US008263125B2

(12) United States Patent (10) Patent No.: US 8.263,125 B2 Vaya et al. (45) Date of Patent: *Sep. 11, 2012

(54) DOSAGE FORM FOR HIGH DOSE-HIGH (52) U.S. Cl...... 424/469: 424/464; 424/465; 424/468 SOLUBLITY ACTIVE INGREDIENTS THAT (58) Field of Classification Search ...... None PROVIDES FOR MIMEDIATE RELEASE AND See application file for complete search history. MODIFIED RELEASE OF THE ACTIVE INGREDIENTS (56) References Cited (75) Inventors: Navin Vaya, Gujarat (IN); Rajesh Singh Karan, Gujarat (IN); Sunil Sadanand U.S. PATENT DOCUMENTS Nadkarni, Gujarat (IN); Vinod Kumar 3,048,526 A * 8, 1962 Boswell ...... 424,472 3,336,200 A 8, 1967 Krause et al. Gupta, Gujarat (IN) 4,139,589 A * 2/1979 Beringer et al...... 264/250 4,503,031 A * 3/1985 Glassman ...... 424/467 (73) Assignee: Torrent Pharmaceuticals Limited, 4,996,061 A * 2/1991 Webb et al...... 424/475 Ahmedabad (IN) 5,445,829 A * 8/1995 Paradissis et al. ... 424/480 5,738,874. A * 4/1998 Conte et al...... 424/472 (*) Notice: Subject to any disclaimer, the term of this 5,840,332 A * 1 1/1998 Lerner et al...... 424/464 5,985,843. A 1 1/1999 Higo et al. patent is extended or adjusted under 35 6,001,391 A 12/1999 Zeidler et al. U.S.C. 154(b) by 0 days. 6,238,699 B1 5, 2001 Rubin 6,372.254 B1 * 4/2002 Ting et al...... 424/473 This patent is Subject to a terminal dis 6,660,300 B1* 12/2003 Timmins et al. ... 424/469 claimer. 2004/0156902 A1* 8, 2004 Lee et al...... 424/473 (21) Appl. No.: 11/134,633 FOREIGN PATENT DOCUMENTS WO WO/O 1/72286 10, 2001 (22) Filed: May 19, 2005 * cited by examiner (65) Prior Publication Data Primary Examiner — Anand Desai US 2006/OO24365A1 Feb. 2, 2006 Assistant Examiner — Melissa Mercier Related U.S. Application Data (74) Attorney, Agent, or Firm — Hedman & Costigan, P.C.: James V. Costigan (63) Continuation-in-part of application No. 10/630,446, filed on Jul. 29, 2003, now Pat. No. 7,985,422. (57) ABSTRACT (30) Foreign Application Priority Data A dosage form comprising of a high dose, high solubility active ingredient as modified release and a low dose active Aug. 5, 2002 (IN) ...... 697 FMUMA2002 ingredient as immediate release where the weight ratio of Aug. 5, 2002 (IN) ...... 699/MUMA2002 immediate release active ingredient and modified release Jan. 22, 2003 (IN) ...... 8OfMUMA2003 active ingredient is from 1:10 to 1:15000 and the weight of Jan. 22, 2003 (IN) ...... 82/MUMA2003 modified release active ingredient per unit is from 500 mg to 1500 mg; a process for preparing the dosage form. (51) Int. Cl. A6 IK 9/26 (2006.01) A6 IK9/20 (2006.01) 30 Claims, 10 Drawing Sheets

-- U.S. Patent Sep. 11, 2012 Sheet 1 of 10 US 8,263,125 B2

FIGURE - -

FIGURE 2

FIGURE 3 U.S. Patent Sep. 11, 2012 Sheet 2 of 10 US 8,263,125 B2

FIGURE 4 (a)

7

FIGURE 4 (b)

U.S. Patent Sep. 11, 2012 Sheet 3 of 10 US 8,263,125 B2

FIGURE 5

20

OO

80

60

40

20

C. 2 g 6. 8 O 2 4 e. 8 20 22 24 26 Tite ho: U.S. Patent Sep. 11, 2012 Sheet 4 of 10 US 8,263,125 B2

FIGURE 6

2 O -

O O

8 O 264 OOO

O 2 4 6 8 O 2 1 4 16 8 2C 2 2 24 26 Time (hour) U.S. Patent Sep. 11, 2012 Sheet 5 of 10 US 8,263,125 B2

FIGURE 7

60

4 O

2 O

O ------O 2 4 6 8 O 12 4 6. 18 2O 22 24 26 Time (hour) U.S. Patent Sep. 11, 2012 Sheet 6 of 10 US 8,263,125 B2

FIGURE 8

O 4 8 12 6 2O 24 Tirne Hours) U.S. Patent Sep. 11, 2012 Sheet 7 of 10 US 8,263,125 B2

FIGURE 9

35OO

3OOO

25 OO

2OOO

5 OO

4 8 l2 6. 2O 24 Time Hours) U.S. Patent Sep. 11, 2012 Sheet 8 of 10 US 8,263,125 B2

FIGURE 10

O 2 4 6. 8 O 12 4 6. 18 2C 22 24 Time Hours) U.S. Patent Sep. 11, 2012 Sheet 9 of 10 US 8,263,125 B2

FIGURE 11

27 OO

2 4 O O

21 OO

1800

15OO

12OO

9 OO

6OO

3OO

O 2 4 6 8 10 2 14 16 18 20 22 24 Time Hours) U.S. Patent Sep. 11, 2012 Sheet 10 of 10 US 8,263,125 B2

