USOO8268352B2

(12) United States Patent (10) Patent No.: US 8,268,352 B2 Vaya et al. (45) Date of Patent: *Sep. 18, 2012

(54) MODIFIED RELEASE COMPOSITION FOR (56) References Cited HIGHLY SOLUBLE DRUGS U.S. PATENT DOCUMENTS (75) Inventors: Navin Vaya, Gujarat (IN); Rajesh Singh 2,566,582 A 7, 1951 Rotner Karan, Gujarat (IN); Sunil Sadanand 2.968, 158 A 1/1961 Ruschig et al. Nadkarni, Gujarat (IN); Vinod Kumar 3,097,242 A 7, 1963 Hoehn et al. Gupta, Gujarat (IN) 3,174,901 A 3, 1965 Sterne 3,454,635 A 7/1969 Weber et al. 3,654,357 A 4, 1972 Bretschneider et al. (73) Assignee: Torrent Pharmaceuticals Limited, 3,668,215 A 6/1972 Plumpe et al. Ahmedabad (IN) 3,669,966 A 6/1972 Ambrogi 3,708.486 A 2f1973 Kutter et al. (*) Notice: Subject to any disclaimer, the term of this 3,801,495 A 4, 1974 Gould patent is extended or adjusted under 35 3,957,833. A 5, 1976 Chodnekar et al. U.S.C. 154(b) by 0 days. (Continued) This patent is Subject to a terminal dis claimer. FOREIGN PATENT DOCUMENTS EP OOO82O3 A1 2, 1980 (21) Appl. No.: 11/134,632 (Continued) (22) Filed: May 19, 2005 OTHER PUBLICATIONS (65) Prior Publication Data Merck index citations of Niacin and Sodium Valproate, accessed on Aug. 4, 2008.* US 2006/OO18934 A1 Jan. 26, 2006 (Continued) Related U.S. Application Data (63) Continuation-in-part of application No. 10/630,348, Primary Examiner — Anand Desai filed on Jul. 29, 2003, now Pat. No. 8,216,609. Assistant Examiner — Melissa Mercier (74) Attorney, Agent, or Firm — Hedman & Costigan; James (30) Foreign Application Priority Data V. Costigan Aug. 5, 2002 (IN) ...... 696/MUMA2003 (57) ABSTRACT Aug. 5, 2002 (IN) ...... 698/MUMA2002 A novel modified release dosage form comprising of a high Jan. 22, 2003 (IN) ...... 81 FMUMA2003 solubility active ingredient, which utilizes dual retard tech nique to effectively reduce the quantity of release controlling (51) Int. Cl. agents. Present invention can optionally comprise addition A6 IK 9/26 (2006.01) ally another active ingredient as an immediate release form or A6 IK9/20 (2006.01) modified release form. Present invention also relates to a (52) U.S. Cl...... 424/469: 424/464; 424/465; 424/468 process for preparing the said formulation. (58) Field of Classification Search ...... None See application file for complete search history. 21 Claims, 5 Drawing Sheets

US 8,268,352 B2 Page 2

U.S. PATENT DOCUMENTS 6,048,883 A 4/2000 Haigh et al. 4,080.472 A 3, 1978 Bohuon 6,296,874 B1 10/2001 Cutie 4,363.802 A 12, 1982 Matsumura et al. & E. R 29: SE. 236. A 38. St. stal 6,660,300 B1* 12/2003 Timmins et al...... 424/469 4725,610 A 2, 1988 NE th 6,790,459 B1 9/2004 Cheng et al. 4775.687. A 10/1988 NE tal. 6,866,866 B1 3/2005 Chen et al. 479.25 A 13/1988 Myroe 2004/0022849 A1 2/2004 Castan et al. 3. A S. g E. et al. FOREIGN PATENT DOCUMENTS W W4- Indley 5,061,717. A 10/1991 Clarket al. EP O155845 A1 9, 1985 5,098,725 A 3, 1992 Rotman et al. EP O332332 A1 9, 1989 5,104,888 A 4, 1992 Yoshioka et al. EP 0428312 A2 5, 1991 5, 183,823. A 2f1993 Sohda et al. EP O533933 A1 3/1993 5,225.426 A 7/1993 Miyaoka et al. EP O842925 A1 5, 1998 5,232,945 A 8, 1993 Hulin WO WO92, 185O1 10, 1992 5,264.451 A 1 1/1993 Kees WO WO93/O2O79 2, 1993 5,306,726 A 4, 1994 Hulin WO WO93/22445 11, 1993 5,334,604 A 8, 1994 Goldstein et al. WO WO94/05659 3, 1994 5,399,357 A 3/1995 Akiyama et al...... 424/457 5,472,704 A 12, 1995 Santus et al...... 424/435 OTHER PUBLICATIONS 5,478,852 A 12/1995 Olefsky et al. 5,589,492 A 12/1996 Haigh Merck Index citations for niacin and sodium valproate.* 5,945,125 A 8, 1999 Kim 6,031,004 A 2, 2000 Timmins et al. * cited by examiner U.S. Patent Sep. 18, 2012 Sheet 1 of 5 US 8,268,352 B2

FIGURE 1 (a)

FIGURE 1 (b)

U.S. Patent Sep. 18, 2012 Sheet 2 of 5 US 8,268,352 B2

FIGURE 2

120 e 100 468 OOO 2 O

O 2 4 6 8 1 O 12 14 16 18 2O 22 24 26 Time (hour ) U.S. Patent Sep. 18, 2012 Sheet 3 of 5 US 8,268,352 B2

e

------O 2 4 6 8 O 12 14 16 18 2O 22 24 26 Time (hollr) U.S. Patent Sep. 18, 2012 Sheet 4 of 5 US 8,268,352 B2

FIGURE 4

120

1 OO

80

60

40

20

O t -- O 2 4. 6 8 10 12 14 Time (hour) U.S. Patent Sep. 18, 2012 Sheet 5 of 5 US 8.268,352 B2

