone, Sanguinarium Chloride, Saperconazole, Saprisartan, Saprop Tazolol Hydrochloride, Tebufelone, Tebuduine, Technetium terin, Saquinavir, Sarafloxacin Hydrochloride, Saralasin Tc 99 m Bicisate, Teclozan, Tecogalan Sodium, Teecleukin, Acetate, SarCNU, Sarcophytol A, SargramoStim, Sarmox Teflurane, Tegafur, Tegretol, Teicoplanin, telenzepine, tellu icillin, Sarpicillin, Sarpogrelate, Saruplase, Saterinone, Sati rapyrylium, telmesteine, telmisartan, telomerase inhibitors, grel, Satumomab pendetide, Schick Test Control, Scopafun Teloxantrone Hydrochloride, Teludipine Hydrochloride, gin, Scopolamine Hydrobromide, Scrazaipine Temafloxacin Hydrochloride, Tematropium Methyl sulfate, Hydrochloride, Sdi 1 mimetics, Secalciferol, Secobarbital, Temazepam, Temelastine, temocapril, Temocillin, temopor Seelzone, Seglitide Acetate, Selegiline, Selegiline Hydro fin, temozolomide, Tenidap, TenipoSide, tenosal, tenoxicam, chloride, Selenium Sulfide, Selenomethionine Se 75, Selfo tepirindole, Tepoxalin, Teprotide, teraZosin, Terbinafine, tel, Sematilide, Semduramicin, Semotiadil, Semustine, Sense Terbutaline Sulfate, Terconazole, terfenadine, terflavoxate, oligonucleotides, Sepazonium Chloride, Seperidol Hydro terguride, Teriparatide Acetate, terlakiren, terlipressin, chloride, Seprilose, Seproxetine Hydrochloride, Seractide terodiline, Teroxalene Hydrochloride, Teroxirone, tertatolol, Acetate, Sergolexole Maleate, Serine, Sermetacin, Sermo TeSicam, Tesimide, TeStolactone, Testosterone, Tetracaine, relin Acetate, Sertaconazole, Sertindole, Sertraline, Setip tetrachlorodecaoxide, Tetracycline, Tetrahydrozoline tiline, Setoperone, Sevirumab, Sevoflurane, SeZolamide, Hydrochloride, Tetramisole Hydrochloride, Tetrazolast Sibopirdine, Sibutramine Hydrochloride, signal transduc Meglumine, tetraZomine, TetrofoSmin, Tetroquinone, tion inhibitors, Silandrone, silipide, silteplase, Silver Nitrate, Tetroxoprim, Tetrydamine, thaliblastine, Thalidomide, Simendan, SimtraZene, Simvastatin, Sincalide, Sinefungin, Theofibrate, Theophylline, Thiabendazole, Thiamiprine, Sinitrodil, Sinnabidol, Sipatrigine, Sirolimus, Sisomicin, Sito Thiamphenicol, Thiamylal, Thiazesim Hydrochloride, Thi gluSide, sizofiran, Sobu ZOxane, Sodium AmyloSulfate, azinamium Chloride, Thiethylperazine, Thimerfonate Sodium Iodide I 123, Sodium Nitroprusside, Sodium Oxy Sodium, Thimerosal, thiocoraline, thiofedrine, Thioguanine, bate, Sodium phenylacetate, Sodium Salicylate, Solverol, thiomarinol, Thiopental Sodium, thioperamide, Thior Solypertine Tartrate, Somalapor, Somantadine Hydrochlo idazine, Thiotepa, Thiothixene, Thiphenamil Hydrochloride, ride, Somatomedin B, Somatomedin C, Somatrem, Somatro Thiphencillin Potassium, Thiram, Thozalinone, Threonine, pin, Somenopor, Somidobove, Sonermin, Sorbinil, Sorivu Thrombin, thrombopoietin, thrombopoietin mimetic, thy dine, Sotalol, Soterenol Hydrochloride, Sparfloxacin, malfasin, thymopoietin receptor agonist, thymotrinan, Thy Sparfosate Sodium, Sparfosic acid, SparSomycin, Sparteine romedan Hydrochloride, Thyroxine 1125, Thyroxine 1131, US 2006/0024365 A1 Feb. 2, 2006 36