FIGURE 12

2OO

18O

16O

14 O

120

100

60

AO

O 4 8 12 16 2O 24 Time Hours) US 8,263,125 B2 1. 2 DOSAGE FORM FOR HIGH DOSE-HIGH Block Jurgen et. al. describes in PCT application No. WO SOLUBILITY ACTIVE INGREDIENTS THAT 01/72286 A1 a formulation of vitamin composition whereas a PROVIDES FOR IMMEDIATE RELEASE AND beadlet comprises a slow release core coated by a controlled MODIFIED RELEASE OF THE ACTIVE release coating. The Sustained release core is coated with an INGREDIENTS immediate release layer. Richard Ting and Charles Hscao describes in U.S. Pat. No. This application is a continuation-in-part of Ser. No. 6,372.254B1 a press coated, pulsatile active ingredient deliv ery system which comprises a core of immediate release, 10/630,446, filed Jul. 29, 2003 now U.S. Pat. No. 7,985,422. enveloped by an extended release compartment. FIELD OF INVENTION 10 The need to use active ingredients with different and complementary mechanisms of action frequently arises in This invention relates to a dosage form comprising of a treatment of diabetes. There are several reasons to do this, high dose, high solubility active ingredient as modified namely, the disease itself is progressive, with deterioration of release and a low dose active ingredient as immediate release glycemic control over time; mono-therapeutic attempts to 15 achieve and maintain glycemic control often fail in the long where the weight ratio of immediate release active ingredient run; multiple defects in the disease and consequently primary and modified release active ingredient is from 1:1 to 1:15000 drug failures (1.2.3). and the weight of modified release high dose high solubility Current guidelines for combination therapy advise the use active ingredient per unit is from 500 mg to 1500 mg and the of agents with differing and complementary mechanisms of weight of immediate release active ingredient is up to 500mg: action in order to maximize therapeutic activity and reduce a process for preparing the formulation. Low dose active toxicity. Earlier introduction of combination therapy is ingredient in present invention can optionally be also in a increasingly being recommended. The commonly combined form of modified release. active ingredients include biguanides (metformin)+Sulpho nylureas, biguanides--PPAR2 agonists(thiazolidinediones), BACKGROUND OF THE INVENTION 25 Sulphonylureas--thiazolidinediones, non-Sulfonylurea secre tagogues (repaglinide)+biguanides etc. Fixed dose combina Combining two active ingredients in one pharmaceutical tions of many of the above mentioned co-administer active unit to improve patient compliance is known in literature. It ingredients have also been approved by the FDA. Most of can be either in the form of two or more active ingredients in these combinations are conventional formulations combined immediate release form or a combination of immediate 30 together into a single tablet. However, because of the dispar release and modified release form. There are various tech ity in the duration of action (half-life), these combinations are niques by which the combination of immediate release and given twice or thrice a day. modified release is formulated in single dosage form. To reduce this disparity in the duration of action, a novel Several examples of formulations having combination of strategy would be to combine a Sustained release formulation immediate release active ingredient and modified release 35 of one active ingredient (shorter duration of action) with active ingredient are described below. conventional formulation (long duration of action) of another Shoichi Higo and Kazuo Igusa describes in U.S. Pat. No. active ingredient. This would make it possible to give the 5.985,843 various types of pharmaceutical formulations, active ingredients in same dosing frequency. which consists of a delayed release of sucralfate and an imme This type of combination will give better compliance and a diate release fraction of another active ingredient. The phar 40 relative freedom from mealtime drug administration, thus, maceutical dosage forms are a tablet formulation containing improving the quality of life. More importantly, because of immediate release and delayed release granules; a two or prolonged duration of action, it shall produce a strictercontrol three layer tablet; a tablet with delayed release core sur of blood glucose and consequently less diabetic complica rounded by immediate release shell; a delayed release tablet/ tions. granule coated with a film of immediate release active ingre 45 The techniques described above do not work well when the dient. difference in the dose of active ingredients are high for Similarly Jurgen Zeidler et. al describes in U.S. Pat. No. example where the weight ratio of active ingredients is from 6,001.391 a process for producing solid combination tablets, 1:1 to 1: 15000 and the dose of modified release active ingre which have at least two phases. The one of the two phases is dient per unit is from 500 mg to 1500 mg. The techniques processed by melt extrusion technique and contains a water 50 described in the prior art do not give good results when the soluble or swellable binder. active ingredient is highly soluble. The weight of the dosage A compressed V-shaped center scored double layer tablet is form becomes very high, or complicated process for manu disclosed by George M. Krause et. al in U.S. Pat. No. 3,336, facturing is required, or accurate dosing of low dose active 200, one layer of which contains immediate release Active ingredient is difficult when the techniques reported in the Ingredient and the other layer contains Sustained release 55 prior art are utilized to make formulation with high dose, high Active Ingredient. The tablet is divisible in two equal halves. solubility active ingredient in the form of modified release Similarly Jacob A. Glassman described in U.S. Pat. No. and low dose active ingredient into immediate release or 4.503,031 a super fast starting, slow release medicinal tablet, modified release form where the weight ratio of low dose wherein the tablet is comprised of two layers of compressed active ingredient and high dose, high solubility active ingre matrix that arefused together by means of readily dissolvable 60 dient is from 1:1 to 1:15000 and the weight of modified adhesive Substance. release active ingredient per unit is from 500 mg to 1500 mg Allan A. Rubin describes in U.S. Pat. No. 6,238,699 B1 a and also it is inconvenient to Swallow due to large size. pharmaceutical dosage form of carbidopa and levodopa Accordingly a need exists for a dosage form providing where both the Active Ingredients are present as immediate combination of immediate release and modified release active release and sustained release. The formulation is in the form 65 ingredients and providing solution to problems associated of inlay tablet or bilayered tablet or a capsule containing with dosage forms described in prior art. Further, the dosage pellets. form should be simple and economical to produce. US 8,263,125 B2 3 4 Therefore an object of the present invention is a dosage The present invention also provides a novel process for form of combination of a high dose, high solubility active preparing the novel formulations of the invention. ingredient as modified release and a low dose active ingredi The present invention further provides a method of treating ent as immediate release where the weight ratio of immediate an animal, particularly a human in need of treatment utilizing release active ingredient and modified release active ingredi the active agents, comprising administering a therapeutically ent is from 1:1 to 1:15000 and the weight of modified release effective amount of composition or solid oral dosage form active ingredient per unit is from 500 mg to 1500 mg. according to the invention to provide administration of two Another object of the present invention is a dosage form, active ingredients one in immediate release and other in which is Suitable for Swallowing for humans containing two modified release form. active ingredients one of which is in modified release form 10 and other in immediate release form. DETAILED DESCRIPTION OF THE INVENTION Accordingly, an object of the present invention to provide a dosage form, which uses dual retard technique to control the This invention relates to a novel dosage form of combina release of the high dose, high solubility active ingredient and tion of high dose high solubility active ingredient, as modified significantly reduce the amount of release controlling agents 15 release and low dose active ingredient as immediate release, which are otherwise required in very high quantity and make Suitable for Swallowing comprising dual retard technique to the dosage form very bulky and therefore pose difficulty in control the release of the high dose high solubility active Swallowing. ingredient, with Sufficient reduction in the amount of release A further object of the present invention is to provide a controlling agent, without interfering the release of each dosage form, containing one active ingredient in an immedi other. Low dose active ingredient in present invention can ate release form and another active ingredient as modified optionally be also in a form of modified release. release and the release or disintegration of the immediate The term “modified release' as used herein in relation to release active ingredient is not hindered by the modified the composition according to the invention or a rate control release ingredient. 25 ling polymer or used in any other context means release, Another object of the present invention is to provide a which is not immediate release and is taken to encompass dosage form, which effectively avoids the problem of sepa controlled release, Sustained release, prolonged release, ration of layers of multilayered tablets. timed release, retarded release, extended release and delayed A further object of the present invention is a formulation, release. The term “modified release dosage form as used which gives accurate dosing and is prepared by conventional 30 herein can be described as dosage forms whose drug-release and simple processes. characteristics of time course and/or location are chosen to A further object of the present invention is to provide a accomplish therapeutic or convenience objectives not offered dosage form, which can be given twice a day or more prefer by conventional dosage forms such as a solution oran imme ably can be given once a day. diate release dosage form. Modified release solid oral dosage A further object of the present invention is to provide a 35 forms include both delayed and extended release drug prod dosage form, wherein low dose active ingredient can option ucts (as per US FDA guideline for SUPAC-MR: Modified ally be also in a form of modified release. Release Solid Oral Dosage Forms). The term “immediate release' as used herein in relation to SUMMARY OF THE INVENTION composition according to the invention or used in any other 40 context means release which is not modified release and The above objects are realized by a dosage form, which is releases more than 70% of the active ingredient within 60 comprised of an inner portion and an outer portion. The inner minutes. The term “immediate release dosage form' as used portion is Surrounded by the outer portion in Such a manner herein can be described as dosage form which allows the drug that only one surface of the inner portion is exposed. The to dissolve in the gastrointestinal contents, with no intention inner portion contains a low dose active ingredient in imme 45 of delaying or prolonging the dissolution or absorption of the diate release form and the outer portion contains a high dose, drug (as per US FDA guideline for SUPAC-MR: Modified high solubility active ingredient as modified release. The Release Solid Oral Dosage Forms). weight of the immediate release low dose active ingredient The term “dosage form denotes any form of the formula and high dose, high solubility modified release active ingre tion that contains an amount Sufficient to achieve a therapeu dient is from 1:1 to 1:15000 and the weight of modified 50 tic effect with a single administration. release active ingredient per unit is from 500 mg to 1500 mg. The term “active ingredient” refers to an agent, active Low dose active ingredient in present invention can option ingredient compound or other substance, or compositions and ally be also in a form of modified release. mixture thereof that provide some pharmacological, often The present invention also provides Solid oral dosage form beneficial, effect. Reference to a specific active ingredient comprising a composition according to the invention. 55 shall include where appropriate the active ingredient and its The present invention also teaches the use of dual retard pharmaceutically acceptable salts. technique to effectively control the release rate of modified The term “high dose' as used herein refers to the weight of release active ingredient by using Small quantity of release active ingredient in unit dosage form according to the inven controlling agents. This dual retard technique thus Suffi tion is from 500 mg to 1500 mg. ciently reduces the size of the dosage form, which is conve 60 The term “low dose' as used herein refers to the weight of nient for Swallowing. the active ingredient in unit dosage form according to the The present invention further teaches the use of hydropho invention is less than or equal to 50 mg or may comprise up to bic release controlling agents, which do not hinder the release but not including 500 mg or from more than 50 mg up to but of the low dose active ingredient. no including 500 mg, preferably from 60 mg up to 400 mg or The present invention further provides the dosage form that 65 more preferable from 75 mg to 350 mg. The term “high effectively prevents the problem of separation of the layers of solubility” as used herein in relation to high dose active the multilayered tablets. ingredient means that from less than 1 part to 300 parts of US 8,263,125 B2 5 6 water or less than 1 part to 30 parts of water will be required agent; estrogen receptor agonist; fibrinolytic; fluorescent to dissolve 1 part of active ingredient. agent, free oxygen radical scavenger, gastric acid Supressant; The invention provides a novel dosage form of high dose, gastrointestinal motility effector; glucocorticoid; hair growth high solubility active ingredient as modified release and a low stimulant; hemostatic; histamine H2 receptor antagonists; dose active ingredient as immediate release where the weight hormone; hypocholesterolemic; hypoglycemic; hypolipi ratio of immediate release active ingredient and modified demic; hypotensive; imaging agent; immunizing agent; release active ingredient is from 1:10 to 1:15000 or 1:1 to immunomodulator; immunoregulator; immunostimulant; 1:15000 and the weight of modified release antidiabetic immunosuppressant, keratolytic; LHRHagonist; mood regu active ingredient per unit is from 500 mg to 1500 mg; a lator, mucolytic; mydriatic; nasal decongestant; neuromus process for preparing the dosage form. 10 cular blocking agent; neuroprotective; NMDA antagonist; The dosage form comprises of two parts (i) inner portion as non-hormonal sterol derivative; plasminogenactivator, plate an immediate release and (ii) outer portion as modified let activating factor antagonist, platelet aggregation inhibitor; release. The two parts are compressed together in Such a way psychotropic; radioactive agent; scabicide; sclerosing agent; that one Surface of the inner portion remains exposed and the sedative; sedative-hypnotic; selective adenosine A1 antago remaining Surfaces are covered by the outer portion. 15 nist; Serotonin antagonist; serotonin inhibitor, serotonin (i) Inner portion—Inner portion comprises of a low dose receptor antagonist; Steroid; thyroid hormone; thyroid inhibi active ingredient and includes one or more commonly used tor; thyromimetic; tranquilizer, amyotrophic lateral sclerosis excipients in oral immediate release pharmaceutical formu agent; cerebral ischemia agent, Paget’s disease agent; lations. Low dose active ingredient in present invention can unstable angina agent; vasoconstrictor; vasodilator, wound be either as an immediate release form or optionally as a healing agent; Xanthine oxidase inhibitor. modified release form. Examples of low dose active ingredient comprise but are The low dose active ingredient can be present in the form of not limited to 16-alpha fluorocstradiol. 16-alpha-gitoxin, a free base or in the form of pharmaceutically acceptable 16-epiestriol, 17 alpha dihydroequilenin, 17 alpha estradiol, salts. Pharmaceutically acceptable salts forming part of this 17 beta estradiol, 17 hydroxy progesterone, lalpha-hydrox invention are intended to define but not limited to salts of the 25 yvitamin D2,1-dodecpyrrolidinone, 20-epi-1.25 dihydrox carboxylic acid moiety Such as alkali metal salts like Li, Na yvitamin D3, 22-oxacalcitriol. 2CVV. 2'-nor-cGMP 3-isobu and K salts; alkaline earth metal salts like Ca and Mg salts; tyl GABA, 5-ethynyluracil, 6-FUDCA, 7-methoxytacrine, salts of organic bases such as lysine, arginine, guanidine, Abamectin, abanoquil, abecarnil, abiraterone, Ablukast, diethanolamine, choline, and the like: ammonium or Substi Ablukast Sodium, Acadesine, acamprosate, Acarbose, Ace tuted ammonium salts and aluminium salts. Salts may be acid 30 butolol, Acecainide Hydrochloride, Aceclidine, aceclofenae, addition salts which defines but not limited to sulfates, Acedapsone, Aceglutamide Aluminum, Acemannan, nitrates, phosphates, perchlorates, borates, hydrohalides, Acetaminophen, Acetazolamide, Acetohexamide, Acetohy acetates, tartrates, maleates, citrates, succinates, palmoates, droxamic Acid, acetomepregenol, Acetophenazine Maleate, methanesulfonates, benzoates, salicylates, hydroxynaph Acetosulfone Sodium, Acetylcholine Chloride, Acetylcys thoates, benzensulfonates, ascorbates, glycerophosphates, 35 teine, acetyl-L-carnitine, acetylmethadol, Acifran, acipimox, ketoglutarates and the like. acitemate, Acitretin, Acivicin, Aclarubicin, aclatonium, Further, the low dose active ingredient, where applicable, Acodazole Hydrochloride, aconiazide, Acrisorcin, Acrivas may be present either in the form of one substantially opti tine, Acronine, Actisomide, Actodigin, Acyclovir, acylful cally pure enantiomer or as a mixture of enantiomers or Vene, adafenoxate, adapalene, Adapalene, adatanserin, Ada polymorphs thereof. 40 tanserin Hydrochloride, adecypenol, adecypenol, Adefovir, In the dosage form of the present invention, the inner adelmidrol, ademetionine, Adenosine, Adinazolam, Adiphei portion may optionally contain more than one low dose active nine Hydrochloride, adiposin, Adozelesin, adrafinil, Adrena ingredient. lone, airbutamine, alacepril, Alamecin, Alanine, Alaproclate, In the dosage form of the present invention, the inner alaptide, Albendazole, albolabrin, Albuterol, Albutoin, portion may optionally contain more than one low dose 45 Alclofenae, Alclometasone Dipropionate, Alcloxa, aldecal antidiabetic active ingredient. mycin, Aldesleukin, Aldioxa, Alendronate Sodium, allen The low dose active ingredient is in the form of immediate dronic acid, alentemol, Alentemol Hydrobromide, Aletamine release and has dose of 500 mg or less. Hydrochloride, Aleuronium Chloride, Alexidine, alfacalci The low dose active ingredient comprises of the following dol, Alfentanil Hydrochloride, alfuzosin, Algestone therapeutic classes but not limited to adrenergic agent; 50 Acetonide, alglucerase, Aliflurane, alinastine, Alipamide, adrenocortical steroid; adrenocortical Suppressant, aldoster Allantoin, Allobarbital, Allopurinol, ALL-TK antagonists, one antagonist; amino acid; anabolic; analeptic; analgesic; Alonimid, alosetron, Alosetron Hydrochloride, Alovudine, anesthetic; anorectic; anti-acne agent; anti-adrenergic; anti Alpertine, Alpha Amylase, alpha idoSone, Alpidem, Alpra allergic; anti-amebic; anti-anemic; anti-anginal; anti-ar Zolam, Alprenolol Hydrochloride, Alprenoxime Hydrochlo thritic; anti-asthmatic; anti-atherosclerotic; antibacterial; 55 ride, Alprostadil, Alrestatin Sodium, Altanserin Tartrate, anticholinergic; anticoagulant; anticonvulsant; antidepres Alteplase. Althiazide. Altretamine, altromycin B, Alverinc Sant; antidiabetic; antidiarrheal; antidiuretic; anti-emetic; Citrate, Alvircept Sudotox, Amadinone Acetate, Amantadine anti-epileptic; antifibrinolytic; antifungal; antihemorrhagic; Hydrochloride, ambamustine, Ambomycin, Ambruticin, antihistamine; antihyperlipidemia; antihypertensive; antihy Ambuphylline, Ambuside, Amcinafal, Amcinonide, Amdi potensive; anti-infective; anti-inflammatory; antimicrobial; 60 nocillin, Amdinocillin Pivoxil, Amedalin Hydrochloride, antimigraine; antimitotic; antimycotic, antinauseant, antine amelometaSone, Ameltolide, Amesergide, Ametantrone oplastic, antineutropenic, antiparasitic; antiproliferative; Acetate, ameZinium metilsulfate, amfebutamone, Amfenac antipsychotic; antirheumatic; antiseborrheic; antisecretory; Sodium, Amflutizole, Amicycline, Amidephrine Mesylate, antispasmodic; antithrombotic; anti-ulcerative; antiviral; amidox, Amifloxacin, amifostine, Amikacin, Amiloride appetite Suppressant, blood glucose regulator, bone resorp 65 Hydrochloride, Aminacrine Hydrochloride, Aminobenzoate tion inhibitor, bronchodilator, cardiovascular agent; cholin Potassium, Aminobenzoate Sodium, Aminocaproic Acid, ergic; depressant; diagnostic aid; diuretic: dopaminergic Aminoglutethimide, Aminohippurate Sodium, aminole US 8,263,125 B2 7 8 Vulinic acid, Aminophylline. A minorex, Aminosalicylate Hydrochloride, Beractant, Beraprost, Berefrine, berlafenone, Sodium, Aminosalicylic acid, Amiodarone, Amiprilose bertosamil, Berythromycin, besipirdine, beta-alethine, Hydrochloride, Amiquinsin Hydrochloride, amisulpride, betaclamycin B. Betamethasone, betamipron, betaxolol. Amitraz, Amitriptyline Hydrochloride, AmlexanoX, amlo Betaxolol Hydrochloride, Bethanechol Chloride, Bethani dipine, Amobarbital Sodium, Amodiaquine, Amodiaquine dine Sulfate, betulinic acid, bevantolol, Bevantolol Hydro Hydrochloride. Amorolfine, Amoxapine, Amoxicillin, chloride, Bezafibrate, bFGF inhibitor, Bialamicol Hydro Amphecloral, Amphetamine Sulfate, Amphomycin, Ampho chloride, Biapenem, Bicalutamide, Bici fadine tericin B, Ampicillin, ampiroxicam, AmpyZine Sulfate, Hydrochloride, Biclodil Hydrochloride, Bidisomide, bife Amquinate, Amrinone, amrinone, amrubicin, Amsacrine, melane, Bifonazole, bimakalim, bimithil, Bindarit, Binira amylin, amythiamicin, Anagestone Acetate, anagrelide, 10 mycin, binospirone, bioxalomycin alpha2, Bipenamol Anakinra, ananain, anaritide, Anaritide Acetate, Anastrozole, Hydrochloride, Biperiden, Biphenamine Hydrochloride, bir Anazolene Sodium, Ancrod, andrographolide, Androstenedi iperone, bisantrene, bisaramil, bisaziridinylspermine, bis one, angiogenesis inhibitors, Angiotensin Amide, Ani benzimidazole A, bis-benzimidazole B, bisnafide, Bisobrin doXime, Anileridine, Anilopam Hydrochloride, Aniracetam, Lactate, Bisoprolol, Bispyrithione Magsulfex, bistramide D, Anirolac, Anisotropine Methylbromide, Anistreplase, Ani 15 bistramide K, bistratene A, Bithionolate Sodium, Bitolterol traZafen, anordrin, antagonist D, antagonist G, antarelix, Mesylate, Bivalirudin, Bizelesin, Bleomycin Sulfate, Bolan Antazoline Phosphate, Anthelmycin, Anthralin, Anthramy diol Dipropionate, Bolasterone, Boldenone Undecylenate, cin, antiandrogen, Acedapsone, Felbamate, antiestrogen, boldine, Bolenol, Bolmantalate, bopindolol, Bosentan, Boxi antineoplaston, Antipyrine, antisense oligonucleotides, apa dine, brefeldin, breflate, Brequinar Sodium, Bretazenil, doline, apafant, Apalcillin Sodium, apaxifylline, ApaZone, Bretylium Tosylate, Brifentanil Hydrochloride, brimonidine, aphidicolin glycinate, Apixifylline, Apomorphine Hydro Brinolase, Brocresine, Brocrinat, Brofoxine, Bromadoline chloride, apraclonidine, Apraclonidine Hydrochloride, Apra Maleate, Bromazepam, Bromchlorenone, Bromelains, bro mycin, Aprindine, Aprindine Hydrochloride, aprosulate mfenac, Brominidione, Bromocriptine, Bromodiphenhy Sodium, Aprotinin, Aptazapine Maleate, aptiganel, apurinic dramine Hydrochloride, Bromoxamide, Bromperidol, Bro acid, apurinic acid, aranidipine, Aranotin, Arbaprostil, 25 mperidol Decanoate, Brompheniramine Maleate, arbekicin, arbidol, Arbutamine Hydrochloride, Arclofenin, Broperamole, Bropirimine, Brotizolam, Bucainide Maleate, Ardeparin Sodium, argatroban, Arginine, Argipressin Tan bucindolol, Buclizine Hydrochloride, Bucromarone, Budes nate, Arildone, aripiprazol, arotinolol, Arpinocid, Arteflene, onide, budipine, budotitane, Buformin, Bumetamide, Artilide Fumarate, asimadoline, aspalatone, Asparaginase, Bunaprolast, bunazosin, Bunolol Hydrochloride, Bupico Asparic Acid, Aspartocin, asperfuran, Aspirin, aspoxicillin, 30 mide, Bupivacaine Hydrochloride, Buprenorphine Hydro Asprelin, Astemizole, Astromicin Sulfate, asulacrine, ata chloride, Bupropion Hydrochloride, Buramate, Buserelin mestane, Atenolol, atevirdine, Atipamezole, Atiprosin Male Acetate, Buspirone Hydrochloride, Busulfan, Butabarbital, ate, Atolide, Atorvastatin Calcium, Atosiban, Atovaquone, Butacetin, Butaclamol Hydrochloride, Butalbital, Butamben, atpenin B, Atracurium Besylate, atrimustine, atrinositol, Butamirate Citrate. Butaperazine. Butaprost, Butedronate Atropine, Auranofin, aureobasidin A, Aurothioglucose, 35 Tetrasodium, butenafine, Buterizine, buthionine sulfoximine, Avilamycin, Avoparcin, Avridine, AXid, axinastatin 1, axin Butikacin, Butilfenin, Butirosin Sulfate, Butixirate, butixo astatin 2, axinastatin 3, AZabon, AZacitidinie, AZaclorzine cort propionate, Butoconazole Nitrate, Butonate, Butopam Hydrochloride, AZaconazole, azadirachtine, AZalanstat ine. Butoprozine Hydrochloride, Butorphanol, Butoxamine Dihydrochloride, Azaloxan Fumarate, AZanator Maleate, Hydrochloride. Butriptyline Hydrochloride, Cactinomycin, AZanidazole, AZaperone, AZaribine, AZaserine, azasetron, 40 Cadexomer Iodine, Caffeine, calanolide A, Calcifediol, Cal AZatadine Maleate, AZathioprine, AZathioprine Sodium, aza cipotriene, calcipotriol, Calcitonin, Calcitriol, Calcium toxin, azatyrosine, azelaic acid, azelastine, azelnidipine, Undecylenate, calphostin C, Calusterone, Cambendazole, AZepindole, AZetepa, azimilide, Azithromycin, AZlocillin, camonagrel, camptothecin derivatives, canarypox IL-2, can AZolimine, AZosemide, AZotomycin, AZtreonam, desartan, Candicidin, candoXatril, candoXatrilat, Caniglib AZumolene Sodium, Bacampicillin Hydrochloride, baccatin 45 ose, Canrenoate Potassium, Canrenone, capecitabine, III, Bacitracin, Baclofen, bacoside A, bacoside B, bactobola Capobenate Sodium, Capobenic Acid, Capreomycin Sulfate, mine, balanol, balaZipone, balhimycin, balofloxacin, bal capiromab, capsaicin, Captopril, Capuride, Caracemide, Car salazide, Bambermycins, bambuterol, Bamethan Sulfate, bachol, Carbadox, Carbamazepine, Carbamide Peroxide, Bamifylline Hydrochloride, Bamidazole, baohuoside 1, Bar Carbantel Lauryl Sulfate, Carbaspirin Calcium, Carbazeran, mastine, barnidipine, Basifungin, Batanopride Hydrochlo 50 carbazomycin C, Carbenicillin Potassium, Carbenoxolone ride, batebulast, Batelapine Maleate, Batimastat, beauveri Sodium, Carbetimer, carbetocin, Carbidopa, Carbidopa cin, Becanthone Hydrochloride, becaplermin, becliconazole, Levodopa, Carbinoxamine Maleate, Carbiphene Hydrochlo Beclomethasone Dipropionate, befloxatone, Beinserazide, ride, Carbocloral, Carbocysteine, Carbol-Fuchsin, Carbopl Belfosdil, Belladonna, Beloxamide, Bemesetron, Bemitra atin, Carboprost, carbovir, carboxamide-amino-triaZo-le. dine, Bemoradan, Benapryzine Hydrochloride, Benazepril 55 carboxyamidotriazole, carboxymethylated beta-1,3-glucan, Hydrochloride, Benazeprilat, Bendacalol Mesylate, Carbuterol Hydrochloride, CaRest M3, Carfentanil Citrate, Bendazac, Bendroflumethiazide, benflumetol, benidipine, Carisoprodol, Carmantadine, Carmustine, CARN 700, Cami Benorterone, Benoxaprofen, Benoxaprofen, Benoximate dazole, CaroXaZone, carperitide, Carphenazine Maleate, Car Hydrochloride, Benperidol, Bentazepam, Bentiromide, Ben profen, Carsatirin Succinate, Cartazolate, carteolol, Carteolol urestat, Benzbromarone, Benzethonium Chloride, Benzetim 60 Hydrochloride, cartilage derived inhibitor, Carubicin Hydro ide Hydrochloride, Benzilonium Bromide, BenZindopyrine chloride, Carumonam Sodium, carvedilol, carvotroline, Car Hydrochloride, benzisoxazole, Benzocaine, benzochlorins, votroline Hydrochloride, carzelesin, casein kinase inhibitors Benzoctamine Hydrochloride, Benzodepa, benzoidazoxan, (ICOS), castanospermine, caurumonam, cebaracetam, Benzonatate, Benzoyl Peroxide, Benzoylpas Calcium, ben cecropin B, Cedefingol, Cefaclor, Cefadroxil, Cefamandole, Zoylstaurosporine, BenZquinamide, BenZthiazide, benz 65 Cefaparole, Cefatrizine, Cefazaflur Sodium, Cefazolin, Cef tropine, Benztropine Mesylate, Benzydamine Hydrochlo buperaZone, cefcapene pivoxil, cefdaloXime pentexiltosilate, ride, Benzylpenicilloyl Polylysine, bepridil, Bepridil Cefdinir, cefditoren pivoxil, Cefepime, cefetamet, Cefetecol, US 8,263,125 B2 10 cefixime, cefluprenam, Cefinenoxime Hydrochloride, Cefin Coumadin, Coumermycin, crambescidin 816, Crilvastatin, etazole, cefminlox, cefodizime, Cefonicid Sodium, Cefop crisinatol, Cromitrile Sodium, Cromolyn Sodium, Crotami eraZone Sodium, Ceforamide, cefoselis, Cefotaxime Sodium, ton, cryptophycin 8, cucumariosid Cuprimyxin, curacin A, Cefotetan, cefotiam, Cefoxitin, cefoZopran, cefpimizole, curdlan Sulfate, curiosin, Cyclacillin, Cyclazocine, cycla Ce?piramide, cefpirome, cefpodoxime proxetil, cefprozil, Zosin, cyclic HPMPC, Cyclindole, Cycliramine Maleate, Cefroxadine, cefsulodin, Ceftazidime, cefteram, ceftibuten, Cyclizine, Cyclobendazole, cyclobenzaprine, cyclobut A, Ceftizoxime Sodium, ceftriaxone, Cefuroxime, celastrol, cyclobut G, cyclocapron, Cycloguanil Pamoate, Cyclohex celikalim, celiprolol, cepacidine A, Cephacetrile Sodium, imide, cyclopentanthraquinones, Cyclopenthiazide, Cyclo Cephalexin, Cephaloglycin, Cephaloridine, Cephalothin pentolate Hydrochloride, Cyclophenazine Hydrochloride, Sodium, Cephapirin Sodium, Cephradine, cericlamine, ceriv 10 Cyclophosphamide, cycloplatam, Cyclopropane, Cyclos astatin, Ceronapril, certoparin Sodium, Ceruletide, Cetaben erine, cyclosin, Cyclosporine, cyclothialidine, Cyclothiazide, Sodium, Cetalkonium Chloride, Cetamolol Hydrochloride, cyclothiazomycin, Cyheptamide, cypemycin, Cypenamine cetiedil, cetirizine, Cetophenicol, Cetraxate Hydrochloride, Hydrochloride, Cyprazepam, Cyproheptadine Hydrochlo cetrorelix, Cetylpyridinium Chloride, Chenodiol, Chlophedi ride, Cyprolidol Hydrochloride, cyproterone, Cyproximide, anol Hydrochloride, Chloral Betaine, Chlorambucil, 15 Cysteamine, Cysteine Hydrochloride, Cystine, Cytarabine, Chloramphenicol, Chlordantoin, Chlordiazepoxide, Chlo Cytarabine Hydrochloride, cytarabine ocfosfate, cytochala rhexidine Gluconate, chlorins, Chlormadinone Acetate, chlo sin B, cytolytic factor, cytostatin, Dacarbazine, dacliximab, roorienticin A, Chloroprocaine Hydrochloride, Chloropropa dactimicin, Dactinomycin, daidzein, Daledalin Tosylate, dal mide, Chloroquine, chloroquinoxaline Sulfonamide, fopristin, Dalteparin Sodium, Daltroban, Dalvastatin, danap Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxyle aroid, DanaZol, Dantrolene, daphlnodorin A, dapiprazole, nol, Chlorphenesin Carbamate, Chlorpheniramine Maleate, dapitant, Dapoxetine Hydrochloride, Dapsone, Daptomycin, Chlorpromazine, Chlorpropamide, Chlorprothixene, Chlo DarglitaZone Sodium, darifenacin, darlucin A, Darodipine, rtetracycline Bisulfate, Chlorthalidone, ChlorZoxazone, darsidomine, Daunorubicin Hydrochloride, Dazadrol Male Cholestyramine Resin, Chromonar Hydrochloride, cibenzo ate, Dazepinil Hydrochloride, Dazmegrel, Dazopride Fuma line, cicaprost, Ciclafrine Hydrochloride, Ciclazindol, 25 rate, Dazoxiben Hydrochloride, Debrisoquin Sulfate, Decit ciclesonide, cicletanine, Ciclopirox, Cicloprofen, ciclo abine, deferiprone, deflazacort, Dehydrocholic Acid, prolol, Cidofovir, Cidoxepin Hydrochloride, Cifenline, dehydrodidemnin B, Dehydroepiandrosterone, delapril, Ciglitazone, Ciladopa Hydrochloride, cilansetron, Cilastatin Delapril Hydrochloride, Delavirdine Mesylate, delequamine, Sodium, Cilazapril, cilnidipine, Cilobamine Mesylate, cilo delfaprazine, Delmadinone Acetate, delmopinol, delphini bradine, Cillofungin, cilostazol, Cimaterol, Cimetidine, 30 din, Demecarium Bromide, Demeclocycline, Demecycline, cimetropium bromide, Cinalukast, Cinanserin Hydrochlo Demoxepam, Denofungin, deoxypyridinoline, Depakote, ride, Cinepazet Maleate, Cinflumide, Cingestol, cinitapride, deprodone, Deprostil, depsidomycin, deramciclane, derma Cinnamedrine, Cinnarizine, cinolazepam, Cinoxacin, Cin tan sulfate, Desciclovir, Descinolone Acetonide, Desflurane, perene, Cinromide, CintaZone, Cintriamide, Cioteronel, Desipramine Hydrochloride, desirudin, Deslanoside, Cipamfylline, Ciprefadol Succinate, Ciprocinonide, Ciprofi 35 deslorelin, desmopressin, desogestrel, Desonide. Des brate, Ciprofloxacin, ciprostene, Ciramadol, Cirolemycin, Oximetasone, desoxoamiodarone, Desoxycorticosterone cisapride, cisatracurium besilate, Cisconazole, Cisplatin, cis Acetate, detajmium bitartrate, Deterenol Hydrochloride, porphyrin, cistinexine, citalopram, Citenamide, citicoline, Detirelix Acetate, Devazepide, Dexamethasone, Dexamisole, citreamicin alpha, cladribine, Clamoxyquin Hydrochloride, Dexbrompheniramine Maleate, Dexchlorpheniramine Male Clarithromycin, clausenamide, Clavulanate Potassium, Cla 40 ate, Dexclamol Hydrochloride, Dexetimide, Dexfenflu Zolam, Clazolimine, clebopride, Clemastine, Clentiazem ramine Hydrochloride, dexifosfamide, Deximafen, Dexi Maleate, Clidinium Bromide, clinafloxacin, Clindamycin, vacaine, dexketoprofen, dexloxiglumide, Dexmedetomidine, Clioquinol, Clioxamide, Cliprofen, clobazam, Clobetasol Dexormaplatin, Dexoxadrol Hydrochloride, Dexpanthenol, Propionate, Clobetasone Butyrate, Clocortolone Acetate, Dexpemedolac, Dexpropranolol Hydrochloride, Dexrazox Clodanolene, Clodazon Hydrochloride, clodronic acid, Clo 45 ane, dexSotalol, dextrin 2-sulphate, Dextroamphetamine, fazimine, Clofibrate, Clofilium Phosphate, Clogestone Dextromethorphan, Dextrorphan Hydrochloride, Dextrothy Acetate, Clomacran Phosphate, Clomegestone Acetate, roxine Sodium, dexVerapamil, DeZaguanine, dezinamide, Clometherone, clomethiazole, clomifene analogues, Clomi dezocine, Diacetolol Hydrochloride, Diamocaine Cycla norex, Clomiphene, Clomipramine Hydrochloride, Clon mate, Diapamide, Diatrizoate Meglumine, Diatrizoic Acid, azepam, Clonidine, Clonitrate, Clonixeril, Clonixin, Clopa 50 Diaveridine, Diazepam, Diaziquone, Diazoxide, Dibenzepin mide, Clopenthixol, Cloperidone Hydrochloride, Hydrochloride, Dibenzothiophene, Dibucaine, Dichliorvos, clopidogrel, Clopimozide, Clopipazan Mesylate, Clopirac, Dichloralphenazone, Dichlorphenamide, Dicirenone, Cloprednol, Cloprostenol Sodium, Clorazepate Dipotassium, Diclofenac Sodium, Dicloxacillin, dicranin, Dicumarol, Clorethate, Clorexolone, Cloroperone Hydrochloride, Clor Dicyclomine Hydrochloride, Didanosine, didemnin B, prenaline Hydrochloride, Clorsulon, Clortermine Hydro 55 didox, Dienestrol, dienogest, Diethylcarbamazine Citrate, chloride, Closantel, Closiramine Aceturate, Clothiapine, diethylhomospermine, diethylnorspermine, Diethylpropion Clothixamide Maleate Cloticasone Propionate, Clotrima Hydrochloride, Diethylstilbestrol. Difenoximide Hydrochlo Zole, Cloxacillin BenZathine, Cloxyquin, Clozapine, ride. Difenoxin, Diflorasone Diacetate. Difloxacin Hydro Cocaine, Coccidioidin, Codeine, Codoxime, Colchicine, chloride, Difluanine Hydrochloride, Diflucortolone. Diflu colestimide, Colestipol Hydrochloride, Colestolone, Col 60 midone Sodium, Diflunisal, Difluprednate. Diftalone, forsin, Colfosceril Palmitate, Colistimethate Sodium, Colis Digitalis, Digitoxin, Digoxin, Dihexyverine Hydrochloride, tin Sulfate, collismycin A, collismycin B, Colterol Mesylate, dihydrexidine, dihydro-5-azacytidine, Dihydrocodeine combretastatin A4, combretastatin analogue, complestatin, Bitartrate, Dihydroergotamine Mesylate, Dihydroestoster conagenin, Conorphone Hydrochloride, contignasterol, con one, Dihydrostreptomycin Sulfate, Dihydrotachysterol, dihy tortrostatin, Cormethasone Acetate, Corticorelin Ovine Tri 65 drotaxol. 9-, Dilantin, Dilevalol Hydrochloride, Diltiazem flutate, Corticotropin, Cortisone Acetate, Cortivazol, Corto Hydrochloride, Dimefadane, Dimefline Hydrochloride, doxone, cosalane, costatolide, Cosyntropin, cotinine, Dimenhydrinate, Dimercaprol, Dimethadione, Dimethin US 8,263,125 B2 11 12 dene Maleate, Dimethisterone, dimethyl prostaglandin Al, Fenoprofen, Fenoterol, Fenpipalone, Fenprinast Hydrochlo Dimethyl Sulfoxide, dimethylhomospermine, dimiracetam, ride, Fenprostalene, Fenguizone, fenretinide, fenspiride, Fen Dimoxamine Hydrochloride, Dinoprost, Dinoprostone, tanyl Citrate, Fentiazac, Fenticlor, fenticonazole, Fenyripol Dioxadrol Hydrochloride, dioxamycin, Diphenhydramine Hydrochloride, fepradinol, ferpifosate sodium, ferristene, Citrate, Diphenidol, Diphenoxylate Hydrochloride, diphenyl ferrixan, Ferrous Sulfate, Dried, Ferumoxides, ferumoxsil, spiromustine, Dipivefin Hydrochloride, Dipivefrin, diplien Fetoxylate Hydrochloride, fexofenadine, Fezolamine Fuma cyprone, diprafenone, dipropylnorspermine, Dipyridamole, rate, Fiacitabine, Fialuridine, Fibrinogen 1 125, filgrastim, Dipyrithione, Dipyrone, dirithromycin, discodermolide, Dis Filipin, finasteride, Flavodilol Maleate, flavopiridol, Flavox obutamide, Disofenin, Disopyramide, Disoxaril, disulfiram, ate Hydrochloride, Flazalone, flecainide, flerobuterol, Ditekiren, Divalproex Sodium, Dizocilpine Maleate, Dob 10 Fleroxacin, flesinoxan, Flestolol Sulfate, Fletazepam, fle utamine, docarpamine, Docebenone, Docetaxel, Docona Zelastine, flobufen, Floctafenine, flomoxef, Flordipine, flo Zole, docosanol, dolfetilide, dolasetron, Ebastine, ebiratide, rfenicol, florifenine, flosatidil, Flosequinan, Floxacillin, ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdlisteron, Floxuridine, fluasterone, Fluazacort, Flubanilate Hydrochlo echicetin, echistatin, Echothiophate Iodide, Eclanamine ride, Flubendazole, Flucindole, Flucloronide, Fluconazole, Maleate, EclaZolast, ecomustine, Econazole, ecteinascidin 15 Flucytosine, Fludalanine, Fludarabine Phosphate, Fludazo 722, edaravone, Edatrexate, edelfosine, Edifolone Acetate, nium Chloride, Fludeoxyglucose F 18, Fludorex, Fludrocor edobacomab, Edoxudine, edrecolomab, Edrophonium Chlo tisone Acetate, Flufenamic Acid, Flufenisal, Flumazenil, flu ride, edroxyprogesteone Acetate, efegatran, eflornithine, mecinol, Flumequine, Flumeridone, Flumethasone, efonidipine, egualcen, Elantrine, eleatonin, elemene, eletrip Flumetramide, Flumezapine, Fluminorex, Flumizole, Flu tan, elgodipine, eliprodil, Elsamitrucin, eltenae, Elucaine, moxonide, flunarizine, Flunidazole, Flunisolide, Fluni emalkalim, emedastine, Emetine Hydrochloride, emiglitate, trazepam, Flumixin, fluocalcitriol, Fluocinolone Acetonide, Emilium Tosylate, emitefur, emoctakin, Enadoline Hydro Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorescein, chloride, enalapril, Enalaprilat, Enalkiren, enaZadrem, fluorodaunorunicin hydrochloride, Fluorodopa F 18, Fluo Encyprate, Endralazine Mesylate, Endrysone, Enflurane, rometholone, Fluorouracil, Fluotracen Hydrochloride, Flu englitaZone, Enilconazole, Enisoprost, Enlimomab, Enlopl 25 oxetine, Fluoxymesterone, fluparoxan, Fluperamide, Fluper atin, Enofelast, Enolicam Sodium, Enoxacin, enoxacin, olone Acetate, Fluphenazine Decanoate, flupirtine, enoxaparin Sodium, Enoxaparin Sodium, Enoximone, Fluprednisolone, FluproduaZone, Fluprostenol Sodium, Flu Empiroline Phosphate, Enprofylline, Enpromate, entacapone, quaZone, Fluradoline Hydrochloride, Flurandrenolide, Flu enterostatin, Enviradene, Enviroxime, Ephedrine, Epicillin, razepam Hydrochloride, Flurbiprofen, Fluretofen, flurithro Epimestrol, Epinephrine, Epinephryl Borate, Epipropidine, 30 mycin, Flurocitabine, Flurofamide, Flurogestone Acetate, Epirizole, epirubicin, Epitetracycline Hydrochloride, Epithi Flurothyl, Fluroxene, Fluspiperone, Fluspirilene, Fluticasone azide, Epoetin Alfa, Epoetin Beta, Epoprostenol, Epopros Propionate, flutrimazole, Flutroline, fluvastatin, Fluvastatin tenol Sodium, epoxymeXrenone, epristeride, Eprosartan, Sodium, fluvoxamine, Fluzinamide, Folic Acid, Follicle eptastigmine, equilenin, Equilin, ErbuloZole, erdosteine, regulatory protein, Folliculostatin, Fomepizole, Fonazine Ergoloid Mesylates, Ergonovine Maleate, Ergotamine Tar 35 Mesylate, forasartan, forfenimex, forfenirmex, formestane, trate, ersentilide, Ersofermin, erythritol, Erythrityl Tetrani Formocortal, formoterol, Fosarilate, Fosazepam, Foscarnet trate, Erythromycin, Esmolol Hydrochloride, Esorubicin Sodium, fosfomycin, Fosfonet Sodium, fosinopril, Fosinop Hydrochloride, Esprocquin Hydrochloride, Estazolam, Estra rilat, fosphenyloin, Fosquidone, Fostedil, fostriecin, fote diol, Estramustine, estramustine analogue, EstraZinol Hydro mustine, Fuchsin, Basic, Fumoxicillin, Fungimycin, Fura bromide, Estriol, Estrofurate, estrogen agonists, estrogen 40 profen, Furazolidone. Furazolium Chloride. Furegrelate antagonists, Estrogens, Conjugated Estrogens, Esterified Sodium, Furobufen, Furodazole, Furosemide, Fusidate Estrone, Estropipate, esuprone, Etafedrine Hydrochloride, Sodium, Fusidic Acid, gabapentin, Gadobenate Dimeglu Etanidazole, etanterol, Etarotene, Etazolate Hydrochloride, mine, gadobenic acid, gadobutrol, Gadodiamide, gadolinium Eterobarb, ethacizin, Ethacrynate Sodium, Ethacrynic Acid, texaphyrin, Gadopentetate Dimeglumine, gadoteric acid, Ethambutol Hydrochloride, Ethamivan, Ethanolamine Ole 45 Gadoteridol, Gadoversetamide, galantamine, galdansetron, ate, Ethehlorvynol, Ether, Ethinyl estradiol, Ethiodized Oil, Galdansetron Hydrochloride, Gallamine Triethiodide, gal Ethionamide, Ethonam Nitrate, Ethopropazine Hydrochlo lium nitrate, gallopamil, galocitabine, Gamfexine, gamolenic ride, Ethosuximide, Ethotoin, Ethoxazene Hydrochloride, acid, Ganciclovir, ganirelix, gelatinase inhibitors, Gemca Ethybenztropine, Ethyl Chloride, Ethyl Dibunate, Ethylestre diol, Gemcitabine, Gemeprost, Gemfibrozil, Gentamicin Sul nol, Ethyndiol, Ethynerone, Ethynodiol Diacetate, Etibenda 50 fate, Gentian Violet, gepirone, Gestaclone, Gestodene, Zole, Etidocaine, Etidronate Disodium, Etidronic Acid, Etife Gestonorone Caproate, Gestrinone, Gevotroline Hydrochlo nin, Etintidine Hydrochloride, etizolam, Etodolac, ride, girisopam, glaspimod, glaucocalyxin A, Glemanserin, Etofenamate, Etoformin Hydrochloride, Etomidate, Gliamilide, Glibornuride, Glicetanile Sodium, Gliflumide, Etonogestrel, Etoperidone Hydrochloride, Etoposide, Eto Glimepiride, Glipizide, Gloximonam, Glucagon, glutapy prine, Etoxadrol Hydrochloride, Etozolin, etrabamine, Etreti 55 rone, glutathione inhibitors, Glutethimide, Glyburide, glyco nate, Etryptamine Acetate, Eucatropine Hydrochloride, pine, glycopril, Glycopyrrolate, Glyhexamide, Glymidine Eugenol, Euprocin Hydrochloride, eveninomicin, Exameta Sodium, Glyoctamide, Glyparamide, Gold Au 198, Gona Zime, examorelin, Exaprolol Hydrochloride, exemestane, doctrinins, Gonadorelin, Gonadotropins, Goserelin, Grami fadrozole, faerieflungin, Famciclovir, Famotidine, Fampri cidin, Granisetron, grepafloxacin, Griseofulvin, Guaiapate, dine, fantofarone, Fantridone Hydrochloride, faropenem, 60 Guaithylline, GuanabenZ, Guanabenz, Acetate, Guanadrel fasidotril, fasudil, fazarabine, fedotozine, felbamate, Felbi Sulfate, Guancydine, Guanethidine Monosulfate, Guanfa nac, Felodipine, Fely pressin, Fenalamide, Fenamole, Fen cine Hydrochloride, Guanisoquin Sulfate, Guanoclor Sulfate, bendazole, Fenbufen, Fencibutirol, Fenclofenac, Fenclonine, Guanoctine Hydrochloride, Guanoxabenz, Guanoxan Sul Fenclorac, Fendosal, Fenestrel, Fenethylline Hydrochloride, fate, Guanoxyfen Sulfate, Gusperimus Trihydrochloride, Fenfluramine Hydrochloride, Fengabine, Fenimide, Fen 65 Halazepam, Halcinonide, halichondrin B. Halobetasol Pro isorex, Fenmetozole Hydrochloride, Fenmetramide, pionate, halofantrine, Halofantrine Hydrochloride, Fenobam, Fenoctimine Sulfate, fenofibrate, fenoldopam, Halofenate, Halofuginone Hydrobromide, halomon, US 8,263,125 B2 13 14 Halopemide, Haloperidol, halopredone, Haloprogesterone, Ketoconazole, Ketoprofen, Ketorfanol, ketorolac, Ketotifen Haloprogin, Halothane, Halquinols, Hamycin, Han memo Fumarate, Kitasamycin, Labetalol Hydrochloride, Lacid pausal gonadotropins, hatomamicin, hatomarubigin A, ipine, lacidipine, lactitol, lactivicin, laennec, lafutidine, hatomarubigin B, hatomarubigin C, hatomarubigin D. Hep lamellarin-N triacetate, lamifiban, Lamivudine, Lamotrigine, arin Sodium, hepsulfam, heregulin, Hetacillin, Heteronium lanoconazole, Lanoxin, lanperisone, lanreotide, Lansopra Bromide, Hexachlorophene: Hydrogen Peroxide, Hexafluo Zole, latanoprost, lateritin, laurocapram, Lauryl Isoquino renium Bromide, hexamethylene bisacetamide, Hexedine, linium Bromide, Lavoltidine Succinate, lazabemide, Lecimi Hexobendine, Hexoprenaline Sulfate, Hexylresorcinol, His bide, leinamycin, lemildipine, leminoprazole, lenercept, tamine Phosphate. Histidine, Histoplasmin, Histrelin, Homa Leniquinsin, lenograstim, Lenperone, lentinan Sulfate, leptin, tropine Hydrobromide, Hoquizil Hydrochloride, Human 10 leptolstatin, lercanidipine, Lergotrile, lerisetron, Letimide chorionic gonadotropin, Hycanthone, Hydralazine Hydro Hydrochloride, letraZuril, letrozole, Leucine, leucomyzin, chloride, Hydralazine Polistirex, Hydrochlorothiazide, Leuprolide Acetate, leuprolide-estrogen-progesterone, leu Hydrocodone Bitartrate, Hydrocortisone, Hydroflumethiaz prorelin, Levamfetamine Succinate, levamisole, Levdob ide, Hydromorphone Hydrochloride, Hydroxyamphetamine utamine Lactobionate, Leveromakalim, levetiracetam, Hydrobromide, Hydroxychloroquine Sulfate, Hydroxyphe 15 Leveycloserine, levobetaxolol, levobunolol, levobupiv namate, Hydroxyprogesterone Caproate, Hydroxyurca, acaine, levocabastine, levocarnitine, Levodopa, levodro Hydroxyzine Hydrochloride, Hymecromone, Hyoscyamine, propizine, levofloxacin, Levofuraltadone, Levoleucovorin hypericin, Ibafloxacin, ibandronic acid, ibogaine, Ibopamine, Calcium, Levomethadyl Acetate, Levomethadyl Acetate ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icatibant Hydrochloride, levomoprolol, Levonantradol Hydrochloride, Acetate, Ichthammol. Icotidine, idarubicin, idoxifene, Idoxu Levonordefrin, Levonorgestrel, Levopropoxyphene Napsy ridine, idramantone, Iemefloxacin, Iesopitron, Ifetroban, late, Levopropylcillin Potassium, levormeloxifene, Levor Ifosfamide, Ilepeimide, illimaquinone, ilmofosine, illomastat, phanol Tartrate, levosimendan, levoSulpiride, Levothyroxine Ilonidap, illoperidone, iloprost, Imafen Hydrochloride, Ima Sodium, Levoxadrol Hydrochloride, Lexipafant, Lexithro Zodan Hydrochloride, imidapril, imidazenil, imidazoacri mycin, liarozole, Libenzapril, Lidamidine Hydrochloride, dones, Imidecyl Iodine, Imidocarb Hydrochloride, Imidoline 25 Lidocaine, Lidofenin, Lidoflazine, Lifarizine, Lifibrate, Lifi Hydrochloride. Imidurea, Imiloxan Hydrochloride, Imi brol, Linarotene, Lincomycin, linear polyamine analogue, penem, Imipramine Hydrochloride, imiquimod, immuno Linogliride, Linopirdine, linotroban, linsidomine, lintitript, stimulant peptides, Impromidine Hydrochloride, India lintopride, Liothyronine I 125, liothyronine sodium, Liotrix, crinone, Indapamide, Indecainide Hydrochloride, lirexapride, lisinopril, lissoclinamide 7. Lixazinone Sulfate, Indeloxazine Hydrochloride, Indigotindisulfonate Sodium, 30 lobaplatin, Lobenzarit Sodium, Lobucavir, Lodelaben, indinavir, Indocyanine Green, Indolapril Hydrochloride, Iodoxamide, Lofemizole Hydrochloride, Lofentanil Oxalate, Indolidan, indometacin, Indomethacin Sodium, Indoprofen, Lofepramine Hydrochloride, Lofexidine Hydrochloride, indoramin, Indorenate Hydrochloride, Indoxole, Indriline lombricine, Lomefloxacin, lomerizine, Lometraline Hydro Hydrochloride, inocoterone, inogatran, inolimomab, Inositol chloride, lometrexol, Lomofungin, Lomoxicam, Lomustine, Niacinate, Insulin, interferons, interleukins, Intrazole, Intrip 35 Lonapalene, lonazolac, lonidamine, Loperamide Hydrochlo tyline Hydrochloride, iobenguane, Iobenzamic Acid, iobitri ride, loracarbef, Lorajmine Hydrochloride, loratadine, dol, Iocarmate Meglumine, Iocarmic Acid, Iocetamic Acid, Lorazepam, Lorbamate, Lorcainide Hydrochloride, Lore Iodamide, Iodine, Iodipamide Meglumine, Iodixanol, clezole, Loreinadol, lorglumide, Lorimetazepam, Lornoxi iodoamiloride, Iodoantipyrine I 131, Iodocholesterol I 131, cam, lornoxicam, Lortalamine, Lorzafone, losartan, losiga iododoxorubicin, Iodohippurate Sodium I 131, Iodopyracet I 40 mone, losoxantrone, Losulazine Hydrochloride, loteprednol, 125. Iodoquinol, Iodoxamate Meglumine, Iodoxamie Acid, lovastatin, loviride, Loxapine, Loxoribine, lubeluzole, Ioglicic Acid, Iofetamine Hydrochloride I 123, iofratol, Lucanthone Hydrochloride, Lufironil, Lurosetron Mesylate, Ioglucol, Ioglucomide, Ioglycamic Acid, Iogulamide, lurtotecan, luteinizing hormone, lutetium, Lutrelin Acetate, Iohexol, iomeprol, Iomethin I 125, Iopamidol, Iopanoic Acid, luZindole, Lyapolate Sodium, Lycetamine, lydicamycin, iopentol, Iophendylate, Ioprocemic Acid, iopromide, 45 Lydimycin, Lynestrenol, Lypressin, Lysine, lysofylline, lyso Iopronic Acid, Iopydol, Iopy done, iopyrol, Iosefamic Acid, staphin, lytic peptides, Maduramicin, Mafenide, magainin 2 Ioseric Acid, IoSulamide Meglumine, IoSumetic Acid, Iota amide, Magnesium Salicylate, Magnesium Sulfate, mag Sul, Iotetric Acid, Iothalamate Sodium, Iothalamic Acid, iot nolol, maitansine, Malethamer, mallotochromene, malloto riside, Iotrolan, Iotroxic Acid, Iotyrosine I 131, Ioversol, Iox japonin, Malotilate, malotilate, mangafodipir, manidipine, agiate Sodium, Ioxaglate Meglumine, Ioxaglic Acid, ioXilan, 50 maniwamycin A, Mannitol, mannostatin A, manumycin E, Ioxotrizoic Acid, ipazilide, ipenoxazone, ipidacrine, Ipodate manumycin F. mapinastine, Maprotiline, marimastat, Martek Calcium, ipomeanol, 4-, Ipratropium Bromide, ipriflavone, 8708, Martek 92211, Masoprocol, maspin, massetolide, Iprindole, profenin, Ipronidazole, Iproplatin, Iproxamine matrilysin inhibitors, Maytansine, Mazapertine Succiniate, Hydrochloride, ipsapirone, irbesartan, irinotecan, irloxacin, Mazindol, Mebendazole, Mebeverine Hydrochloride, iroplact, irsogladine, Irtemazole, isalsteine, Isamoxole, 55 Mebrofenin, Mebutamate, Mecamylamine Hydrochloride, isbogrel, Isepamicin, isobengaZole, Isobutamben, Isocarbox Mechlorethamine Hydrochloride, Meclocycline, Meclofe azid, Isoconazole, Isoetharine, isofloxythepin, Isoflupredone namate Sodium, Mecloqualone, Meclorisone Dibutyrate, Acetate, Isoflurane, Isoflurophate, isohomohalicondrin B, Medazepam Hydrochloride, Medorinone, Medrogestone, Isoleucine, Isomazole Hydrochloride, Isomylamine Hydro Medroxalol, Medroxyprogesterone, Medrysone, Meelizine chloride, Isoniazid, Isopropamide Iodide, Isopropyl Alcohol, 60 Hydrochloride, Mefenamic Acid, Mefenidil, Mefenorex isopropyl unoprostone, Isoproterenol Hydrochloride, Isosor Hydrochloride, Mefexamide, Mefloquine Hydrochloride, bide, Isosorbide Mononitrate, Isotiquimide, Isotretinoin, Mefruside, Megalomicin Potassium Phosphate, Megestrol Isoxepac, Isoxicam, IsoxSuprine Hydrochloride, isradipine, Acetate, Meglumine, Meglutol, Melengestrol Acetate, Meli itameline, itasetron, ItaZigrel, itopride, Itraconazole, Iver tracen Hydrochloride, Melphalan, Memotine Hydrochloride, mectin, jasplakinolide, Josamycin, kahalalide F, Kalafungin, 65 Menabitan Hydrochloride, Menoctone, menogaril, Menotro Kanamycin Sulfate, Ketamine Hydrochloride, Ketanserin, pins, Meobentine