FIGURE 5

- 1600 H 5th 14 OO

12 OO

- 1 OOO t -- 8 OO

g 6OO O 400 ? ? 2 OO r ?h- O - -- O 4. 8 12 16 20 24

Time Hours US 8,268,352 B2 1. 2 MODIFIED RELEASE COMPOSITION FOR and that swells following hydration. The ratio of inner solid HIGHLY SOLUBLEDRUGS phase to outer continuous phase is 0.5:1 to about 4:1. The major limitation of this invention is that it provides a very This application is a continuation-in-part of Ser. No. bulky formulation for higher doses of the metformin hydro 10/630,348, filed Jul. 29, 2003 now U.S. Pat. No. 8,216,609. 5 chloride that is very inconvenient for human consumption. For instance, example cited provides formulation of 500 mg FIELD OF INVENTION metforminhydrochloride with tablet weight of 1.0gm. Hence restricting to the low dose sustained release tablets of 500 mg This invention relates to a modified release dosage form or slightly more and making it obligatory to take two tablets comprising of a high solubility active ingredient, which ulti 10 lizes dual retard technique to effectively reduce the quantity of 500 mg each time to provide sustain action. The cited of release controlling agents. Present invention can optionally example teaches use of combination of atleast one hydro comprise additionally another active ingredient as an imme philic polymer and which is a essential part for Swelling. Non diate release form or modified release form. Present invention swellable or nonerodeble formulations are not included in the invention. also relates to a process for preparing the said formulation. 15 PCT application No. WO 02/28.181 A1 describes a mono BACKGROUND OF THE INVENTION lithic sustained release formulation of metformin hydrochlo ride. The method of making the formulation involves hot melt It is well known to those skilled in the art that the blood granulation followed by wet granulation with binders or levels of drugs need to be maintained above a minimum extrusion. The formulation essentially requires binder and effective level and below its minimum toxic level in order to auxiliary pharmaceutically acceptable excipients. The for obtain the desired therapeutic effects and to minimize side mulation consists of metformin hydrochloride polymer and effects. Unfortunately, the pharmacokinetic properties (ab or hydrophobic material. The dosage form release more than Sorption, elimination and metabolism) of most drugs are Such 90% of the drug within 8 hours. that they need to be administered three to four times a day. 25 Similarly U.S. Pat. No. 6,340,475 B2 assigned to Depomed This kind of a dosing regimen is very inconvenient and leads Inc. describes monolithic controlled release formulation of to reduction in patient compliance. Reduction of dosing regi highly water soluble drugs including metformin hydrochlo men from three times a day (t.i.d.) to twice daily (b.i.d.) to ride. The formulation Swells when ingested thus prolonging once a day results in increased convenience and comfort and its residence time in the stomach. The formulations are made therefore increased patient compliance. Drugs that are 30 of hydrophilic polymers, which results in swellable and erod administered in the form of conventional tablets of capsules ible matrix. become available to body fluids at a rate that is initially very Another method of prolonging the release of a highly high, followed by a rapid decline. For many drugs, this deliv water-soluble drug is disclosed in International Patent appli ery pattern results in a transient overdose, followed by a long cation publication no. WO 96/26718, published Sep. 6, 1996. period of under dosing. This is a pattern of limited clinical 35 The method of this publication is the incorporation of the drug usefulness. The delivery pattern was improved in the 1970s into a polymeric matrix to form a tablet that is administered with the introduction of a variety of modified delivery sys orally. The polymer is water-swellable yet erodible in gastric tems. Modified release formulations, which are effective in fluids. maintaining the therapeutic blood levels over, extended peri Similarly Chih-Ming Chen in international patent applica ods of time result in optimal therapy. They not only reduce the 40 tion number WO 02/36100 describes a once a formulation of frequency of dosing, but they also reduce the severity and metforminhydrochloride which is based on osmotically con frequency of side effects, as they maintain Substantially con trolled technique and that is non expandable in nature and has stant blood levels and avoid the fluctuations associated with a passage in the coating membrane for release of drug. the conventional immediate release formulations adminis Kim et al. in U.S. Pat. No. 6,337,091 describes a matrix tered three to four times a day. 45 based controlled release formulation for highly soluble drugs There are a number of different modified release dosage over long periods of time. The release controlling agent is a forms available commercially. However, some of these are Swellable gum which encapsulates or make granules of drug, expensive to manufacture and can be difficult to swallow, which is then disposed in more swellable erodible polymers particularly in elderly patients. Many of these modified deliv such as HPMC or poly(ethyleneoxide). ery systems utilize hydrophilic, polymeric matrices that pro 50 These systems can provide for modified release for vide useful levels of control to the delivery of sparingly selected active ingredients like active ingredients with low soluble drugs. For soluble drugs, however, and particularly dose or low water solubility. However, when a highly soluble for highly soluble drugs, such matrices do not provide or high dose active ingredient is used, most of these systems adequate control over the release rate, instead resulting in a have the disadvantages such as comparatively low payload of release that approximates first-order kinetics and may have a 55 active ingredient thus making dosage form bulky and expen problem of dose dumping or burst release. However, since sive or lead to burst effect or prolonged release of active many modified release dosage forms contain comparatively ingredient for a shorter duration or use of complex manufac large amounts of active ingredient it is often necessary to turing procedure and/or equipment. include large amounts of suitable excipients to achieve appro There exists a need for compositions and process for mak priate controlled release profiles. Clearly, this will tend to 60 ing orally deliverable dosage form containing highly soluble increase the size of the dosage form. active ingredient as modified release that overcomes the prob The various techniques to make modified release dosage lems discussed above. This invention addresses the need. form of drugs as described in prior art are as follows— Therefore, it would be of considerable clinical benefit to One method of prolonging the release of a highly water design a dosage form with high pay load of highly soluble soluble drug is disclosed PCT Patent application no. WO99/ 65 active ingredient that would be much easier for the patient to 47128. Abiphasic controlled release delivery system for met swallow. This type oftechnology could also be used to reduce formin hydrochloride, which has prolonged gastric residence the size of many existing drug formulations. US 8,268,352 B2 3 4 Therefore an object of the present invention is a modified herein can be described as dosage forms whose drug-release release dosage form of high solubility active ingredient. characteristics of time course and/or location are chosen to The second object of the present invention is a modified accomplish therapeutic or convenience objectives not offered release dosage form with high payload of active ingredient, by conventional dosage forms such as a solution oran imme which is suitable for swallowing for humans. diate release dosage form. Modified release solid oral dosage Yet another object of the present invention is to provide a forms include both delayed and extended release drug prod dosage form, which uses dual retard technique to control the ucts (as per US FDA guideline for SUPAC-MR: Modified release of the high solubility active ingredient and signifi Release Solid Oral Dosage Forms). cantly reduce the amount of release controlling agents which The term “dosage form denotes any form of the formula are otherwise required in very high quantity and make the 10 tion that contains an amount Sufficient to achieve a therapeu dosage form very bulky and therefore pose difficulty in Swal tic effect with a single administration. lowing. The term “active ingredient” refers to an agent, active A further object of the present invention is to provide a ingredient compound or other substance, or compositions and dosage form, which gives accurate dosing and is simple to mixture thereof that provide some pharmacological, often prepare. 