Tiacrilast, Tiacrilast Sodium, tiagabine, Tiamenidine, Verlukast, Verofylline, Veroxan, Verteporfin, Vesnarinone, tianeptine, tiapafant, Tiapamil Hydrochloride, Tiaramide vexibinol, Vidarabine, vigabatrin, Viloxazine Hydrochlo Hydrochloride, Tiazofurin, Tibenelast Sodium, Tibolone, ride, Vinblastine Sulfate, vinburnine citrate, Vincofos, vin Tibric Acid, Ticabesone Propionate, Ticarbodine, Ticarcillin conate, Vincristine Sulfate, Vindesline, Vindesline Sulfate, Cresyl Sodium, Ticlatone, ticlopidine, Ticrynafen, tienox Vinepidine Sulfate, Vinglycinate Sulfate, Vinleurosine Sul olol, Tifurac Sodium, Tigemonam Dicholine, Tigestol, Tile fate, Vinorelbine, Vinpocetine, Vintoperol, VinXaltine, Vinzo tamine Hydrochloride, Tilidine Hydrochloride, tilisolol, til lidine Sulfate, Viprostol, Virginiamycin, Viridofulvin, noprofen arbamel, Tilorone Hydrochloride, Tiluldronate ViroXime, Vitaxin, Volazocine, Voriconazole, Vorozole, VOX Disodium, tiludronic acid, Timefurone, Timobesone ergolide, Warfarin Sodium, Xamoterol, Xanomeline, Xan Acetate, Timolol, tin ethyl etiopurpurin, Tinabinol, Timida Oxate Sodium, Xanthinol Niacinate, Xemilofiban, Xenalipin, Zole, Tinzaparin Sodium, Tioconazole, TiodaZosin, Tiodo Xenbucin, Xilobam, Ximoprofen, Xipamide, Xorphanol nium Chloride, Tioperidone Hydrochloride, Tiopinac, Mesylate, Xylamidine Tosylate, Xylazine Hydrochloride, Tiospirone Hydrochloride, Tiotidine, tiotropium bromide, Xylometazoline Hydrochloride, Xylose, yangambin, Zab Tioxidazole, Tipentosin Hydrochloride, Tipredane, Tipre icipril, Zacopride, Zafirlukast, Zalcitabine, Zaleplon, nolol Hydrochloride, Tiprinast Meglumine, Tipropidil ZaloSpirone, Zaltidine Hydrochloride, Zaltoprofen, Zan Hydrochloride, Tiqueside, Tiquinamide Hydrochloride, amivir, Zankiren, Zanoterone, Zantac, Zarirlukast, Zatebra tirandaly digin, Tirapazamine, tirilazad, tirofiban, tiropra dine, Zatosetron, Zatosetron Maleate, Zenarestat, Zenazocine mide, titanocene dichloride, Tixanox, Tixocortol Pivalate, MeSylate, Zeniplatin, Zeranol, Zidometacin, Zidovudine, Tizanidine Hydrochloride, Tobramycin, Tocainide, Tocam Zifrosilone, Zilantel, Zilascorb, Zileuton, Zimeldine Hydro phyl, Tofenacin Hydrochloride, Tolamolol, Tolazamide, chloride, Zinc Undecylenate, Zindotrine, Zinoconazole Tolazoline Hydrochloride, Tolbutamide, Tolcapone, Tolci Hydrochloride, Zinostatin, Zinterol Hydrochloride, Zin clate, Tolfamide, Tolgabide, lamotrigine, Tolimidone, Tolin ViroXime, Ziprasidone, Zobolt, Zofenopril Calcium, Zofeno date, Tolimetin, Tolnaftate, TolpoVidone 1 131, Tolpyrra prilat, Zolamine Hydrochloride, Zolazepam Hydrochloride, mide, Tolrestat, Tomelukast, Tomoxetine Hydrochloride, Zoledronie acid, Zolertine Hydrochloride, Zolmitriptan, Tonazocine MeSylate, Topiramate, topotecan, Topotecan Zolpidem, Zomepirac Sodium, Zometapine, ZonicleZole Hydrochloride, topSentin, Topterone, Toquizine, torasemide, Hydrochloride, Zonisamide, Zopiclone, Zopolrestat, Zorba toremifene, Torsemide, ToSifen, ToSufloxacin, totipotent mycin, Zorubicin Hydrochloride, Zotepine, Zucapsaicin, Stem cell factor, Tracazolate, trafermin, Tralonide, Tramadol JTT-501 (PNU-182716) (Reglitazar), AR-H039242, MCC Hydrochloride, Tramazoline Hydrochloride, trandolapril, 555 (Netoglitazone), AR-HO49020, Tesaglitazar), CS-011 Tranexamic Acid, Tranilast, Transcainide, translation inhibi (CI-1037), GW-409544X, KRP-297, RG-12525, tors, traxanox, Trazodone Hydrochloride, Trazodone-HCL, BM-15.2054, CLX-0940, CLX-0921, DRF-2189, Trebenzomine Hydrochloride, Trefentanil Hydrochloride, GW-1929, GW-9820, LR-90, LY-510929, NIP-221, NIP Treloxinate, Trepipam Maleate, Trestolone Acetate, tretin 223, JTP-20993, LY 29311 Na, FK 614, BMS 298585, R oin, Triacetin, triacetyluridine, Triafungin, Triamcinolone, 483, TAK 559, DRF 2725 (Ragaglitazar), L-686398, Triampyzine Sulfate, Triamterene, Triazolam, Tribenoside, L-168049, L-805645, L-054852, Demethyl asteriquinone tricaprilin, Tricetamide, Trichlormethiazide, trichohyalin, B1 (L-783281), L-363586, KRP-297, P32/98, CRE-16336 triciribine, Tricitrates, Triclofenol piperazine, Triclofos and EML-16257. and pharmaceutically acceptable salts Sodium, Triclonide, trientine, Trifenagrel, triflavin, Triflo therof. cin, Triflubazam, Triflumidate, Trifluoperazine Hydrochlo 24. A dosage form according to claim 1, wherein the high ride, Trifluperidol, Triflu promazine, Triflupromazine Hydro dose, high Solubility active ingredient comprises dose from chloride, Trifluridine, Trihexyphenidyl Hydrochloride, 500 mg to 1500 mg. TriloStane, TrimaZOsin Hydrochloride, trimegestone, Trime 25. A dosage form according to claim 1, wherein the high prazine Tartrate, Trimethadione, Trimethaphan Camsylate, dose, high Solubility active ingredient is Selected from the Trimethobenzamide Hydrochloride, Trimethoprim, Trime group comprising of adrenergic agent, adrenocortical Ste toZine, Trimetrexate, Trimipramine, Trimoprostil, Trimox roid; adrenocortical SuppreSSant; aldosterone antagonist; amine Hydrochloride, Triolein 1125, Triolein 1131, Tri amino acid; anabolic; analeptic, analgesic, anesthetic, OXifene Mesylate, Tripamide, Tripelennamine anorectic; anti-acne agent, anti-adrenergic, anti-allergic; Hydrochloride, Triprolidine Hydrochloride, Triptorelin, anti-amebic, anti-anemic, anti-anginal; anti-arthritic, anti TriSulfapyrimidines, Troclosene Potassium, troglitaZone, asthmatic, anti-atherosclerotic, antibacterial; anticholin Trolamine, Troleandomycin, trombodipine, trometamol, ergic, anticoagulant; anticonvulsant, antidepressant, antidia Tropanserin Hydrochloride, Tropicamide, tropine ester, tro betic, antidiarrheal; antidiuretic, anti-emetic, anti-epileptic, pisetron, trospectomycin, trovafloxacin, troVirdine, Tryp antifibrinolytic, antifungal; antihemorrhagic, antihistamine; tophan, Tuberculin, Tubocurarine Chloride, Tubulozole antihyperlipidemia; antihypertensive; antihypotensive; anti Hydrochloride, tucarcsol, tulobuterol, turosteride, Tybam infective; anti-inflammatory; antimicrobial; antimigraine; ate, tylogenin, Tyropanoate Sodium, Tyrosine, Tyrothricin, antimitotic, antimycotic, antinauseant, antineoplastic, tyrphostins, ubenimex, Uldazepam, Undecylenic Acid, antineutropenic, antiparasitic, antiproliferative; antipsy Uracil Mustard, urapidil, Urea, Uredepa, uridine triphos chotic, antirheumatic, antiseborrheic, antisecretory; antis phate, Urofollitropin, Urokinase, Ursodiol, Valaciclovir, pasmodic, antithrombotic, anti-ulcerative, antiviral; appetite Valine, Valnoctamide, Valproate Sodium, Valproic Acid, SuppreSSant; blood glucose regulator, bone resorption Valsartan, Vamicamide, Vanadeine, Vancomycin, Vaminolol, inhibitor; bronchodilator, cardiovascular agent; cholinergic; Vapi.prost Hydrochloride, Vapreotide, variolin B, Vaso depressant, diagnostic aid; diuretic, dopaminergic agent; pressin, Vecuronium Bromide, velaresol, Velnacrine Male estrogen receptor agonist, fibrinolytic, fluorescent agent; ate, Venlafaxine, Veradoline Hydrochloride, Veramine, Vera free oxygen radical Scavenger; gastric acid SupreSSant; gas pamil Hydrochloride, verdins, Verilopam Hydrochloride, trointestinal motility effector; glucocorticoid; hair growth US 2006/0024365 A1 Feb. 2, 2006 37