Sulfate, Mepartricin, Mepenzolate Bro Ketazocine, Ketazolam, Kethoxal, Ketipramine Fumarate, mide, Meperidine Hydrochloride, Mephentermine Sulfate, US 8,263,125 B2 15 16 Mephenyloin, Mephobarbital, Mepivacaine Hydrochloride, ride, napavin, Naphazoline Hydrochloride, naphterpin, Meprobamate, Meptazinol Hydrochloride, Mequidox, Mera Naproxen, NaproXol, napsagatran, Naranol Hydrochloride, lein Sodium, merbarone, Mercaptopurine, Mercufenol Chlo Narasin, naratriptan, nartograstim, nasaruplase, Natamycin, ride, Mercury, Ammoniated, Merisoprol Hg 197, Mero nateplase, Naxagolide Hydrochloride, Nebivolol, Nebramy penem, Mesalamine, MeseclaZone, Mesoridazine, cin, nedaplatin, Nedocromil, Nefazodone Hydrochloride, Mesterolone, Mestranol, Mesuprine Hydrochloride, Metalol Neflumozide Hydrochloride, Nefopam Hydrochloride, Hydrochloride, Metaproterenol Polistirex, Metaraminol NeleZaprine Maleate, Nemazoline Hydrochloride, nemoru Bitartrate, Metaxalone, Meteneprost, meterelin, Metformin, bicin, Neomycin Palmitate, Neostigmine Bromide, Methacholine Chloride, Methacycline, Methadone Hydro neridronic acid, Netilmicin Sulfate, neutral endopeptidase, chloride, Methadyl Acetate, Methalthiazide, Methamphet 10 Neutramycin, Nevirapine, Nexeridine Hydrochloride, Nia amine Hydrochloride, Methaqualone, Methazolamide, cin, Nibroxane, Nicardipine Hydrochloride, Nicergoline, Methdilazine, Methenamine, Methenolone Acetate, Meth Niclosamide, Nicorandil, Nicotinyl Alcohol, Nifedipine, etoin, Methicillin Sodium, Methimazole, methioninase, Nifirmerone, Nifluridide, Nifuradene, Nifuraldezone, Nifu Methionine, Methisazone, Methixene Hydrochloride, ratel, Nifuratrone, Nifurdazil, Nifurimide, Nifurpirinol, Methocarbamol, Methohexital Sodium, Methopholine, 15 Nifurcquinazol, Nifurthiazole, nilutamide, Nilvadipine, Methotrexate, Methotrimeprazine, methoxatone, Methoxy Nimazone, Nimodipine, niperotidine, niravoline, Niridazole, flurane, MethSuximide, Methyclothiazide, Methyl Palmox nisamycin, Nisbuterol Mesylate, nisin, Nisobamate, Nisol irate, Methylatropine Nitrate, Methylbenzethonium Chlo dipine, Nisoxetine, Nisterime Acetate, Nitarsone, nitazoxa ride, Methyldopa, Methyldopate Hydrochloride, Methylene mide, nitecapone, Nitrafudam Hydrochloride, Nitralamine Blue, Methylergonovine Maleate, methylhistamine, R-alpha, Hydrochloride, Nitramisole Hydrochloride, Nitrazepam, methylinosine monophosphate, Methylphenidate Hydro Nitrendipine, Nitrocycline, Nitrodan, Nitrofurantoin, Nitro chloride, Methylprednisolone, Methyltestosterone, Meth furaZone, Nitroglycerin, Nitromersol, Nitromide, ynodiol Diacelate, Methysergide, Methysergide Maleate, Nitromifene Citrate, Nitrous Oxide, nitroxide antioxidant, Metiamide, Metiapine, Metioprim, metipamide, Metipra nitrullyn, Nivazol, Nivinedone Sodium, Nizatidine, nolol, Metizoline Hydrochloride, Metkephamid Acetate, 25 Noberastine, Nocodazole, Nogalamycin, Nolinium Bromide, metoclopramide, Metocurine Iodide, Metogest, Metolazone, Nomifensine Maleate, Noracymethadol Hydrochloride, Nor Metopimazine, Metoprine, Metoprolol, Metoquizine, metri bolethone, Norepinephrine Bitaritrate, Norethindrone, Nor fonate, Metrizamide, Metrizoate Sodium, Metronidazole, ethynodrel, Norfloxacin, Norflurane, Norgestimate, Norg Meturedepa, Metyrapone, Metyrosine, Mexiletine Hydro estomet, Norgestrel, Nortriptyline Hydrochloride, chloride, Mexrenoate Potassium, Mezlocillin, mfonelic Acid, 30 Noscapine, Novobiocin Sodium, N-substituted benzaimides, Mianserin Hydrochloride, mibefradil, Mibefradil Dihydro Nufenoxole, Nylestriol, Nystatin, O6-benzylguanine, Obi chloride, Mibolerone, michellamine B. Miconazole, micro doxime Chloride, Ocaperidone, Ocfentanil Hydrochloride, colin A, Midaflur, Midazolam Hydrochloride, midodrine, Ocinaplon, Octanoic Acid, Octazamide, Octenidine Hydro mifepristone, Mifobate, miglitol, millacemide, milameline, chloride, Octodrine, Octreotide, Octriptyline Phosphate, mildronate, Milenperone, Milipertine, milnacipran, Mil 35 Ofloxacin, Oformine, okicenone, Olanzapine, oligonucle rinone, miltefosine, Mimbane Hydrochloride, minaprine, otides, olopatadine, olprinone, olSalazine, Olsalazine Minaxolone, Minocromil, Minocycline, Minoxidil, Miofla Sodium, Olvanil, omeprazole, onapristone, ondansetron, Zine Hydrochloride, miokamycin, mipragoside, mirfentanil, Ontazolast, Oocyte maturation inhibitor, Opipramol Hydro mirimostim, Mirincamycin Hydrochloride, Mirisetron Male chloride, oracin, Orconazole Nitrate, Orgotein, Orlislat, ate, Mirtazapine, mismatched double stranded RNA, Mis 40 Ormaplatin, Ormetoprim, Ornidazole, Orpanoxin, onidazole, Misoprostol, Mitindomide, Mitocarcin, Mitocro Orphenadrine Citrate, osaterone, otenzepad, Oxacillin min, Mitogillin, mitoguaZone, mitolactol, Mitomalcin, Sodium, Oxagrelate, oxaliplatin, Oxamarin Hydrochloride, Mitomycin, mitonafide, Mitosper, Mitotane, mitoxantrone, oxamisole, Oxamniquine, Oxandrolone, Oxantel Pamoate, mivacurium chloride, mivaZerol, mixanpril, Mixidine, mizo Oxaprotiline Hydrochloride, Oxaprozin, Oxarbazole, Oxato lastine, mizoribine, Moclobemide, modafinil, Modaline Sul 45 mide, oxaunomycin, Oxazepam, oXcarbazepine, Oxen fate, Modecainide, moexipril, mofarotene, Mofegiline dolone, Oxethazaine, Oxetorone Fumarate, Oxfendazole, Hydrochloride, mofeZolac, molgramoStim, MolinaZone, Oxfenicine, Oxibendazole, oxiconazole, Oxidopamine, Molindone Hydrochloride, Molsidomine, mometasone, Oxidronic Acid, Oxifungin Hydrochloride, Oxilorphan, Oxi Monatepil Maleate, Monensin, Monoctanoin, Montelukast monam, Oximonam Sodium, OXiperomide, oxiracetam, Sodium, montirelin, mopidamol, moracizine, Morantel Tar 50 Oxiramide, Oxisuran, Oxmetidine Hydrochloride, oxo trate, Moricizine, Morniflumate, Morphine Sulfate, Mor dipine, Oxogestone Phenpropionate, Oxolinic Acid, Oxpre rhuate Sodium, mosapramine, mosapride, motilide, Motre nolol Hydrochloride, Oxtriphylline, Oxybutynin Chloride, tinide, Moxalactam Disodium, Moxazocine, moxiraprine, Oxychlorosene, Oxycodone, Oxymetazoline Hydrochloride, MoXnidazole, moxonidine, Mumps Skin Test Antigen, mus Oxymetholone, Oxymorphone Hydrochloride, Oxypertine, tard anticancer agent, Muzolimine, mycaperoxide B. Myco 55 Oxyphenbutazone, Oxypurinol, Oxytetracycline, Oxytocin, phenolic Acid, myriaporone, Nabazenil, Nabilone, Nabitan oZagrel, Ozolinone, Paclitaxel, palauamine, Paldimycin, pali Hydrochloride, Naboctate Hydrochloride, Nabumetone, navir, palmitoylrhizoxin, Palmoxirate Sodium, pamaqueside, N-acetyldinaline, Nadide, nadifloxacin, Nadolol, nadroparin Pamatolol Sulfate, pamicogrel, Pamidronate Disodium, pam calcium, nafadotride, nafamo.stat, nafarelin, Nafcillin idronic acid, Panadiplon, panamesine, panaxytriol, Panco Sodium, Nafenopin, Nafimidone Hydrochloride, Naflocort, 60 pride, Pancuronium Bromide, panipenem, pannorin, Nafomine Malate, Nafoxidine Hydrochloride, Nafronyl panomifene, pantethine, pantoprazole, Papaverine Hydro Oxalate, Naftifine Hydrochloride, naftopidil, naglivan, chloride, parabactin, Parachlorophenol, Paraldehyde, nagrestip, Nalbuphine Hydrochloride, Nalidixate Sodium, Paramethasone Acetate, Paranyline Hydrochloride, Parapen Nalidixic Acid, nalmefene, Nalmexone Hydrochloride, Zolate Bromide, Pararosaniline Pamoate, Parbendazole, Par naloxone-pentazocine, Naltrexone, NamoXyrate, Nan 65 conazole Hydrochloride, Paregoric, Pareptide Sulfate, Par drolone Phenpropionate, Nantradol Hydrochloride, Napacta gyline Hydrochloride, parnaparin Sodium, Paromomycin dine Hydrochloride, napadisilate, Napamezole Hydrochlo Sulfate, Paroxetine, parthenolide, Partricin, Paulomycin, US 8,263,125 B2 17 18 paZelliptine, PaZinaclone, PaZoxide, paZufloxacin, pefloxa chloride, Prochlorperazine, Procinonide, Proclonol, Procy cin, pegaspargase, Pegorgotein, Pelanserin Hydrochloride, clidine Hydrochloride, Prodilidine Hydrochloride, Prodolic peldesine, Peliomycin, Pelretin, Pelrinone Hydrochloride, Acid, Profadol Hydrochloride, Progabide, Progesterone, Pro Pemedolac, Pemerid Nitrate, pemirolast, Pemoline, Pename glumide, Proinsulin Human, Proline, Prolintane Hydrochlo cillin, Penbutolol Sulfate, Penciclovir, Penfluridol, Penicillin ride, Promazine Hydrochloride, Promethazine Hydrochlo G BenZathine, Penicillin G Potassium, Penicillin G Procaine, ride, Propafenone Hydrochloride, propagermanium, Penicillin G Sodium, Penicillin V, Penicillin V BenZathine, Propanidid, Propantheline Bromide, Proparacaine Hydro Penicillin V Hydrabamine, Penicillin V Potassium, Pent chloride, Propatyl Nitrate, propentofylline, Propenzolate abamate, Pentaerythritol Tetranitrate, pentafuside, pentami Hydrochloride, Propikacin, Propiomazine, Propionic Acid, dine, pentamorphone, Pentamustine, Pentapiperium Methyl 10 propionylcarnitine, L-, propiram, propiram-paracetamol. sulfate, Pentazocine, Pentetic Acid, Pentiapine Maleate, propiverine, Propofol, Propoxycaine Hydrochloride, Pro pentigetide, Pentisomicin, Pentizidone Sodium, Pentobar poxyphene Hydrochloride, Propranolol Hydrochloride, Pro bital, Pentomone, Pentopril, pentosan, pentostatin, Pentoxi pulsid, propyl bis-acridone, Propylhexedrine, Propyliodone, fylline, Pentrinitrol, pentrozole, Peplomycin Sulfate, Pepsta Propylthiouracil, ProquaZone, Prorenoate Potassium, tin, perflubron, perfofamide, Perfosfamide, pergolide, 15 Proroxan Hydrochloride, Proscillaridin, Prostalene, prostra Perhexiline Maleate, perillyl alcohol, Perindopril, perindop tin, Protamine Sulfate, protegrin, Protirelin, protosufloxacin, rilat, Perlapine, Permethrin, perospirone, Perphenazine, Protriptyline Hydrochloride, Proxazole, Proxazole Citrate, Phenacemide, phenaridine, phenazinomycin, Phenazopyri Proxicromil, Proxorphan Tartrate, prulifloxacin, Pseu dine Hydrochloride, Phenbutazone Sodium Glycerate, Phen doephedrine Hydrochloride, Puromycin, purpurins, carbamide, Phencyclidine Hydrochloride, Phendimetrazine Pyrabrom, Pyrantel Pamoate, Pyrazinamide, Pyrazofurin, Tartrate, Phenelzine Sulfate, Phenmetrazine Hydrochloride, pyrazoloacridine, Pyridostigmine Bromide, Pyrilamine Phenobarbital, Phenoxybenzamine Hydrochloride, Phen Maleate, Pyrimethamine, Pyrinoline, Pyrithione Sodium, procoumon, phenserine, phensuccinal, PhenSuximide, Phen Pyrithione Zinc, Pyrovalerone Hydrochloride, Pyroxamine termine, Phentermine Hydrochloride, phentolamine mesi Maleate, Pyrrocaine, Pyrroliphene Hydrochloride, Pyrrolni late, Phentoxifylline, Phenyl Aminosalicylate, phenylacetate, 25 trin, Pyrvinium Pamoate, Quadazocine Mesylate, Quazepam, Phenylalanine, phenylalanyl ketoconazole, Phenylbutazone, Quazinone, QuaZodine, QuaZolast, quetiapine, quiflapon, Phenylephrine Hydrochloride, Phenylpropanolamine Hydro quinagolide, Quinaldine Blue, quinapril, Quinaprilat, chloride, Phenylpropanolamine Polistirex, Phenyramidol Quinazosin Hydrochloride, Quinbolone, Quinctolate, Quin Hydrochloride, Phenyloin, phosphatase inhibitors, Physos decamine Acetate, Quindonium Bromide, Quinelorane tigmine, picenadol, picibanil, Picotrin Diolamine, picroliv, 30 Hydrochloride, Quinestrol, Quinfamide, Quingestanol picumeterol, pidotimod, Pifamine, Pilocarpine, pilsicainide, Acetate, Quingestrone, Quinidine Gluconate, Quinielorane pimagedine, Pimetine Hydrochloride, pimilprost, Pimoben Hydrochloride, Quinine Sulfate, Quinpirole Hydrochloride, dan, Pimozide, Pinacidil, Pinadoline, Pindolol, pinnenol, Quinterenol Sulfate, Quinuclium Bromide, Quinupristin, pinocebrin, Pinoxepin Hydrochloride, pioglitaZone, Pipam Quipazine Maleate, Rabeprazole Sodium, Racephenicol, perone, Pipazethate, pipecuronium bromide, Piperacetazine, 35 Racepinephrine, rafantagonists, Rafoxamide, Ralitoline, ral Piperacillin Sodium, Piperamide Maleate, piperazine, Pipo oxifene, raltitrexed, ramatroban, Ramipril, Ramoplanin, broman, Piposulfan, Pipotiazine Palmitate, Pipoxolan ramosetron, ranelic acid, Ranimycin, Ranitidine, ranolazine, Hydrochloride, Piprozolin, Piquindone Hydrochloride, Rauwolfia Serpentina, recainam, Recainam Hydrochloride, Piquizil Hydrochloride, Piracetam, Pirandamine Hydrochlo Reclazepam, regavirumab, RegramoStim, Relaxin, Relomy ride, pirarubicin, Pirazmonam Sodium, Pirazolac, Pirbenicil 40 cin, Remacemide Hydrochloride, Remifentanil Hydrochlo lin Sodium, Pirbuterol Acetate, Pirenperone, Pirenzepine ride, Remiprostol, Remoxipride, Repirinast, Repromicin, Hydrochloride, piretamide, Pirfenidone, Piridicillin Sodium, Reproterol Hydrochloride, Reserpine, resinferatoxin, Resor Piridironate Sodium, Piriprost, piritrexim, Pirlimycin Hydro cinol, retelliptine demethylated, reticulon, reviparin Sodium, chloride, pirlindole, pirmagrel, Pirmenol Hydrochloride, revizinone, rhenium Re 186 etidronate, rhizoxin, Ribaminol, Pirnabine, Piroctone, Pirodavir, pirodomast, Pirogliride Tar 45 Ribavirin, Riboprine, ribozymes, ricasetron, Ridogrel, trate, Pirolate, Pirolazamide, Piroxantrone Hydrochloride, Rifabutin, Rifametane, Rifamexil, Rifamide, Rifampin, Rifa Piroxicam, Piroximone, Pirprofen, Pirquinozol, Pirsidomine, pentine, Rifaximin, RII retinamide, rilopirox, Riluzole, Prenylamine, Pituitary, Posterior, Pivampicillin Hydrochlo rimantadine, Rimcazole Hydrochloride, Rimexolone, Rimit ride, Pivopril, Pizotyline, placetin A, platinum compounds, erol Hydrobromide, rimoprogin, riodipine, Rioprostil, platinum-triamine complex, Plicamycin, Plomestane, Pobi 50 Ripazepam, ripisartan, Risedronate Sodium, risedronic acid, lukast Edamine, Podofilox, Poisonoak Extract, Poldine Risocaine, Risotilide Hydrochloride, rispenzepine, Risper Methylsulfate, Poliglusam, Polignate Sodium, Polymyxin B dal, Risperidone, Ritanserin, ritipenem, Ritodrine, Sulfate, Polythiazide, Ponalrestat, Porfimer Sodium, Porfiro Ritolukast, ritonavir, rizatriptan benzoate, Rocastine Hydro mycin, Potassium Chloride, Potassium Iodide, Potassium chloride, Rocuronium Bromide, Rodocaine, Roflurane, Permanganate, Povidone-Iodine, Practolol, Pralidoxime 55 Rogletimide, rohitukine, rokitamycin, Roletamicide, Rolga Chloride, Pramiracetam Hydrochloride, Pramoxine Hydro midine, Rolicyprine, Rolipram, Rolitetracycline, Rolodine, chloride, Pranolium Chloride, Pravadoline Maleate, Pravas RomaZarit, romurtide, Ronidazole, ropinirole, Ropitoin tatin (Pravachol), Prazepam, Prazosin, Prazosin Hydrochlo Hydrochloride, ropivacaine, Ropizine, roquinimex, Rosa ride, Prednazate, Prednicarbate, Prednimustine, ramicin, Rosoxacin, Rotoxamine, roXaitidine, Roxarsone, Prednisolone, Prednisone, Prednival, Pregnenolone Succini 60 roXindole, roXithromycin, rubiginone B1, ruboxyl, rufloxa ate, Prenalterol Hydrochloride, Pridefine Hydrochloride, cin, rupatidine, Rutamycin, ruzadolane, Sabeluzole, Safingol. Prifelone, Prilocalne Hydrochloride, Prilosec, Primaquine safironil, saintopin, salbutamol, R-Salcolex, Salethamide Phosphate, Primidolol, Primidone, Prinivil, Prinomide Maleate, Salicyl Alcohol, Salicylamide, Salicylate Meglu Tromethamine, Prinoxodan, Prizidilol Hydrochloride, mine, Salicylic Acid, Salmeterol, Salnacedin, Salsalate, Proadifen Hydrochloride, Probenecid, Probicromil Calcium, 65 sameridine, Sampatrilat, Sancycline, Sanfetrinem, Sangui Probucol, Procainamide Hydrochloride, Procaine Hydro narium Chloride, Saperconazole, saprisartan, sapropterin, chloride, Procarbazine Hydrochloride, Procaterol Hydro saquinavir, Sarafloxacin Hydrochloride, Saralasin Acetate, US 8,263,125 B2 19 20 SarCNU, sarcophytol A, SargramoStim, Sarmoxicillin, Sarpi Sulfate, Temazepam, Temelastine, temocapril, Temocillin, cillin, Sarpogrelate, Saruplase, Saterinone, satigrel, Satumo temoporfin, temozolomide, Tenidap, Teniposide, tenosal, mab pendetide, Schick Test Control, Scopafungin, Scopola tenoxicam, tepirindole, Tepoxalin, Teprotide, teraZosin, Ter mine Hydrobromide, Scrazaipine Hydrochloride, Sdi 1 binafine, Terbutaline Sulfate, Terconazole, terfenadine, ter mimetics, Secalciferol, Secobarbital, Seelzone, Seglitide flavoxate, terguride, Teriparatide Acetate, terlakiren, terlip Acetate, selegiline, Selegiline Hydrochloride, Selenium Sul ressin, terodiline, Teroxalene Hydrochloride, Teroxirone, fide, Selenomethionine Se 75, Selfotel, sematilide, semdu tertatolol, Tesicam, Tesimide, Testolactone, Testosterone, ramicin, Semotiadil, Semustine, sense oligonucleotides, Tetracaine, tetrachlorodecaoxide, Tetracycline, Tetrahydro Sepazonium Chloride, Seperidol Hydrochloride, Seprilose, Zoline Hydrochloride, Tetramisole Hydrochloride, Tetrazo Seproxetine Hydrochloride, Seractide Acetate, Sergolexole 10 last Meglumine, tetraZomine, Tetrofosmin, Tetroquinone, Maleate, Serine, Sermetacin, Sermorelin Acetate, sertacona Tetroxoprim, Tetrydamine, thaliblastine, Thalidomide, Zole, sertindole, Sertraline, Setiptiline, Setoperone, Theofibrate. Theophylline. Thiabendazole. Thiamiprine, sevirumab, sevoflurane, sezolamide, Sibopirdine, Sibutra Thiamphenicol. Thiamylal. Thiazesim Hydrochloride. Thi mine Hydrochloride, signal transduction inhibitors, Silan azinamium Chloride. Thiethylperazine. Thimerfonate drone, silipide, silteplase, Silver Nitrate, simendan, Simtra 15 Sodium, Thimerosal, thiocoraline, thiofedrine. Thioguanine, Zene, Simvastatin, Sincalide, Sineflungin, sinitrodil, thiomarinol, Thiopental Sodium, thioperamide. Thior sinnabidol, Sipatrigine, Sirolimus, Sisomicin, Sitogluside, idazine. Thiotepa, Thiothixene. Thiphenamil Hydrochloride, sizofiran, sobuzoxane, Sodium Amylosulfate, Sodium Iodide Thiphencillin Potassium, Thiram, Thozalinone. Threonine, I 123, Sodium Nitroprusside, Sodium Oxybate, sodium phe Thrombin, thrombopoietin, thrombopoietin mimetic, thy nylacetate, Sodium Salicylate, solverol, Solypertine Tartrate, malfasin, thymopoietin receptor agonist, thymotrinan, Thy Somalapor. Somantadine Hydrochloride, somatomedin B, romedan Hydrochloride, Thyroxine 1 125, Thyroxine 1 131, Somatomedin C, somatrem, somatropin, Somenopor, Somi Tiacrilast, Tiacrilast Sodium, tiagabine, Tiamenidine, tianep dobove, Sonermin, Sorbinil, Sorivudine, Sotalol, Soterenol tine, tiapafant, Tiapamil Hydrochloride, Tiaramide Hydro Hydrochloride, Sparfloxacin, Sparfosate Sodium, sparfosic chloride, Tiazofurin, Tibenelast Sodium, Tibolone, Tilbric acid, Sparsomycin, Sparteine Sulfate, Spectinomycin Hydro 25 Acid, Ticabesone Propionate, Ticarbodine, Ticarcillin Cresyl chloride, spicamycin D. Spiperone, Spiradoline Mesylate, Sodium, Ticlatone, ticlopidine, Ticrynafen, tienoxolol, Tifu Spiramycin, Spirapril Hydrochloride, Spiraprilat, Spiroger rac Sodium, Tigemonam Dicholine, Tigestol, Tiletamine manium Hydrochloride, Spiromustine, Spironolactone, Hydrochloride, Tilidine Hydrochloride, tilisolol, tilnoprofen Spiroplatin, SpiroXasone, splenopentin, spongistatin 1, arbamel, Tilorone Hydrochloride, Tiludronate Disodium, Sprodiamide, squalamine, Stallimycin Hydrochloride, Stan 30 tiludronic acid, Timefurone, Timobesone Acetate, Timolol, nous Pyrophosphate, Stannous Sulfur Colloid, Stanozolol, tin ethyl etiopurpurin, Tinabinol, Timidazole, Tinzaparin Statolon, staurosporine, stavudine, Steffimycin, Stenbolone Sodium, Tioconazole, TiodaZosin, Tiodonium Chloride, Tio Acetate, stepronin, Stilbazium Iodide, Stilonium Iodide, peridone Hydrochloride, Tiopinac, Tiospirone Hydrochlo stipiamide, Stiripentol, stobadine, Streptomycin Sulfate, ride, Tiotidine, tiotropium bromide, Tioxidazole, Tipentosin Streptonicozid, Streptonigrin, Streptozocin, Stromelysin 35 Hydrochloride, Tipredane, Tiprenolol Hydrochloride, Tipri inhibitors, Strontium Chloride Sr 89, succibun, Succimer, nast Meglumine, Tipropidil Hydrochloride, Tiqueside, Succinylcholine Chloride. Sucralfate. Sucrosofate Potas Tiquinamide Hydrochloride, tirandalydigin, Tirapazamine, sium, Sudoxicam, Sufentanil, Sufotidine, Sulazepam, Sul tirilazad, tirofiban, tiropramide, titanocene dichloride, Tix bactam Pivoxil, Sulconazole Nitrate, Sulfabenz, Sulfabenza anox, Tixocortol Pivalate, Tizanidine Hydrochloride, Tobra mide, Sulfacetamide, Sulfacytine, Sulfadiazine, Sulfadoxine, 40 mycin, Tocainide, Tocamphyl, Tofenacin Hydrochloride, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sul Tolamolol, Tolazamide, Tolazoline Hydrochloride, Tolbuta famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sul mide, Tolcapone, Tolciclate, Tolfamide, Tolgabide, lamot famoxole, Sulfanilate Zinc, Sulfanitran, sulfasalazine, Sulfa rigine, Tolimidone, Tolindate, Tolmetin, Tolnaftate, Tolpovi somizole, Sulfazamet, Sulfinalol Hydrochloride, sulfinosine, done 1 131, Tolpyrramide, Tolrestat, Tomelukast, Sulfinpyrazone, Sulfisoxazole, Sulfomyxin, Sulfonterol 45 Tomoxetine Hydrochloride, Tonazocine Mesylate, Topira Hydrochloride, sulfoxamine, Sulinldac, Sulmarin, Sulnida mate, topotecan, Topotecan Hydrochloride, topsentin, Zole, Suloctidil, Sulofenur, Sulopenem, Suloxifen Oxalate, Topterone, Toquizine, torasemide, toremifene, Torsemide, Sulpiride, Sulprostone, Sultamicillin, Sulthiame, sultopride, Tosifen, Tosufloxacin, totipotent stem cell factor, Traca Sulukast, Sumarotene, Sumatriptan, Suncillin Sodium, Supro Zolate, trafermin, Tralonide, Tramadol Hydrochloride, Tra clone, Suprofen, Suradista, Suramin, Surfomer, Suricainide 50 mazoline Hydrochloride, trandolapril, Tranexamic Acid, Tra Maleate, Suritozole, Suronacrine Maleate, Suxemerid Sul nilast, Transcainide, translation inhibitors, traxanox, fate, Swainsonine, Symakalim, Symclosene, Symetine Trazodone Hydrochloride, Trazodone-HCL, Trebenzomine Hydrochloride, synthetic glycosaminoglycans, Taciamine Hydrochloride, Trefentanil Hydrochloride, Treloxinate, Hydrochloride, Tacrine Hydrochloride, Tacrolimus, Talampi Trepipam Maleate, Trestolone Acetate, tretinoin, Triacetin, cillin Hydrochloride, Taleranol, Talisomycin, tallimustine, 55 triacetyluridine, Triafungin, Triamcinolone, TriampyZine Talmetacin, Talniflumate, Talopram Hydrochloride, Talos Sulfate, Triamterene, Triazolam, Tribenoside, tricaprilin, alate, Tametraline Hydrochloride, Tamoxifen, Tampramine Tricetamide, Trichlormethiazide, trichohyalin, triciribine, Fumarate, Tamsulosin Hydrochloride, Tandamine Hydro Tricitrates, Triclofenol piperazine, Triclofos Sodium, Tri chloride, tandospirone, tapgen, taprostene, Tasosartan, tauro clonide, trientine, Trifenagrel, triflavin, Triflocin, Trifluba mustine, Taxane, Taxoid, Tazadolene Succinate, taZanolast, 60 Zam, Triflumidate, Trifluoperazine Hydrochloride, Triflu tazarotene, Tazifylline Hydrochloride, Tazobactam, peridol, Triflupromazine, Triflupromazine Hydrochloride, Tazofelone, Tazolol Hydrochloride, Tebufelone, Tebuquine, Trifluridine, Trihexyphenidyl Hydrochloride, Trilostane, Tri Technetium Tc 99 m Bicisate, Teclozan, Tecogalan Sodium, maZosin Hydrochloride, trimegestone, Trimeprazine Tar Teecleukin, Teflurane, Tegafur, Tegretol, Teicoplanin, telen trate, Trimethadione, Trimethaphan Camsylate, Tri Zepine, tellurapyrylium, telmesteine, telmisartan, telomerase 65 methobenzamide Hydrochloride, Trimethoprim, inhibitors, Teloxantrone Hydrochloride, Teludipine Hydro Trimetozine, Trimetrexate, Trimipramine, Trimoprostil, Tri chloride, Temafloxacin Hydrochloride, Tematropium Methyl moxamine Hydrochloride, Triolein 1 125, Triolein 1 131, US 8,263,125 B2 21 22 Trioxifene Mesylate, Tripamide, Tripelennamine Hydrochlo microcrystalline celluloses such as those sold under the Trade ride, Triprolidine Hydrochloride, Triptorelin, Trisulfapyrim Mark Avicel PH 101, Avicel PH 102, Avicel PH 112, Avicel idines, Troclosene Potassium, troglitaZone, Trolamine, Trole PH 200, Avicel PH301 and Avicel PH 302; lactose such as andomycin, trombodipine, trometamol, Tropanserin lactose monohydrate, lactose anhydrous and Pharmatose Hydrochloride, Tropicamide, tropine ester, tropisetron, tros 5 DCL21 (Pharmatose is a Trade Mark), including anhydrous, pectomycin, trovafloxacin, troVirdine, Tryptophan, Tubercu monohydrate and spray dried forms; dibasic calcium phos lin, Tubocurarine Chloride, Tubulozole Hydrochloride, phate Such as Emcompress (Emcompress is a Trade Mark); tucarcsol, tulobuterol, turosteride, Tybamate, tylogenin, mannitol; Pearlitol SD200 (Pearlitol SD200 is a trade mark); Tyropanoate Sodium, Tyrosine, Tyrothricin, tyrphostins, ube starch; Sorbitol; Sucrose; and glucose. nimex, Uldazepam, Undecylenic Acid, Uracil Mustard, ura 10 Suitable binders include for example starch, povidone, pidil, Urea, Uredepa, uridine triphosphate, Urofollitropin, hydroxypropylmethylcellulose, pregelatinised starch, Urokinase, Ursodiol, Valaciclovir, Valine, Valnoctamide, Val proate Sodium, Valproic Acid, Valsartan, Vamicamide, Vana hydroxypropylcellulose and/or mixtures of the foregoing. deine, Vancomycin, Vaninolol, Vapiprost Hydrochloride, Suitable lubricants, including agents that act on the flowabil Vapreotide, variolin B. Vasopressin, Vecuronium Bromide, 15 ity of the powder to be compressed are, for example, colloidal velaresol, slilcon dioxide such as Aerosil 200 (Aerosil is a Trade Mark); Velnacrine Maleate, Venlafaxine, Veradoline Hydrochlo talc.; Stearic acid, magnesium Stearate, calcium Stearate and ride, Veramine, Verapamil Hydrochloride, verdins, Verilopam Sodium Stearyl fumarate. Hydrochloride, Verlukast, Verofylline, Veroxan, verteporfin, Suitable disintegrants include for example lightly Vesnarinone, vexibinol, Vidarabine, vigabatrin, Viloxazine crosslinked polyvinyl pyrrolidone, corn starch, potato starch, Hydrochloride, Vinblastine Sulfate, vinburnine citrate, Vin maize starch and modified starches, croScarmellose Sodium, cofos, Vinconate, Vincristine Sulfate, Vindesine, Vindesine cross-povidone, Sodium starch glycolate and combinations Sulfate, Vinepidine Sulfate, Vinglycinate Sulfate, Vinleuro and mixtures thereof. sine Sulfate, vinorelbine, Vinpocetine, Vintoperol, Vinxaltine, The amount of release controlling agent(s) to be used in Vinzolidine Sulfate, Viprostol, Virginiamycin, Viridofulvin, 25 will be determined based on drug release rate etc. Viroxime, vitaxin, Volazocine, Voriconazole, Vorozole, VOX The release controlling agents(s) are selected from alkyl ergolide, Warfarin Sodium, Xamoterol, Xanomeline, Xanox celluloses, hydroxyalkyl celluloses, cellulose ethers, cellu ate Sodium, Xanthinol Niacinate, xemilofiban, Xenalipin, lose esters, nitro celluloses, polymers of acrylic and meth Xenbucin, Xilobam, Ximoprofen, Xipamide, Xorphanol acrylic acids and esters thereof, polyamides, polycarbonates, Mesylate, Xylamidine Tosylate, Xylazine Hydrochloride, 30 polyalkylenes, polyalkylene glycols, polyalkylene terephtha Xylometazoline Hydrochloride, Xylose, yangambin, Zab lates, polyvinyl esters, polyvinylpyrrolidone, polyglycolides, icipril, Zacopride, Zafirlukast, Zalcitabine, Zaleplon, polysiloxanes and polyurethanes and co-polymers thereof. Zalospirone, Zaltidine Hydrochloride, Zaltoprofen, Zan The high water soluble/permeable release controlling amivir, Zankiren, Zanoterone, Zantac, Zarirlukast, Zatebra agents is Suitably polyvinyl alcohol, polyvinylpyrrolidone, dine, Zatosetron, Zatosetron Maleate, Zenarestat, Zenazocine 35 methylcellulose, hydroxypropylcellulose, hydroxypropylm Mesylate, Zeniplatin, Zeranol, Zidometacin, Zidovudine, ethyl cellulose or polyethylene glycol, alginates, polyacrylic Zifrosilone, Zilantel, Zilascorb, Zileuton, Zimeldine Hydro acids, Xanthun gum or a mixture thereof. chloride, Zinc Undecylenate, Zindotrine, Zinoconazole The low water soluble/permeable release controlling Hydrochloride, Zinostatin, Zinterol Hydrochloride, Zin agents is suitably ethylcellulose, cellulose acetate, cellulose viroxime, ziprasidone, Zobolt, Zofenopril Calcium, Zofeno 40 propionate (lower, medium or higher molecular weight), cel prilat, Zolamine Hydrochloride, Zolazepam Hydrochloride, lulose acetate propionate, cellulose acetate butyrate, cellulose Zoledronie acid, Zollertine Hydrochloride, Zolmitriptan, acetate phthalate, cellulose triacetate, poly(methyl methacry Zolpidem, Zomepirac Sodium, Zometapine, ZonicleZole late), poly(ethyl methacrylate), poly(butyl methacrylate), Hydrochloride, Zonisamide, Zopiclone, Zopolrestat, Zorba poly(isobutyl methacrylate), and poly (hexyl methacrylate). mycin, Zorubicin Hydrochloride, Zotepine, Zucapsaicin. 45 Poly(isodecyl methacrylate), poly (lauryl methacrylate), poly Further examples of low dose, antidiabetic active ingredi (phenyl methacrylate), poly (methyl acrylate), poly (isopro ents comprises of but not limited to JTT-501 (PNU-182716) pyl acrylate), poly (isobutyl actylate), poly (octadecyl acry (Reglitazar), AR-HO39242, MCC-555 (Netoglitazone), AR late), waxes such as beeswax, carnauba wax, microcrystalline H049020 Tesaglitazar), CS-011 (CI-1037), GW-409544x, wax, and OZokerite; fatty alcohols such ascetostearyl alcohol, KRP-297, RG-12525, BM-15.2054, CLX-0940, CLX-0921, 50 Stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty DRF-2189, GW-1929, GW-9820, LR-90, LY-510929, NIP acid esters such as glyceryl monostearate, glyceryl distearate, 221, NIP-223, JTP-20993, LY 29311 Na, FK 614, BMS glycerol monooleate, acetylated monoglycerides, tristearin, 298585, R 483, TAK 559, DRF 2725 (Ragaglitazar), tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyc L-686398, L-168049, L-805645, L-054852, Demethyl aste eryl behenate, and hydrogenated castor oil or a mixture riquinone B1 (L-783281), L-363586, KRP-297, P32/98, 55 thereof. CRE-16336 and EML-16257. The non-biodegradable materials are selected from but are As indicated above the inner portion of the present inven not limited to Ammonio methacrylate copolymers type A and tion may comprise auxiliary excipients such as for example B as described in USP, Polyacrylate dispersion 30% as diluents, binders, lubricants, Surfactants, disintegrants, plas described in Ph. Eur, Polyvinyl acetate dispersion, cellulose ticisers, anti-tack agents, opacifying agents, pigments, and 60 derivatives such as ethylcellulose, cellulose acetate waxes such like. As will be appreciated by those skilled in the art, the Such as beeswax, carnauba wax, microcrystalline wax, and exact choice of excipient and their relative amounts will oZokerite; fatty alcohols such as cetostearyl alcohol, Stearyl depend to some extent on the final oral dosage form. alcohol; cetyl alcohol and myristyl alcohol; and fatty acid Suitable diluents include for example pharmaceutically esters such as glyceryl monostearate, glyceryl distearate, acceptable inert fillers such as microcrystalline cellulose, lac 65 glycerol monooleate, acetylated monoglycerides, tristearin, tose, starch, dibasic calcium phosphate, Saccharides, and/or tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyc mixtures of the foregoing. Examples of diluents include eryl behenate, and hydrogenated castor oil. US 8,263,125 B2 23 24 The mucoadhesive release controlling agents are selected The high dose, high solubility active ingredient is in the from but are not limited to carbopol, sodium carboxymethyl form of modified release and has dose from 500 mg to 1500 cellulose, hydroxypropyl cellulose, hydroxypropylmethyl mg. The high dose, high solubility active ingredient com cellulose, hydroxyethyl cellulose, methyl cellulose, sodium prises of the following therapeutic classes but not limited to hyaluronate, gaur gum, Sodium alginate, polycabophil. adrenergic agent, adrenocortical steroid; adrenocortical Sup starch, dextran or chitosan. pressant; aldosterone antagonist; amino acid; anabolic; ana The ammonio methacrylate co-polymers are preferably leptic; analgesic; anesthetic; anorectic; anti-acne agent; anti selected from the group consisting of poly(ethyl acrylate, adrenergic; anti-allergic; anti-amebic; anti-anemic; anti methyl methacrylate, trimethylammonioethyl methacrylate anginal; anti-arthritic; anti-asthmatic; anti-atherosclerotic; chloride) 1:2:0.1; poly(ethyl acrylate, methyl methacrylate, 10 antibacterial; anticholinergic; anticoagulant; anticonvulsant; trimethylamonioethyl methacrylate chloride) 1:2:0.2 and antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti poly(ethyl acrylate, methyl methacrylate) 1:1. emetic; anti-epileptic; antifibrinolytic; antifungal; antihem Active ingredients especially the poorly soluble active orrhagic; antihistamine; antihyperlipidemia; antihyperten ingredients mentioned above can be micronized to increase 15 sive; antihypotensive; anti-infective; anti-inflammatory; solubility and/or bioavialability. antimicrobial; antimigraine; antimitotic; antimycotic, antin (ii) Outer Portion: The outer portion comprises of a) Micro auseant, antineoplastic, antineutropenic, antiparasitic; anti matrix particles containing high dose, high solubility active proliferative; antipsychotic; antirheumatic; antiseborrheic; ingredient and one or more hydrophobic release controlling antisecretory; antispasmodic; antithrombotic; anti-ulcer agent, b) Coating of Micro matrix particles with one or more ative; antiviral; appetite Suppressant, blood glucose regulator; hydrophobic release controlling agents. The outer portion bone resorption inhibitor; bronchodilator; cardiovascular may also include one or more commonly used excipients in agent; cholinergic; depressant; diagnostic aid; diuretic; oral pharmaceutical formulations. The release of the high dopaminergic agent; estrogen receptor agonist; fibrinolytic; dose, high solubility active ingredient is controlled through fluorescent agent; free oxygen radical Scavenger, gastric acid dual retard technique. The dual retard technique is a combi 25 Supressant; gastrointestinal motility effector, glucocorticoid: nation of matrix formulations and reservoir formulations. hair growth stimulant; hemostatic; histamine H2 receptor First the micro matrix particles of high dose, high solubility antagonists; hormone; hypocholesterolemic; hypoglycemic; dose active ingredient and one or more hydrophobic release hypolipidemic; hypotensive; imaging agent; immunizing controlling agents are formed and then these are further agent; immunomodulator, immunoregulator, immunostimu coated with one or more release controlling agents. Thus the 30 lant; immunosuppressant; keratolytic; LHRH agonist; mood dual retard release technique presents the double barriers and regulator, mucolytic; mydriatic; nasal decongestant; neuro effectively controls the diffusion of the high dose, high solu muscular blocking agent; neuroprotective: NMDA antago bility active ingredients from the present invention in predict nist; non-hormonal sterol derivative; plasminogen activator; able manner and also significantly reduces the amount of platelet activating factor antagonist; platelet aggregation release controlling agents which are otherwise required in 35 inhibitor, psychotropic; radioactive agent; Scabicide; Scleros very high quantity and make the dosage form very bulky and ing agent; sedative; sedative-hypnotic; selective adenosine therefore pose difficulty in swallowing. The other advantages A1 antagonist; serotonin antagonist; serotonin inhibitor; of the present invention are such as it reduces the chances of serotonin receptor antagonist; Steroid; thyroid hormone; thy dose dumping, unnecessary burst effects and failure of the roid inhibitor, thyromimetic; tranquilizer; amyotrophic lat system, which are otherwise usually associated with simple 40 eral Sclerosis agent; cerebral ischemia agent, Paget’s disease matrix or reservoir systems. agent; unstable angina agent; vasoconstrictor; vasodilator; Further advantages of present invention include the disin wound healing agent; Xanthine oxidase inhibitor. tegration of inner portion is not hindered as nons wellable Examples of high dose, high solubility active ingredients release controlling agents are used which do not Swell and comprise of but not limited to potassium chloride, metformin maintain the shape during operation and it effectively pre 45 hydrochloride, phenformin, buformin, clindamycin, hydrox vents the separation of the layers of the multilayered tablets yurea, eprosartan; erythromycin, lactobionate, Vancomycin which is normally associated with normal multilayered tab hydrochloride, balsalazide disodium, Sodium valproate, nia lets. cin, aminocaproic acid, acetaminophen, Ciprofloxacin, que The high dose, high solubility active ingredient can be tiapine. Other drugs suitable for use and meeting the solubil present in the form of a free base or in the form of pharma 50 ity and dose criteria described above will be apparent to those ceutically acceptable salts. Pharmaceutically acceptable salts skilled in the art. forming part of this invention are intended to define but not In the dosage form of the present invention, the outer limited to salts of the carboxylic acid moiety such as alkali portion may optionally contain more than one high dose high metal salts like Li, Na and K salts; alkaline earth metal salts solubility active ingredient. like Ca and Mg salts; salts of organic bases such as lysine, 55 In the dosage form of the present invention, the outer arginine, guanidine, diethanolamine, choline, and the like; portion may optionally contain more than one high dose high ammonium or Substituted ammonium salts and aluminium solubility antidiabetic active ingredient. salts. Salts may be acid addition salts which defines but not As indicated above the outer portion of the present inven limited to Sulfates, nitrates, phosphates, perchlorates, borates, tion may comprise auxiliary excipients such as for example hydrohalides, acetates, tartrates, maleates, citrates, succi 60 lubricants, plasticisers, anti-tack agents, opacifying agents, nates, palmoates, methanesulfonates, benzoates, Salicylates, pigments, and Such like. As will be appreciated by those hydroxynaphthoates, benzensulfonates, ascorbates, glycero skilled in the art, the exact choice of excipient and their phosphates, ketoglutarates and the like. Further, the high relative amounts will depend to some extent on the final oral dose, high solubility active ingredient, where applicable, may dosage form. be present either in the form of one substantially optically 65 Suitable lubricants, including agents that act on the pure enantiomer or as a mixture of enantiomers or polymor flowability of the powder to be compressed are, for example, phs thereof. colloidal silicon dioxide such as Aerosil 200 (Aerosil is a US 8,263,125 B2 25 26 Trade Mark); talc, Stearic acid, magnesium Stearate, calcium example, adipates, azelates, benzoates, citrates, isoebucaes, Stearate and sodium Stearyl fumarate. phthalates, sebacates, Stearates, tartrates, polyhydric alcohols In micro matrix particles, the active ingredient and one or and glycols. more hydrophobic release controlling agents are preferably Representative plasticisers include acetylated monoglyc present in a ratio of from 100:1 to 100:75, more particularly erides; butyl phthalylbutyl gylcolate: dibutyl tartrate; diethyl from 100:2.5 to 100:50, still more preferably from 100:2.5 to phthalate; dimethyl phthalate, ; ethyl phthalyl ethylglycolate: 100:30 and most preferably from 100:2.5 to 100:20. glycerin; ethylene glycol, propylene glycol; Triethylcitrate; In outer portion, micro matrix particles and coating of one triacetin; tripropinoin, diacetin: dibutyl phthalate; acetyl or more hydrophobic release controlling agents are prefer monoglyceride; polyethylene glycols; castor oil; triethyl cit 10 rate; polyhydric alcohols, acetate esters, glycerol triacetate, ably present in a ratio of from 100:0.5 to 100:75, more par acetyl triethylcitrate, dibenzyl phthalate, dihexyl phthalate, ticularly from 100:2.5 to 100:50, still more preferably from butyloctyl phthalate, disononyl phthalate, butyloctyl phtha 100:2.5 to 100:30 and most preferably from 100:2.5 to 100: late, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, 2O. diethylexyl phthalate, di-n-octyl phthalate, di-I-octyl phtha According to one embodiment the release controlling 15 late, di-I-decyl phthalate, di-n-undecyl phthalate, di-n-tride agents are pharmaceutically excipients, which are hydropho cyl phthalate, tri-2-ethylexyl trimellitate, di-2-ethylexyl adi bic in nature. pate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, The polymers that can be used to form the rate-controlling dibutyl sebacate, glyceryl monocaprylate, glycerol distearate membrane or micromatrix are described in greater detail and glyceryl monocaprate. The amount of plasticiser to be herein below. used is from about 1% to 50% based on the weight of the dry The hydrophobic release controlling agents are selected release controlling agent(s). The amount of release control from but are not limited to Ammonio methacrylate copoly ling agent(s) to be used in forming the outer portion will be mers type A and B as described in USP, methacrylic acid determined based on various parameters such as the desired copolymer type A, B and C as described in USP, Polyacrylate delivery properties, including the amount of active ingredient dispersion 30% as described in Ph. Eur., Polyvinyl acetate 25 to be delivered, the active ingredient release rate desired, and dispersion, ethylcellulose, cellulose acetate, cellulose propi the size of the micro matrix particles. onate (lower, medium or higher molecular weight), cellulose The novel dosage form of the present invention can be acetate propionate, cellulose acetate butyrate, cellulose manufactured by the following procedure: acetate phthalate, cellulose triacetate, poly(methyl methacry Inner Portion late), poly(ethyl methacrylate), poly(butyl methacrylate), 30 The granules of the inner portion can be manufactured in poly(isobutyl methacrylate), and poly (hexyl methacrylate). accordance with usual techniques in which the active ingre Poly(isodecyl methacrylate), poly (lauryl methacrylate), poly dient and other excipients are mixed and granulated by adding (phenyl methacrylate), poly (methyl acrylate), poly (isopro solution of binder in a low or high shear mixer or by fluidized pyl acrylate), poly (isobutyl actylate), poly (octadecyl acry bed granulation. The granulate is dried, preferably in a fluid 35 ized bed dryer. The dried granulate is sieved and mixed with late), waxes such as beeswax, carnauba wax, microcrystalline lubricants and disintegrants. Alternatively the manufacture of wax, and OZokerite; fatty alcohols such as cetostearyl alcohol, granules of inner portion can be made by direct mixing of the Stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty directly compressible excipients or by roller compaction. acid esters such as glyceryl monostearate, glycerol distearate; B) Outer Portion glycerol monooleate, acetylated monoglycerides, tristearin, 40 The micro matrix particles of the outer portion can be tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyc manufactured in accordance with usual techniques in which eryl behenate, and hydrogenated castor oil. the active ingredient and one or more hydrophobic release According to an especially preferred embodiment the controlling agents are mixed and granulated by adding Sol release controlling agents contains ammonio methacrylate vent in a low or high shear mixer or by fluidized bed granu co-polymers and fatty acid esters as hereinafter described. 45 lator. The granulate is dried, preferably in a fluidized bed The suitable hydrophobic agents are polymers sold under the dryer. The dried granulate is sized. The sizing of the micro Trade Mark Eudragit RS (Ammonio Methacrylate Copoly matrix particles can be done using oscillating granulator, mer type BUSP), (Eudragit NE 30D (Polyacrylate dispersion comminuting mill or any other conventional method. The 30% Ph. Eur), Eudragit RL (Ammonio Methacrylate sieve used for the sizing can have openings from 0.25 mm to Copolymer type AUSP) and Kollicoat SR30 Dandfatty acid 50 5 mm. Alternatively the micro matrix particles can be made esters such as glyceryl behenate, glycerol distearate and by extrusion, spheronization or by roller compaction. The hydrogenated castor oil. Eudragit polymers are polymeric micro matrix particles can be coated by a solution of one or lacquer Substances based on acrylate and/or methacrylates. more hydrophobic release controlling agents by any known The outer portion can also include one or more commonly method, including spray application. Spraying can be carried used excipients in oral pharmaceutical formulations. 55 out using a fluidized bedcoated (preferably Wurster coating), Representative commonly used excipients in oral pharma or in a pan coating system. Alternatively the coating of the ceutical formulations include talc, fumed silica, glyceryl micro matrix particles with one or more rate controlling monostearate, magnesium Stearate, calcium Stearate, kaolin, agents can be done by hot melt process using a granulator or colloidal silica, gypsum, Tween 80, Geleol pastiles (trade fluidized bed coated (preferably Wurster coating), or in a pan mark), micronised silica and magnesium trisilicate. The 60 coating system. quantity of commonly used excipients in oral pharmaceutical Tablet Compression formulations used is from about 0.5% to about 200% by The compression of tablets is carried out on usual press weight, preferably from 2 to 100% more particularly 10 to coaters (e.g. machines of the Manesty, Cadmach or Kilian) 60% based on the total dry weight of the polymer. with slight modification. The device such as feed frame and The outer portion can also include a material that improves 65 hoppers making top layer are eliminated. The granules of the the processing of the release controlling agents. Such mate inner layer are charged in the hopper of the machine com rials are generally referred to as "plasticisers” and include, for pressing first layer and the granules of the outer layer are US 8,263,125 B2 27 28 charged in the hopper of the machine compressing the coat dosage forms inspite of that the figures clearly shows that dual ing. On operation only the bottom layer of the coating (outer retard technology significantly reduces the burst effect and portion) is deposited into the die and the first layer is placed effectively controls the release rate of the high dose, high on it. The compression wheels then embed the first layer in the solubility active ingredient for prolonged period. granules of the outer layer, displacing some of latter to form DESCRIPTION OF THE PREFERRED sides, and finally press the whole into the tablet. The resultant EMBODIMENTS tablet has inner portion covered by the outer portion from all the sides except top surface that remains uncovered and the The following examples further illustrate but by no means level of the inner portion and the outer portion is same. The limit the present invention. tablets can be made of various sizes and shapes. The present 10 The dissolution of novel dosage form of the present inven invention uses round punch tooling with upper flat bottom tion was determined by following method. punches and lower flat bottom beveled edges lower punches for the compression of inner portion and oblong shaped flat bottom beveled edges punches for the compression of the For sodium valproate outer portion. 15 instrument Apparatus I, USP (basket) Revolution 60 min. BRIEF DESCRIPTION OF THE DRAWINGS Temperature 37 - O.S. C. Dissolution medium 1000 ml pH 6.8 buffer FIG. 1 is a plan view of the dosage form described in the For niacin present invention; instrument Apparatus I, USP (Basket) FIG. 2 is an edge view of the dosage form described in the Revolution 100/min. present invention; Temperature 37 - O.S. C. FIG.3 is a transverse section view as seen along the line3-3 Dissolution medium 900 in O.1 NHCI of FIG. 1; For lamotrigine FIG. 4 (a) is a cross section of coated micro matrix particles 25 prepared by spheronization and coating for the purpose of instrument Apparatus II, USP (Paddle) Revolution 100/min. illustration only. Temperature 37 - O.S. C. FIG. 4 (b) is a cross section of coated micro matrix particles Dissolution medium 1OOO in O.OO1 NHCI prepared by granulation and coating for the purpose of illus For pravastatin Sodium tration only. 30 FIG. 5 is a plot of % active ingredient versus time for instrument Apparatus II, USP (Paddle) Revolution 100/min. immediate release and modified release active agent; Temperature 37 - O.S. C. FIG. 6 is a plot of % active ingredient versus time for Dissolution medium 900 ml pH 6.8 buffer modified release active agent prepared using dual retard tech For metformin hydrochloride nique as described in the present invention and prepared 35 without retard release technique as per examples 1 and 3; instrument Apparatus II, USP (Paddle) FIG. 7 is a plot of % active ingredient versus time for Revolution 50/min. modified release active agent prepared using dual retard tech Temperature 37 - O.S. C. nique as described in the present invention and prepared Dissolution medium 900 in O.1 NHCI without retard release technique as per examples 2 and 4. For rosiglitaZone maleate FIG. 8 is a plot of metformin plasma concentration versus 40 instrument Apparatus II, USP (Paddle) Revolution 100/min. time for test (a) and reference (b) formulation; Temperature 37 - O.S. C. FIG. 9 is a plot of rosiglitazone plasma concentration ver Dissolution medium SOO in O.O1 NHCI sus time for test (a) and reference (b) formulation; For glimepiride FIG. 10 is a plot of metformin plasma concentration versus time for test (a and b) and reference (c) formulation; 45 instrument Apparatus II, USP (Paddle) FIG. 11 is a plot of metformin plasma concentration versus Revolution 75/min. time for test (a) and reference (b) formulation; Temperature 37 - O.S. C. FIG. 12 is a plot of rosiglitaZone plasma concentration Dissolution medium 500 ml 0.5% sodium lauryl versus time for test (a) and reference (b) formulation; sulfate in water Referring to FIGS. 1 to 3, a dosage form 4 as described in 50 the present invention having an inner portion 1 containing low The composition of outer portion in the dosage form com dose active ingredient as immediate release and outer portion prising high dose high solubility antidiabetic active ingredi 2 containing high dose, high solubility active ingredient as ent is as follows— modified release. FIG. 4(a)& 4(b) shows the cross section of the coated micro matrix particles 5 and having 6 a high dose, high solubility active ingredient, 7 hydrophobic release con 55 trolling agent and 8 a coating of hydrophobic release control Micro matrix particles ling agent. FIG. 5 shows the release profile of a low dose Metformin hydrochloride 75% Wiw to 99% Wiw active ingredient as immediate release 9 and the release pro Eudragit RS 1% Wiw to 25% Wiw file of a high solubility active ingredient as modified release Coated micro matrix particles 10. FIGS. 6 and 7 shows release of high dose, high solubility 60 active agent 11 & 12 and 15 & 16 as per example 1 & 2 Micro matrix particles 70% wiw to 99% Wiw respectively from a dosage form prepared using dual retard Hydrogenated castor oil 1% Wiw to 30% Wiw technique as described in the present invention and release of Magnesium stearate 0% Wiw to 2% Wiw high dose, high solubility active agent 13 & 14 and 17 & 18 as per example 3 & 4 respectively from a dosage form prepared 65 The dissolution of high dose high solubility ingredient of without using dual retard release technique. The total quantity the formulation of the present invention is achieved not more of the hydrophobic release controlling agent is same in all the than 45% in 1 hour and from 25 to 90% in six hours. US 8,263,125 B2 29 30 The dissolution of metformin hydrochloride is achieved TABLE 1-continued not more than 50% in 1 hour, and from 30 to 90% is in four hours and not less than 65% in 12 hours. Dissolution profile of tablet (A After oral administration of a dosage form of the present Niacin Pravastatin sodium invention the maximum plasma concentration can be achieved between 700 ng/ml and 2500 ng/ml, preferably from Time Time 900 ng/ml to 2400 ng/ml and more preferably from 1000 (hour) % Released (min) % Released ng/ml to 2350 ng/ml. The in vivo mean dissolution time 6 37.4 (MDT) of the dosage form of the present invention is 4 to 6 8 41.9 10 10 47.1 hours. The minimum plasma concentration (at 24 hours) of 12 SO.6 the said dosage form ranges between 0 to 450 ng/ml after oral 14 54.6 administration. 24 67.7