15 beneficial, effect. Reference to a specific active ingredient A further object of the present invention is to provide a shall include where appropriate the active ingredient and its dosage form, which can be given twice a day or more prefer pharmaceutically acceptable salts. ably can be given once a day. The term “high solubility” as used herein in relation to A further object of the present invention is to provide a active agent means that from less than 1 part to 300 parts of dosage form, which can optionally comprise additionally water or less than 1 part to 30 parts of water will be required another active ingredient as an immediate release form or to dissolve 1 part of active ingredient. modified release form. The invention provides a novel modified release dosage form of high solubility active ingredient, which utilizes dual SUMMARY OF THE INVENTION retard technique to effectively reduce the quantity of release 25 controlling agents and a process for preparing the dosage The above objects are realized by a dosage form, which form. comprises of a) Micro matrix particles containing high solu The dosage form comprises of a) Micro matrix particles bility active ingredient and one or more hydrophobic release containing, high solubility active ingredient and one or more controlling agent, b) Coating of Micro matrix particles with hydrophobic release controlling agent, b) Coating of Micro one or more hydrophobic release controlling agents. It may 30 matrix particles with one or more hydrophobic release con optionally also include one or more commonly used excipi trolling agents. It may optionally also include one or more ents in oral pharmaceutical formulations. The present inven commonly used excipients in oral pharmaceutical formula tion also provides solid oral dosage form comprising a com tions. The release of high solubility active ingredient is con position according to the invention. Optionally, it may also trolled through dual retard technique. The dual retard tech comprise additionally another active ingredient as an imme 35 nique is a combination of matrix formulations and reservoir diate release form or modified release form. formulations. First the micromatrix particles of high solubil The present invention also teaches the use of dual retard ity dose active ingredient and one or more hydrophobic technique to effectively control the release rate of modified release controlling agents are formed and then these are fur release active ingredient by using Small quantity of release ther coated with one or more release controlling agents. Thus controlling agents. This dual retard technique thus Suffi 40 the dual retard release technique presents the double barriers ciently reduces the size of the dosage form, which is conve and effectively controls the diffusion of the high solubility nient for Swallowing. active ingredients from the present invention in predictable The present invention further teaches the use of hydropho manner and also significantly reduces the amount of release bic release controlling agents. controlling agents which are otherwise required in very high The present invention also provides a novel process for 45 quantity and make the dosage form very bulky and therefore preparing the novel formulations of the invention. pose difficulty in Swallowing. The other advantages of the The present invention further provides a method of treating present invention are Such as it reduces the chances of dose an animal, particularly a human in need of treatment utilizing dumping, unnecessary burst effects and failure of the system, the active agents, comprising administering a therapeutically which are otherwise usually associated with simple matrix or effective amount of composition or solid oral dosage form 50 reservoir systems. according to the invention to provide administration of active Optionally, it may also contain another active ingredient as ingredients. an immediate release form or modified release form. The high solubility active ingredient can be present in the DETAILED DESCRIPTION OF THE INVENTION form of a free base or in the form of pharmaceutically accept 55 able salts. Pharmaceutically acceptable salts forming part of This invention relates to a modified release dosage form this invention are intended to define but not limited to salts of comprising of a high solubility active ingredient prepared by the carboxylic acid moiety Such as alkali metal salts like Li, using dual retard technique to control the release of the high Na and K salts; alkaline earth metal salts likeCa and Mg salts: solubility active ingredient and to increase the payload of salts of organic bases such as lysine, arginine, guanidine, high solubility active ingredient 60 diethanolamine, choline, and the like: ammonium or Substi The term “modified release' as used herein in relation to tuted ammonium salts and aluminium salts. Salts may be acid the composition according to the invention or a rate control addition salts which defines but not limited to sulfates, ling polymer or used in any other context means release, nitrates, phosphates, perchlorates, borates, hydrohalides, which is not immediate release and is taken to encompass acetates, tartrates, maleates, citrates, succinates, palmoates, controlled release, Sustained release, prolonged release, 65 methanesulfonates, benzoates, salicylates, hydroxynaph timed release, retarded release, extended release and delayed thoates, benzensulfonates, ascorbates, glycerophosphates, release. The term “modified release dosage form as used ketoglutarates and the like. US 8,268,352 B2 5 6 Further, high solubility active ingredient, where appli tatin Sodium; Potassium chloride; Primaquine phosphate: cable, may be present either in the form of one substantially Promethazine; Promethazine hydrochloride; Proponolol optically pure enantiomer or as a mixture of enantiomers or hydrochloride: Propoxyphene hydrochloride; Pseudophe polymorphs thereof. drine hydrochloride: Pyridostigmine bromide: Pyridoxine The high solubility active ingredients comprises of the hydrochloride: Quinapril hydrochloride; Quetiapine; Rami following therapeutic classes but not limited to adrenergic pril; Ranitidine hydrochloride: Risedronate sodium; Rosigli agent, adrenocortical steroid; adrenocortical Suppressant; taZone maleate; Sodium valproate; Salbutamol sulfate; Sta aldosterone antagonist; amino acid; anabolic; analeptic; anal Vudine; Sumatriptan Succinate; Terazosin hydrochloride; gesic; anesthetic; anorectic; anti-acne agent; anti-adrenergic; Tetracycline hydrochloride; Timolol meleate; Tramodol anti-allergic; anti-amebic; anti-anemic; anti-anginal; anti-ar 10 hydrochloride: Valacyclovir hydrochloride; Vancomycin; thritic; anti-asthmatic; anti-atherosclerotic; antibacterial; Venlafaxine hydrochloride: Verapamil hydrochloride; anticholinergic; anticoagulant; anticonvulsant; antidepres Wafarin sodium and the active ingredients described in U.S. Sant; antidiabetic; antidiarrheal; antidiuretic; anti-emetic; Pat. Nos. 2,968, 158, 3,097,242, 3,454,635, 3,654,357, 3,668, anti-epileptic; antifibrinolytic; antifungal; antihemorrhagic; 215, 3,669,966, 3,708,486, 3,801,495, 5,104,888, 5,232,945, antihistamine; antihyperlipidemia; antihypertensive; antihy 15 5,264,451, 5,478,852, 6,296,874, 3,957,853, 4,080,472, potensive; anti-infective; anti-inflammatory; antimicrobial; 3,174,901, 4,835,184, 6,031,004 and European patent publi antimigraine; antimitotic; antimycotic, antinauseant, antine cation numbers EP0008203, EP0032128, EPO139421, oplastic, antineutropenic, antiparasitic; antiproliferative; EP0155845, EP0177353, EP0208420, EP0257881, antipsychotic; antirheumatic; antiseborrheic; antisecretory; EP0306228, EP0319189, EP0332331, EP0332332, antispasmodic; antithrombotic; anti-ulcerative; antiviral; EP0428312, EP0489663, EP0508740, EP0528734, appetite Suppressant, blood glucose regulator, bone resorp EP0533933, EP0833933, EP87112480.6 and Japanese patent tion inhibitor, bronchodilator, cardiovascular agent; cholin number 05271204 and United Kingdom patent numbers ergic; depressant; diagnostic aid; diuretic: dopaminergic 5504078, GB2088365A and PCT patent application numbers agent; estrogen receptor agonist; fibrinolytic; fluorescent WO91/19702, WO92/03425, WO92/18501, WO93/02079, agent, free oxygen radical scavenger, gastric acid Supressant; 25 WO93/21166, WO93/22445, WO94/01420, WO94/05659. gastrointestinal motility effector; glucocorticoid; hair growth The quantity of the high solubility active ingredient for e.g. stimulant; hemostatic; histamine H2 receptor antagonists; as mentioned above can be less than or equal to 1500 mg. hormone; hypocholesterolemic; hypoglycemic; hypolipi A dosage form of the present invention may optionally demic; hypotensive; imaging agent; immunizing agent; contain more than one high solubility active ingredient. immunomodulator; immunoregulator; immunostimulant; 30 A dosage form of the present invention may optionally immunosuppressant, keratolytic; LHRHagonist; mood regu contain more than one antidiabetic active ingredient. lator; mucolytic; mydriatic; nasal decongestant; neuromus As indicated above the outer portion of the present inven cular blocking agent; neuroprotective; NMDA antagonist; tion may comprise auxiliary excipients such as for example non-hormonal sterol derivative; plasminogenactivator, plate lubricants, plasticisers, anti-tack agents, opacifying agents, let activating factorantagonist, platelet aggregation inhibitor, 35 pigments, and Such like. As will be appreciated by those psychotropic; radioactive agent; scabicide; sclerosing agent; skilled in the art, the exact choice of excipient and their sedative; sedative-hypnotic; selective adenosine Al antago relative amounts will depend to some extent on the final oral nist, serotonin antagonist; serotonin inhibitor, serotonin dosage form. receptor antagonist; Steroid; thyroid hormone; thyroid inhibi Suitable lubricants, including agents that act on the tor; thyromimetic; tranquilizer, amyotrophic lateral Sclerosis 40 flowability of the powder to be compressed are, for example, agent; cerebral ischemia agent, Paget’s disease agent; colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a unstable angina agent; vasoconstrictor; vasodilator, wound Trade Mark); talc, Stearic acid, magnesium Stearate, calcium healing agent; Xanthine oxidase inhibitor. Stearate and sodium Stearyl fumarate. Examples of high solubility active ingredients comprises In micro matrix particles, the active ingredient and one or of but not limited to Abacavir sulfate; Aminocaproic acid; 45 more hydrophobic release controlling agents are preferably Alendronate sodium; Amitriptyline hydrochloride: Amphet present in a ratio of from 100:1 to 100:75, more particularly amine; Acetaminophen; Atropine Sulfate; Balsalazide; Ben from 100:2.5 to 100:50, still more preferably from 100:2.5 to Zepril hydrochloride; Bisoprolol fumarate:Bupropion hydro 100:30 and most preferably from 100:2.5 to 100:20. chloride; Buformin; Captopril; Cetrizine hydrochloride: Micro matrix particles and coating of one or more hydro Ciprofloxacin; Clindamycin; Chlorpheniramine maleate; 50 phobic release controlling agents are preferably present in a Chlorpromazine hydrochloride; Clomipramine hydrochlo ratio of