Stimulant; hemoStatic; histamine H2 receptor antagonists, as modified release, in which the Outer portion comprises a) hormone; hypocholesterolemic, hypoglycemic, hypolipi micro matrix particles and b) coating on micro matrix demic, hypotensive; imaging agent, immunizing agent; particles. immunomodulator; immunoregulator; immunostimulant; 35. Adosage form according to claim 34, which is a tablet, immunosuppressant, keratolytic, LHRH agonist, mood in which the inner portion is covered by the Outer portion regulator, mucolytic, mydriatic, nasal decongestant; neuro from all the Sides except top Surface that remains uncovered. muscular blocking agent; neuroprotective; NMDA antago 36. A dosage form according to claim 34, wherein the nist; non-hormonal Sterol derivative, plasminogen activator; doasge form is with Sufficient reduction in the amount of platelet activating factor antagonist, platelet aggregation release controlling agent. inhibitor, psychotropic, radioactive agent, Scabicide, Scle 37. A dosage form according to claim 34, wherein the rosing agent, Sedative, Sedative-hypnotic, Selective adenos micro matrix particles comprises one or more hydrophobic ine Al antagonist, Serotonin antagonist, Serotonin inhibitor; release controlling agents. Serotonin receptor antagonist; Steroid; thyroid hormone; 38. A dosage form according to claim 37, wherein the thyroid inhibitor; thyromimetic; tranquilizer; amyotrophic hydrophobic release controlling agents are Selected from the lateral Sclerosis agent; cerebral ischemia agent, Paget's group comprising of ammonio methacrylate copolymers disease agent; unstable angina agent; vasoconstrictor; type A and B as described in USP, methacrylic acid copoly vasodilator, wound healing agent; Xanthine oxidase inhibitor mer type A, B and C as described in USP, polyacrylate and the like. dispersion 30% as described in Ph. Eur., polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose pro 26. A dosage form according to claim 1, wherein the high pionate (lower, medium or higher molecular weight), cellu dose, high Solubility active ingredient is Selected from the lose acetate propionate, cellulose acetate butyrate, cellulose group comprising of metformin hydrochloride, phenformin, acetate phthalate, cellulose triacetate, poly(methyl meth buformin, potassium chloride, clindamycin, hydroxyurea, acrylate), poly(ethyl methacrylate), poly(butyl methacry eprosartan erythromycin, lactobionate, Vancomycin hydro late), poly(isobutyl methacrylate), poly (hexyl methacry chloride, balsalazide disodium, Sodium Valproate, niacin, late), poly(isodecyl methacrylate), poly (lauryl aminocaproic acid, acetaminophen ciprofloxacin, quetiapine methacrylate), poly(phenyl methacrylate), poly (methyl or pharmaceutically acceptable Salts thereof. acrylate), poly (isopropyl acrylate), poly (isobutyl actylate), 27. A dosage form according to claim 1, wherein inner poly (octadecyl acrylate), waxes Such as beeswax, carnauba portion may optionally contain more than one low dose wax, microcrystalline wax, and ozokerite; fatty alcohols active ingredients. Such as cetoStearyl alcohol, Stearyl alcohol, cetyl alcohol 28. A dosage form according to claim 1, wherein the and myristyl alcohol; and fatty acid esterS Such as glyceryl dissolution of high dose, high Solubility active ingredient is monoStearate, glycerol monooleate, acetylated monoglycer not more than 45% in 1 hour and between 25% to 90% in 6 ides, triStearin, tripalmitin, cetyl esters wax, glyceryl palmi hours. toStearate, glyceryl behenate, glycerol distearate and hydro 29. A dosage form according to claim 1, wherein the genated castor oil. dosage form can be given twice a day or more preferably can 39. A dosage form according to claim 38, wherein the be given once a day oral formulation. hydrophobic release controlling agent(s) is selected prefer 30. A dosage form according to claim 1, is used for human ably from ammonio methacrylate co-polymers. beings. 