EXAMPLES 15 Example 1 TABLE 2 Dissolution profile of tablet (B Production of Inner Portion 11.71% w/w of pravastatin sodium is mixed with 52.62% Niacin Pravastatin sodium w/w of lactose monohydrate and 22.22% w/w starch and the Time Time mixture is granulated in a binder of 2.22 V povidone in water (hour) % Released (min) % Released and then dried. The granules are sieved and mixed with 1.11% 1 9.8 45 84.1 W/w magnesium Stearate, 9.0 g sodium starch glycolate, 2 15.3 60 85.6 0.11% w/w lake of sunset yellow. This mixture is compressed 4 24.7 to 90 mg weight tablets having a diameter of 6.35 mm. 25 6 28.7 2) Production of Outer Portion 8 31.4 10 35.7 A) Micro matrix particles-90.91% w/w of niacin is mixed 12 39.1 with 9.09% w/w of Eudragit RSPO (Ammonio Methacry 14 41.9 late Copolymer type B USP) and the mixture is granulated 24 51.5 with a solvent mixture of acetone and methylene chloride 30 and then dried. The granules are sized. B) Coating of Micro matrix particles 85.84% w/w of micro matrix particles is charged in fluidized bed processor. Example 2 13.61% w/w of hydrogenated castor oil is dissolved in acetone and this coating solution is sprayed to coat the 35 1) Production of Inner Portion micro matrix particles. The coated micro matrix particles 38.47% w/w of lamotrigine is mixed with 2.71% w/w of are sieved and mixed with 0.86% w/w magnesium stearate. crosspovidone and 0.18% w/w colloidal silicon dioxide and 3) Compression of Tablets the mixture is granulated in a binder of 0.71% w/w povidone Tablet (A)—90 mg granules of inner portion are pressed to in water and then dried. The granules are sieved and mixed tablets (equal to 10 mg pravastatin) using 6.35 mm round 40 with 28.70% w/w of Mannitol (Pearlitol SD 200 R.T.M.), punches and 643 mg granules of outer portion (equal to 500 12.31% w/w of crosspovidone, 2.31% w/w of magnesium mg niacin) are compressed using 14.95x8.35 mm oblong stearate, 6.15% w/w aspartame, 2.31% w/w talc, 5.0% w/w punches. flavour and 1.15% w/w of colloidal silicon dioxide. This Tablet (B) 90 mg granules of inner portion are pressed to mixture is compressed to 65 mg weight tablets having a tablets (equal to 10 mg pravastatin) using 6.35 mm round 45 diameter of 5.55 mm. punches and 1286 mg granules of outer portion (equal to 2) Production of Outer Portion 1000 mg niacin) are compressed using 20.3x9.8 mm A) Micro matrix particles-90.91% w/w of sodium valproate is oblong punches. The compression is done on press coater mixed with 9.09% w/w of Eudragit RSPO (Ammonio machine in Such a manner that the resultant tablet has inner Methacrylate Copolymer type B USP) and the mixture is portion covered by the outer portion from all the sides 50 granulated with a solvent mixture of acetone and methyl except top surface that remains uncovered and the level of ene chloride and then dried. The granules are sized. the inner portion and the outer portion is on the same B) Coating of Micro matrix particles 85.84% w/w of micro Surface. matrix particles is charged in fluidized bed processor. The dissolution rate of the novel dosage form was deter 13.61% w/w of hydrogenated castor oil is dissolved in mined (Table 1 and 2) 55 acetone and this coating solution is sprayed to coat the micro matrix particles. The coated micro matrix particles TABLE 1. are sieved and mixed with 0.86% w/w magnesium stearate. Compression of Tablets Dissolution profile of tablet (A Tablet (A)—65 mg granules of inner portion are pressed to 60 tablets (equal to 25 mglamotrigine) using 5.55 mm round Niacin Pravastatin sodium punches and 643 mg granules of outer portion (equal to 500 Time Time mg Sodium valproate) are compressed using 14.95x8.35 (hour) % Released (min) % Released mm oblong punches. 1 12.4 45 83.8 Tablet (B)—65 mg granules of inner portion are pressed to 2 19.1 60 84.1 65 tablets (equal to 25 mglamotrigine) using 5.55 mm round 4 29.4 punches and 1286 mg granules of outer portion (equal to 1000 mg sodium valproate) are compressed using 20.3x9.8 US 8,263,125 B2 31 32 mm oblong punches. The compression procedure is same TABLE 5 as Example 1. The dissolution rate of the novel dosage form was determined (Table 3 and 4) Dissolution profile of tablet (A Niacin Pravastatin sodium TABLE 3 Time Time Dissolution profile of tablet (A (hour) % Released (min) % Released