from 100:0.5 to 100:75, more particularly from 100: ride; Clonidine hydrochloride; Clopidogrel bisulfate; Clox 2.5 to 100:50, still more preferably from 100:2.5 to 100:30 acillin Sodium: Codeine phosphate; Colchicines; Cyclophos and most preferably from 100:2.5 to 100:20. phamide; Diethylcarbamazine citrate; DL-methionine: According to one embodiment the release controlling Eprosartan; Ethembutol hydrochloride; Ethosuximide: 55 agents are pharmaceutically excipients, which are hydropho Erythromycin; Ferrous sulfate: Fluoxetine hydrochloride: bic in nature. Fosinopril sodium; Gabapentin: Hydralazine hydrochloride: The polymers that can be used to form the rate-controlling Hydrocodone bitartrate; Hydroxyzine hydrochloride: membrane or micromatrix are described in greater detail Hydroxyurea; Indinavir sulfate; Isoniazid: Isosorbide herein below. moninitrate; Lactobionate; Lamivudine; Levamisole hydro 60 The hydrophobic release controlling agents are selected chloride; Levofloxacin: Lisinopril; Losartan potassium; Met from but are not limited to Ammonio methacrylate copoly formin hydrochloride; Methylphenidate hydrochloride: mers type A and B as described in USP, methacrylic acid Metoprolol tartrate; Minocycline hydrochloride; Mon copolymer type A, B and C as described in USP, Polyacrylate telukast sodium; Naproxen Sodium; Neostigmine bromide; dispersion 30% as described in Ph. Eur., Polyvinyl acetate Nicotinamide: Niacin; Nifurtimox; Nortriptyline hydrochlo 65 dispersion, ethylcellulose, cellulose acetate, cellulose propi ride; Olanzepine; Oxybytynin chloride; Penicillamine: Peni onate (lower, medium or higher molecular weight), cellulose cillin V potassium; Phenyloin sodium; Phenformin; Pravas acetate propionate, cellulose acetate butyrate, cellulose US 8,268,352 B2 7 8 acetate phthalate, cellulose triacetate, poly(methyl methacry The amount of plasticiser to be used is from about 1% to late), poly(ethyl methacrylate), poly(butyl methacrylate), 50% based on the weight of the dry release controlling poly(isobutyl methacrylate), and poly (hexyl methacrylate). agent(s). Poly(isodecyl methacrylate), poly (lauryl methacrylate), poly The amount of release controlling agent(s) to be used in (phenyl methacrylate), poly (methyl acrylate), poly (isopro forming the outer portion will be determined based on various pyl acrylate), poly (isobutyl actylate), poly (octadecyl acry parameters such as the desired delivery properties, including late), waxes such as beeswax, carnauba wax, microcrystalline the amount of active ingredient to be delivered, the active wax, and OZokerite; fatty alcohols such as cetostearyl alcohol, ingredient release rate desired, and the size of the micro Stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty matrix particles. 10 Part comprising another active ingredient—It comprises of acid esters such as glyceryl monostearate, glyceryl distearate, active ingredient(s) and includes one or more commonly used glycerol monooleate, acetylated monoglycerides, tristearin, excipients in oral immediate release or modified release phar tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyc maceutical formulations. eryl behenate, and hydrogenated castor oil. The active ingredient(s) can be present in the form of a free According to an especially preferred embodiment the 15 base or in the form of pharmaceutically acceptable salts. release controlling agent contains ammonio methacrylate co Pharmaceutically acceptable salts forming part of this inven polymers and fatty acid esters as hereinafter described. tion are intended to define but not limited to salts of the The suitable hydrophobic agents are polymers sold under carboxylic acid moiety Such as alkali metal salts like Li, Na the Trade Mark Eudragit RS (Ammonio Methacrylate and K salts; alkaline earth metal salts like Ca and Mg salts; Copolymer type B USP), Eudragit NE 30D (Polyacrylate salts of organic bases such as lysine, arginine, guanidine, dispersion 30% Ph., Eur), Eudragit RL (Ammonio Meth diethanolamine, choline, and the like: ammonium or Substi acrylate Copolymer type AUSP) and Kollicoat SR 30 Dand tuted ammonium salts and aluminium salts. Salts may be acid fatty acid esters such as glyceryl behenate, and hydrogenated addition salts which defines but not limited to sulfates, castor oil. Eudragit polymers are polymeric lacquer Sub nitrates, phosphates, perchlorates, borates, hydrohalides, stances based on acrylate and/or methacrylates. 25 acetates, tartrates, maleates, citrates, succinates, palmoates, The dosage form can also include one or more commonly methanesulfonates, benzoates, salicylates, hydroxynaph used excipients in oral pharmaceutical formulations. thoates, benzensulfonates, ascorbates, glycerophosphates, The ammonio methacrylate co-polymers are preferably ketoglutarates and the like. selected from the group consisting of poly(ethyl acrylate, Further, active ingredient(s), where applicable, may be methyl methacrylate, trimethylammonioethyl methacrylate 30 present either in the form of one substantially optically pure chloride) 1:2:0.1: poly(ethyl acrylate, methyl methacrylate, enantiomer or as a mixture of enantiomers or polymorphs trimethylamonioethyl methacrylate chloride) 1:2:0.2 and thereof. poly(ethyl acrylate, methyl methacrylate) 1:1. The active ingredient(s) comprises of the following thera Representative commonly used excipients in oral pharma peutic classes but not limited to adrenergic agent, adrenocor 35 tical steroid; adrenocortical Suppressant; aldosterone antago ceutical formulations include talc, fumed silica, glyceryl nist; amino acid; anabolic; analeptic; analgesic; anesthetic; monostearate, magnesium Stearate, calcium Stearate, kaolin, anorectic; anti-acne agent; anti-adrenergic; anti-allergic; colloidal silica, gypsum, Tween 80, Geleol pastiles (trade anti-amebic; anti-anemic; anti-anginal; anti-arthritic; anti mark), micronised silica and magnesium trisilicate. asthmatic; anti-atherosclerotic; antibacterial; anticholin The quantity of commonly used excipients in oral pharma 40 ergic; anticoagulant; anticonvulsant, antidepressant; antidia ceutical formulations used is from about 2% to about 500% betic; antidiarrheal; antidiuretic; anti-emetic; anti-epileptic; by weight, preferably from 2 to 100% more particularly 10 to antifibrinolytic; antifungal; antihemorrhagic; antihistamine; 60% based on the total dry weight of the polymer. antihyperlipidemia; antihypertensive; antihypotensive; anti The dosage form can also include a material that improves infective; anti-inflammatory; antimicrobial; antimigraine; the processing of the release controlling agents. Such mate 45 antimitotic; antimycotic, antinauseant, antineoplastic, rials are generally referred to as "plasticisers” and include, for antineutropenic, antiparasitic; antiproliferative; antipsy example, adipates, azelates, benzoates, citrates, isoebucaes, chotic; antirheumatic; antiseborrheic; antisecretory; antis phthalates, sebacates, Stearates, tartrates, polyhydric alcohols pasmodic; antithrombotic; anti-ulcerative; antiviral; appetite and glycols. Suppressant; blood glucose regulator, bone resorption inhibi Representative plasticisers include acetylated monoglyc 50 tor, bronchodilator; cardiovascular agent; cholinergic; erides; butyl phthalylbutyl gylcolate: dibutyl tartrate; diethyl depressant; diagnostic aid; diuretic: dopaminergic agent; phthalate; dimethyl phthalate; ethyl phthalyl ethylglycolate: estrogen receptoragonist; fibrinolytic; fluorescentagent, free glycerin; ethylene glycol, propylene glycol; Triethylcitrate; oxygen radical Scavenger; gastric acid Supressant, gas triacetin; tripropinoin, diacetin: dibutyl phthalate; acetyl trointestinal motility effector; glucocorticoid; hair growth monoglyceride; polyethylene glycols; castor oil; triethyl cit 55 stimulant; hemostatic; histamine H2 receptor antagonists; rate; polyhydric alcohols, acetate esters, glycerol triacetate, hormone; hypocholesterolemic; hypoglycemic; hypolipi acetyl triethylcitrate, dibenzyl phthalate, dihexyl phthalate, demic; hypotensive; imaging agent; immunizing agent; butyloctyl phthalate, disononyl phthalate, butyloctyl phtha immunomodulator; immunoregulator; immunostimulant; late, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, immunosuppressant, keratolytic; LHRHagonist; mood regu diethylexyl phthalate, di-n-octyl phthalate, di-1-octyl phtha 60 lator, mucolytic; mydriatic; nasal decongestant; neuromus late, di-1-decyl phthalate, di-n-undecyl phthalate, di-n-tride cular blocking agent; neuroprotective; NMDA antagonist; cyl phthalate, tri-2-ethylexyl trimellitate, di-2-ethylexyl adi non-hormonal sterol derivative; plasminogenactivator, plate pate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, let activating factor antagonist, platelet aggregation inhibitor; dibutyl sebacate, glyceryl monocaprylate, glycerol distear psychotropic; radioactive agent; scabicide; sclerosing agent; ate, glyceryl monocaprate, nicotine, oxybutamine chloride, 65 sedative; sedative-hypnotic; selective adenosine Al antago perinodopril erbumine, pilocorpine, poldine methyl Sulfate nist; Serotonin antagonist; serotonin inhibitor, serotonin and Zalcitane. receptor antagonist; Steroid; thyroid hormone; thyroid inhibi US 8,268,352 B2 10 tor; thyromimetic; tranquilizer, amyotrophic lateral Sclerosis traZafen, anordrin, antagonist D, antagonist G, antarelix, agent; cerebral ischemia agent, Paget’s disease agent; Antazoline Phosphate, Anthelmycin, Anthralin, Anthramy unstable angina agent; vasoconstrictor; vasodilator, wound cin, antiandrogen, Acedapsone, Felbamate, antiestrogen, healing agent; Xanthine oxidase inhibitor. antineoplaston, Antipyrine, antisense oligonucleotides, apa Examples of active ingredient comprises of but not limited doline, apafant, Apalcillin Sodium, apaxifylline, ApaZone, tO— aphidicolin glycinate, Apixifylline, Apomorphine Hydro 16-alpha fluorocstradiol. 