40. A dosage form according to claim 39, wherein the 31. A process for the preparation of a dosage form preferred ammonio methacrylate co-polymers are Selected comprising a) preparation of inner portion and b) prepara from Eudragit RSPO (Ammonio Methacrylate Copolymer tion of outer portion. type B USP), Eudragit RL (Ammonio Methacrylate Copoly 32. A process for the preparation of a dosage form as mer type A USP) and Eudragit NE30D (Polyacrylate dis claimed loin claim 30, wherein preparation of Outer portion persion 30% Ph. Eur). comprising a) preparing a micro matrix particles containing 41. A dosage form according to claim 34, wherein in high dose, high Solubility active ingredient and one or more micro matrix particles, the hypolipidemic active ingredient hydrophobic release controlling agent and b) coating the and one or more hydrophobic release controlling agents are Said micro matrix particles containing high Solubility active present in a ratio of from 100:1 to 100:75. ingredient and one or more hydrophobic release controlling 42. A dosage form according to claim 41, wherein in agent. micro matrix particles, the hypolipidemic active ingredient 33. A dosage form according to claim 1, wherein outer and one or more hydrophobic release controlling agents are portion may optionally contain more than one high dose present preferably in ratio of from 100:2.5 to 100:50. high Solubility active ingredients. 43. A dosage form according to claim 41, wherein in 34. A dosage form of combination of high dose high micro matrix particles, the hypolipidemic active ingredient Solubility hypolipidemic active ingredient is as modified and one or more hydrophobic release controlling agents are release and low dose hypolipidemic or antithrombotic active present more preferably in ratio of from 100:2.5 to 100:30 ingredient as immediate release, Suitable for Swallowing; 44. A dosage form according to claim 41, wherein in comprising of dual retard technique to control the release of micro matrix particles, the hypolipidemic active ingredient the high dose high Solubility hypolipidemic active ingredi and one or more hydrophobic release controlling agents are ent wherein Said dosage form comprising of an inner portion present most preferably in ratio of from 100:2.5 to 100:20. having a low dose hypolipidemic or antithrombotic active 45. A dosage form according to claim 34, wherein coating ingredient as immediate release and an outer portion having of micro matrix particles comprises one or more hydropho a high dose high Solubility hypolipidemic active ingredient bic release controlling agents. US 2006/0024365 A1 Feb. 2, 2006 38

46. A dosage form according to claim 45, wherein the thrombotic active ingredient and modified release hypolipi hydrophobic release controlling agents are Selected from the demic active ingredient is from 1:1 to 1:15000 group comprising of ammonio methacrylate copolymers 53. A dosage form according to claim 34, wherein the low type A and B as described in USP, methacrylic acid copoly dose hypolipidemic or antithrombotic active ingredient can mer type A, B and C as described in USP, polyacrylate optionally be also in a form of modified release. dispersion 30% as described in Ph. Eur, polyvinyl acetate 54. A dosage form according to claim 34, wherein the low dispersion, ethylcellulose, cellulose acetate, cellulose pro dose hypolipidemic or