Sodium valproate Lamotrigine 1 30.1 45 75.9 2 43.6 60 80.9 Time Time 10 (hour) % Released (min) % Released 4 61.6 6 74.1 1 23.3 15 83.5 8 83.9 2 36.3 30 88.6 10 92.1 4 55.1 45 91.6 12 99.4 6 67.5 60 92.8 15 24 102.6 8 77.0 10 83.8 12 88.9 14 92.5 TABLE 6 24 104.6 Dissolution profile of tablet (B Niacin Pravastatin sodium

TABLE 4 Time Time Dissolution profile of tablet (B (hour) % Released (min) % Released 25 1 29.9 45 89.6 Sodium valproate Lamotrigine 2 36.3 60 90.0 4 52.8 Time Time 6 63.4 (hour) % Released (min) % Released 8 73.5 10 77.8 1 19.0 15 90.3 30 12 84.5 2 29.5 30 95.6 24 90.5 4 45.2 45 98.3 6 55.9 8 6S.O 10 71.9 12 77.8 35 Example 4 14 82.4 24 95.8 1) Production of Inner Portion Dosage forms described in the examples 3 and 4 are pre Same as for Example 2 pared by not coating the micro matrix particles of the outer 40 2) Production of Outer Portion portion but the hydrophobic release controlling agent is 77.76% w/w of sodium valproate is mixed with 7.78% w/w mixed with the micro matrix particles. The sole purpose of of Eudragit RSPO (Ammonio Methacrylate Copolymer type these examples is to demonstrate the usefulness of the present BUSP) and the mixture is granulated with a solvent mixture invention as described earlier. The examples clearly show that of acetone and methylene chloride and then dried. The gran the rate of release of the modified release active ingredient is 45 ules are sized and mixed with 13.61% w/w of hydrogenated significantly faster than the present invention. castor oil and 0.86% w/w of magnesium stearate. 3) Compression of Tablets Example 3 Tablet (A)—Same as for Example 2 50 Production of Inner Portion Tablet (B)—Same as for Example 2 The dissolution rate of the novel dosage form was deter Same as for Example 1 mined (Table 7 and 8) Production of Outer Portion 77.76% w/w of niacin is mixed with 7.78% w/w of 55 TABLE 7 Eudragit RSPO (Ammonio Methacrylate Copolymer type B USP) and the mixture is granulated with a solvent mixture of Dissolution profile of tablet (A acetone and methylene chloride and then dried. The granules Sodium valproate Lamotrigine are sized and mixed with 13.61% w/w of hydrogenated castor Time Time oil and 0.86% w/w of magnesium stearate. (hour) % Released (min) % Released Compression of Tablets 1 58.3 15 81.8 2 79.9 30 89.8 Tablet (A) Same as for Example 1 4 98.5 45 91.7 6 101.6 60 97.4 Tablet (B)—Same as for Example 1 65 The dissolution rate of the novel dosage form was deter mined (Table 5 and 6) US 8,263,125 B2 33 34 TABLE 8 TABLE 10 Dissolution profile of tablet (B Dissolution profile of tablet (B Sodium valproate Lamotrigine Metformin hydrochloride Rosiglitazone Time Time Time (hour) % Released Time (min) % Released (hour) % Released (min) % Released 38.2 45 96.79 1 SO.2 15 86.1 53.4 60 99.32 2 69.1 30 87.3 69.5 4 91.0 45 92.6 10 78.1 6 101.3 60 98.3 86.8 93.6 97.65 Example 5 15 1) Production of Inner Portion Example 6 5.89% w/w of rosiglitazone maleate is mixed with 55.89% w/w of lactose monohydrate and 22.22% w/w starch and the Production of Inner Portion mixture is granulated in a binder of 2.78% w/wpovidone and Same as for Example 5 2.78% w/w starch in water and then dried. The granules are Production of Outer Portion sieved and mixed with 0.28% w/w magnesium stearate, A) Micro matrix particles-86.96% w/w of metformin hydro 10.00% w/w sodium starch glycolate, 0.17% w/w ferric oxide yellow. This mixture is compressed to 90 mg weight tablets chloride is mixed with 13.07% w/w of Eudragit RS (Am having a diameter of 6.35 mm. monio Methacrylate Copolymer type BUSP) and the mix 2) Production of Outer Portion ture is granulated with a solvent mixture of acetone and A) Micro matrix particles—90.91% w/w of metformin 25 methylene chloride and then dried. The granules are sized. hydrochloride is mixed with 9.09% w/w of Eudragit RS B) Coating of Micro matrix particles 86.40% w/w of micro (Ammonio Methacrylate Copolymer type BUSP) and the matrix particles is charged in fluidized bed processor. mixture is granulated with a solvent mixture of acetone and 13.15% w/w of hydrogenated castor oil is dissolved in methylene chloride and then dried. The granules are sized. acetone and this coating solution is sprayed to coat the B) Coating of Micro matrix particles-85.54% w/w of micro 30 micro matrix particles. The coated micro matrix particles matrix particles is charged in fluidized bed processor. are sieved and mixed with 0.45% w/w magnesium stearate. 13.61% w/w of hydrogenated castor oil is dissolved in Compression of tablets acetone and this coating solution is sprayed to coat the 90 mg granule of inner portion are pressed to tablets micro matrix particles. The coated micro matrix particles (equivalent to 4 mg rosiglitaZone) using 6.35 mm round are sieved and mixed with 0.86% w/w magnesium stearate. 35 punches and 1331 mg granules of outer portion (equivalent to 3) Compression of Tablets 1000 mg metformin hydrochloride) are compressed using Tablet (A)-90 mg granules of inner portion are pressed to 20.3x9.8 mm oval punches. The compression procedure is tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round same as Example 5. punches and 643 mg granules of outer portion (equal to 500 mg metformin hydrochloride) are compressed using The dissolution rate of the novel dosage form was deter 14.95x8.35 mm oblong punches. 40 mined (Table 11) Tablet (B) 90 mg granules of inner portion are pressed to tablets (equal to 4 mg rosiglitaZone) using 6.35 mm round TABLE 11 punches and 1286 mg granules of outer portion (equal to 1000 mg metformin hydrochloride) are compressed using Dissolution profile 20.3x9.8 mm oblong punches. 45 Metformin RosiglitaZone The compression is done on press coater machine in Such a Hydrochloride Maleate manner that the resultant tablet has inner portion covered by the outer portion from all the sides except top surface that Time Time remains uncovered and the level of the inner portion and the (hour) % Released (min) % Released outer portion is on the same Surface. 50 1 32.10 15 75.63 2 41.65 30 88.35 The dissolution rate of the novel dosage form was deter 4 59.05 45 103.49 mined (Table 9 and 10) 6 63.90 60 105.70 8 73.63 TABLE 9 10 79.35 55 12 84.21 Dissolution profile of tablet (A 24 94.91 Metformin hydrochloride Rosiglitazone Time (hour) % Released Time (min) % Released Example 7 1 42.5 15 84.88 60 2 58.0 30 99.02 Production of Inner Portion 4 74.09 45 101.26 Same as for Example 5 6 86.1 60 104.4 Production of Outer Portion 8 97.8 10 101.9 Micro Matrix Particles 12 103.7 65 Same as for Example 5 B) Coating of Micro matrix particles-89.36% w/w of micro matrix particles is charged in fluidized bed processor. US 8,263,125 B2 35 36 10.15% w/w of glycerol distearate type 1 Ph. Eur. (Precirol Example 9 ATO 5 R.T.M.) is dissolved in acetone and this coating Solution is sprayed to coat the micro matrix particles. The Production of Inner Portion coated micro matrix particles are sieved and mixed with 1.11% w/w of glimepiride is mixed with 63.28% w/w of 0.49% w/w magnesium stearate. lactose monohydrate and 22.22% w/w starch and the mixture Compression of Tablets is granulated in a binder of 2.22% w/wpovidone in water and 90 mg granule of inner portion are pressed to tablets (equal then dried. The granules are sieved and mixed with 1.11% to 4 mg rosiglitaZone maleate) using 6.35 mm round punches W/w magnesium Stearate, 10.0% w/w Sodium starch glyco and 1231 mg granules of outer portion (equal to 1000 mg late, 0.06% w/w lake of brilliant blue. This mixture is com metformin hydrochloride) are compressed using 20.3x9.8 10 pressed to 90 mg weight tablets having a diameter of 6.35 mm oval punches. The compression procedure is same as . Example 5. The dissolution rate of the novel dosage form was Production of Outer Portion determined (Table 12) A) Micro matrix particle 83.33% w/w of metformin hydro chloride is mixed with 16.67% w/w of Eudragit RS (Am TABLE 12 15 monio Methacrylate Copolymer type BUSP) and the mix Dissolution profile ture is granulated with a solvent mixture of acetone and methylene chloride and then dried. The granules are sized. Metformin RosiglitaZone Coating of Micro matrix particles-86.46% w/w of micro Hydrochloride Maleate matrix particles is charged in fluidized bed processor. Time Time 12.61% w/w of hydrogenated castor oil is dissolved in (hour) % Released (min) % Released acetone and this coating solution is sprayed to coat the micro matrix particles. The coated micro matrix particles are sieved 1 39.9 15 78.32 2 51.7 30 89.15 and mixed with 0.91% w/w magnesium stearate. 4 692 45 97.13 Compression of Tablets 6 82.5 60 100.57 25 90 mg granule of inner portion are pressed to tablets (equal 8 83.8 to 1 mg glimepiride) using 6.35 mm round punches and 694 10 91.2 12 94.9 mg granules of outer portion (equal to 500 mg metformin 24 99.8 hydrochloride) are compressed using 14.95x8.35 mm oblong punches. The compression procedure is same as Example 5. 30 The dissolution rate of the novel dosage form was deter Example 8 mined Production of Inner Portion TABLE 1.4 2.94% w/w of rosiglitazone maleate is mixed with 87.80% w/w of Mannitol (Pearlitol SD 200 R.T.M.), 6.67% w/w of Dissolution profile crosspovidone, 2.0% w/w of magnesium stearate, 0.56% w/w Metformin of colloidal silicon dioxide and 0.03% w/w ferric oxide red. Hydrochloride Glimepiride This mixture is compressed to 90 mg weight tablets having a diameter of 6.35 mm. Time Time (hour) % Released (min) % Released Production of Outer Portion 40 Same as of Example 5. 1 28.0 15 69.4 Compression of tablets 2 4.O.S 30 91.87 4 57.8 45 99.64 90 mg granule of inner portion are pressed to tablets (equal 6 65.8 60 103.87 to 2 mg rosiglitaZone maleate) using 6.35 mm round punches 8 73.2 and 1281 mg granule of outer portion (equal to 1000 mg 45 10 80.3 metforminhydrochoride) are compressed using 20.3x9.8 mm 12 8S.O oval punches. The compression procedure is same as 24 101.8 Example 5. The dissolution rate of the novel dosage form was deter mined 50 Example 10 TABLE 13 1) Production of Inner Portion Dissolution profile Same as for Example 5 2) Production of Outer Portion Metformin RosiglitaZone 55 Micro Matrix Particles Hydrochloride Maleate Same as for Example 5 Time Time B) Coating of Micro matrix particles—91.21% w/w of micro (hour) % Released (min) % Released matrix particles and 8.29% w/w of hydrogenated castor oil is mixed and charged in planetary mixer which is heated 1 38.29 15 80.2 2 53.40 30 96.1 60 from outside to maintain the temperature approximately 4 69.51 45 103.4 80° C. with the help of a water bath. The above blend is 6 78.11 mixed by running the planetary mixer for 1 hour to coat the 8 86.86 micro matrix particles. The coated micro matrix particles 10 93.60 12 97.65 are sieved and mixed with 0.50% w/w magnesium stearate. 24 100.17 65 3) Compression of Tablets 90 mg granule of inner portion are pressed to tablets (equal to 4 mg rosiglitaZone maleate) using 6.35 mm round punches US 8,263,125 B2 37 38 and 1206 mg granules of outer portion (equal to 1000 mg TABLE 17 metformin hydrochloride) are compressed using 20.3x9.8 mm oval punches. The compression procedure is same as Dissolution profile of tablet (B Example 5. Metformin The dissolution rate of the novel dosage form was deter 5 hydrochloride Rosiglitazone mined Time Time (hour) % Released (min) % Released TABLE 1.5 1 S.O.3 15 99.22 10 2 70.5 30 105.26 Dissolution profile 4 88.0 45 107.53 Metformin RosiglitaZone 6 100.9 60 107.53 Hydrochloride Maleate

Time Time (hour) % Released (min) % Released 15 Example 12 1 25.7 30 85.9 Production of Inner Portion 2 36.6 45 100.3 4 49.1 60 104.9 Same as for Example 7. 6 57.5 Production of Outer Portion 8 66.5 A) Micro matrix particles-93.02% w/w of metformin hydro 10 71.3 12 76.O chloride is mixed with 6.98% w/w of Eudragit RS (Ammo 14 90.7 nio Methacrylate Copolymer type BUSP) and the mixture is granulated with a solvent mixutre of acetone and meth ylene chloride and then dried. The granules are sized. Dosage forms described in the example 11 are prepared by 25 B) Coating of Micro matrix particles 85.18% w/w of micro not coating the micro matrix particles of the outer portion but matrix particles is charged in fluidized bed processor. the hydrophobic release controlling agent is mixed with the 13.87% w/w of hydrogenated castor oil is dissolved in micro matrix particles. The Sole purpose of these examples is acetone and this coating solution is sprayed to coat the to demonstrate the usefulness of the present invention as micro matrix particles. The coated micro matrix particles described earlier. The examples clearly show that the rate of 30 are sieved and mixed with 0.95% w/w magnesium stearate. 3) Compression of Tablets release of the modified release active ingredient is signifi 90 mg granule of inner portion are pressed to tablets (equal cantly faster than the present invention. to 4 mg rosiglitaZone) using 6.35 mm round punches and 1262 mg granules of outer portion (equal to 1000 mg met Example 11 formin hydrochloride) are compressed using 20.3x9.8 mm 35 oblong punches. The compression procedure is same as Example 5. 1) Production of Inner Portion The dissolution rate of the novel dosage form was deter Same as for Example 5 mined