16alpha-gitoxin, 16-epiestriol, 17 chloride, apraclonidine, Apraclonidine Hydrochloride, Apra alpha dihydroequilenin, 17 alpha estradiol, 17beta estradiol, mycin, Aprindine, Aprindine Hydrochloride, aprosulate 17 hydroxy progesterone, 1alpha-hydroxyvitamin D2, Sodium, Aprotinin, Aptazapine Maleate, aptiganel, apurinic 1-dodecpyrrolidinone, 20-epi-1.25 dihydroxyvitamin D3, 10 acid, apurinic acid, aranidipine, Aranotin, Arbaprostil, 22-oxacalcitriol, 20VV. 2'-nor-cGMP 3-isobutyl GABA, arbekicin, arbidol, Arbutamine Hydrochloride, Arclofenin, 5-ethynyluracil, 6-FUDCA, 7-methoxytacrine, Abamectin, Ardeparin Sodium, argatroban, Arginine, Argipressin Tan abanoquil, abecarnil, abiraterone, Ablukast, Ablukast nate, Arildone, aripiprazol, arotinolol, Arpinocid, Arteflene, Sodium, Acadesine, acamprosate, Acarbose, Acebutolol. Artilide Fumarate, asimadoline, aspalatone, Asparaginase, Acecainide Hydrochloride, Aceclidine, aceclofenae, 15 Aspartic Acid, Aspartocin, asperfuran, Aspirin, aspoxicillin, Acedapsone, Aceglutamide Aluminum, Acemannan, Asprelin, Astemizole, Astromicin Sulfate, asulacrine, ata Acetaminophen, Acetazolamide, Acetohexamide, Acetohy mestane, Atenolol, atevirdine, Atipamezole, Atiprosin Male droxamic Acid, acetomepregenol, Acetophenazine Maleate, ate, Atolide, Atorvastatin Calcium, Atosiban, Atovaquone, Acetosulfone Sodium, Acetylcholine Chloride, Acetylcys atpenin B, Atracurium Besylate, atrimustine, atrinositol, teine, acetyl-L-carnitine, acetylmethadol, Acifran, acipimox, Atropine, Auranofin, aureobasidin A, Aurothioglucose, acitemate, Acitretin, Acivicin, Aclarubicin, aclatonium, Avilamycin, Avoparcin, Avridine, AXid, axinastatin 1, axin Acodazole Hydrochloride, aconiazide, Acrisorcin, Acrivas astatin 2, axinastatin 3, AZabon, AZacitidinie, AZaclorzine tine, Acronine, Actisomide, Actodigin, Acyclovir, acylful Hydrochloride, AZaconazole, azadirachtine, AZalanstat Vene, adafenoxate, adapalene, Adapalene, adatanserin, Ada Dihydrochloride, Azaloxan Fumarate, AZanator Maleate, tanserin Hydrochloride, adecypenol, adecypenol, Adefovir, 25 AZanidazole, AZaperone, AZaribine, AZaserine, azasetron, adelmidrol, ademetionine, Adenosine, Adinazolam, Adiphei AZatadine Maleate, AZathioprine, AZathioprine Sodium, aza nine Hydrochloride, adiposin, Adozelesin, adrafinil, Adrena toxin, azatyrosine, azelaic acid, azelastine, azelnidipine, lone, airbutamine, alacepril, Alamecin, Alanine, Alaproclate, AZepindole, AZetepa, azimilide, Azithromycin, AZlocillin, alaptide, Albendazole, albolabrin, Albuterol, Albutoin, AZolimine, AZosemide, AZotomycin, AZtreonam, Alclofenae, AlclometaSone Dipropionate, Alcloxa, aldecal 30 AZumolene Sodium, Bacampicillin Hydrochloride, baccatin mycin, Aldesleukin, Aldioxa, Alendronate Sodium, allen III, Bacitracin, Baclofen, bacoside A, bacoside B, bactobola dronic acid, alentemol, Alentemol Hydrobromide, Aletamine mine, balanol, balazipone, balhimycin, balofloxacin, bal Hydrochloride, Aleuronium Chloride, Alexidine, alfacalci salazide, Bambermycins, bambuterol, Bamethan Sulfate, dol, Alfentanil Hydrochloride, alfuzosin, Algestone Bamifylline Hydrochloride, Bamidazole, baohuoside 1, Bar Acetonide, alglucerase, Aliflurane, alinastine, Alipamide, 35 mastine, barnidipine, Basifungin, Batanopride Hydrochlo Allantoin, Allobarbital, Allopurinol, ALL-TK antagonists, ride, batebulast, Batelapine Maleate, Batimastat, beauveri Alonimid, alosetron, Alosetron Hydrochloride, Alovudine, cin, Becanthone Hydrochloride, becaplermin, becliconazole, Alpertine, Alpha Amylase, alpha idoSone, Alpidem, Alpra Beclomethasone Dipropionate, befloxatone, Beinserazide, Zolam, Alprenolol Hydrochloride, Alprenoxime Hydrochlo Belfosdil, Belladonna, Beloxamide, Bemesetron, Bemitra ride, Alprostadil, Alrestatin Sodium, Altanserin Tartrate, 40 dine, Bemoradan, Benapryzine Hydrochloride, Benazepril Alteplase. Althiazide. Altretamine, altromycin B, Alverinc Hydrochloride, Benazeprilat, Bendacalol Mesylate, Citrate, Alvircept Sudotox, Amadinone Acetate, Amantadine Bendazac, Bendroflumethiazide, benflumetol, benidipine, Hydrochloride, ambamustine, Ambomycin, Ambruticin, Benorterone, Benoxaprofen, Benoxaprofen, Benoximate Ambuphylline, Ambuside, Amcinafal, Amcinonide, Amdi Hydrochloride, Benperidol, Bentazepam, Bentiromide, Ben nocillin, Amdinocillin Pivoxil, Amedalin Hydrochloride, 45 urestat, Benzbromarone, Benzethonium Chloride, Benzetim amelometaSone, Ameltolide, Amesergide, Ametantrone ide Hydrochloride, Benzilonium Bromide, BenZindopyrine Acetate, amezinium metilsulfate, amfebutamone, Amfenac Hydrochloride, benzisoxazole, Benzocaine, benzochlorins, Sodium, Amflutizole, Amicycline, Amidephrine Mesylate, Benzoctamine Hydrochloride, Benzodepa, benzoidazoxan, amidox, Amifloxacin, amifostine, Amikacin, Amiloride Benzonatate, Benzoyl Peroxide, Benzoylpas Calcium, ben Hydrochloride, Aminacrine Hydrochloride, Aminobenzoate 50 Zoylstaurosporine, BenZquinamide, BenZthiazide, benz Potassium, Aminobenzoate Sodium, Aminocaproic Acid, tropine, Benztropine Mesylate, Benzydamine Hydrochlo Aminoglutethimide, Aminohippurate Sodium, aminole ride, Benzylpenicilloyl Polylysine, bepridil, Bepridil 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, 55 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, 60 Hydrochloride, Biclodil Hydrochloride, Bidisomide, bife Amquinate, Amrinone, amrinone, amrubicin, Amsacrine, melane, Bifonazole, bimakalim, bimithil, Bindarit, Binira amylin, amythiamicin, Anagestone Acetate, anagrelide, 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 65 benzimidazole A, bis-benzimidazole B, bisnafide, Bisobrin doXime, Anileridine, Anilopam Hydrochloride, Aniracetam, Lactate, Bisoprolol, Bispyrithione Magsulfex, bistramide D, Anirolac, Anisotropine Methylbromide, Anistreplase, Ani bistramide K, bistratene A, Bithionolate Sodium, Bitolterol US 8,268,352 B2 11 12 Mesylate, Bivalirudin, Bizelesin, Bleomycin Sulfate, Bolan Chloramphenicol, Chlordantoin, Chlordiazepoxide, Chlo diol Dipropionate, Bolasterone, Boldenone Undecylenate, rhexidine Gluconate, chlorins, Chlormadinone Acetate, chlo boldine, Bolenol, Bolmantalate, bopindolol, Bosentan, Boxi roorienticin A, Chloroprocaine Hydrochloride, Chloropropa dine, brefeldin, breflate, Brequinar Sodium, Bretazenil, mide, Chloroquine, chloroquinoxaline Sulfonamide, Bretylium Tosylate, Brifentanil Hydrochloride, brimonidine, Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxyle Brinolase, Brocresine, Brocrinat, Brofoxine, Bromadoline nol, Chlorphenesin Carbamate, Chlorpheniramine Maleate, Maleate, Bromazepam, Bromchlorenone, Bromelains, bro Chlorpromazine, Chlorpropamide, Chlorprothixene, Chlo mfenac, Brominidione, Bromocriptine, Bromodiphenhy rtetracycline Bisulfate, Chlorthalidone, ChlorZoxazone, dramine Hydrochloride, Bromoxanide, Bromperidol, Bro Cholestyramine Resin, Chromonar Hydrochloride, cibenzo mperidol Decanoate, Brompheniramine Maleate, 10 line, cicaprost, Ciclafrine Hydrochloride, Ciclazindol, Broperamole, Bropirimine, Brotizolam, Bucainide Maleate, ciclesonide, cicletanine, Ciclopirox, Cicloprofen, ciclo bucindolol, Buclizine Hydrochloride, Bucromarone, Budes prolol, Cidofovir, Cidoxepin Hydrochloride, Cifenline, onide, budipine, budotitane, Buformin, Bumetamide, Ciglitazone, Ciladopa Hydrochloride, cilansetron, Cilastatin Bunaprolast, bunazosin, Bunolol Hydrochloride, Bupico Sodium, Cilazapril, cilnidipine, Cilobamine Mesylate, cilo mide, Bupivacaine Hydrochloride, Buprenorphine Hydro 15 bradine, Cillofungin, cilostazol, Cimaterol, Cimetidine, chloride, Bupropion Hydrochloride, Buramate, Buserelin cimetropium bromide, Cinalukast, Cinanserin Hydrochlo Acetate, Buspirone Hydrochloride, Busulfan, Butabarbital, ride, Cinepazet Maleate, Cinflumide, Cingestol, cinitapride, Butacetin, Butaclamol Hydrochloride, Butalbital, Butamben, Cinnamedrine, Cinnarizine, cinolazepam, Cinoxacin, Cin Butamirate Citrate. Butaperazine. Butaprost, Butedronate perene, Cinromide, CintaZone, Cintriamide, Cioteronel, Tetrasodium, butenafine, Buterizine, buthionine sulfoximine, Cipamfylline, Ciprefadol Succinate, Ciprocinonide, Ciprofi Butikacin, Butilfenin, Butirosin Sulfate, Butixirate, butixo brate, Ciprofloxacin, ciprostene, Ciramadol, Cirolemycin, cort propionate, Butoconazole Nitrate, Butonate, Butopam cisapride, cisatracurium besilate, Cisconazole, Cisplatin, cis ine. Butoprozine Hydrochloride, Butorphanol, Butoxamine porphyrin, cistinexine, citalopram, Citenamide, citicoline, Hydrochloride. Butriptyline Hydrochloride, Cactinomycin, citreamicin alpha, cladribine, Clamoxyquin Hydrochloride, Cadexomer Iodine, Caffeine, calanolide A, Calcifediol, Cal 25 Clarithromycin, clausenamide, Clavulanate Potassium, Cla cipotriene, calcipotriol, Calcitonin, Calcitriol, Calcium Zolam, Clazolimine, clebopride, Clemastine, Clentiazem Undecylenate, calphostin C, Calusterone, Cambendazole, Maleate, Clidinium Bromide, clinafloxacin, Clindamycin, camonagrel, camptothecin derivatives, canarypox IL-2, can Clioquinol, Clioxanide, Cliprofen, clobazam, Clobetasol desartan, Candicidin, candoxatril, candoXatrilat, Caniglib Propionate, Clobetasone Butyrate, Clocortolone Acetate, ose, Canrenoate Potassium, Canrenone, capecitabine, 30 Clodanolene, Clodazon Hydrochloride, clodronic acid, Clo Capobenate Sodium, Capobenic Acid, Capreomycin Sulfate, fazimine, Clofibrate, Clofilium Phosphate, Clogestone capiromab, capsaicin, Captopril, Capuride, Caracemide, Car Acetate, Clomacran Phosphate, Clomegestone Acetate, bachol, Carbadox, Carbamazepine, Carbamide Peroxide, Clometherone, clomethiazole, clomifene analogues, Clomi Carbantel Lauryl Sulfate, Carbaspirin Calcium, Carbazeran, norex, Clomiphene, Clomipramine Hydrochloride, Clon carbazomycin C, Carbenicillin Potassium, Carbenoxolone 35 azepam, Clonidine, Clonitrate, Clonixeril, Clonixin, Clopa Sodium, Carbetimer, carbetocin, Carbidopa, Carbidopa mide, Clopenthixol, Cloperidone Hydrochloride, Levodopa, Carbinoxamine Maleate, Carbiphene Hydrochlo clopidogrel, Clopimozide, Clopipazan Mesylate, Clopirac, ride, Carbocloral, Carbocysteine, Carbol-Fuchsin, Carbopl Cloprednol, Cloprostenol Sodium, Clorazepate Dipotassium, atin, Carboprost, carbovir, carboxamide-amino-triaZo-le. Clorethate, Clorexolone, Cloroperone Hydrochloride, Clor carboxyamidotriazole, carboxymethylated beta-1,3-glucan, 40 prenaline