antithrombotic active ingredient pionate (lower, medium or higher molecular weight), cellu comprises dose less than or equal to 500 mg. lose acetate propionate, cellulose acetate butyrate, cellulose 55. Adosage form according to claim 34, wherein the high acetate phthalate, cellulose triacetate, poly(methyl meth dose high Solubility hypolipidemic is niacin or its pharma acrylate), poly(ethyl methacrylate), poly(butyl methacry ceutically acceptable Salts. late), poly(isobutyl methacrylate), poly (hexyl methacry 56. late), poly(isodecyl methacrylate), poly (lauryl 57. Adosage form according to claim 34, wherein the high methacrylate), poly(phenyl methacrylate), poly (methyl dose high Solubility hypolipidemic active ingredient com acrylate), poly (isopropyl acrylate), poly(isobutyl actylate), prises dose from 500 mg to 1500 mg. poly (octadecyl acrylate), waxes Such as beeswax, carnauba 58. A dosage form according to claim 34, is once a day wax, microcrystalline wax, and OZokerite; fatty alcohols oral formulation. Such as cetoStearyl alcohol, Stearyl alcohol, cetyl alcohol 59. A dosage form according to claim 34, is used for and myristyl alcohol; and fatty acid esterS Such as glyceryl human beings. monoStearate; glycerol monooleate, acetylated monoglycer ides, triStearin, tripalmitin, cetyl esters wax, glyceryl palmi 60. A dosage form according to claim 34, wherein the low toStearate, glyceryl behenate, glycerol distearate and hydro dose antithrombotic active ingredient is aspirin. genated castor oil. 61. A dosage form according to claim 34, wherein the low 47. A dosage form according to claim 46, wherein the dose hypolipidemic is Selected from group consisting of hydrophobic release controlling agent(s) is selected from Statin compounds. fatty acid esters. 62. A dosage form according to claim 34, wherein inner 48. A dosage form according to claim 47, wherein the portion may optionally contain more than one active ingre hydrophobic release controlling agents are Selected from the dients. group comprising of hydrogenated castor oil and glycerol 63. A dosage form according to claim 34, wherein outer distearate. portion may optionally contain more than one active ingre 49. A dosage form according to claim 34, wherein in outer dients. portion, micro matrix particles and coating of one or more 64. A process for the preparation of a dosage form as hydrophobic release controlling agents are present in a ratio claimed in claim 34, comprising a) preparation of inner of from 100:0.5 to 100:75. portion and b) preparation of outer portion. 50. A dosage form according to claim 49, wherein in outer 65. A process for the preparation of a dosage form as portion, micro matrix particles and coating of one or more claimed in claim 64, wherein preparation of outer portion hydrophobic release controlling agents are present prefer comprising a) preparing a micro matrix particles containing ably in a ratio of from 100:1 to 100:50. high dose, hypolipidemicactive ingredient and one or more 51. A dosage form according to claim 49, wherein in outer hydrophobic release controlling agent and b) coating the portion, micro matrix particles and coating of one or more Said micro matrix articles containing high dose hypolipi hydrophobic release controlling agents are more preferably demic active ingredient and one or more hydrophobic present in a ratio of from 100:2.5 to 100:20. release controlling agent. 52. A dosage form according to claim 34, wherein the weight ratio of immediate release hypolipidemic or anti k k k k k