2) Production of Outer Portion 40 77.76% w/w of metformin hydrochloride is mixed with TABLE 1.8 7.780% w/w of Eudragit RS (Ammonio Methacrylate Dissolution profile Copolymer type BUSP) and the mixture is granulated with a Metformin solvent mixture of acetone and methylene chloride and then Hydrochloride Rosiglitazone dried. The granules are sized and mixed with 13.61% w/w of 45 hydrogenated castor oil and 0.86% w/w of magnesium Stear Time Time ate. (hour) % Released (min) % Released 3) Compression of Tablets 1 40.9 45 89.68 2 52.2 60 91.42 Tablet (A) Same as for Example 5 50 4 68.4 Tablet (B)—Same as for Example 5 6 79.2 8 886 The dissolution rate of the novel dosage form was deter 10 99.9 mined (Table 16 and 17) 12 101S TABLE 16 55 Dissolution profile of tablet (A Example 13 Metformin Production of Inner Portion hydrochloride Rosiglitazone Same as for Example 7. 60 Production of Outer Portion Time Time A) Micro matrix particles—Same as for Example 12. (hour) % Released (min) % Released B) Coating of Micro matrix particles-88.70% w/w of micro 1 63.9 15 100.08 matrix particles is charged in fluidized bed processor. 2 85.5 30 106.41 10.31% w/w of hydrogenated castor oil is dissolved in 4 102.1 45 109.77 65 acetone and this coating solution is sprayed to coat the micro matrix particles. The coated micro matrix particles are sieved and mixed with 0.99% w/w magnesium stearate. US 8,263,125 B2 39 40 Compression of Tablets nio Methacrylate Copolymer type B USP) and 4.55% w/w 90 mg granule of inner portion are pressed to tablets (equal of Eudragit RL (Ammonio Methacrylate Copolymer type to 4 mg rosiglitaZone) using 6.35 mm round punches and A USP) and the mixture is granulated with a solvent mix 1212 mg granules of outer portion (equal to 1000 mg met formin hydrochloride) are compressed using 20.3x9.8 mm ture of acetone and methylene chloride and then dried. The oblong punches. The compression procedure is same as granules are sized. Example 5. B) Coating of Micro matrix particles 85.47% w/w of micro The dissolution rate of the novel dosage form was deter matrix particles is charged in fluidized bed processor. mined (Table 19) 13.60% w/w of hydrogenated castor oil is dissolved in 10 acetone and this coating solution is sprayed to coat the TABLE 19 micro matrix particles. The coated micro matrix particles are sieved and mixed with 0.93% w/w magnesium stearate. Dissolution profile Compression of Tablets Metformin Hydrochloride Rosiglitazone 15 90 mg granule of inner portion are pressed to tablets (equal Time Time to 4 mg rosiglitaZone) using 6.35 mm round punches and (hour) % Released (min) % Released 1287 mg granules of outer portion (equal to 1000 mg met 1 44.50 15 79.9 formin hydrochloride) are compressed using 20.3x9.8 mm 2 S8.90 30 89.9 oblong punches. The compression procedure is same as 4 76.90 45 95.8 Example 5. 6 91.40 60 1OO6 8 102.40 The dissolution rate of the novel dosage form was deter mined (Table 21) Example 14 TABLE 21 25 Production of Inner Portion Dissolution profile Same as for Example 11. Production of Outer Portion Metformin Hydrochloride RosiglitaZone A) Micro matrix particles—Same as for Example 12. B) Coating of Micro matrix particles-90.56% w/w of micro 30 Time Time matrix particles is charged in fluidized bed processor. (hour) % Released (min) % Released 8.42% w/w of hydrogenated castor oil is dissolved in acetone and this coating solution is sprayed to coat the 1 34.8 45 92.65 micro matrix particles. The coated micro matrix particles 2 48.3 60 97.02 are sieved and mixed with 1.01% w/w magnesium stearate. 35 4 66.2 Compression of Tablets 6 79.3 90 mg granule of inner portion are pressed to tablets (equal 8 85.9 to 4 mg rosiglitaZone) using 6.35 mm round punches and 10 92.6 1187 mg granules of outer portion (equal to 1000 mg met 12 97.6 formin hydrochloride) are compressed using 20.3x9.8 mm 40 oblong punches. The compression procedure is same as Example 5. The dissolution rate of the novel dosage form was deter Example 16 mined (Table 20) 45 Production of Inner Portion TABLE 20 Same as for Example 7. Dissolution profile Production of Outer Portion Metformin Hydrochloride RosiglitaZone 50 A) Micro matrix particles—Same as for Example 15. Time Time B) Coating of Micro matrix particles-94.66% w/w of micro (hour) % Released (min) % Released matrix particles is charged in fluidized bed processor. 1 4240 45 86.OS 4.30% w/w of hydrogenated castor oil is dissolved in 2 S8.1 60 90.73 acetone and this coating solution is sprayed to coat the 4 75.9 55 6 86.5 micro matrix particles. The coated micro matrix particles 8 94.5 are sieved and mixed with 1.03% w/w magnesium stearate. 10 99.0 Compression of Tablets 90 mg granule of inner portion are pressed to tablets (equal 60 to 4 mg rosiglitaZone) using 6.35 mm round punches and Example 15 1162 mg granules of outer portion (equal to 1000 mg met Production of Inner Portion formin hydrochloride) are compressed using 20.3x9.8 mm Same as for Example 7. oblong punches. The compression procedure is same as Production of Outer Portion 65 Example 5. A) Micro matrix particles-90.91% w/w of metformin hydro The dissolution rate of the novel dosage form was deter chloride is mixed with 4.55% w/w of Eudragit RS (Ammo mined (Table 22) US 8,263,125 B2 41 42 TABLE 22 1263 mg granules of outer portion (equal to 1000 mg met formin hydrochloride) are compressed using 20.3x9.8 mm Dissolution profile oblong punches. The compression procedure is same as Metformin Hydrochloride Rosiglitazone Example 5. The dissolution rate of the novel dosage form was deter Time Time (hour) % Released (min) % Released mined (Table 24) 1 47.56 45 92.94 TABLE 24 2 61.93 60 96.70 4 82.42 10 Dissolution profile 6 96.O 8 1OOO Metformin Hydrochloride Rosiglitazone Time Time (hour) % Released (min) % Released Example 17 15 1 38.7 30 78.66 2 52.9 45 8347 1) Production of Inner Portion 4 71.6 60 88.06 Same as for Example 7. 6 82.3 2) Production of Outer Portion 8 91.3 A) Micro matrix particles—Same as for Example 5. 10 97.3 B) Coating of Micro matrix particles-88.92% w/w of micro 12 101.1 matrix particles is charged in fluidized bed processor. 10.11% w/w of hydrogenated castor oil is dissolved in acetone and this coating solution is sprayed to coat the Example 19 micro matrix particles. The coated micro matrix particles 25 are sieved and mixed with 0.97% w/w magnesium stearate. Production of Inner Portion 3) Compression of Tablets 2.22% w/w of glimepiride is mixed with 62.17% w/w of 90 mg granule of inner portion are pressed to tablets (equal lactose monohydrate and 22.22% w/w starch and the mixture to 4 mg rosiglitaZone) using 6.35 mm round punches and is granulated in a binder of 2.22% w/wpovidone in water and 1237 mg granules of outer portion (equal to 1000 mg met 30 then dried. The granules are sieved and mixed with 0.56% formin hydrochloride) are compressed using 20.3x9.8 mm W/w magnesium Stearate, 10.0% w/w Sodium starch glyco oblong punches. The compression procedure is same as late, 0.06% w/w lake of erythrocine and 0.56% w/w colloidal Example 5. silicon dioxide. This mixture is compressed to 90 mg weight The dissolution rate of the novel dosage form was deter tablets having a diameter of 6.35 mm. Production of outer mined (Table 23) 35 portion—same as for example 18. Compression of tablets TABLE 23 90 mg granule of inner portion are pressed to tablets (equal to 2 mg glimepiride) using 6.35 mm round punches and 1263 Dissolution profile mg granules of outer portion (equal to 1000 mg metformin hydrochloride) are compressed using 20.3x9.8 mm oblong Metformin Hydrochloride RosiglitaZone 40 punches. The compression procedure is same as Example 5. Time Time The dissolution rate of the novel dosage form was deter (hour) % Released (min) % Released mined (Table 25) 1 3S.O 15 69.2 2 47.3 30 79.5 45 TABLE 25 4 60.8 45 85.7 6 72.5 60 90.4 Dissolution profile 8 81.8 10 89.2 Metformin Hydrochloride Glimepiride 12 94.1 Time Time 24 98.2 50 (hour) % Released (min) % Released 1 38.79 45 100.7 2 54.12 60 102.2 Example 18 4 69.54 6 82.04 1) Production of Inner Portion 55 8 89.78 Same as for Example 7. 10 95.06 2) Production of Outer Portion 12 100.48 A) Micro matrix particles—Same as for Example 5. B) Coating of Micro matrix particles-87.09% w/w of micro matrix particles is charged in fluidized bed processor. 60 Example 20 11.88% w/w of hydrogenated castor oil is dissolved in acetone and this coating solution is sprayed to coat the Determination of relative bioavailability of Metformin sus micro matrix particles. The coated micro matrix particles tained release formulation with respect to metformin imme are sieved and mixed with 1.03% w/w magnesium stearate. diate release tablet. 3) Compression of Tablets 65 The study was carried out to demonstrate the Sustained 90 mg granule of inner portion are pressed to tablets (equal release characteristic of metformin in the combination for to 4 mg rosiglitaZone) using 6.35 mm round punches and mulation and to evaluate the relative bioavailability of com US 8,263,125 B2 43 44 bination formulation of sustained release Metformin hydro precipitated with 2.0 ml acetonitrile. Samples were centri chloride and RosiglitaZone maleate versus metformin fuged and Supernatant aliquot was washed with dichlo immediate release tablet 2x500 mg (marketed as Glycomet? romethane. After centrifugation, aqueous layer was injected by USV Ltd.: India.) and rosiglitazone immediate release On HPLC. tablets 4 mg (marketed as Enselin? by Torrent pharma Ltd.: Analysis of RosiglitaZone: India.). Estimation of RosiglitaZone in plasma samples was carried Methodology: out by LC-MS/MS. Briefly 0.1 ml of plasma sample was The biostudy had an open label, randomized two period, precipitated with 0.25 ml acetonitrile. Samples were centri two treatment, two way single dose crossover study with 7 fuged and supernatant aliquot was analyzed by LC-MS/MS. days washout period between treatment days. 10 Non-compartmental Pharmacokinetic assessment was Pharmacokinetic Results: based on the plasma levels of Metformin and Rosiglitazone The Summary of the statistical analysis and confidence measured by blood sampling. Blood samples were obtained intervals of the Pharmacokinetic parameters is contained in before dosing and at the following times after administration Tables 26 & 27. The mean plasma concentration versus time of test and reference formulations; 15 curve is depicted in FIG. 8 (metformin) & FIG. 9 (rosiglita Pre-dose, 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, Zone) wherein curve a represents Test Formulation and curve 10.0, 12.0, 15.0, 18.0, and 24.0 hours. b represents Reference Formulation. Number of Subjects and Study Population: Twelve (12) volunteers were enrolled and all of them com pleted the study. All 12 volunteers were included in the Phar TABLE 26 macokinetic and safety analyses. Bioavailability Summary and Analysis - Metformin SR Criteria for Inclusion: AUCo ng *hr 15980 - 3456 19551 - 426S Healthy male volunteers aged between 18 to 45 years. AUCo. ng * hr 14983 - 293O 19091 - 4200 Test Formulation, Dose and Mode of Administration: Cmax ng/ml 1737.61 - 249.09 2S58.37 - 623. OS Test Formulation: 4 mg/1000 mg Rosiglitazone/Met C24, ng/ml 113.87 - 91.05 56.44 - 37.94 formin SR prepared as per the invention disclosed in the 25 Tmax hir 5.42 - O.68 4.42 + 0.88 examples. T1/2 hir 4.71 - 1.36 4.26 + 1.14 Volunteers received a single oral dose of above products with 200 ml of water following high calorie diet (-800 Kcal). Reference Product, Dose and Mode of Administration: TABLE 27 Reference: Immediate release 4 mg Enselin plus Glyco 30 mate (2x500 mg) Bioavailability Summary and Analysis - Volunteers received a single oral dose of above products with 200 ml of water following high calorie diet (-800 Kcal). AUCo ng hr/ml 1851 - 414 1730 - 465 Pharmacokinetics: AUCo. ng *hriml 1795 - 401 1676 - 438 Cmax ng/ml 243.48 - 40.78 247.48 - 45.38 The following Pharmacokinetic parameters were calcu 35 C24, ng/ml 6.36 - 5.19 3.37 - 4.36 lated using non compartments methods: the area under the Tmax hir 3.75 - 1.03 3.25 + 1.66 drug plasma concentration curve from time of dosing to the t1/2 hir 3.73 - 0.60 3.63 - 0.79 time of last sampling point (AUCo.); the area under the drug plasma concentration versus time curve extrapolated to infin ity (AUC or ); the maximum measured concentration of Conclusion: the drug in the plasma (C) and the time at which this 40 Metformin intest formulation has shown sustained release concentration was measured (t); the concentration at 24 characteristics with lower Cand prolongedt (Figure 8). hours (C); the time taken for drug plasma concentration to The relative bioavailability of both the components was stud decrease by 50% (t); and the terminal first-order elimina ied. tion rate constant (K). Area Under the curve (AUC) is the integral part of drug 45 Example 21 blood level over time from Zero to infinity and is a measure of quantity of drug absorbed and in the body. Determination of Relative Bioavailability of Two Formula AUC (0-t) represents area under the curve from Zero to time t, tions with Different Release Profiles: where t represents the time at which last blood sample was A biostudy was carried out with the preliminary objective taken. 50 of comparing the relative bioavailability of the 1000 mg met AUC (0-1) represents area under the curve from Zero to formin sustained release formulations (A & B) relative to infinity. immediate release metformintablets 2x500 mg (marketed as Elimination halflife of a drug is the time in hours necessary Glycomet" by USV Ltd.: India.). A secondary objective was to reduce the drug concentration in the blood, plasma or serum to /2 after equilibrium is reached. to characterize the plasma concentration profile of metformin C is the peak plasma concentration achieved after the 55 in the sustained release formulation relative to immediate administration of the drug. release formulation i.e. Glycomet' 2x500 mg tablets. T is the time to reach peak plasma concentration. Methodology: Statistical Methods: The biostudy had an open label, randomized, three periods, Descriptive statistics of relevant Pharmacokinetic param three treatment, three way, single dose crossover design with eters were performed. An analysis of variance (ANOVA) was 60 7 days washout period between treatment days. used to assess treatment differences. Non-compartmental Pharmacokinetic assessment was Methods used for analysis of Metforminand Rosiglitazone in based on the plasma levels of metformin measured by blood plasma samples: sampling. Blood samples were obtained before dosing and at Analysis of Metformin: the following times after administration of test and reference Estimation of Metformin in plasma samples was carried 65 formulations; out by High Performance Liquid Chromatography and UV Pre-dose, 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, detection at 234 nm. Briefly 0.5 ml of plasma sample was 10.0, 12.0, 15.0, and 24.0 hours. US 8,263,125 B2 45 46 Number of Subjects and Study Population: Methodology: Twelve (12) volunteers were enrolled and 11 of them com The biostudy had an open label, randomized two period, pleted the study. All 12 volunteers were included in the Phar two treatment, two way single dose crossover study with 7 macokinetic and safety analyses. days washout period between treatment days. Criteria for Inclusion: Non-compartmental Pharmacokinetic assessment was Healthy male volunteers aged between 18 to 45 years. based on the plasma levels of Metformin and Rosiglitazone Test product, Dose and Mode of Administration: measured by blood sampling. Blood samples were obtained Formulation A: 4 mg/1000 mg Rosiglitazone/Metformin before dosing and at the following times after administration dosage form prepared as per the invention disclosed in the of test and reference formulations; 10 Pre-dose, 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, examples. Formulation B: 4 mg/1000 mg Rosiglitazone/Met 10.0, 12.0, 15.0, 18.0, and 24.0 hours. formin SR dosage form prepared as per the invention dis Number of Subjects and Study Population: closed in the examples. Sixteen (16) volunteers were enrolled and 15 of them com In the morning, Volunteers received a single oral dose of pleted the study. All 15 volunteers were included in the Phar above products with 200 ml of water following high calorie 15 macokinetic and safety analyses. diet (-800 Kcal). Criteria for Inclusion: Reference Product, Dose and Mode of Administration: Healthy male volunteers aged between 18 to 45 years. Test Product, Dose and Mode of Administration: Formulation C: Immediate release 4 mg Enselin plus Test Formulation: 4 mg/1000 mg Rosiglitazone/Met Glycomate (2x500 mg) formin Sustained release dosage form prepared as per the In the morning, Volunteers received a single oral dose of invention disclosed in the examples. Volunteers received a above products with 200 ml of water following high calorie single oral dose of above products with 200 ml of water diet (-800 Kcal) following high calorie dinner (~1400 KCal). Pharmacokinetics: Reference Product, Dose and Mode of Administration: Same as for example 20. Reference: 4 mg. Avandia? plus Glucophage XR2 (2x500 Statistical Methods: 25 mg) Volunteers received a single oral dose of above products Same as for example 20. with 200 ml of water following calorie dinner (~1400 Kcal). Methods used for analysis of Metforminand Rosiglitazone in Pharmacokinetics: plasma samples: Same as for example 20. Same as for example 20. Statistical Methods: Pharmacokinetic Results: 30 Descriptive statistics of relevant Pharmacokinetic param eters were performed. An analysis of variance (ANOVA) was The Summary of the statistical analysis and confidence used to assess treatment differences. intervals of the Pharmacokinetic parameters is contained in Westlake's 90% confidence interval for the ratio of two formulations for log transformed data were calculated, and to TABLE 28 test that the difference between two formulations are within 35 The mean plasma concentration versus time curve is the (80 to 125%) limits. depicted in FIG. 10. wherein curve a represents Formulation A, Methods used for analysis of Metforminand Rosiglitazone in curve b represents Formulation B and curve c represents the plasma samples: Formulation C. Same as for example 20. Pharmacokinetic Results: AUCo ng * hr/m 16508+ 17762- 15985 40 AUCo. ng * hr/m 15899- 14989- 1SSS8-- The Summary of the statistical analysis and confidence Cmax ng/ml 18O1.72- 1551.O1- 2121.96 intervals of the Pharmacokinetic parameters is contained in C24, ng/ml 79.58- 204.96- 45.48 Table 29 & 30. The mean plasma concentration versus time Tmax Hr 5.36 - 0.51 S.46 - O.78 4.OO -- 0.74 curve is depicted in FIG. 11 (Metformin) & 12 (Rosiglita T1/2 Hr 4.08 - 1.32 7.23 - 345 4.61 + 1.54 Zone) wherein curve a represents Test Formulation and curve 45 b represents Reference Formulation. Conclusion: Both the formulations according to the invention tested had TABLE 29 reduced C compared to that of the reference product (Gly comet” tablets), with Formulation B being significantly Bioavailability Summary and Analysis - Metformin SR reduced. Thet of both the formulations according to inven 50 AUCo if nghrim 16939- 16396- 83.84 11.6.16 AUCo. nghrim 16107- 15951- 87.33 112.67 tion were prolonged relative to that of Glycomet” tablets. The Cmax ng/ml 1515.29- 1558.78- 90.89 109.11 concentration at 24 hours (C) of Formulation B was almost C24 , ng/ml 120.10- 79.63 4.5 times higher than Glycomet” tablets and almost 2.6 times Tmax hir 7.64+ 8.86+ higher than Formulation A. T1/2 hir 4.12+ 3.36+ 55 Example 22 Determination of Relative Bioavailability of Metformin Sus TABLE 30 tained Release Formulations Bioavailability Summary and Analysis - RosiglitaZone (4 mg) The study was carried out to assess the effect of night time 60 AUCo if nghrim 13O8- 1258 - 331 85.73 11427 administration and to evaluate the relative bioavailability of AUCo. nghrim 1266+ 1234 - 324 86.61 11339 combination formulation of sustained release Metforminand Cmax ng/ml 145.70- 161.83- 80.88 11912 RosiglitaZone (prepared as per the invention disclosed in the C24 , ng/ml 6.O7- 1.80 + 3.11 examples) versus metformin Sustained release tablet (mar Tmax hir S.O7- 4.13 + 1.91 keted as Glucophage XR" by Bristol Myers Squibb, USA.) 65 T1/2 hir 3.59- 3.32 - 0.59 and rosiglitaZone immediate release tablet (marketed as Avandia' by Glaxo Smithkline; United Kingdom.). US 8,263,125 B2 47 48 Conclusion: solubility active ingredient, wherein the dual retard technique The relative bioavailability study shown that bioequiva- is a combination of matrix formulation and reservoir formu lance was achieved between the 4 mg/1000 mg combination lation comprises formulation and the respective components, for both AUC (a) micro matrix particles consisting of a high dose, high and C. parameters (Table 29 & 30). Moreover, in the test 5 Solubility active ingredient and one or more hydropho formulation, the concentration of Metformin at 24 hrs was bic release controlling agents wherein the ratio of high almost 1.5 times more than Glucophage XR (FIG. 11) dose, high solubility active ingredient and hydrphobic wherein curve a represents Test formulation and b represents release controlling agent is in the range of 100:2.5 to Reference formulation (Table 29). Similarly Rosiglitazone 100:30 and component of the test formulation also shown higher concen- 10 (b) coating of one or more hydrophobic release controlling tration at 24 hrs as that of Avandia' (FIG. 12; wherein curve a agents on said micro matrix particles, wherein the ratio represents Test Formulation and curveb represents Reference of micro matrix particles and hydrophobic release con Formulation and Table 30). trolling agent is in the range of 100:2.5 to 100:30 wherein the weight ratio of the immediate release low Example 23 15 dose active ingredient and high dose, high solubility modified release active ingredient is from 1:1 to 1:15000 1) Production of Inner Portion wherein the claimed dosage form does not provide burst 69.61% w/w of Aspirin coated granules (Aspirin 96% w/w, release. 2.0% w/w hydrogenated castor oil & 2.0% w/w citric acid 2. A dosage form according to claim 1, wherein the hydro anhydrous coated) mixed with the mixture of 11.56% WW of 20 phobic release controlling agents are selected from the group microcrystalline cellulose (PH1 12, dried), 7.17% w/w consisting of poly(ethyl acrylate, methyl methacrylate, trim sodium starch Glycolate (dried), 2.24% w/w citric acid anhy- ethylammonioethyl methacrylate chloride) 1:2:0.1; poly drous, 4.48% w/w talc, 1.79% w/w colloidal silicon dioxide, (ethyl acrylate, methyl methacrylate, trimethylamonioethyl 1.79% w/w stearic acid and 1.35% w/w hydrogenated veg- methacrylate chloride) 1:2:0.2 and poly(ethyl acrylate, etable oil. 25 methyl methacrylate) 1:1; polyvinyl acetate dispersion, eth Production of Outer Portion ylcellulose, cellulose acetate, cellulose propionate (lower, A) Micro matrix particles 93.02% w/w of nicotinic acid is medium or higher molecular weight), cellulose acetate pro mixed with 6.98% w/w of Eudragit RS PO (Ammonio pionate, cellulose acetate butyrate, cellulose acetate phtha Methacrylate Copolymer type B USP) and the mixture is late, cellulose triacetate, poly(methyl methacrylate), poly granulated with a solvent mixture of acetone and methyl- 30 (ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl ene chloride and then dried. The granules are sized through methacrylate), poly (hexyl methacrylate), poly(isodecyl 11.0 mm screen. methacrylate), poly (lauryl methacrylate), poly(phenyl meth B) Coating of Micro matrix particles-92.67% w/w of micro acrylate), poly (methyl acrylate), poly (isopropyl acrylate), matrix particles is charged in fluidized bed processor. poly (isobutyl actylate), poly (octadecyl acrylate), waxes 6.47% W/W of hydrogenated castor oil is dissolved in 35 selected from the group consisting of beeswax, carnauba acetone and this coating solution is sprayed to coat the wax, selected from the group consisting of cetostearyl alco micro matrix particles. The coated micro matrix particles hol, Stearyl alcohol; cetyl alcohol and myristyl alcohol; and are sieved and mixed with 0.86% w/w magnesium stearate. fatty acid esters glyceryl monostearate, glycerol distearate, Compression of Tablets glycerol monooleate, acetylated monoglycerides, tristearin, Tablet (A)-483.17 mg granules of inner portion are pressed 40 tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyc to tablets (equal to 325.0 mg aspirin) using 15.0x6.35 mm eryl behenate and hydrogenated castor oil. plain, capsule shape punches with one side break line and 3. A dosage form according to claim 2, wherein the hydro 1160 mg granules of Outer portion (equal to 1000 mg phobic release controlling agent(s) is selected from the group nicotinic acid) are compressed using 20.3x9.8 mm plain, consisting of poly(ethyl acrylate, methyl methacrylate, trim capsule shape punches. 45 ethylammonioethyl methacrylate chloride) 1:2:0.1: poly Tablet (B) 223.0 mg granules of inner portion are pressed to (ethyl acrylate, methyl methacrylate, trimethylamonioethyl tablets (equal to 150.0 mg aspirin) using 13.5x6.35 mm methacrylate chloride) 1:2:0.2 and poly(ethyl acrylate, plain, capsule shape punches with one side break line and methyl methacrylate) 1:1. 1160 mg granules of outer portion (equal to 1000 mg 4. A dosage form according to claim3, wherein the hydro nicotinic acid) are compressed using 20.3x9.8 mm plain, 50 phobic release controlling agent is poly(ethyl acrylate, capsule shape punches. The compression is done on press methyl methacrylate, trimethylammonioethyl methacrylate coater machine in Such a manner that the resultant tablet chloride) 1:2:0.1. has inner portion covered by the outer portion from all the 5. A dosage form according to claim 1, wherein in micro sides except top surface that remains uncovered and the matrix particles, the active ingredient and one or more hydro level of the inner portion and the outer portion is on the 55 phobic release controlling agents are present in a ratio offrom same Surface. 100:25 to 100:20. What is claimed is: 6. A dosage form according to claim3, wherein the hydro 1. A dosage form of combination of high dose high solu- phobic release controlling agents are selected from the group bility active ingredient, as modified release and low dose consisting of poly(ethyl acrylate, methyl methacrylate, trim active ingredient as immediate release suitable for Swallow- 60 ethylammonioethyl methacrylate chloride) 1:2:0.1: poly ing; comprising an inner portion having a low dose active (ethyl acrylate, methyl methacrylate, trimethylamonioethyl ingredient as immediate release and an outer portion having a methacrylate chloride) 1:2:0.2 and poly(ethyl acrylate, high dose, high solubility active ingredient as modified methyl methacrylate) 1:1; polyvinyl acetate dispersion, eth release, wherein said inner portion is covered by the outer ylcellulose, cellulose acetate, cellulose propionate (lower, portion from all the sides except a top surface that remains 65 medium or higher molecular weight), cellulose acetate pro uncovered; wherein the outer portion prepared by using dual pionate, cellulose acetate butyrate, cellulose acetate phtha retard technique to control the release of high dose, high late, cellulose triacetate, poly(methyl methacrylate), poly US 8,263,125 B2 49 50 (ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl 11. A dosage form according to claim 10, wherein the low methacrylate), poly (hexyl methacrylate), poly(isodecyl dose active ingredient is selected from the group consisting of methacrylate), poly (lauryl methacrylate), poly(phenyl meth 16-alpha fluorocstradiol, 16-alpha-gitoxin, 16-epiestriol, 17 acrylate), poly (methyl acrylate), poly (isopropyl acrylate), alpha dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, poly (isobutyl actylate), poly (octadecyl acrylate), waxes 17 hydroxy progesterone, lalpha-hydroxyvitamin D2, selected from the group consisting of beeswax, carnauba 1-dodecpyrrolidinone, 20-epi-1.25 dihydroxyvitamin D3, wax, microcrystalline wax, and oZokerite; fatty alcohols 22-oxacalcitriol. 2'-nor-cGMP 3-isobutyl GABA, 5-ethyny selected from the group consisting of cetostearyl alcohol, luracil, 6-FUDCA, 7-methoxytacrine, Abamectin, abanoquil, Stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty abecarnil, abiraterone, Ablukast, Ablukast Sodium, 10 Acadesine, acamprosate, Acarbose, Acebutolol, Acecainide acid esters selected from the group consisting of glyceryl Hydrochloride, Aceclidine, aceclofenac, Acedapsone, Ace monostearate, glycerol distearate, glycerol monooleate, glutamide Aluminum, Acemannan, Acetaminophen, Aceta acetylated monoglycerides, tristearin, tripalmitin, cetyl esters Zolamide, Acetohexamide, Acetohydroxamic Acid, acetome wax, glyceryl palmitostearate, glyceryl behenate glycerol pregenol, Acetophenazine Maleate, Acetosulfone Sodium, distearate, and hydrogenated castor oil. 15 Acetylcholine Chloride, Acetylcysteine, acetyl-L-carnitine, 7. A dosage form according to claim 6, wherein the hydro acetylmethadol, Acifran, acipimox, acitemate, Acitretin, phobic release controlling agent(s) is selected from fatty Acivicin, Aclarubicin, aclatonium, Acodazole Hydrochlo acids selected from the group consisting of glyceryl ride, aconiazide, Acrisorcin, Acrivastine, Acronize, Actiso monostearate, glycerol distearate, glycerol monoleate, acety mide, Actodigin, Acyclovir, acylfulvene, adafenoxate, ada lated monoglycerides, tristearin, tripalmitin, cetyl esters wax, palene, Adapalene, adatanserin, Adatanserin Hydrochloride, glyercyl palmitostearate, glyceryl behenate, glycerol distear adecypenol, adecypenol, Adefovir, adelmidrol, ademetion ate, and hydrogenated castor oil. ine, Adenosine, Adinazolam, Adiphenine Hydrochloride, 8. A dosage form according to claim 7, wherein the hydro adiposin, AdoZelesin, adrafinil, Adrenalone, arbutamine, ala phobic release controlling agents is selected from the group cepril, Alamycin Alaproclate, alaptide, Albendazole, albola consisting of hydrogenated castor oil and glycerol distearate. 