Hydrochloride, Clorsulon, Clortermine Hydro Carbuterol Hydrochloride, CaRest M3, Carfentanil Citrate, chloride, Closantel, Closiramine Aceturate, Clothiapine, Carisoprodol, Carmantadine, Carmustine, CARN 700, Cami Clothixamide Maleate Cloticasone Propionate, Clotrima dazole, Caroxazone, carperitide, Carphenazine Maleate, Car Zole, Cloxacillin BenZathine, Cloxyquin, Clozapine, profen, Carsatirin Succinate, Cartazolate, carteolol, Carteolol Cocaine, Coccidioidin, Codeine, Codoxime, Colchicine, Hydrochloride, cartilage derived inhibitor, Carubicin Hydro 45 colestimide, Colestipol Hydrochloride, Colestolone, Col chloride, Carumonam Sodium, carvedilol, carvotroline, Car forsin, Colfosceril Palmitate, Colistimethate Sodium, Colis votroline Hydrochloride, carzelesin, casein kinase inhibitors tin Sulfate, collismycin A, collismycin B, Colterol Mesylate, (ICOS), castanospermine, caurumonam, cebaracetam, combretastatin A4, combretastatin analogue, complestatin, cecropin B, Cedefingol, Cefaclor, Cefadroxil, Cefamandole, conagenin, Conorphone Hydrochloride, contignasterol, con Cefaparole, Cefatrizine, Cefazaflur Sodium, Cefazolin, Cef 50 tortrostatin, Cormethasone Acetate, Corticorelin Ovine Tri buperaZone, cefcapene pivoxil, cefdaloXime pentexiltosilate, flutate, Corticotropin, Cortisone Acetate, Cortivazol, Corto Cefdinir, cefditoren pivoxil, Cefepime, cefetamet, Cefetecol, doxone, cosalane, costatolide, Cosyntropin, cotinine, 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, 55 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, 60 imide, cyclopentanthraquinones, Cyclopenthiazide, Cyclo Cephalexin, Cephaloglycin, Cephaloridine, Cephalothin pentolate Hydrochloride, Cyclophenazine Hydrochloride, Sodium, Cephapirin Sodium, Cephradine, cericlamine, ceriv 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, 65 Hydrochloride, Cyprazepam, Cyproheptadine Hydrochlo cetrorelix, Cetylpyridinium Chloride, Chenodiol, Chlophedi ride, Cyprolidol Hydrochloride, cyproterone, Cyproximide, anol Hydrochloride, Chloral Betaine, Chlorambucil, Cysteamine, Cysteine Hydrochloride, Cystine, Cytarabine, US 8,268,352 B2 13 14 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, tan, elgodipine, eliprodil, Elsamitrucin, eltenae, Elucaine, dapitant, Dapoxetine Hydrochloride, Dapsone, Daptomycin, emalkalim, emedastine, Emetine Hydrochloride, emiglitate, DarglitaZone Sodium, darifenacin, darlucin A, Darodipine, Emilium Tosylate, emitefur, emoctakin, Enadoline Hydro darsidomine, Daunorubicin Hydrochloride, Dazadrol Male chloride, enalapril, Enalaprilat, Enalkiren, enazadrem, ate, Dazepinil Hydrochloride, Dazmegrel, Dazopride Fuma Encyprate, Endralazine Mesylate, Endrysone, Enflurane, rate, Dazoxiben Hydrochloride, Debrisoquin Sulfate, Decit 10 englitaZone, Enilconazole, Enisoprost, Enlimomab, Enlopl abine, deferiprone, deflazacort, Dehydrocholic Acid, atin, Enofelast, Enolicam Sodium, Enoxacin, enoxacin, dehydrodidemnin B, Dehydroepiandrosterone, delapril, enoxaparin Sodium, Enoxaparin Sodium, Enoximone, Delapril Hydrochloride, Delavirdine Mesylate, delequamine, Empiroline Phosphate, Enprofylline, Enpromate, entacapone, delfaprazine, Delmadinone Acetate, delmopinol, delphini enterostatin, Enviradene, Enviroxime, Ephedrine, Epicillin, din, Demecarium Bromide, Demeclocycline, Demecycline, 15 Epimestrol, Epinephrine, Epinephryl Borate, Epipropidine, Demoxepam, Denofungin, deoxypyridinoline, Depakote, Epirizole, epirubicin, Epitetracycline Hydrochloride, Epithi deprodone, Deprostil, depsidomycin, deramciclane, derma azide, Epoetin Alfa, Epoetin Beta, Epoprostenol, Epopros tan sulfate, Desciclovir, Descinolone Acetonide, Desflurane, tenol Sodium, epoxymeXrenone, epristeride, Eprosartan, Desipramine Hydrochloride, desirudin, Deslanoside, eptastigmine, equilenin, Equilin, ErbuloZole, erdosteine, deslorelin, desmopressin, desogestrel, Desonide. Des Ergoloid Mesylates, Ergonovine Maleate, Ergotamine Tar Oximetasone, desoxoamiodarone, Desoxycorticosterone trate, ersentilide, Ersofermin, erythritol, Erythrityl Tetrani Acetate, detajmium bitartrate, Deterenol Hydrochloride, trate, Erythromycin, Esmolol Hydrochloride, Esorubicin Detirelix Acetate, Devazepide, Dexamethasone, Dexamisole, Hydrochloride, Esproquin Hydrochloride, Estazolam, Estra Dexbrompheniramine Maleate, Dexchlorpheniramine Male diol, Estramustine, estramustine analogue, EstraZinol Hydro ate, Dexclamol Hydrochloride, Dexetimide, Dexfenflu 25 bromide, Estriol, Estrofurate, estrogen agonists, estrogen ramine Hydrochloride, dexifosfamide, Deximafen, Dexi antagonists, Estrogens, Conjugated, Estrogens, Esterified, vacaine, dexketoprofen, dexloxiglumide, Dexmedetomidine, Estrone, Estropipate, esuprone, Etafedrine Hydrochloride, Dexormaplatin, Dexoxadrol Hydrochloride, Dexpanthenol, Etanidazole, etanterol, Etarotene, Etazolate Hydrochloride, Dexpemedolac, Dexpropranolol Hydrochloride, Dexrazox Eterobarb, ethacizin, Ethacrynate Sodium, Ethacrynic Acid, ane, dexSotalol, dextrin 2-sulphate, Dextroamphetamine, 30 Ethambutol Hydrochloride, Ethamivan, Ethanolamine Ole Dextromethorphan, Dextrorphan Hydrochloride, Dextrothy ate, Ethelhlorvynol, Ether, Ethinyl estradiol, Ethiodized Oil, roxine Sodium, deXVerapamil, Dezaguanine, dezinamide, Ethionamide, Ethonam Nitrate, Ethopropazine Hydrochlo dezocine, Diacetolol Hydrochloride, Diamocaine Cycla ride, Ethosuximide, Ethotoin, Ethoxazene Hydrochloride, mate, Diapamide, Diatrizoate Meglumine, Diatrizoic Acid, Ethybenztropine, Ethyl Chloride, Ethyl Dibunate, Ethylestre Diaveridine, Diazepam, Diaziquone, Diazoxide, Dibenzepin 35 nol, Ethyndiol, Ethynerone, Ethynodiol Diacetate, Etibenda Hydrochloride, Dibenzothiophene, Dibucaine, Dichliorvos, Zole, Etidocaine, Etidronate Disodium, Etidronic Acid, Etife Dichloralphenazone, Dichlorphenamide, Dicirenone, nin, Etintidine Hydrochloride, etizolam, Etodolac, Diclofenac Sodium, Dicloxacillin, dicranin, Dicumarol, Etofenamate, Etoformin Hydrochloride, Etomidate, Dicyclomine Hydrochloride, Didanosine, didemnin B, Etonogestrel, Etoperidone Hydrochloride, Etoposide, Eto didox, Dienestrol, dienogest, Diethylcarbamazine Citrate, 40 prine, Etoxadrol Hydrochloride, Etozolin, etrabamine, Etreti diethylhomospermine, diethylnorspermine, Diethylpropion nate, Etryptamine Acetate, Eucatropine Hydrochloride, Hydrochloride, Diethylstilbestrol. Difenoximide Hydrochlo Eugenol, Euprocin Hydrochloride, eveninomicin, Exameta ride. Difenoxin, Diflorasone Diacetate. Difloxacin Hydro Zime, examorelin, Exaprolol Hydrochloride, exemestane, chloride, Difluanine Hydrochloride, Diflucortolone, Diflu fadrozole, faerieflungin, Famciclovir, Famotidine, Fampri midone Sodium, Diflunisal, Difluprednate. Diftalone, 45 dine, fantofarone, Fantridone Hydrochloride, faropenem, Digitalis, Digitoxin, Digoxin, Dihexyverine Hydrochloride, fasidotril, fasudil, fazarabine, fedotozine, felbamate, Felbi dihydrexidine, dihydro-5-azacytidine, Dihydrocodeine nac, Felodipine, Fely pressin, Fenalamide, Fenamole, Fen Bitartrate, Dihydroergotamine Mesylate, Dihydroestoster bendazole, Fenbufen, Fencibutirol, Fenclofenac, Fenclonine, one, Dihydrostreptomycin Sulfate, Dihydrotachysterol, dihy Fenclorac, Fendosal, Fenestrel, Fenethylline Hydrochloride, drotaxol. 9-, Dilantin, Dilevalol Hydrochloride, Diltiazem 50 Fenfluramine Hydrochloride, Fengabine, Fenimide, Fen Hydrochloride, Dimefadane, Dimefline Hydrochloride, isorex, Fenmetozole Hydrochloride, Fenmetramide, Dimenhydrinate, Dimercaprol, Dimethadione, Dimethin Fenobam, Fenoctimine Sulfate, fenofibrate, fenoldopam, dene Maleate, Dimethisterone, dimethyl prostaglandin A1, Fenoprofen, Fenoterol, Fenpipalone, Fenprinast Hydrochlo Dimethyl Sulfoxide, dimethylhomospermine, dimiracetam, ride, Fenprostalene, Fenguizone, fenretinide, fenspiride, Fen Dimoxamine Hydrochloride, Dinoprost, Dinoprostone, 55 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 60 Filipin, finasteride, Flavodilol Maleate, flavopiridol, Flavox obutamide, Disofenin, Disopyramide, Disoxaril, disulfiram, ate Hydrochloride, Flazalone, flecainide, flerobuterol, Ditekiren, Divalproex Sodium, Dizocilpine Maleate, Dob 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, 65 Floxuridine, fluasterone, Fluazacort, Flubanilate Hydrochlo echicetin, echistatin, Echothiophate Iodide, Eclanamine ride, Flubendazole, Flucindole, Flucloronide, Fluconazole, Maleate, EclaZolast, ecomustine, Econazole, ecteinascidin Flucytosine, Fludalanine, Fludarabine Phosphate, Fludazo US 8,268,352 B2 15 16 nium Chloride, Fludeoxyglucose F 18, Fludorex, Fludrocor namate, Hydroxyprogesterone Caproate, Hydroxyurca, tisone Acetate, Flufenamic Acid, Flufenisal, Flumazenil, flu Hydroxyzine Hydrochloride, Hymecromone, Hyoscyamine, mecinol, Flumequine, Flumeridone, Flumethasone, hypericin, Ibafloxacin, ibandronic acid, ibogaine, Ibopamine, Flumetramide, Flumezapine, Fluminorex, Flumizole, Flu ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icatibant moxonide, flunarizine, Flunidazole, Flunisolide, Fluni Acetate, Ichthammol. Icotidine, idarubicin, idoxifene, Idoxu trazepam, Flumixin, fluocalcitriol, Fluocinolone Acetonide, ridine, idramantone, Iemefloxacin, Iesopitron, Ifetroban, Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorescein, Ifosfamide, Ilepeimide, illimaquinone, ilmofosine, illomastat, fluorodaunorunicin hydrochloride, Fluorodopa F 18, Fluo Ilonidap, illoperidone, iloprost, Imafen Hydrochloride, Ima rometholone, Fluorouracil, Fluotracen Hydrochloride, Flu Zodan Hydrochloride, imidapril, imidazenil, imidazoacri oxetine, Fluoxymesterone, fluparoxan, Fluperamide, Fluper 10 dones, Imidecyl Iodine, Imidocarb Hydrochloride, Imidoline olone Acetate, Fluphenazine Decanoate, flupirtine, Hydrochloride. Imidurea, Imiloxan Hydrochloride, Imi Fluprednisolone, FluproduaZone, Fluprostenol Sodium, Flu penem, Imipramine Hydrochloride, imiquimod, immuno quaZone, Fluradoline Hydrochloride, Flurandrenolide, Flu stimulant peptides, Impromidine Hydrochloride, Inda razepam Hydrochloride, Flurbiprofen, Fluretofen, flurithro crinone, Indapamide, Indecainide Hydrochloride, mycin, Flurocitabine, Flurofamide, Flurogestone Acetate, 15 Indeloxazine Hydrochloride, Indigotindisulfonate