25 brin, Albuterol, Albutoin, Alclofenac, Alclometasone Dipro 9. A dosage form according to claim 1, wherein the low pionate, Alcloxa, aldecalmycin, Aldesleukin, Aldioxa, dose active ingredient comprises dose less than or equal to Alendronate Sodium, alendronic acid, alentemol, Alentemol 500 mg. Hydrobromide, Aletamine Hydrochloride, Aleuronium Chlo 10. A dosage form according to claim 1, wherein the low ride, Alexidine, alfacalcidol, Alfentanil Hydrochloride, alfu dose active ingredient is selected from the group consisting of 30 Zosin, Algestone Acetonide, alglucerase, Aliflurane, alinas adrenergic agent, adrenocortical steroid; adrenocortical Sup tine, Alipamide, Allantoin, Allobarbital, Allopurinol, ALL pressant; aldosterone antagonist; amino acid; anabolic; ana TK antagonists, Alonimid, alosetron, Alosetron leptic; analgesic; anesthetic; anorectic; anti-acne agent; anti Hydrochloride, Alovudine, Alpertan, Alpha Amylase, alpha adrenergic; anti-allergic; anti-amebic; anti-anemic; anti idosone, Alpidem, Alprazolam, Alprenolol Hydrochloride, anginal; anti-arthritic; anti-asthmatic; anti-atherosclerotic; 35 Alprenoxime Hydrochloride, Alprostadil. Alrestatin Sodium, antibacterial; anticholinergic; anticoagulant; anticonvulsant; Altanserin Tartrate. Alteplase. Althiazide, Altretamine, altro antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti mycin B, Alverine Citrate, Alvircept Sudotox, Amadinone emetic; anti-epileptic; antifibrinolytic; antifungal; antihem Acetate, Amantadine Hydrochloride, ambamustine, Ambo orrhagic; antihistamine; antihyperlipidemia; antihyperten mycin, Ambruticin, Ambuphylline, Ambuside, Amcinafal, sive; antihypotensive; anti-infective; anti-inflammatory; 40 Amcinonide, Amdinocillin, Amdinocillin Pivoxil, Amedalin antimicrobial; antimigraine; antimitotic; antimycotic, antin Hydrochloride, amelometasone, Ameltolide, Amesergide, auseant, antineoplastic, antineutropenic, antiparasitic; anti Ametantrone Acetate, ameZinium methylsulfate, amfebuta proliferative; antipsychotic; antirheumatic; antiseborrheic; mone, Amfenac Sodium, Amflutizole, Amicycline, antisecretory; antispasmodic; antithrombotic; anti-ulcer Amidephrine Mesylate, amidox, Amifloxacin, amifostine, ative; antiviral; appetite Suppressant, blood glucose regulator, 45 Amikacin, Amiloride Hydrochloride, Aminacrine Hydro bone resorption inhibitor; bronchodilator; cardiovascular chloride, Aminobenzoate Potassium, Aminobenzoate agent; cholinergic; depressant; diagnostic aid; diuretic; Sodium, Aminocaproic Acid, Aminoglutethimide, Amino dopaminergic agent; estrogen receptor agonist; fibrinolytic; hippurate Sodium, aminolevulinic acid, Aminophylline. A fluorescent agent; free oxygen radical Scavenger, gastric acid minorex, Aminosalicylate Sodium, Aminosalicylic acid, Supressant; gastrointestinal motility effector, glucocorticoid: 50 Amiodarone, Amiprilose Hydrochloride, Amiquinsin Hydro hair growth stimulant; hemostatic; histamine H2 receptor chloride, amisulpride, Amitraz, Amitriptyline Hydrochlo antagonists; hormone; hypocholesterolemic; hypoglycemic; ride, AmlexanoX, amlodipine, Amobarbital Sodium, Amodi hypolipidemic; hypotensive; imaging agent; immunizing aquin, Amodiaquin Hydrochloride, Amorolfine, Amoxapine, agent; immunomodulator, immunoregulator, immunostimu Amoxicillin, Amphecloral, Amphetamine Sulfate, Ampho lant; immunosuppressant; keratolytic; LHRH agonist; mood 55 mycin, Amphotericin B, Ampicillin, ampiroXicam, Ampy regulator, mucolytic; mydriatic; nasal decongestant; neuro Zine Sulfate, Amquinate, Amrinone, amrinone, amrubicin, muscular blocking agent; neuroprotective; NMDA antago Amsacrine, amylin, amythiamicin, Anagestone Acetate, nist; non-hormonal sterol derivative; plasminogen activator; anagrelide, Anakinra, ananain, anaritide, Anaritide Acetate, platelet activating factor antagonist; platelet aggregation Anastrozole, Anazolene Sodium, Ancrod, andrographolide, inhibitor, psychotropic; radioactive agent; Scabicide; scleros 60 Androstenedione, angiogenesis inhibitors, Angiotensin ing agent; sedative; sedative-hypnotic; selective adenosine Amide, Anidoxime, Anileridine, Anilopam Hydrochloride, A1 antagonist; serotonin antagonist; serotonin inhibitor; Aniracetam, Anirolac, Anisotropine Methylbromide, Anis serotonin receptor antagonist; Steroid; thyroid hormone; thy treplase, AnitraZafen, anordrin, antagonist D, antagonist G. roid inhibitor, thyromimetic; tranquilizer, amyotrophic lat antarelix, Antazoline Phosphate, Anthelmycin, Anthralin, eral Sclerosis agent; cerebral ischemia agent, Paget’s disease 65 Anthramycin, antiandrogen, Acedapsone, Felbamate, anties agent; unstable angina agent; vasoconstrictor; vasodilator, trogen, antineoplaston, Antipyrine, antisense oligonucle wound healing agent; and Xanthine oxidase inhibitor. otides, apadoline, apafant, Apalcillin Sodium, apaxifylline, US 8,263,125 B2 51 52 ApaZone, aphidicolin glycinate, Apixifylline, Apomorphine Maleate, Bromazepam, Bromchlorenone, Bromelains, bro Hydrochloride, apraclonidine, Apraclonidine Hydrochloride, mfenac, Bromindione, Bromocriptine, Bromodiphenhy Apramycin, Aprindine, Aprindine Hydrochloride, aprosulate dramine Hydrochloride, Bromoxamide, Bromperidol, Bro Sodium, Aprotinin, Aptazapine Maleate, aptiganel, apurinic mperidol Decanoate, Brompheniramine Maleate, acid, aranidipine, Aranotin, Arbaprostil, arbekacin, arbidol. Broperamole, Bropirimine, Brotizolam, Bucainide Maleate, Arbutamine Hydrochloride, Arclofenin, Ardeparin Sodium, bucindolol, Buclizine Hydrochloride, Bucromarone, Budes argatroban, Arginine, Argipressin Tannate, Arildone, arip onide, budipine, budotitane, Buformin, Bumetanide, iprazole, arotinolol, Arprinocid, Arteflene, Artilide Fumarate, Bunaprolast, bunazosin, Bunolol Hydrochloride, Bupico asimadoline, aspalatone, Asparaginase, Aspartic Acid, Aspar mide, Bupivacaine Hydrochloride, Buprenorphine Hydro tocin, asperfuran, Aspirin, aspoxicillin, Asprelin, Astemizole, 10 chloride, Bupropion Hydrochloride, Buramate, Buserelin Astromicin Sulfate, asulacrine, atameStane, Atenolol, atevir Acetate, Buspirone Hydrochloride, Busulfan, Butabarbital, dine, Atipamezole, Atiprosin Maleate, Atolide, Atorvastatin Butacetin, Butaclamol Hydrochloride, Butalbital, Butamben, Calcium, Atosiban, Atovaquone, atpenin B, Atracurium Butamirate Citrate. Butaperazine. Butaprost, Butedronate Besylate, atrimustine, atrinositol, Atropine, Auranofin, aure Tetrasodium, butenafine. Buterazine, buthionine sulfox obasidin A, Aurothioglucose, Avilamycin, Avoparcin, AVri 15 imine, Butikacin, Butilfenin, Butirosin Sulfate, Butixirate, dine, axinastatin 1, axinastatin 2, axinastatin 3, AZabon, AZa butixocort propionate. Butoconazole Nitrate. Butonate, citidinie, AZaclorzine Hydrochloride, AZaconazole, Butopamine, Butoprozine Hydrochloride. Butorphanol, azadirachtin, AZalanstat Dihydrochloride, AZaloxan Fuma Butoxamine Hydrochloride, Butriptyline Hydrochloride, rate, AZanator Maleate, AZanidazole, AZaperone, AZaribine, Cactinomycin, Cadexomer Iodine, Caffeine, calanolide A, AZaserine, aZasetron, AZatadine Maleate, AZathioprine, AZa Calcifediol, Calcipotriene, calcipotriol, Calcitonin, Cal thioprine Sodium, azatoxin, azatyrosine, azelaic acid, azelas citriol, Calcium Undecylenate, calphostin C, Calusterone, tine, azelnidipine, AZepindole, AZetepa, azimilide, Azithro Cambendazole, camonagrel, camptothecin derivatives, mycin, AZlocillin, AZolitmin, AZosemide, AZomycin canarypox IL-2, candesartan, Candicidin, candoXatril, can Aztreonam, AZulene Sodium, Bacampicillin Hydrochloride, doXatrilat, Caniglibose, Canrenoate Potassium, Canrenone, baccalin III, Bacitracin, Baclofen, bacoside A, bacoside B, 25 capecitabine, Capobenate Sodium, Capobenic Acid, Capreo bactobolamine, balanol, balaZipone, balhimycin, balofloxa mycin Sulfate, capromab, capsaicin, Captopril, Capuride, cin, balsalazide, Bambermycins, bambuterol, Bamethan Sul Caracemide, Carbachol, Carbadox, Carbamazepine, Carba fate, Bamifylline Hydrochloride, Bamidazole, baohuoside 1, mide Peroxide, Carbantel Lauryl Sulfate, Carbaspirin Cal Barmastine, barnidipine, Basifungin, Batanopride Hydro cium, Carbazeran, carbazomycin C, Carbenicillin Potassium, chloride, batebulast, Batelapine Maleate, Batimastat, beau 30 Carbenoxolone Sodium, Carbetimer, carbetocin, Carbidopa, vericin, Becanthone Hydrochloride, becaplermin, beclicona Carbidopa-Levodopa, Carbinoxamine Maleate, Carbiphene Zole, Beclomethasone Dipropionate, befloxatone, Hydrochloride, Carbocloral, Carbocysteine, Carbol-Fuchsin, Benserazide, Belfosdil, Belladonna, Beloxamide, Carboplatin, Carboprost, carbovir, carboxamide-amino Bemesetron, Bemitradine, Bemoradan, Benapryzine Hydro triaZo-le, carboxyamidotriazole, carboxymethylated beta-1, chloride, Benazepril Hydrochloride, Benazeprilat, Benda 35 3-glucan, Carbuterol Hydrochloride, Carfentanil Citrate, calol Mesylate, Bendazac, Bendroflumethiazide, benflume Carisoprodol, Carmantadine, Carmustine, Camidazole, Car tol, benidipine, Benorterone, Benoxaprofen, Benoxaprofen, oxazone, carperitide, Carphenazine Maleate, Carprofen, Car Benoximate Hydrochloride, Benperidol, Bentazepam, Ben satirin Succinate, Cartazolate, carteolol, Carteolol Hydrochlo tiromide, Benurestat, BenZbromarone, Benzethonium Chlo ride, cartilag derived inhibitor, Carubicin Hydrochloride, ride, Benzetimide Hydrochloride, Benzilonium Bromide, 40 Carumonam Sodium, carvedilol, carvotroline, Carvotroline Benzindopyrine Hydrochloride, benzisoxazole, Benzocaine, Hydrochloride, carZelesin, casein kinase inhibitors, castano benzochlorins, Benzoctamine Hydrochloride, Benzodepa, spermine, carumonam, cebaracetam, cecropins, Cedefingol. benzoidazoxan, BenZonatate, Benzoyl Peroxide, Benzoylpas Cefaclor, Cefadroxil, Cefamandole, Cefaparole, Cefatrizine, Calcium, benzoylstaurosporine, BenZquinamide, BenZthiaz Cefazaflur Sodium, Cefazolin, CefbuperaZone, cefcapene ide, benztropine, Benztropine Mesylate, Benzydamine 45 pivoxil, cefdaloxime pentexil tosilate, Cefdinir, cefditoren Hydrochloride, Benzylpenicilloyl Polylysine, bepridil, pivoxil, Cefepime, cefetamet, Cefetecol, cefixime, ceflupre Bepridil Hydrochloride, Beractant, Beraprost, Berefrine, ber nam, Cefinenoxime Hydrochloride, Cefnetazole, fminox, lafenone, bertosamil, Berythromycin, besipirdine, beta-ala cefodizime, CefonicidSodium, CefoperaZone Sodium, Cefo nine, betaclamycin B. Betamethasone, betamipron, betax ranide, cefoselis, Cefotaxime Sodium, Cefotetan, cefotiam, olol, Betaxolol Hydrochloride, Bethanechol Chloride, 50 Cefoxitin, cefoZopran, cefpimizole, Ce?piramide, cefpirome, Bethanidine Sulfate, betulinic acid, bevantolol, Bevantolol cefpodoxime proxetil, cefprozil, Cefroxadine, cefsulodin, Hydrochloride, Bezafibrate, bFGF inhibitor, Bialamicol Ceftazidime, cefteram, ceftibuten, Ceftizoxime Sodium, Hydrochloride, Biapenem, Bicalutamide, Biciifadine Hydro ceftriaxone, Cefuroxime, celastrol, celikalim, celiprolol. chloride, Biclodil Hydrochloride, Bidisomide, bifemelane, cepacidine A, Cephacetrile Sodium, Cephalexin, Cepha Bifonazole, bimakalim, bimethyl, Bindarit, Biniramycin, 55 loglycin, Cephaloridine, Cephalothin Sodium, Cephapirin binospirone, bioxalomycin alpha2, Bipenamol Hydrochlo Sodium, Cephradine, cericlamine, cerivastatin, Ceronapril, ride, Biperiden, Biphenamine Hydrochloride, biriperone, certoparin sodium, Ceruletide, Cetabon Sodium, Cetalko bisantrene, bisaramil, bisaziridinylspermine, bis-benzimida nium Chloride, Cetamolol Hydrochloride, cetiedil, cetirizine, Zole A, bis-benzimidazole B, bisnafide, Bisobrin Lactate, Cetophenicol, Cetraxate Hydrochloride, cetrorelix, Cetylpy Bisoprolol, Bispyrithione Magsulfex, bistramide D, bistra 60 ridinium Chloride, Chenodiol, Chlophedianol Hydrochlo mide K, bistratene A, Bithionolate Sodium, Bitolterol Mesy ride, Chloral Betaine, Chlorambucil, Chloramphenicol, late, Bivalirudin, Bizelesin, Bleomycin Sulfate, Bolandiol Chlordantoin, Chlordiazepoxide, Chlorhexidine Gluconate, Dipropionate, Bolasterone, Boldenone Undecylenate, bol chlorine, Chlormadinone Acetate, chloroorienticin A, Chlo dine, Bolenol, Bolmantalate, bopindolol, Bosentan, Boxi roprocaine Hydrochloride, Chloropropamide, Chloroquine, dine, brefeldin, breflate, Brequinar Sodium, Bretazenil, 65 chloroquinoxaline sulfonamide, Chlorothiazide, Chlorotria Bretylium Tosylate, Brifentanil Hydrochloride, brimonidine, nisene, Chloroxine, Chloroxylenol, Chlorphenesin Carbam Brinolase, Brocresine, Brocrinat, Brofoxine, Bromadiolone ate, chlorpheniramine Maleate, Chlorpromazine, Chlorpro US 8,263,125 B2 53 54 pamide, Chlorprothixene, Chlortetracycline Bisulfate, darsidomine, Daunorubicin Hydrochloride, Dazadrol Male Chlorthalidone, ChlorZoxazone, Cholestyramine Resin, ate, Dazepinil Hydrochloride, Dazmegrel, Dazopride Fuma Chromonar Hydrochloride, cibenzoline, cicaprost, Ciclafrine rate, Dazoxiben Hydrochloride, Debrisoquin Sulfate, Decit Hydrochloride, Ciclazindol, ciclesonide, cicletanine, Ciclo abine, deferiprone, deflazacort, Dehydrocholic Acid, pirox, Cicloprofen, cicloprolol, Cidofovir, Cidoxepin Hydro dehydrodidemnin B, Dehydroepiandrosterone, delapril, chloride, Cifenline, Ciglitazone, Ciladopa Hydrochloride, Delapril Hydrochloride, Delavirdine Mesylate, delequamine, cilansetron, Cilastatin Sodium, Cilazapril, cilnidipine, Cilo delfaprazine, Delmadinone Acetate, delmopinol, delphini bamine Mesylate, cilobradine, Cillofungin, ciloStaZol. din, Demecarium Bromide, Demeclocycline, Demecycline, Cimaterol, Cimetidine, cimetropium bromide, Cinalukast, Demoxepam, Denofungin, deoxypyridinoline, Depakote, Cinanserin Hydrochloride, Cinepazet Maleate, Cinflumide, 10 deprodone, Deprostil, depsidomycin, deramciclane, derma Cingestol, cinitapride, Cinnamedrine, Cinnarizine, cino tan sulfate, Desciclovir, Descinolone Acetonide, Desflurane, lazepam, Cinoxacin, Cinperene, Cinromide, CintaZone, Cin Desipramine Hydrochloride, desirudin, Deslanoside, triamide, Cioteronel, Cipamfylline, Ciprefadol Succinate, deslorelin, desmopressin, desogestrel, Desonide. Des Ciprocinonide, Ciprofibrate, Ciprofloxacin, ciprostene, Cira Oximetasone, desoxoamiodarone, Desoxycorticosterone madol, Cirolemycin, cisapride, cisatracurium besylate, 15 Acetate, detajmium bitartrate, Deterenol Hydrochloride, Cisconazole, Cisplatin, cis-porphyrin, cistinexine, citalo Detirelix Acetate, Devazepide, Dexamethasone, Dexamisole, pram, Citenamide, citicoline, citreamicin alpha, cladribine, Dexbrompheniramine Maleate, Dexchlorpheniramine Male Clamoxyquin Hydrochloride, Clarithromycin, clausena ate, Dexclamol Hydrochloride, Dexetimide, Dexfenflu mide, Clavulanate Potassium, Clazolam, Clazolimine, clebo ramine Hydrochloride, dexifosfamide, Deximafen, Dexi pride, Clemastine, Clentiazem Maleate, Clidinium Bromide, vacaine, dexketoprofen, dexloxiglumide, Dexmedetomidine, clinafloxacin, Clindamycin, Clioquinol, Clioxanide, Clipro Dexormaplatin, Dexoxadrol Hydrochloride, Dexpanthenol, fen, clobazam, Clobetasol Propionate, Clobetasone Butyrate, Dexpemedolac, Dexpropranolol Hydrochloride, Dexrazox Clocortolone Acetate, Clodanolene, Clodazon Hydrochlo ane, dexSotalol, dextrin 2-sulphate, Dextroamphetamine, ride, clodronic acid, Clofazimine, Clofibrate, Clofilium Phos Dextromethorphan, Dextrorphan Hydrochloride, Dextrothy phate, Clogestone Acetate, Clomacran Phosphate, Clomege 25 roxine Sodium, dexVerapamil, DeZaguanine, dezinamide, stone Acetate, Clometherone, clomethiazole, clomifene dezocine, Diacetolol Hydrochloride, Diamocaine Cycla analogues, Clominorex, Clomiphene, Clomipramine Hydro mate, Diapamide, Diatrizoate Meglumine, Diatrizoic Acid, chloride, Clonazepam, Clonidine, Clonitrate, Clonixeril, Diaveridine, Diazepam, Diaziquone, Diazoxide, Dibenzepin Clonixin, Clopamide, Clopenthixol, Cloperidone Hydro Hydrochloride, Dibenzothiophene, Dibucaine, Dichlorvos, chloride, clopidogrel, Clopimozide, Clopipazan Mesylate, 30 Dichloralphenazone, Dichlorphenamide, Dicirenone, Clopirac, Cloprednol, Cloprostenol Sodium, Clorazepate Diclofenac Sodium, Dicloxacillin, dicranin, Dicumarol, Dipotassium, Clorethate, Clorexolone, Cloroperone Hydro Dicyclomine Hydrochloride, Didanosine, didemnin B, didoc, chloride, Clorprenaline Hydrochloride, Clorsulon, Clorter Dienestrol, dienogest, Diethylcarbamazine Citrate, diethyl mine Hydrochloride, Closantel, Closiramine Aceturate, homospermine, diethylnorspermine, Diethylpropion Hydro Clothiapine, Clothixamide Maleate Cloticasone Propionate, 35 chloride, Diethylstilbestrol. Difenoximide Hydrochloride, Clotrimazole, Cloxacillin Benzathine, Cloxyquin, Clozap Difenoxin, Diflorasone Diacetate. Difloxacin Hydrochloride, ine, Cocaine, Coccidioidin, Codeine, Codoxime, Colchicine, Difluanine Hydrochloride, Diflucortolone. Diflumidone colestimide, Colestipol Hydrochloride, Colestolone, Col Sodium, Diflunisal, Difluprednate. Diftalone, Digitalis, Digi forsin, Colfosceril Palmitate, Colistimethate Sodium, Colis toxin, Digoxin, Dihexyverine Hydrochloride, dihydrexidine, tin Sulfate, collismycin A, collismycin B, Colterol Mesylate, 40 dihydro-5-azacytidine, Dihydrocodeine Bitartrate, Dihydro combretastatin A4, combretastatin analogue, complestatin, ergotamine Mesylate, Dihydroestosterone, Dihydrostrepto conagenin, Conorphone Hydrochloride, contignasterol, con mycin Sulfate, Dihydrotachysterol, dihydrotaxol. Dilantin, tortrostatin, Cormethasone Acetate, Corticorelin Ovine Tri Dilevalol Hydrochloride, Diltiazem Hydrochloride, Dime flutate, Corticotropin, Cortisone Acetate, Cortivazol, Corto fadane, Dimefline Hydrochloride, Dimenhydrinate, Dimer doxone, cosalane, costatolide, Cosyntropin, cotinine, 45 caprol, Dimethadione, Dimethindene Maleate, Dimethister Coumadin, Coumermycin, crambescidin 816, Crilvastatin, one, dimethyl prostaglandin Al, Dimethyl Sulfoxide, crisinatol, Cromitrile Sodium, Cromolyn Sodium, Crotami dimethylhomospermine, dimiracetam, Dimoxamine Hydro ton, cryptophycin 8, cucumariosid Cuprimyxin, curacin A, chloride, Dinoprost, Dinoprostone, Dioxadrol Hydrochlo curdlan Sulfate, curiosin, Cyclacillin, Cyclazocine, cyclazo ride, dioxamycin, Diphenhydramine Citrate, Diphenidol, cin, cyclic HPMPC, Cyclindole, Cycliramine Maleate, 50 Diphenoxylate Hydrochloride, diphenyl spiromustine, Cyclizine, Cyclobendazole, cyclobenzaprine, cyclobut A, Dipivefrin Hydrochloride, Dipivefrin, dipliencyprone, cyclobut G, cyclocapron, Cycloguanil Pamoate, Cyclohex diprafenone, dipropylnorspermine, Dipyridamole, Dipy imide, cyclopentanthraquinones, Cyclopenthiazide, Cyclo rithione, Dipyrone, dirithromycin, discodermolide, Disob pentolate Hydrochloride, Cyclophenazine Hydrochloride, utamide, Disofenin, Disopyramide, Disoxaril, disulfiram, Cyclophosphamide, cycloplatin, Cyclopropane, Cycloserine, 55 Ditekiren, Divalproex Sodium, Dizocilpine Maleate, Dob cycloSon, Cyclosporin, cyclothialidine, Cyclothiazide, utamine, docarpamine, Docebenone, Docetaxel, Docona cyclothiazomycin, Cyheptamide, cypemycin, Cypenamine Zole, docosanol, dolfetilide, dolasetron, Ebastine, ebiratide, Hydrochloride, Cyprazepam, Cyproheptadine Hydrochlo ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdyster ride, Cyprolidol Hydrochloride, cyproterone, Cyproximide, one, echicetin, echistatin, Echothiophate Iodide, Eclanamine Cysteamine, Cysteine Hydrochloride, Cystine, Cytarabine, 60 Maleate, EclaZolast, ecomustine, Econazole, ecteinascidin Cytarabine Hydrochloride, cytarabine Ocfosfate, cytochala 722, edaravone, Edatrexate, edelfosine, Edifolone Acetate, sin B, cytolytic factor, cytostatin, Dacarbazine, dacliximab, edobacomab, Edoxudine, edrecolomab, Edrophonium Chlo dactimicin, Dactinomycin, daidzein, Daledalin Tosylate, dal ride, edroxyprogesteone Acetate, efegatran, eflornithine, fopristin, Dalteparin Sodium, Daltroban, Dalvastatin, danap efonidipine, egualcen, Elantrine, eleatonin, elemene, eletrip aroid, DanaZol, Dantrolene, daphlnodorin A, dapiprazole, 65 tan, elgodipine, eliprodil, Elsamitrucin, eltenac, Elucaine, dapitant, Dapoxetine Hydrochloride, Dapsone, Daptomycin, emalkalim, emedastine, Emetine Hydrochloride, emiglitate, DarglitaZone Sodium, darifenacin, darlucin A, Darodipine, Emilium Tosylate, emitefur, emoctakin, Enadoline Hydro US 8,263,125 B2 55 56 chloride, enalapril, Enalaprilat, Enalkiren, enaZadrem, hydrochloride, Fluorodopa F 18, Fluorometholone, Fluorou Encyprate, Endralazine Mesylate, Endrysone, Enflurane, racil, Fluotracer Hydrochloride, Fluoxetine, Fluoxymester englitaZone, Enilconazole, Enisoprost, Enlimomab, Enlopl one, fluparoxan, Fluperamide, Fluperolone Acetate, atin, Enofelast, Enolicam Sodium, Enoxacin, enoxacin, Fluphenazine Decanoate, flupirtine, Fluprednisolone, Flup enoxaparin Sodium, Enoxaparin Sodium, Enoximone, roquaZone, Fluprostenol Sodium, FluquaZone, Fluradoline Empiroline Phosphate, Enprofylline, Enpromate, entacapone, Hydrochloride, Flurandrenolide, Flurazepam Hydrochloride, enterostatin, Enviradene, Enviroxime, Ephedrine, Epicillin, Flurbiprofen, Fluretofen, flurithromycin, Flurocitabine, Epimestrol, Epinephrine, Epinephryl Borate, Epipropidine, Flurofamide, Flurogestone Acetate, Flurothyl, Fluroxene, Epirizole, epirubicin, Epitetracycline Hydrochloride, Epithi Fluspiperone, Fluspirilene, Fluticasone Propionate, flutrima azide, Epoetin Alfa, Epoetin Beta, Epoprostenol, Epopros 10 Zole, Flutroline, fluvastatin, Fluvastatin Sodium, fluvoxam tenol Sodium, epoxymeXrenone, epristeride, Eprosartan, ine, Fluzinamide. Folic Acid, Follicle regulatory protein, Fol eptastigmine, equilenin, Equilin, ErbuloZole, erdosteine, liculostatin, Fomepizole, Fonazine Mesylate, forasartan, Ergoloid Mesylates, Ergonovine Maleate, Ergotamine Tar forfenimex, forfenirmex, formestane, Formocortal, formot trate, ersentilide, Ersofermin, erythritol, Erythrityl Tetrani erol, Fosarilate, Fosazepam, Foscarnet Sodium, fosfomycin, trate, Erythromycin, Esmolol Hydrochloride, Esorubicin 15 Fosfonet Sodium, fosinopril, Fosinoprilat, fosphenytoin, Hydrochloride, Esprocquin Hydrochloride, Estazolam, Estra Fosquidone, Fostedil, fostriecin, fotemustine, Fuchsin, Basic, diol, Estramustine, estramustine analogue, EstraZinol Hydro Fumoxicillin, Fungimycin, Furaprofen, Furazolidone. Fura bromide, Estriol, Estrofurate, estrogen agonists, estrogen Zolium Chloride. Furegrelate Sodium, Furobufen, Furoda antagonists, Estrogens, Conjugated Estrogens, Esterified Zole, Furosemide, Fusidate Sodium, Fusidic Acid, gabapen Estrone, Estropipate, esuprone, Etafedrine Hydrochloride, tin, Gadobenate Dimeglumine, gadobenic acid, gadobutrol, Etanidazole, etanterol, Etarotene, Etazolate Hydrochloride, Gadodiamide, gadolinium texaphyrin, Gadopentetate Eterobarb, ethacizin, Ethacrynate Sodium, Ethacrynic Acid, Dimegiumine, gadoteric acid, Gadoteridol, Gadoverseta Ethambutol Hydrochloride, Ethamivan, Ethanolamine Ole mide, galantamine, galdansetron, Galdansetron Hydrochlo ate, Ethehlorvynol, Ether, Ethinyl estradiol, Ethiodized Oil, ride, Gallamine Triethiodide, gallium nitrate, gallopamil, Ethionamide, Ethonam Nitrate, Ethopropazine Hydrochlo 25 galocitabine, Gamfexine, gamolenic acid, Ganciclovir, ride, Ethosuximide, Ethotoin, Ethoxazene Hydrochloride, ganirelix, gelatinase inhibitors, Gemcadiol, Gemcitabine, Ethybenztropine, Ethyl Chloride, Ethyl Dibunate, Ethylestre Gemeprost, Gemfibrozil, Gentamicin Sulfate, Gentian Vio nol, Ethynodiol, Ethynerone, Ethynodiol Diacetate, let, gepirone, Gestaclone, Gestodene, Gestonorone Caproate, Etibendazole, Etidocaine, Etidronate Disodium, Etidronic Gestrinone, GeVotroline Hydrochloride, girisopam, glaspi Acid, Etifenin, Etintidine Hydrochloride, etizolam, Etodolac, 30 mod, glaucocalyxin A, Glemanserin, Gliamilide, Glibornu Etofenamate, Etoformin Hydrochloride, Etomidate, ride, Glicetanile Sodium, Gliflumide, Glimepiride, Glipizide, Etonogestrel, Etoperidone Hydrochloride, Etoposide, Eto Gloximonam, Glucagon, glutapyrone, glutathione inhibitors, prine, Etoxadrol Hydrochloride, Etozolin, etrabamine, Etreti Glutethimide, Glyburide, glycophene, glycopril, Glycopyr nate, Etryptamine Acetate, Eucatropine Hydrochloride, rolate, Glyhexamide, Glymidine Sodium, Glyoctamide, Gly Eugenol, Euprotin Hydrochloride, eveminomicin, Exameta 35 paramide, Gold Au 198, Gonadoctrinins, Gonadorelin, Gona Zime, examolin, Exaprolol Hydrochloride, exemestane, dotropins, Goserelin, Gramicidin, Granisetron, fadrozole, faerieflungin, Famciclovir, Famotidine, Fampri grepafloxacin, Griseofulvin, Guaiapate, Guaithylline, Gua dine, fantofarone, Fantridone Hydrochloride, faropenem, nabenz, Guanabenz Acetate, Guanadrel Sulfate, Guancydine, fasidotril, fasudil, fazarabine, fedotozine, felbamate, Felbi Guanethidine Monosulfate, Guanfacine Hydrochloride, nac, Felodipine, Felypressin, Fenalamide, Fenarole, Fen 40 Guanisoquin Sulfate, Guanoclor Sulfate, Guanoctine Hydro bendazole, Fenbufen, Fencibutirol, Fenclofenac, Fenclonine, chloride, Guanoxabenz, Guanoxan Sulfate, Guanoxyfen Sul Fenclor, Fendosal, Fenestrel, Fenethylline Hydrochloride, fate, Gusperimus Trihydrochloride, Halazepam, Halcinon Fenfluramine Hydrochloride, Fengabine, Fenimide, Fen ide, halichondrin B. Halobetasol Propionate, halofantrine, isorex, Fenmetozole Hydrochloride, Fenmetramide, Halofantrine Hydrochloride, Halofenate, Halofuginone Fenobam, Fenoctimine Sulfate, fenofibrate, fenoldopam, 45 Hydrobromide, halomonth, Halopemide, Haloperidol, halo Fenoprofen, Fenoterol, Fenpipalone, Fenprinast Hydrochlo predone, Haloprogesterone, Haloprogin, Halothane, ride, Fenprostalene, Fenguizone, fenretinide, fenspiride, Fen Halduinols, Hamycin, Han memopausal gonadotropins, tanyl Citrate, Fentiazac, Fenticlor, fenticonazole, Fenyripol hatomamicin, hatomarubigin A, hatomarubigin B, hatomaru Hydrochloride, fepradinol, ferpifosate sodium, ferristene, bigin C, hatomarubigin D. Heparin Sodium, hepsulfam, ferrixan, Ferrous Sulfate, Dried, Ferumoxides, ferumoxsil, 50 heregulin, Hetacillin, Heteronium Bromide, Hexachlo Fetoxylate Hydrochloride, fexofenadine, Fezolamine Fuma rophene:Hydrogen Peroxide, Hexafluorenium Bromide, hex rate, Fiacitabine, Fialuridine, Fibrinogen/125, filgrastim, Fil amethylene bisacetamide, Hexedine, Hexobendine, Hexo ipin, finasteride, Flavodilol Maleate, flavopiridol, Flavoxate prenaline Sulfate, Hexylresorcinol, Histamine Phosphate, Hydrochloride, Flazalone, flecainide, flerobuterol, Fleroxa Histidine. Histoplasmin, Histrelin, Homatropine Hydrobro cin, flesinoxan, Flestolol Sulfate, Fletazepam, flezelastine, 55 mide, Hoquizil Hydrochloride, Human chorionic gonadotro flobufen, Floctafenine, flomoxef, Flordipine, florfenicol, flo pin, Hycanthone, Hydralazine Hydrochloride, Hydralazine rifenine, flosatidil, Flosequinan, Floxacillin, Floxuridine, flu Polistirex, Hydrochlorothiazide, Hydrocodone Bitartrate, asterone, Fluazacort, Flubanilate Hydrochloride, Flubenda Hydrocortisone, Hydroflumethiazide, Hydromorphone Zole, Flucindole, Flucloronide, Fluconazole, Flucytosine, Hydrochloride, Hydroxyamphetamine Hydrobromide, Fludalanine, Fludarabine Phosphate, Fludazonium Chloride, 60 Hydroxychloroquine Sulfate, Hydroxyphenamate, Hydrox Fludeoxyglucose F 18, Fludorex, Fludrocortisone Acetate, yprogesterone Caproate, Hydroxyurea, Hydroxy Zine Hydro Flufenamic Acid, Flufenisal, Flumazenil, flumecinol, Flume chloride, Hymecromone, Hyoscyamine, hypericin, Ibafloxa quine, Flumeridone, Flumethasone, Flumetramide, Flumeza cin, ibandronic acid, ibogaine, Ibopamine, ibudilast, pine, Fluminorex, Flumizole, Flumoxonide, flunarizine, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icatibant Acetate, Flunidazole, Flunisolide, Flunitrazepam, Flunixin, fluocal 65 Ichthammol, Icotidine, idarubicin, idoxifene, Idoxuridine, citriol, Fluocinolone Acetonide, Fluocinonide, Fluocortin idramantone, Iomefloxacin, Iesopitron, Ifetroban, Ifosfa Butyl, Fluocortolone, Fluorescein, fluorodaunorunicin mide, Ilepeimide, ilimaquinone, ilmofosine, ilomastat, US 8,263,125 B2 57 58 Ilonidap, illoperidone, iloprost, Imafen Hydrochloride, Ima ride, Lexipafant, Lexithromycin, liarozole, LibenZapril, Zodan Hydrochloride, imidapril, imidazenil, imidazoacri Lidamidine Hydrochloride, Lidocaine, Lidofenin, Lidofla dones, Imidecyl Iodine, Imidocarb Hydrochloride, Imidoline Zine, Lifarizine, Lifibrate, Lifibrol, Linarotene, Lincomycin, Hydrochloride. Imidurea, Imiloxan Hydrochloride, Imi linear polyamine analogue, Linogliride, Linopirdine, penem, Imipramine Hydrochloride, imiquimod, immuno linotroban, linsidomine, lintitript, lintopride, Liothyronine I stimulant peptides, Impromidine Hydrochloride, India 125, liothyronine sodium, Liotrix, lirexapride, lisinopril, lis crinone, Indapamide, Indecainide Hydrochloride, soclinamide 7, Lixazinone Sulfate, lobaplatin, Lobenzarit Indeloxazine Hydrochloride, Indigotindisulfonate Sodium, Sodium, Lobucavir, Lodelaben, Lodoxamide, Lofemizole indinavir, Indocyanine Green, Indolapril Hydrochloride, Hydrochloride, Lofentanil Oxalate, Lofepramine Hydrochlo Indolidan, indometacin, Indomethacin Sodium, Indoprofen, 10 ride, Lofexidine Hydrochloride, lombricine, Lomefloxacin, indoramin, Indorenate Hydrochloride, Indoxole, Indriline lomerizine, Lometraline Hydrochloride, lometrexol, Lomo Hydrochloride, inocoterone, inogatran, inolimomab, Inositol fungin, Lomoxicam, Lomustine, Lonapalene, lonazolac, Niacinate, Insulin, interferons, interleukins, IntraZone, Intrip lonidamine, Loperamide Hydrochloride, loracarbef, tyline Hydrochloride, iobenguane, Iobenzamic Acid, iobitri Lorajmine Hydrochloride, loratadine, Lorazepam, Lorbam dol, Iocarmate Meglumine, Iocarmic Acid, Iocetamic Acid, 15 ate, Lorcainide Hydrochloride, Loreclezole, Loreinadol, lor Iodamide, Iodine, Iodipamide Meglumine, Iodixanol, glumide, Lorimetazepam, Lornoxicam, lornoxicam, Lorta iodoamiloride, Iodoantipyrine I 131, Iodocholesterol I 131, lamine, LorZafone, losartan, losigamone, losoxantrone, iododoxorubicin, Iodohippurate Sodium I 131, Iodopyracet I Losulazine Hydrochloride, loteprednol, lovastatin, loviride, 125. Iodoquinol, Iodoxamate Meglumine, Iodoxamic Acid, Loxapine, Loxoribine, lubeluzole, Lucanthone Hydrochlo Ioglicic Acid, Iofetamine Hydrochloride I 123, iofratol, ride, Lufironil, Lurosetron Mesylate, lurtotecan, luteinizing Ioglucol, Ioglucomide, Ioglycamic Acid, Iogulamide, hormone, lutetium, Lutrelin Acetate, luzindole, Lyapolate Iohexol, iomeprol, Iomethin I Iopronic Acid, iopromide, Sodium, Lycetamine, lydicamycin, Lydimycin, Lynestrenol, Iopronic Acid, Iopydol, Iopy done, iopydol, Iosefamic Acid, Lypressin, Lysine, lysofylline, lysostaphin, lytic peptides, Ioseric Acid, IoSulamide Meglumine, IoSumetic Acid, Iota Maduramicin, Mafenide, magainin 2 amide, Magnesium Sul, Iotetric Acid, Iothalamate Sodium, Iothalamic Acid, iot 25 Salicylate, Magnesium Sulfate, magnolol, maitansine, Male riside, Iotrolan, Iotroxic Acid, Iotyrosine 1 131, Ioversol, thamer, mallotochromene, mallotojaponin, Malotilate, malo Ioxagiate Sodium, Ioxaglate Meglumine, Ioxaglic Acid, iox tilate, mangafodipir, manidipine, maniwamycin A, Mannitol, ilan, Ioxotrizoic Acid, ipazilide, ipenoxazone, ipidacrine, mannostatin A, manumycin E, manumycin F. mapinastine, Ipodate Calcium, ipomeanol, 4-, Ipratropium Bromide, ipri Maprotiline, marimastat, Martek 8708, Martek 92211, Maso flavone, Iprindole, Iprofenin, Ipronidazole, Iproplatin, IproX 30 procol, maspin, massetolide, matrilysin inhibitors, May amine Hydrochloride, ipsapirone, irbesartan, irinotecan, tansine, Mazapertine Succiniate, Mazindol, Mebendazole, irloxacin, iroplact, irsogladine, Irtemazole, isalsteine, Mebeverine Hydrochloride, Mebrofenin, Mebutamate, Isamoxole, isbogrel, Isepamicin, isobengaZole, Isobutamben, Mecamylamine Hydrochloride, Mechlorethamine Hydro Isocarboxazid, Isoconazole, Isoetharine, isofloxythepin, chloride, Meclocycline, Meclofenamate Sodium, Mecloqua Isoflupredone Acetate, Isoflurane, Isoflurophate, isohomo 35 lone, Meclorisone Dibutyrate, Medazepam Hydrochloride, halicondrin B, Isoleucine, Isomazole Hydrochloride, Isomy Medorinone, Medrogestone, Medroxalol, Medroxyprogest lamine Hydrochloride, Isoniazid, Isopropamide Iodide, Iso erone, Medrysone, Meclizine Hydrochloride, Mefenamic propyl Alcohol, isopropyl unoprostone, Isoproterenol Acid, Mefenidil, Mefenorex Hydrochloride, Mefexamide, Hydrochloride, Isosorbide, Isosorbide Mononitrate, Iso Mefloquine Hydrochloride, Mefruside, Megalocin Potas tiquimide, Isotretinoin, Isoxepac, Isoxicam, ISOXSuprine 40 sium Phosphate, Megestrol Acetate, Meglumine, Meglutol, Hydrochloride, isradipine, itameline, itasetron, ItaZigrel, ito Melengestrol Acetate, Melitracen Hydrochloride, Mel pride, Itraconazole, Ivermectin, jasplakinolide, Josamycin, phalan, Memotine Hydrochloride, Menabitan Hydrochlo kahalalide F, Kalafungin, Kanamycin Sulfate, Ketamine ride, Menoctone, menogaril, Menotropins, Meobentine Sul Hydrochloride, Ketanserin, Ketazocine, Ketazolam, fate, Mepartricin, Mepenzolate Bromide, Meperidine Kethoxal, Ketipramine Fumarate, Ketoconazole, Ketoprofen, 45 Hydrochloride, Mephentermine Sulfate, Mephenyloin, Ketorfanol, ketorolac, Ketotifen Fumarate, Kitasamycin, Mephobarbital, Mepivacaine Hydrochloride, Meprobamate, Labetalol Hydrochloride, Lacidipine, lacidipine, lactitol, lac Meptazinol Hydrochloride, Mequidox, Meralein Sodium, tivicin, laennec, lafutidine, lamellarin-N triacetate, lamifiban, merbarone, Mercaptopurine, Mercufenol Chloride, Mercury, Lamivudine, Lamotrigine, lanoconazole, Lanoxin, lan Ammoniated, Merisoprol Hg 197, Meropenem, Mesalamine, perisone, lanreotide, Lansoprazole, latanoprost, lateritin, lau 50 Meseclazone, Mesoridazine, Mesterolone, Mestranol, Mesu rocapram, Lauryl Isoquinolinium Bromide, LaVoltidine Suc prine Hydrochloride, Metalon Hydrochloride, Metaproter cinate, lazabemide, Lecimibide, lenamycin, lemildipine, enol Polistirex, Metaraminol Bitartrate, Metaxalone, leminoprazole, lenercept, Leniquinsin, lenograstim, Lemper Meteneprost, meterelin, Metformin, Methacholine Chloride, one, lentinan Sulfate, leptin, leptolstatin, lercanidipine, Ler Methacycline, Methadone Hydrochloride, MethadylAcetate, gotrile, lerisetron, Letimide Hydrochloride, letraZuril, letro 55 Methalthiazide, Methamphetamine Hydrochloride, Meth Zole, Leucine, leucomycin, Leuprolide Acetate, leuprolide-- aqualone, Methazolamide, Methdilazine, Methenamine, estrogen-progesterone, leuprorelin, Levamfetamine Methenolone Acetate, Methetoin, Methicillin Sodium, Succinate, levamisole, Levdobutamine Lactobionate, Methimazole, methioninase, Methionine, MethisaZone, Leveromakalim, levetiracetam, Levocycloserine, levobetax Methixene Hydrochloride, Methocarbamol, Methohexital olol, levobunolol, levobupivacaine, levocabastine, levocar 60 Sodium, Methopholine, Methotrexate, Methotrimeprazine, nitine, Levodopa, levodropropizine, levofloxacin, Levofural methoxadone, Methoxyflurane, Methsuximide, Methy tadone, Levoleucovorin Calcium, Levomethadyl Acetate, clothiazide, Methyl 10 Palmoxirate, Methylatropine Nitrate, Levomethadyl Acetate Hydrochloride, levomoprolol, Levo Methylbenzethonium Chloride, Methyldopa, Methyldopate nantradol Hydrochloride, Levonordefrin, Levonorgestrel, Hydrochloride, Methylene Blue, Methylergonovine Maleate, Levopropoxyphene Napsylate, Levopropylcillin Potassium, 65 methylhistamine, R-alpha, methylinosine monophosphate, levormeloxifene, Levorphanol Tartrate, levosimendan, levo Methylphenidate Hydrochloride, Methylprednisolone, Sulpiride, Levothyroxine Sodium, Levoxadrol Hydrochlo Methyltestosterone, Ethynodiol Diacelate, Methysergide, US 8,263,125 B2 59 60 Methysergide Maleate, Metiamide, Metiapine, Metioprim, antioxidant, nitrullyn, Nivazol, Nivinedone Sodium, Nizati metipamide, Metipranolol, Metizoline Hydrochloride, Met dine, Noberastine, Nocodazole, Nogalamycin, Nolinium kephamid Acetate, metoclopramide, Metocurine Iodide, Bromide, Nomifensine Maleate, Noracymethadol Hydro Metogest, Metolazone, Metopimazine, Metoprin, Meto chloride, Norbolethone, Norepinephrine Bitartrate, Nore prolol, Metoquinone, metrifonate, Metrizamide, Metrizoate thindrone, Norethynodrel, Norfloxacin, Norflurane, Norges Sodium, Metronidazole, Meturedepa, Metyrapone, Mety timate, Norgestomet, Norgestrel, Nortriptyline rosine, Mexiletine Hydrochloride, Mexrenoate Potassium, Hydrochloride, Noscapine, Novobiocin Sodium, N-substi Mezlocillin, amfonelic Acid, Mianserin Hydrochloride, tuted benzaimides, Nufenoxole, Nylestriol, Nystatin, mibefradil, Mibefradil Dihydrochloride, Mibolerone, mich O6-benzylguanine, Obidoxime Chloride, Ocaperidone, ellamine B, Miconazole, microcolin A, Midaflur, Midazolam 10 Ocfentanil Hydrochloride, Ocinaplon, Octanoic Acid, Hydrochloride, midodrine, mifepristone, Mifobate, miglitol, Octazamide, Octenidine Hydrochloride, Octodrine, Oct millacemide, milameline, mildronate, Milenperone, Miliper reotide, Octriptyline Phosphate. Ofloxacin, Oformine, oki tine, milnacipran, Milrinone, miltefosine, Mimbane Hydro cenone, Olanzapine, oligonucleotides, olopatadine, chloride, minaprine, Minaxolone, Minocromil, Minocycline, olprinone, olsalazine, Olsalazine Sodium, Olvanil, omepra Minoxidil, Mioflazine Hydrochloride, miokamycin, mipra 15 Zole, onapristone, ondansetron, Ontazolast, Oocyte matura goside, mirfentanil, mirimostim, Mirincamycin Hydrochlo tion inhibitor, Opipramol Hydrochloride, oracin, Orconazole ride, Mirisetron Maleate, Mirtazapine, mismatched double Nitrate, Orgotein, Orlislat, Ormaplatin, Ormetoprim, Ornida stranded RNA, Misonidazole, Misoprostol, Mitindomide, Zole, Orpanoxin, Orphenadrine Citrate, osaterone, otenZe Mitocarcin, Mitocromin, Mitogillin, mitoguaZone, mitolac pad, Oxacillin Sodium, Oxagrelate, Oxaliplatin, OXamarin tol, Mitomalcin, Mitomycin, mitonafide, Mitosper, Mitotane, Hydrochloride, oxamisole, Oxamniquine, Oxandrolone, mitoxantrone, mivacurium chloride, mivaZerol, mixanpril, Oxantel Pamoate, Oxaprotiline Hydrochloride, Oxaprozin, Mixidine, mizolastine, mizoribine, Moclobemide, modafinil, Oxarbazole, Oxatomide, oxaunomycin, Oxazepam, oXcarba Modalina Sulfate, Modecainide, moexipril, mofarotene, Zepine, Oxendolone, Oxethazaine, Oxetorone Fumarate, Mofegiline Hydrochloride, mofezolac, molgramostim, Moli Oxfendazole, Oxfenicine, Oxibendazole, oxiconazole, Oxi naZone, Molindone Hydrochloride, Molsidomine, mometa 25 dopamine, Oxidronic Acid, Oxifungin Hydrochloride, sone, Monatepil Maleate, Monensin, Monoctanoin, Mon Oxilorphan, Oximonam, Oximonam Sodium, Oxiperomide, telukast Sodium, montirelin, mopidamol, moracizine, oxiracetam, Oxiramide, Oxisuran, Oxmetidine Hydrochlo Morantel Tartrate, Moricizine, Morniflumate, Morphine Sul ride, oxodipine, Oxogestone Phenpropionate, Oxolinic Acid, fate, Morrhuate Sodium, mosapramine, mosapride, motilide, Oxprenolol Hydrochloride, Oxtriphylline, Oxybutynin Chlo Motretinide, Moxalactam Disodium, Moxazocine, moxira 30 ride, Oxychlorosene, Oxycodone, Oxymetazoline Hydro prine, Moxinidazole, moXonidine, Mumps SkinTest Antigen, chloride, Oxymetholone, Oxymorphone Hydrochloride, mustard anticancer agent, Muzolimine, mycaperoxide B, Oxypertine, Oxyphenbutazone, Oxypurinol, Oxytetracy Mycophenolic Acid, myriaporone, Nabazenil, Nabilone, cline, Oxytocin, OZagrel, Ozolinone, Paclitaxel, palauamine, Nabitan Hydrochloride, Naboctate Hydrochloride, Nabume Paldimycin, palinavir, palmitoylrhizoxin, Palmoxirate tone, N-acetyldinaline, Nadide, nadifloxacin, Nadolol. 35 Sodium, pamaqueside, Pamatolol Sulfate, pamicogrel, Pam nadroparin calcium, nafadotride, nafamoStat, nafarelin, idronate Disodium, pamidronic acid, Panadiplon, pan Nafcillin Sodium, Nafenopin, Nafimidone Hydrochloride, amesine, panaxytriol, Pancopride, Pancuronium Bromide, Naflocort, Nafomine Maleate, Nafoxidine Hydrochloride, panipenem, pannorin, panomifene, pantethine, pantoprazole, Nafronyl Oxalate, Naftifine Hydrochloride, naftopidil, nagli Papaverine Hydrochloride, parabactin, Parachlorophenol, van, nagrestip, Nalbuphine Hydrochloride, Nalidixate 40 Paraldehyde, Paramethasone Acetate, Paranyline Hydrochlo Sodium, Nalidixic Acid, nalmefene, Nalmexone Hydrochlo ride, Parapenzolate Bromide, Pararosaniline Pamoate, Par ride, naloxone-pentazocine, Naltrexone, NamoXyrate, Nan bendazole, Parconazole Hydrochloride, Paregorico, Parep drolone Phenpropionate, Nantradol Hydrochloride, Napacta tide Sulfate, Pargyline Hydrochloride, parnaparin sodium, dine Hydrochloride, napadisilate, Napamezole Paromomycin Sulfate, Paroxetine, parthenolide, Partricin, Hydrochloride, napavin, Naphazoline Hydrochloride, naph 45 Paucimycin, paZelliptine, PaZinaclone, PaZoxide, paZufloxa terpin, Naproxen, NaproXol, napsagatran, Naranol Hydro cin, pefloxacin, pegaspargase, Pegorgotein, Pelanserin chloride, Narasin, naratriptan, nartograstim, nasaruplase, Hydrochloride, peldesine, Peliomycin, Pelretin, Pelrinone Natamycin, nateplase, Naxagolide Hydrochloride, Nebiv Hydrochloride, Pemedolac, Pemerid Nitrate, pemirolast, olol, Nebramycin, nedaplatin, Nedocromil, Nefazodone Pemoline, Penamecillin, Penbutolol Sulfate, Penciclovir, Hydrochloride, Neflumozide Hydrochloride, Nefopam 50 Penfluridol, Penicillin G BenZathine, Penicillin G Potassium, Hydrochloride, NeleZaprine Maleate, Nemazoline Hydro Penicillin G Procaine, Penicillin G Sodium, Penicillin V, chloride, nemorubicin, Neomycin Palmitate, Neostigmine Penicillin V Benzathine, Penicillin V Hydrabamine, Penicil Bromide, neridronic acid, Netilmicin Sulfate, neutral lin V Potassium, Pentabamate, Pentaerythritol Tetranitrate, endopeptidase, Neutramycin, Nevirapine, Nexeridine pentafuside, pentamidine, pentamorphone, Pentamustine, Hydrochloride, Niacin, Nibroxane, Nicardipine Hydrochlo 55 Pentapiperium Methylsulfate, Pentazocine, Pentetic Acid, ride, Nicergoline, Niclosamide, Nicorandil, Nicotinyl Alco Pentiapine Maleate, pentigetide, Pentisomicin, Pentizidone hol, Nifedipine, Nifirmerone, Nifluridide, Nifuradene, Sodium, Pentobarbital, Pentomone, Pentopril, pentosan, pen Nifuraldezone, Nifuratel, Nifuratrone, Nifurdazil, Nifurim tostatin, Pentoxifylline, Pentrinitrol, pentrozole, Peplomycin ide, Nifurpirinol, Nifurcquinazol, Nifurthiazole, nilutamide, Sulfate, Pepstatin, perflubron, perfosfamide, Perfosfamide, Nilvadipine, Nimazone, Nimodipine, niperotidine, nirav 60 pergolide, Perhexiline Maleate, perillyl alcohol, Perindopril, oline, Niridazole, nisamycin, Nisbuterol Mesylate, nisin, perindoprilat, Perlapine, Permethrin, perospirone, Perphena Nisobamate, Nisoldipine, Nisoxetine, Nisterime Acetate, Zine, Phenacemide, phenaridine, phenazinomycin, Nitarsone, nitazoxanide, nitecapone, Nitrafudam Hydrochlo Phenazopyridine Hydrochloride, Phenbutazone Sodium ride, Nitralamine Hydrochloride, Nitramisole Hydrochlo Glycerate, Phencarbamide, Phencyclidine Hydrochloride, ride, Nitrazepam, Nitrendipine, Nitrocycline, Nitrodan, 65 Phendimetrazine Tartrate, Phenelzine Sulfate, Phenmetra Nitrofurantoin, Nitrofurazone, Nitroglycerin, Nitromersol, zine Hydrochloride, Phenobarbital, Phenoxybenzamine Nitromide, Nitromifene Citrate, Nitrous Oxide, nitroxide Hydrochloride, Phenprocoumon, phenserine, phensuccinal, US 8,263,125 B2 61 62 Phensuximide, Phentermine, Phentermine Hydrochloride, Maleate, Pyrrocaine, Pyrroliphene Hydrochloride, Pyrrolni phentolamine mesylate, Phentoxifylline, Phenyl Aminosali trin, Pyrvinium Pamoate, Quadazocine Mesylate, Quazepam, cylate, phenylacetate, Phenylalanine, phenylalanylketocona Quazinone, QuaZodine, QuaZolast, quetiapine, quiflapon, Zole, Phenylbutazone, Phenylephrine Hydrochloride, Phe quinagolide, Quinaldine Blue, quinapril, Quinaprilat, nylpropanolamine Hydrochloride, Phenylpropanolamine Quinazoline Hydrochloride, Quinbolone, Quinctolate, Quin Polistirex, Phenyramidol Hydrochloride, Phenytoin, phos decamine Acetate, Quindonium Bromide, Quinelorane phatase inhibitors, Physostigmine, picenadol, picibanil, Hydrochloride, Quinestrol, Quinfamide, Quingestanol Picotrin Diolamine, picroliv, picumeterol, pidotimod, Pifar Acetate, Quingestrone, Quinidine Gluconate, Quinelorane nine, illocarpine, pilsicainide, pimagedine, Pimetine Hydro Hydrochloride, Quinine Sulfate, Quinpirole Hydrochloride, chloride, pimilprost, Pimobendan, Pimozide, Pinacidil, Pina 10 Quinterenol Sulfate, Quinuclium Bromide, Quinupristin, doline, Pindolol, pinnenol, pinocebrin, Pinoxepin Quipazine Maleate, Rabeprazole Sodium, Racephenicol, Hydrochloride, pioglitaZone, Pipamperone, Pipazethate, Racepinephrine, rafantagonists, Rafoxanide, Ralitoline, ral pipecuronium bromide, Piperacetazine, Piperacillin Sodium, oxifene, raltitrexed, ramatroban, Ramipril, Ramoplanin, Piperamide Maleate, piperazine, Pipobroman, Piposulfan, ramosetron, ranelic acid, Ranimycin, Ranitidine, ranolazine, Pipotiazine Palmitate, Pipoxolan Hydrochloride, Piprozolin, 15 Rauwolfia Serpentina, recainam, Recainam Hydrochloride, Piquindone Hydrochloride, Piquizil Hydrochloride, Pirac Reclazepam, regavirumab, RegramoStim, Relaxin, Relomy etam, Pirandamine Hydrochloride, pirarubicin, PiraZmonam cin, Remacemide Hydrochloride, Remifentanil Hydrochlo Sodium, Pirazolac, Pirbenicillin Sodium, Pirbuterol Acetate, ride, Remiprostol, Remoxipride, Repirinast, Repromicin, Pirenperone, Pirenzepine Hydrochloride, piretanide, Pirfeni Reproterol Hydrochloride, Reserpine, resinferatoxin, Resor done, Piridicillin Sodium, Piridronate Sodium, Piriprost, piri cinol, retelliptine demethylated, reticulin, reviparin Sodium, trexim, Pirlimycin Hydrochloride, pirlindole, pirmagrel, Pir revizinone, rhenium Re 186 etidronate, rhizoxin, Ribaminol, menol Hydrochloride, Pirnabine, Piroctone, Pirodavir, Ribavirin, Riboprine, ribozymes, ricasetron, Ridogrel, pirodomast, Pirogliride Tartrate, Pirolate, Pirolazamide, Rifabutin, Rifamastene, Rifamexil, Rifamide, Rifampin, Piroxantrone Hydrochloride, Piroxicam, Piroximone, Pirpro Rifapentine, Rifaximin, R11 retinamide, rilopirox, Riluzole, fen, Pirquinozol, Pirsidomine, Prenylamine, Pituitary, Poste 25 rimantadine, Rimazole Hydrochloride, Rimexolone, Rimit rior, Pivampicillin Hydrochloride, Pivopril, Pizotyline, place erol Hydrobromide, rimoprogin, riodipine, Rioprostil, tin A, platinum compounds, platinum-triamine complex, Ripazepam, ripisartan, Risedronate Sodium, risedronic acid, Plicamycin, Plomestane, Pobilukast Edamine, Podofilox, Risocaine, Risotilide Hydrochloride, rispenzepine, Risper Poisonoak Extract, Poldine Methylsulfate, Poliglusam, dal, Risperidone, Ritanserin, ritipenem, Ritodrine, Polignate Sodium, Polymyxin B Sulfate, Polythiazide, 30 Ritolukast, ritonavir, rizatriptan benzoate, Rocastine Hydro Ponalrestat, Porfimer Sodium, Porfiromycin, Potassium chloride, Rocuronium Bromide, Rodocaine, Roflurane, Chloride, Potassium Iodide, Potassium Permanganate, Povi Rogletimide, rohitukine, rokitamycin, Roletamde, Rolgami done-Iodine, Practolol, Pralidoxime Chloride, Pramiracetam dine, Rolicyprine, Rolipram, Rolitetracycline, Rolodine, Hydrochloride, Pramoxine Hydrochloride, Pranolium Chlo RomaZarit, romurtide, Ronidazole, ropinirole, Ropitoin ride, Pravadoline Maleate, Pravastatin (Pravachol), 35 Hydrochloride, ropivacaine, Ropizine, roquinimex, Rosa Prazepam, Prazosin, Prazosin Hydrochloride, Prednazate, ramicin, Rosoxacin, Rotoxamine, roXatidine, Roxarsone, Prednicarbate, Prednimustine, Prednisolone, Prednisone, roXindole, roXithromycin, rubiginone Bi, ruboxyl, rufloxacin, Prednival, Pregnanolone Succiniate, Prenalterol Hydrochlo rupatadine, Rutamycin, ruzadolane, Sabeluzole, Safingol. ride, Pridefine Hydrochloride, Prifelone, Prilocaine Hydro safironil, saintopin, salbutamol, Salcolex, Salethamide Male chloride, Prilosec, Primaquine Phosphate, Primidolol, Primi 40 ate, Salicyl Alcohol, Salicylamide, Salicylate Meglumine, done, Prinivil, prinomide Tromethamine, Prinoxodan, Salicylic Acid, Salmeterol, Salnacedin, Salsalate, sameri Prizidilol Hydrochloride, Proadifen Hydrochloride, dine, Sampatrilat, Sancycline, Sanfetrinem, Sanguinarium Probenecid, Probicromil Calcium, Probucol, Procainamide Chloride, Saperconazole, Saprisartan, sapropterin, Hydrochloride, Procaine Hydrochloride, Procarbazine saquinavir, Sarafloxacin Hydrochloride, Saralasin Acetate, Hydrochloride, Procaterol Hydrochloride, Prochlorperazine, 45 SarCNU, sarcophytol A, SargramoStim, Sarmoxicillin, Sarpi Procinonide, Proclonol, Procyclidine Hydrochloride, Prodi cillin, Sarpogrelate, Saruplase, Saterinone, satigrel, Satumo lidine Hydrochloride, Prodolic Acid, Profadol Hydrochlo mab pendetide, Schick Test Control, Scopafungin, Scopola ride, Progabide, Progesterone, Proglumide, Proinsulin mine Hydrobromide, Serazapine Hydrochloride, Sdi 1 Human, Proline, Prolintane Hydrochloride, Promazine mimetics, Secalciferol, Secobarbital, Seelzone, Seglitide Hydrochloride, Promethazine Hydrochloride, Propafenone 50 Acetate, selegiline, Selegiline Hydrochloride, Selenium Sul Hydrochloride, propagermanium, Propanidid, Propantheline fide, Selenomethionine Se 75, Selfotel, sematilide, semdu Bromide, Proparacaine Hydrochloride, Propatyl Nitrate, pro ramicin, Semotiadil, Semustine, sense oligonucleotides, pentofylline, Propenzolate Hydrochloride, Propikacin, Pro Sepazonium Chloride, Seperidol Hydrochloride, Seprilose, piomazine, Propionic Acid, propionylcarnitine, L-, propiram, Seproxetine Hydrochloride, Seractide Acetate, Sergolexole propiram-paracetamol, propiverine, Propofol, Propoxycaine 55 Maleate, Serine, Sermetacin, Sermorelin Acetate, sertacona Hydrochloride, Propoxyphene Hydrochloride, Propranolol Zole, sertindole, Sertraline, Setiptiline, Setoperone, Hydrochloride, Propulsid, propyl bis-acridone, Propyl sevirumab, sevoflurane, sezolamide, Sibopirdine, Sibutra hexedrine, Propyliodone, Propylthiouracil, ProquaZone, Pro mine Hydrochloride, signal transduction inhibitors, Silan renoate Potassium, Proroxan Hydrochloride, Proscillaridin, drone, silipide, silteplase, Silver Nitrate, simendan, Simtra Prostalene, prostratin, Protamine Sulfate, protegrin, Protire 60 Zene, Simvastatin, Sincalide, Sinefungin, sinitrodil, lin, protosufloxacin, Protriptyline Hydrochloride, Proxazole, sinnabidol, Sipatrigine, Sirolimus, Sisomicin, Sitogluside, Proxazole Citrate, Proxicromil, Proxorphan Tartrate, pruli sizofiran, sobuzoxane, Sodium Amylosulfate, Sodium Iodide floxacin, Pseudoephedrine Hydrochloride, Puromycin, pur I 123, Sodium Nitroprusside, Sodium Oxybate, sodium phe purin, Pyrabrom, Pyrantel, Pamoate, Pyrazinamide, Pyrazo nylacetate, Sodium Salicylate, solverol, Solypertine Tartrate, furin, pyrazoloacridine, Pyridostigmine Bromide, Pyrilamine 65 Somalapor. Somantadine Hydrochloride, somatomedin B, Maleate, Pyrimethamine, Pyrinoline, Pyrithione Sodium, Somatomedin C, somatrem, somatropin, Somenopor, Somi Pyrithione Zinc, Pyrovalerone Hydrochloride, Pyroxamine dobove, Sonermin, Sorbinil, Sorivudine, Sotalol, Soterenol US 8,263,125 B2 63 64 Hydrochloride, Sparfloxacin, Sparfosate Sodium, sparfosic ride, Tiazofurin, Tibenelast Sodium, Tibolone, Tilbric Acid, acid, Sparsomycin, Sparteine Sulfate, Spectinomycin Hydro Ticabesone Propionate, Ticarbodine, Ticarcillin Cresyl chloride, spicamycin, Spiperone, Spiradoline Mesylate, Spi Sodium, Ticlatone, ticlopidine, Ticrynafen, tienoxolol, Tifu ramycin, Spirapril Hydrochloride, Spiraprilat, Spirogerma rac Sodium, Tigemonam Dicholine, Tigestol, Tiletamine nium Hydrochloride, Spiromustine, Spironolactone, Hydrochloride, Tilidine Hydrochloride, tilisolol, tilnoprofen Spiropitan, SpiroXasone, splenopentin, Spongistatin 1, arbamel, Tilorone Hydrochloride, Tiludronate Disodium, Sprodiamide, squalamine, Stallimycin Hydrochloride, Stan tiludronic acid, Timefurone, Timobesone Acetate, Timolol, nous Pyrophosphate, Stannous Sulfur Colloid, Stanozolol, tin ethyl etiopurpurin, Tinabinol, Tinidazole, Tinzaparin Statolon, staurosporine, stavudine, Steffimycin, Stenbolone Sodium, Tioconazole, Tiodazosin, Tiodonium Chloride, Tio Acetate, stepronin, Stilbazium Iodide, Stilonium Iodide, 10 peridone Hydrochloride, Tiopinac, Tiospirone Hydrochlo stipiamide, Stiripentol, stobadine, Streptomycin Sulfate, ride, Tiotidine, tiotropium bromide, Tioxidazole, Tipentosin Streptonicozid, Streptonigrin, Streptozocin, Stromelysin Hydrochloride, Tipredane, Tiprenolol Hydrochloride, Tipri inhibitors, Strontium Chloride Sr 89, succibun, Succimer, nast Meglumine, Tipropidil Hydrochloride, Tiqueside, Succinylcholine Chloride. Sucralfate. Sucrosofate Potas Tiquinamide Hydrochloride, tirandalydigin, Tirapazamine, sium, Sudoxicam, Sufentanil, Sufotidine, Sulazepam, Sul 15 tirilazad, tirofiban, tiropramide, titanocene dichloride, Tix bactam Pivoxil, Sulconazole Nitrate, Sulfabenz, Sulfabenza anox, Tixocortol Pivalate, Tizanidine Hydrochloride, Tobra mide, Sulfacetamide, Sulfacytine, Sulfadiazine, Sulfadoxine, mycin, Tocainide, Tocamphyl, Tofenacin Hydrochloride, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sul Tolamolol, Tolazamide, Tolazoline Hydrochloride, Tolbuta famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sul mide, Tolcapone, Tolciclate, Tolfamide, Tolgabide, lamot famoxole, Sulfanilate Zinc, Sulfanitran, sulfasalazine, Sulfa rigine, Tolimidone, Tolindate, Tolmetin, Tolnaftate, Tolpovi somizole, Sulfazamet, Sulfinalol Hydrochloride, sulfinosine, done 1 131, Tolpyrramide, Tolrestat, Tomelukast, Sulfinpyrazone, Sulfisoxazole, Sulfomyxin, Sulfonterol Tomoxetine Hydrochloride, Tonazocine Mesylate, Topira Hydrochloride, sulfoxamine, Sulindac, Sulmarin, Sulnida mate, topotecan, Topotecan Hydrochloride, topsentin, Zole, Suloctidil, Sulofenur, Sulopenem, Suloxifen Oxalate, Topterone, Toquilone, torasemide, toremifene, Torsemide, Sulpiride, Sulprostone, Sultamicillin, Sulthiame, sultopride, 25 Tosifan, ToSufloxacin, totipotent stem cell factor, Traca Sulukast, Sumarotene, Sumatriptan, Suncillin Sodium, Supro Zolate, trafermin, Tralonide, Tramadol Hydrochloride, Tra clone, Suprofen, Suradista, Suramin, Surfomer, Suricainide mazoline Hydrochloride, trandolapril, Tranexamic Acid, Tra Maleate, Suritozole, Suronacrine Maleate, Suxemerid Sul nilast, Transcainide, translation inhibitors, traxanox, fate, Swainsonine, Symakalim, Symclosene, Symetine Trazodone Hydrochloride, Trazodone-HCL, Trebenzomine Hydrochloride, synthetic glycosaminoglycans, Taciamine 30 Hydrochloride, Trefentanil Hydrochloride, Treloxinate, Hydrochloride, Tacrine Hydrochloride, Tacrolimus, Talampi Trepidam Maleate, Trestolone Acetate, tretinoin, Triacetin, cillin Hydrochloride, Taleranol, Talisomycin, tallimustine, triacetyluridine, Triafungin, Triamcinolone, TriampyZine Talmetacin, Talniflumate, Talopram Hydrochloride, Talos Sulfate, Triamterene, Triazolam, Tribenoside, tricaprilin, alate, Tametraline Hydrochloride, Tamoxifen, Tampramine Tricetamide, Trichlormethiazide, trichohyalin, triciribine, Fumarate, Tamsulosin Hydrochloride, Tandamine Hydro 35 Tricitrates, Triclofenol piperazine, Triclofos Sodium, Tri chloride, tandospirone, tapgen, taprostene, Tasosartan, tauro clonide, trientine, Trifenagrel, triflavin, Triflocin, Trifluba mustine, Taxane, Taxol. Tazadolene Succinate, taZanolast, Zam, Triflumidate, Trifluoperazine Hydrochloride, Triflu tazarotene, Tazifylline Hydrochloride, Tazobactam, peridol, Triflupromazine, Triflupromazine Hydrochloride, Tazofelone, Tazolol Hydrochloride, Tebufelone, Tebuquine, Trifluridine, Trihexyphenidyl Hydrochloride, Trilostane, Tri Technetium Tc 99 m Bicisate, Teclozan, Tecogalan Sodium, 40 maZosin Hydrochloride, trimegestone, Trimeprazine Tar Teecleukin, Teflurane, Tegafur, Tegretol, Teicoplanin, telen trate, Trimethadione, Trimethaphan Camsylate, Tri Zepine, tellurapyrylium, telmesteine, telmisartan, telomerase methobenzamide Hydrochloride, Trimethoprim, inhibitors, Teloxantrone Hydrochloride, Teludipine Hydro Trimetozine, Trimetrexate, Trimipramine, Trimoprostil, Tri chloride, Temafloxacin Hydrochloride, Tematropium Methyl moxamine Hydrochloride, Triolein 1 125, Triolein 1 131, Sulfate, Temazepam, Temelastine, temocapril, Temocillin, 45 Trioxifene Mesylate, Tripamide, Tripelennamine Hydrochlo temoporfin, temozolomide, Tenidap, Teniposide, tenosal, ride, Triprolidine Hydrochloride, Triptorelin, Trisulfapyrim tenoxicam, tepirindole, Tepoxalin, Teprotide, teraZosin, Ter idines, Troclosene Potassium, troglitaZone, Trolamine, Trole binafine, Terbutaline Sulfate, Terconazole, terfenadine, ter andomycin, trombodipine, trometamol, Tropanserin flavoxate, terguride, Teriparatide Acetate, terlakiren, terlip Hydrochloride, Tropicamide, tropine ester, tropisetron, tros ressin, terodiline, Teroxalene Hydrochloride, Teroxirone, 50 pectomycin, trovafloxacin, troVirdine, Tryptophan, Tubercu tertatolol, Tesical, Tesimide, Testolactone, Testosterone, Tet lin, Tubocurarine Chloride, Tubulozole Hydrochloride, racaine, tetrachlorodecaoxide, Tetracycline, TetrahydroZo tucaresol, tulobuterol, turosteride, Tybamate, tylogenin, line Hydrochloride, Tetramisole Hydrochloride, Tetrazolast Tyropanoate Sodium, Tyrosine, Tyrothricin, tyrphostins, ube Meglumine, tetraZomine, Tetrofosmin, Tetroquinone, TetroX nimex, Uldazepam, Undecylenic Acid, Uracil Mustard, ura oprim, Tetrydamine, thaliblastine, Thalidomide, Theofibrate, 55 pidil, Urea, Uredepa, uridine triphosphate, Urofollitropin, Theophylline. Thiabendazole. Thiamiprine. Thiamphenicol, Urokinase, Ursodiol, Valaciclovir, Valine, Valnoctamide, Val Thiamylal. Thiazesim Hydrochloride. Thiazinamium Chlo proate Sodium, Valproic Acid, Valsartan, Vamicamide, Vana ride. Thiethylperazine. Thimerfonate Sodium, Thimerosal, deine, Vancomycin, Vaminolol, Vapiprost Hydrochloride, thiocoraline, thiofedrine. Thioguanine, thiomarinol, Thio Vapreotide, variotin, Vasopressin, Vecuronium Bromide, pental Sodium, thioperamide. Thioridazine. Thiotepa, Thio 60 velaresol, Velnacrine Maleate, Venlafaxine, Veradol Hydro thixene. Thiphenamil Hydrochloride. Thiphencillin Potas chloride, Veramina, Verapamil Hydrochloride, verdins, Ver sium, Thiram, Thozalinone, Threonine, Thrombin, ilopam Hydrochloride, Verlukast, Verofylline, Veroxan, thrombopoietin, thrombopoietin mimetic, thymalfasin, thy verteporfin, Vesnarinone, vexibinol, Vidarabine, vigabatrin, mopoietin receptor agonist, thymotrinan, Thyromedan Viloxazine Hydrochloride, Vinblastine Sulfate, vinburnine Hydrochloride, Thyroxine 1125, Thyroxine 1131, Tiacrilast, 65 citrate, Vincofos, Vinconate, Vincristine Sulfate, Vindesine, Tiacrilast Sodium, tiagabine, Tiamenidine, tianeptine, Vindesine Sulfate, Vinepidine Sulfate, Vinglycinate Sulfate, tiapafant, Tiapamil Hydrochloride, Tiaramide Hydrochlo Vinleurosine Sulfate, vinorelbine, vinpocetine, Vintoperol, US 8,263,125 B2 65 66 vinxaltine, Vinzolidine Sulfate, Viprostol, Virginiamycin, adenosine Al antagonist, serotonin antagonist; serotonin Viridofulvin, Viroxime, Vitacin, Volazocine, Voriconazole, inhibitor; serotonin receptor antagonist; Steroid; thyroid hor Vorozole, voxergolide, Warfarin Sodium, Xamoterol, mone; thyroid inhibitor, thyromimetic; tranquilizer; amyo Xanomeline, Xanoxate Sodium, Xanthinol Niacinate, trophic lateral Sclerosis agent; cerebral ischemia agent, Pag Xemilofiban, Xenalipin, Xenbucin, Xilobam, Ximoprofen, et's disease agent; unstable angina agent; vasoconstrictor; Xipamide, Xorphanol Mesylate, Xylamidine Tosylate, Xyla vasodilator, wound healing agent; and Xanthine oxidase zine Hydrochloride, Xylometazoline Hydrochloride, Xylose, inhibitor. yangambin, Zabicipril, Zacopride, Zafirlukast, Zalcitabine, 14. A dosage form according to claim 1, wherein the high Zaleplon, Zalospirone, Zaltidine Hydrochloride, Zaltoprofen, dose, high solubility active ingredient is selected from the Zanamivir, Zankiren, Zanoterone, Zantac, Zafirlukast, Zate 10 group consisting of metformin hydrochloride, phenformin, bradine, Zatosetron, Zatosetron Maleate, Zenarestat, ZenaZo buformin, potassium chloride, clindamycin, hydroxyurea, cine Mesylate, Zeniplatin, Zeranol, Zidometacin, Zidovu eprosartan, erythromycin, lactobionate, Vancomycin hydro dine, Zifrosilone, Zilantel, Zilascorb, Zileuton, Zimeldine chloride, balsalazide disodium, Sodium valproate, niacin, Hydrochloride, Zinc Undecylenate, Zindotrine, Zinocona aminocaproic acid, acetaminophen ciprofloxacin, quetiapine Zole Hydrochloride, Zinostatin, Zinterol Hydrochloride, Zin 15 and pharmaceutically acceptable salts thereof. viroxime, ziprasidone, Zobolt, Zofenopril Calcium, Zofeno 15. A dosage form according to claim 1, wherein inner prilat, Zolamine Hydrochloride, Zolazepam Hydrochloride, portion may optionally contain more than one low dose active Zoledronic acid, Zollertine Hydrochloride, Zolmitriptan, ingredients. Zolpidem, Zomepirac Sodium, Zometapine, ZonicleZole 16. A process for the preparation of a dosage form as Hydrochloride, Zonisamide, Zopiclone, Zopolrestat, Zorba claimed in claim 1, comprisinga) preparation of inner portion mycin, Zorubicin Hydrochloride, Zotepine, Zucapsaicin, and b) preparation of outer portion. JTT-501 (PNU-182716) (Reglitazar), AR-H039242, MCC 17. A process for the preparation of a dosage form as 555 (Netoglitazone), AR-HO49020, Tesaglitazar), CS-011 claimed in claim 16, wherein preparation of outer portion (CI-1037), GW-409544X, KRP-297, RG-12525, comprisinga) preparing a micro matrix particles consisting of BM-15.2054, CLX-0940, CLX-0921, DRF-2189, GW-1929, 25 high dose, high solubility active ingredient and one or more GW-9820, LR-90, LY-510929, NIP-221, NIP-223, JTP hydrophobic release controlling agent and b) coating the said 20993, LY 29311 Na, FK 614, BMS 298.585, R 483, TAK micro matrix particles containing high solubility active ingre 559, DRF 2725 (Ragaglitazar), L-686398, L-168049, dient and one or more hydrophobic release controlling agent. L-805645, L-054852, Demethyl asteriquinone B1 18. A dosage form of combination of high dose high solu (L-783281), L-363586, KRP-297, P32/98, CRE-16336 and 30 bility hypolipidemic active ingredient as modified release and EML-16257 and pharmaceutically acceptable salts therof. low dose hypolipidemic or antithrombotic active ingredient 12. A dosage form according to claim 1, wherein the high as immediate release, suitable for swallowing; comprising an dose, high solubility active ingredient comprises dose from inner portion having a low dose hypolipidemic or antithrom 500 mg to 1500 mg. botic active ingredient as immediate release and an outer 13. A dosage form according to claim 1, wherein the high 35 portion having a high dose high solubility hypolipidemic dose, high solubility active ingredient is selected from the active ingredient as modified release, wherein said inner por group consisting of adrenergic agent, adrenocortical steroid; tion is covered by the outer portion from all the sides except adrenocortical Suppressant, aldosterone antagonist; amino a top Surface that remains uncovered; wherein said outer acid; anabolic; analeptic; analgesic; anesthetic; anorectic; portion prepared by using dual retard technique to control the anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic; 40 release of high dose high solubility is a combination of matrix anti-anemic; anti-anginal; anti-arthritic; anti-asthmatic; anti formulation and reservoir formulation comprises: atherosclerotic; antibacterial; anticholinergic; anticoagulant; (a) micro matrix particles consisting of a high dose high anticonvulsant; antidepressant; antidiabetic; antidiarrheal; Solubility hypolipidemic active ingredient and one or antidiuretic; anti-emetic; anti-epileptic; antifibrinolytic; anti more hydrophobic release controlling agents wherein fungal; antihemorrhagic; antihistamine; antihyperlipidemia; 45 the ratio of high dose high solubility hypolipidemic antihypertensive; antihypotensive; anti-infective; anti-in active ingredients and hydrophobic release controlling flammatory; antimicrobial; antimigraine; antimitotic; anti agents is in the range of 100-2.5 to 100:30 and mycotic, antinauseant, antineoplastic, antineutropenic, anti (b) a coating of one or more hyrophobic release controlling parasitic; antiproliferative; antipsychotic; antirheumatic; agents on said micro matrix particles, wherein the ratio antiseborrheic; antisecretory; antispasmodic; antithrombotic; 50 of micro matrix particles and hydrophobic release con anti-ulcerative; antiviral; appetite Suppressant, blood glucose trolling agent is in the range of 100:2.5 to 100:30 regulator; bone resorption inhibitor; bronchodilator; cardio wherein the weight ratio of immediate release hypolipi vascular agent; cholinergic; depressant; diagnostic aid; demic or antithrombotic active ingredient and modified diuretic; dopaminergic agent; estrogen receptor agonist; release hypolipidemic active ingredient is from 1:1 to fibrinolytic; fluorescentagent, free oxygen radical Scavenger, 55 1:15000wherein the claimed dosage form does not pro gastric acid Supressant; gastrointestinal motility effector; glu vide burst release. cocorticoid; hair growth stimulant; hemostatic; histamine H2 19. A dosage form according to claim 18, wherein the receptor antagonists; hormone; hypocholesterolemic; hydrophobic release controlling agents are selected from the hypoglycemic; hypolipidemic; hypotensive; imaging agent; group consisting of poly(ethyl acrylate, methyl methacrylate, immunizing agent; immunomodulator; immunoregulator; 60 trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly immunostimulant; immunosuppressant; keratolytic; LHRH (ethyl acrylate, methyl methacrylate, trimethylamonioethyl agonist; mood regulator, mucolytic, mydriatic; nasal decon methacrylate chloride) 1:2:0.2 and poly(ethyl acrylate, gestant; neuromuscular blocking agent; neuroprotective; methyl methacrylate) 1:1 polyvinyl acetate dispersion, ethyl NMDA antagonist; non-hormonal sterol derivative; plasmi cellulose, cellulose acetate, cellulose propionate (lower, nogen activator, platelet activating factor antagonist, platelet 65 medium or higher molecular weight), cellulose acetate pro aggregation inhibitor, psychotropic; radioactive agent; scabi pionate, cellulose acetate butyrate, cellulose acetate phtha cide; sclerosing agent; sedative; sedative-hypnotic; selective late, cellulose triacetate, poly(methyl methacrylate), poly US 8,263,125 B2 67 68 (ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl lated monoglycerides, tristearin, tripalmitin, cetyl esters wax, methacrylate), poly (hexyl methacrylate), poly(isodecyl glyercyl palmitostearate, glyceryl behenate, glycerol distear methacrylate), poly (lauryl methacrylate), poly(phenyl meth ate, and hydrogenated castor oil. acrylate), poly (methyl acrylate), poly (isopropyl acrylate), 23. A dosage form according to claim 22, wherein the poly (isobutyl actylate), poly (octadecylacrylate), waxes hydrophobic release controlling agents are selected from the selected from the group consisting of beeswax, carnauba group consisting of hydrogenated castor oil and glycerol dis wax, microcrystalline wax, and oZokerite; fatty alcohols tearate. selected from the group consisting of cetostearyl alcohol, 24. A dosage form according to claim 18, wherein the low Stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty dose hypolipidemic or antithrombotic active ingredient com 10 prises dose less than or equal to 500 mg. acid esters 25. A dosage form according to claim 18, wherein the high Selected from the group consisting of glyceryl monostear dose high solubility hypolipidemic is niacin or its pharma ate; glycerol monooleate, acetylated monoglycerides, ceutically acceptable salts. tristearin, tripalmitin, cetyl esters wax, glyceryl palmi 26. A dosage form according to claim 18, wherein the high to Stearate, glyceryl behenate, glycerol distearate and 15 dose high solubility hypolipidemic active ingredient com hydrogenated castor oil. prises dose from 500 mg to 1500 mg. 20. A dosage form according to claim 19, wherein the 27. A dosage form according to claim 18, wherein the low hydrophobic release controlling agent(s) is selected from the dose antithrombotic active agent is aspirin. group consisting of poly(ethyl acrylate, methyl methacrylate, 28. A dosage form according to claim 18, wherein the low trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly dose hypolipidemic active ingredient is selected from the (ethyl acrylate, methyl methacrylate, trimethylamonioethyl group consisting of statin compounds. methacrylate chloride) 1:2:0.2 and poly(ethyl acrylate, 29. A process for the preparation of a dosage form as methyl methacrylate) 1:1. claimed in claim 18, comprising a) preparation of inner por 21. A dosage form according to claim 20, wherein the tion and b) preparation of outer portion. ammonio methacrylate co-polymers are selected from the 25 30. A process for the preparation of a dosage form as group consisting of poly(ethyl acrylate, methyl methacrylate, claimed in claim 29, wherein preparation of outer portion trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly comprisinga) preparing a micro matrix particles consisting of (ethyl acrylate, methyl methacrylate, trimethylamonioethyl high dose, hypolipidemic active ingredient and one or more methacrylate chloride) 1:2:0.2 and poly(ethyl acrylate, hydrophobic release controlling agent and b) coating the said methyl methacrylate) 1:1. 30 micro matrix particles consisting of high dose hypolipidemic 22. A dosage form according to claim 6, wherein the hydro active ingredient and one or more hydrophobic release con phobic release controlling agents is selected from fatty acid trolling agent. esters selected from the group consisting of glyceryl monostearate, glycerol distearate, glycerol monoleate, acety