Sodium, Flurothyl, Fluroxene, Fluspiperone, Fluspirilene, Fluticasone indinavir, Indocyanine Green, Indolapril Hydrochloride, Propionate, flutrimazole, Flutroline, fluvastatin, Fluvastatin Indolidan, indometacin, Indomethacin Sodium, Indoprofen, Sodium, fluvoxamine, Fluzinamide, Folic Acid, Follicle indoramin, Indorenate Hydrochloride, Indoxole, Indriline regulatory protein, Folliculostatin, Fomepizole, Fonazine Hydrochloride, inocoterone, inogatran, inolimomab, Inositol Mesylate, forasartan, forfenimex, forfenirmex, formestane, Niacinate, Insulin, interferons, interleukins, Intrazole, Intrip Formocortal, formoterol, Fosarilate, Fosazepam, Foscarnet tyline Hydrochloride, iobenguane, Iobenzamic Acid, iobitri Sodium, fosfomycin, Fosfonet Sodium, fosinopril, Fosinop dol, Iocarmate Meglumine, Iocarmic Acid, Iocetamic Acid, rilat, fosphenyloin, Fosquidone, Fostedil, fostriecin, fote Iodamide, Iodine, Iodipamide Meglumine, Iodixanol, mustine, Fuchsin, Basic, Fumoxicillin, Fungimycin, Fura iodoamiloride, Iodoantipyrine I 131, Iodocholesterol I 131, profen, Furazolidone. Furazolium Chloride. Furegrelate 25 iododoxorubicin, Iodohippurate Sodium I 131, Iodopyracet I Sodium, Furobufen, Furodazole, Furosemide, Fusidate 125. Iodoquinol, Iodoxamate Meglumine, Iodoxamie Acid, Sodium, Fusidic Acid, gabapentin, Gadobenate Dimeglu Ioglicic Acid, Iofetamine Hydrochloride I 123, iofratol, mine, gadobenic acid, gadobutrol, Gadodiamide, gadolinium Ioglucol, Ioglucomide, Ioglycamic Acid, Iogulamide, texaphyrin, Gadopentetate Dimeglumine, gadoteric acid, Iohexol, iomeprol, Iomethin I 125, Iopamidol, Iopanoic Acid, Gadoteridol, Gadoversetamide, galantamine, galdansetron, 30 iopentol, lophendylate, Ioprocemic Acid, iopromide, Galdansetron Hydrochloride, Gallamine Triethiodide, gal Iopronic Acid, Iopydol, Iopy done, iopyrol, Iosefamic Acid, lium nitrate, gallopamil, galocitabine, Gamfexine, gamolenic Ioseric Acid, Iosulamide Meglumine, Iosumetic Acid, Iota acid, Ganciclovir, ganirelix, gelatinase inhibitors, Gemca Sul, Iotetric Acid, Iothalamate Sodium, Iothalamic Acid, iot diol, Gemcitabine, Gemeprost, Gemfibrozil, Gentamicin Sul riside, Iotrolan, Iotroxic Acid, Iotyrosine 1 131, Ioversol, fate, Gentian Violet, gepirone, Gestaclone, Gestodene, 35 Ioxagiate Sodium, Ioxaglate Meglumine, Ioxaglic Acid, iox Gestonorone Caproate, Gestrinone, Gevotroline Hydrochlo ilan, Ioxotrizoic Acid, ipazilide, ipenoxazone, ipidacrine, ride, girisopam, glaspimod, glaucocalyxin A, Glemanserin, Ipodate Calcium, ipomeanol, 4-, Ipratropium Bromide, ipri Gliamilide, Glibornuride, Glicetanile Sodium, Gliflumide, flavone, Iprindole, profenin, Ipronidazole, Iproplatin, IproX Glimepiride, Glipizide, Gloximonam, Glucagon, glutapy amine Hydrochloride, ipsapirone, irbesartan, irinotecan, rone, glutathione inhibitors, Glutethimide, Glyburide, glyco 40 irloxacin, iroplact, irsogladine, Irtemazole, isalsteine, pine, glycopril, Glycopyrrolate, Glyhexamide, Glymidine Isamoxole, isbogrel, Isepamicin, isobengaZole, Isobutamben, Sodium, Glyoctamide, Glyparamide, Gold Au 198, Gona Isocarboxazid, Isoconazole, Isoetharine, isofloxythepin, doctrinins, Gonadorelin, Gonadotropins, Goserelin, Grami Isoflupredone Acetate, Isoflurane, Isoflurophate, isohomo cidin, Granisetron, grepafloxacin, Griseofulvin, Guaiapate, halicondrin B, Isoleucine, Isomazole Hydrochloride, Isomy Guaithylline, GuanabenZ, Guanabenz, Acetate, Guanadrel 45 lamine Hydrochloride, Isoniazid, Isopropamide Iodide, Iso Sulfate, Guancydine, Guanethidine Monosulfate, Guanfa propyl Alcohol, isopropyl unoprostone, Isoproterenol cine Hydrochloride, Guanisoquin Sulfate, Guanoclor Sulfate, Hydrochloride, Isosorbide, Isosorbide Mononitrate, Iso Guanoctine Hydrochloride, Guanoxabenz, Guanoxan Sul tiquimide, Isotretinoin, Isoxepac, Isoxicam, ISOXSuprine fate, Guanoxyfen Sulfate, Gusperimus Trihydrochloride, Hydrochloride, isradipine, itameline, itasetron, ItaZigrel, ito Halazepam, Halcinonide, halichondrin B. Halobetasol Pro 50 pride, Itraconazole, Ivermectin, jasplakinolide, Josamycin, pionate, halofantrine, Halofantrine Hydrochloride, kahalalide F, Kalafungin, Kanamycin Sulfate, Ketamine Halofenate, Halofuginone Hydrobromide, halomon, Hydrochloride, Ketanserin, Ketazocine, Ketazolam, Halopemide, Haloperidol, halopredone, Haloprogesterone, Kethoxal, Ketipramine Fumarate, Ketoconazole, Ketoprofen, Haloprogin, Halothane, Halquinols, Hamycin, Han memo Ketorfanol, ketorolac, Ketotifen Fumarate, Kitasamycin, pausal gonadotropins, hatomamicin, hatomarubigin A, 55 Labetalol Hydrochloride, Lacidipine, lacidipine, lactitol, lac hatomarubigin B, hatomarubigin C, hatomarubigin D. Hep tivicin, laennec, lafutidine, lamellarin-N triacetate, lamifiban, arin Sodium, hepsulfam, heregulin, Hetacillin, Heteronium Lamivudine, Lamotrigine, lanoconazole, Lanoxin, lan Bromide, Hexachlorophene:Hydrogen Peroxide, Hexafluo perisone, lanreotide, Lansoprazole, latanoprost, lateritin, lau renium Bromide, hexamethylene bisacetamide, Hexedine, rocapram, Lauryl Isoquinolinium Bromide, LaVoltidine Suc Hexobendine, Hexoprenaline Sulfate, Hexylresorcinol, His 60 cinate, lazabemide, Lecimibide, leinamycin, lemildipine, tamine Phosphate. Histidine, Histoplasmin, Histrelin, Homa leminoprazole, lenercept, Leniquinsin, lenograstim, Lemper tropine Hydrobromide, Hoquizil Hydrochloride, Human one, lentinan Sulfate, leptin, leptolstatin, lercanidipine, Ler chorionic gonadotropin, Hycanthone, Hydralazine Hydro gotrile, lerisetron, Letimide Hydrochloride, letraZuril, letro chloride, Hydralazine Polistirex, Hydrochlorothiazide, Zole, Leucine, leucomyzin, Leuprolide Acetate, leuprolide-- Hydrocodone Bitartrate, Hydrocortisone, Hydroflumethiaz 65 estrogen-progesterone, leuprorelin, Levamfetamine ide, Hydromorphone Hydrochloride, Hydroxyamphetamine Succinate, levamisole, Levdobutamine Lactobionate, Hydrobromide, Hydroxychloroquine Sulfate, Hydroxyphe Leveromakalim, levetiracetam, Levey closerine, levobetax US 8,268,352 B2 17 18 olol, levobunolol, levobupivacaine, levocabastine, levocar Sodium, Methopholine, Methotrexate, Methotrimeprazine, nitine, Levodopa, levodropropizine, levofloxacin, Levofural methoxatone, Methoxyflurane, Methsuximide, Methy tadone, Levoleucovorin Calcium, Levomethadyl Acetate, clothiazide, Methyl 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, methylhistamine, R-alpha, methylinosine monophosphate, levormeloxifene, Levorphanol Tartrate, levosimendan, levo Methylphenidate Hydrochloride, Methylprednisolone, Sulpiride, Levothyroxine Sodium, Levoxadrol Hydrochlo Methyltestosterone, Methynodiol Diacelate, Methysergide, ride, Lexipafant, Lexithromycin, liarozole, LibenZapril, Methysergide Maleate, Metiamide, Metiapine, Metioprim, Lidamidine Hydrochloride, Lidocaine, Lidofenin, Lidofla 10 metipamide, Metipranolol, Metizoline Hydrochloride, Met Zine, Lifarizine, Lifibrate, Lifibrol, Linarotene, Lincomycin, kephamid Acetate, metoclopramide, Metocurine Iodide, linear polyamine analogue, Linogliride, Linopirdine, Metogest, Metolazone, Metopimazine, Metoprine, Meto linotroban, linsidomine, lintitript, lintopride, Liothyronine I prolol, Metoquizine, metrifonate, Metrizamide, Metrizoate 125, liothyronine sodium, Liotrix, lirexapride, lisinopril, lis Sodium, Metronidazole, Meturedepa, Metyrapone, Mety soclinamide 7, Lixazinone Sulfate, lobaplatin, Lobenzarit 15 rosine, Mexiletine Hydrochloride, Mexrenoate Potassium, Sodium, Lobucavir, Lodelaben, Iodoxamide, Lofemizole Mezlocillin, mfonelic Acid, Mianserin Hydrochloride, mibe Hydrochloride, Lofentanil Oxalate, Lofepramine Hydrochlo fradil, Mibefradil Dihydrochloride, Mibolerone, michel ride, Lofexidine Hydrochloride, lombricine, Lomefloxacin, lamine B, Miconazole, microcolin A, Midaflur, Midazolam lomerizine, Lometraline Hydrochloride, lometrexol, Lomo Hydrochloride, midodrine, mifepristone, Mifobate, miglitol, fungin, Lomoxicam, Lomustine, Lonapalene, lonazolac, millacemide, milameline, mildronate, Milenperone, Miliper lonidamine, Loperamide Hydrochloride, loracarbef, tine, milnacipran, Milrinone, miltefosine, Mimbane Hydro Lorajmine Hydrochloride, loratadine, Lorazepam, Lorbam chloride, minaprine, Minaxolone, Minocromil, Minocycline, ate, Lorcainide Hydrochloride, Loreclezole, Loreinadol, lor Minoxidil, Mioflazine Hydrochloride, miokamycin, mipra glumide, Lorimetazepam, Lornoxicam, lornoxicam, Lorta goside, mirfentanil, mirimoStim, Mirincamycin Hydrochlo lamine, LorZafone, losartan, losigamone, losoxantrone, 25 ride, Mirisetron Maleate, Mirtazapine, mismatched double Losulazine Hydrochloride, loteprednol, lovastatin, loviride, stranded RNA, Misonidazole, Misoprostol, Mitindomide, Loxapine, Loxoribine, lubeluzole, Lucanthone Hydrochlo Mitocarcin, Mitocromin, Mitogillin, mitoguaZone, mitolac ride, Lufironil, Lurosetron Mesylate, lurtotecan, luteinizing tol, Mitomalcin, Mitomycin, mitonafide, Mitosper, Mitotane, hormone, lutetium, Lutrelin Acetate, luZindole, Lyapolate mitoxantrone, mivacurium chloride, mivaZerol, mixanpril, Sodium, Lycetamine, lydicamycin, Lydimycin, Lynestrenol, 30 Mixidine, mizolastine, mizoribine, Moclobemide, modafinil, Lypressin, Lysine, lysofylline, lysostaphin, lytic peptides, Modaline Sulfate. Modecainide, moexipril, mofarotene, Maduramicin, Mafenide, magainin 2 amide, Magnesium Mofegiline Hydrochloride, mofezolac, molgramostim, Moli Salicylate, Magnesium Sulfate, magnolol, maitansine, Male naZone, Molindone Hydrochloride, Molsidomine, mometa thamer, mallotochromene, mallotojaponin, Malotilate, malo sone, Monatepil Maleate, Monensin, Monoctanoin, Mon tilate, mangafodipir, manidipine, maniwamycin A. Mannitol, 35 telukast Sodium, montirelin, mopidamol, moracizine, mannostatin A, manumycin E, manumycin F. mapinastine, Morantel Tartrate, Moricizine, Morniflumate, Morphine Sul Maprotiline, marimastat, Martek 8708, Martek 92211, Maso fate, Morrhuate Sodium, mosapramine, mosapride, motilide, procol, maspin, massetolide, matrilysin inhibitors, May Motretinide, Moxalactam Disodium, Moxazocine, moxira tansine, Mazapertine Succiniate, Mazindol, Mebendazole, prine, Moxinidazole, moXonidine, Mumps SkinTest Antigen, Mebeverine Hydrochloride, Mebrofenin, Mebutamate, 40 mustard anticancer agent, Muzolimine, mycaperoxide B, Mecamylamine Hydrochloride, Mechlorethamine Hydro Mycophenolic Acid, myriaporone, Nabazenil, Nabilone, chloride, Meclocycline, Meclofenamate Sodium, Mecloqua Nabitan Hydrochloride, Naboctate Hydrochloride, Nabume lone, Meclorisone Dibutyrate, Medazepam Hydrochloride, tone, N-acetyldinaline, Nadide, nadifloxacin, Nadolol, Medorinone, Medrogestone, Medroxalol, Medroxyprogest nadroparin calcium, nafadotride, nafamo.stat, nafarelin, erone, Medrysone, Meelizine Hydrochloride, Mefenamic 45 Nafcillin Sodium, Nafenopin, Nafimidone Hydrochloride, Acid, Mefenidil, Mefenorex Hydrochloride, Mefexamide, Naflocort, Nafomine Malate, Nafoxidine Hydrochloride, Mefloquine Hydrochloride, Mefruside, Megalomicin Potas Nafronyl Oxalate, Naftifine Hydrochloride, naftopidil, nagli sium Phosphate, Megestrol Acetate, Meglumine, Meglutol, van, nagrestip, Nalbuphine Hydrochloride, Nalidixate Melengestrol Acetate, Melitracen Hydrochloride, Mel Sodium, Nalidixic Acid, nalmefene, Nalmexone Hydrochlo phalan, Memotine Hydrochloride, Menabitan Hydrochlo 50 ride, naloxone-pentazocine, Naltrexone, NamoXyrate, Nan ride, Menoctone, menogaril, Menotropins, Meobentine Sul drolone Phenpropionate, Nantradol Hydrochloride, Napacta fate, Mepartricin, Mepenzolate Bromide, Meperidine dine Hydrochloride, napadisilate, Napamezole Hydrochloride, Mephentermine Sulfate, Mephenyloin, Hydrochloride, napavin, Naphazoline Hydrochloride, naph Mephobarbital, Mepivacaine Hydrochloride, Meprobamate, terpin, Naproxen, NaproXol, napsagatran, Naranol Hydro Meptazinol Hydrochloride, Mequidox, Meralein Sodium, 55 chloride, Narasin, naratriptan, nartograstim, nasaruplase, merbarone, Mercaptopurine, Mercufenol Chloride, Mercury, Natamycin, nateplase, Naxagolide Hydrochloride, Nebiv Ammoniated, Merisoprol Hg 197, Meropenem, Mesalamine, olol, Nebramycin, nedaplatin, Nedocromil, Nefazodone Meseclazone, Mesoridazine, Mesterolone, Mestranol, Mesu Hydrochloride, Neflumozide Hydrochloride, Nefopam prine Hydrochloride, Metalol Hydrochloride, Metaproter Hydrochloride, NeleZaprine Maleate, Nemazoline Hydro enol Polistirex, Metaraminol Bitartrate, Metaxalone, 60 chloride, nemorubicin, Neomycin Palmitate, Neostigmine Meteneprost, meterelin, Metformin, Methacholine Chloride, Bromide, neridronic acid, Netilmicin Sulfate, neutral Methacycline, Methadone Hydrochloride, MethadylAcetate, endopeptidase, Neutramycin, Nevirapine, Nexeridine Methalthiazide, Methamphetamine Hydrochloride, Meth Hydrochloride, Niacin, Nibroxane, Nicardipine Hydrochlo aqualone, Methazolamide, Methdilazine, Methenamine, ride, Nicergoline, Niclosamide, Nicorandil, Nicotinyl Alco Methenolone Acetate, Methetoin, Methicillin Sodium, 65 hol, Nifedipine, Nifirmerone, Nifluridide, Nifuradene, Methimazole, methioninase, Methionine, MethisaZone, Nifuraldezone, Nifuratel, Nifuratrone, Nifurdazil, Nifurim Methixene Hydrochloride, Methocarbamol, Methohexital ide, Nifurpirinol, Nifurcquinazol, Nifurthiazole, nilutamide, US 8,268,352 B2 19 20 Nilvadipine, Nimazone, Nimodipine, niperotidine, nirav Perhexiline Maleate, perillyl alcohol, Perindopril, perindop oline, Niridazole, nisamycin, Nisbuterol Mesylate, nisin, rilat, Perlapine, Permethrin, perospirone, Perphenazine, Nisobamate, Nisoldipine, Nisoxetine, Nisterime Acetate, Phenacemide, phenaridine, phenazinomycin, PhenaZopyri Nitarsone, nitazoxanide, nitecapone, Nitrafudam Hydrochlo dine Hydrochloride, Phenbutazone Sodium Glycerate, Phen ride, Nitralamine Hydrochloride, Nitramisole Hydrochlo carbamide, Phencyclidine Hydrochloride, Phendimetrazine ride, Nitrazepam, Nitrendipine, Nitrocycline, Nitrodan, Tartrate, Phenelzine Sulfate, Phenmetrazine Hydrochloride, Nitrofurantoin, Nitrofurazone, Nitroglycerin, Nitromersol, Phenobarbital, Phenoxybenzamine Hydrochloride, Phen Nitromide, Nitromifene Citrate, Nitrous Oxide, nitroxide procoumon, phenserine, phensuccinal, PhenSuximide, Phen antioxidant, nitrullyn, Nivazol, Nivinedone Sodium, Nizati termine, Phentermine Hydrochloride, phentolamine mesi dine, Noberastine, Nocodazole, Nogalamycin, Nolinium 10 late, Phentoxifylline, Phenyl Aminosalicylate, phenylacetate, Bromide, Nomifensine Maleate, Noracymethadol Hydro Phenylalanine, phenylalanyl ketoconazole, Phenylbutazone, chloride, Norbolethone, Norepinephrine Bitartrate, Nore Phenylephrine Hydrochloride, Phenylpropanolamine Hydro thindrone, Norethynodrel, Norfloxacin, Norflurane, Norges chloride, Phenylpropanolamine Polistirex, Phenyramidol timate, Norgestomet, Norgestrel, Nortriptyline Hydrochloride, Phenyloin, phosphatase inhibitors, Physos Hydrochloride, Noscapine, Novobiocin Sodium, N-substi 15 tigmine, picenadol, picibanil, Picotrin Diolamine, picroliv, tuted benzaimides, Nufenoxole, Nylestriol, Nystatin, picumeterol, pidotimod, Pifamine, Pilocarpine, pilsicainide, O6-benzylguanine, Obidoxime Chloride, Ocaperidone, pimagedine, Pimetine Hydrochloride, pimilprost, Pimoben Ocfentanil Hydrochloride, Ocinaplon, Octanoic Acid, dan, Pimozide, Pinacidil, Pinadoline, Pindolol, pinnenol, Octazamide, Octenidine Hydrochloride, Octodrine, Oct pinocebrin, Pinoxepin Hydrochloride, pioglitaZone, Pipam reotide, Octriptyline Phosphate. Ofloxacin, Oformine, oki perone, Pipazethate, pipecuronium bromide, Piperacetazine, cenone, Olanzapine, oligonucleotides, olopatadine, Piperacillin Sodium, Piperamide Maleate, piperazine, Pipo olprinone, olsalazine, Olsalazine Sodium, Olvanil, omepra broman, Piposulfan, Pipotiazine Palmitate, Pipoxolan Zole, onapristone, ondansetron, OntaZolast, Oocyte matura Hydrochloride, Piprozolin, Piquindone Hydrochloride, tion inhibitor, Opipramol Hydrochloride, oracin, Orconazole Piquizil Hydrochloride, Piracetam, Pirandamine Hydrochlo Nitrate, Orgotein, Orlislat, Ormaplatin, Ormetoprim, Ornida 25 ride, pirarubicin, Pirazmonam Sodium, Pirazolac, Pirbenicil Zole, Orpanoxin, Orphenadrine Citrate, osaterone, otenZe lin Sodium, Pirbuterol Acetate, Pirenperone, Pirenzepine pad, Oxacillin Sodium, Oxagrelate, oxaliplatin, OXamarin Hydrochloride, piretanide, Pirfenidone, Piridicillin Sodium, Hydrochloride, oxamisole, Oxamniquine, Oxandrolone, Piridironate Sodium, Piriprost, piritrexim, Pirlimycin Hydro Oxantel Pamoate, Oxaprotiline Hydrochloride, Oxaprozin, chloride, pirlindole, pirmagrel, Pirmenol Hydrochloride, Oxarbazole, Oxatomide, oxaunomycin, Oxazepam, oXcarba 30 Pirnabine, Piroctone, Pirodavir, pirodomast, Pirogliride Tar Zepine, Oxendolone, Oxethazaine, Oxetorone Fumarate, trate, Pirolate, Pirolazamide, Piroxantrone Hydrochloride, Oxfendazole, Oxfenicine, Oxibendazole, oxiconazole, Oxi Piroxicam, Piroximone, Pirprofen, Pirquinozol, Pirsidomine, dopamine, Oxidronic Acid, Oxifungin Hydrochloride, Prenylamine, Pituitary, Posterior, Pivampicillin Hydrochlo Oxilorphan, Oximonam, Oximonam Sodium, Oxiperomide, ride, Pivopril, Pizotyline, placetin A, platinum compounds, oxiracetam, Oxiramide, Oxisuran, Oxmetidine Hydrochlo 35 platinum-triamine complex, Plicamycin, Plomestane, Pobi ride, oxodipine, Oxogestone Phenpropionate, Oxolinic Acid, lukast Edamine, Podofilox, Poisonoak Extract, Poldine Oxprenolol Hydrochloride, Oxtriphylline, Oxybutynin Chlo Methylsulfate, Poliglusam, Polignate Sodium, Polymyxin B ride, Oxychlorosene, Oxycodone, Oxymetazoline Hydro Sulfate, Polythiazide, Ponalrestat, Porfimer Sodium, Porfiro chloride, Oxymetholone, Oxymorphone Hydrochloride, mycin, Potassium Chloride, Potassium Iodide, Potassium Oxypertine, Oxyphenbutazone, Oxypurinol, Oxytetracy 40 Permanganate, Povidone-Iodine, Practolol, Pralidoxime cline, Oxytocin, oZagrel, Ozolinone, Paclitaxel, palauamine, Chloride, Pramiracetam Hydrochloride, Pramoxine Hydro Paldimycin, palinavir, palmitoylrhizoxin, Palmoxirate chloride, Pranolium Chloride, Pravadoline Maleate, Pravas Sodium, pamaqueside, Pamatolol Sulfate, pamicogrel, Pam tatin (Pravachol), Prazepam, Prazosin, Prazosin Hydrochlo idronate Disodium, pamidronic acid, Panadiplon, pan ride, Prednazate, Prednicarbate, Prednimustine, amesine, panaxytriol, Pancopride, Pancuronium Bromide, 45 Prednisolone, Prednisone, Prednival, Pregnenolone Succini panipenem, pannorin, panomifene, pantethine, pantoprazole, ate, Prenalterol Hydrochloride, Pridefine Hydrochloride, Papaverine Hydrochloride, parabactin, Parachlorophenol, Prifelone, Prilocalne Hydrochloride, Prilosec, Primaquine Paraldehyde, Paramethasone Acetate, Paranyline Hydrochlo Phosphate, Primidolol, Primidone, Prinivil, Prinomide ride, Parapenzolate Bromide, Pararosaniline Pamoate, Par Tromethamine, Prinoxodan, Prizidilol Hydrochloride, bendazole, Parconazole Hydrochloride, Paregoric, Pareptide 50 Proadifen Hydrochloride, Probenecid, Probicromil Calcium, Sulfate, Pargyline Hydrochloride, parnaparin sodium, Paro Probucol, Procainamide Hydrochloride, Procaine Hydro momycin Sulfate, Paroxetine, parthenolide, Partricin, Paulo chloride, Procarbazine Hydrochloride, Procaterol Hydro mycin, paZelliptine, PaZinaclone, Pazoxide, paZufloxacin, chloride, Prochlorperazine, Procinonide, Proclonol, Procy pefloxacin, pegaspargase, Pegorgotein, Pelanserin Hydro clidine Hydrochloride, Prodilidine Hydrochloride, Prodolic chloride, peldesine, Peliomycin, Pelretin, Pelrinone Hydro 55 Acid, Profadol Hydrochloride, Progabide, Progesterone, Pro chloride, Pemedolac, Pemerid Nitrate, pemirolast, Pemoline, glumide, Proinsulin Human, Proline, Prolintane Hydrochlo Penamecillin, Penbutolol Sulfate, Penciclovir, Penfluridol, ride, Promazine Hydrochloride, Promethazine Hydrochlo Penicillin G BenZathine, Penicillin G Potassium, Penicillin G ride, Propafenone Hydrochloride, propagermanium, Procaine, Penicillin G Sodium, PenicillinV, Penicillin V Ben Propanidid, Propantheline Bromide, Proparacaine Hydro Zathine, Penicillin V Hydrabamine, Penicillin V Potassium, 60 chloride, Propatyl Nitrate, propentofylline, Propenzolate Pentabamate, Pentaerythritol Tetranitrate, pentafuside, pen Hydrochloride, Propikacin, Propiomazine, Propionic Acid, tamidine, pentamorphone, Pentamustine, Pentapiperium propionylcarnitine, L-, propiram, propiram-paracetamol. Methylsulfate, Pentazocine, Pentetic Acid, Pentiapine Male propiverine, Propofol, Propoxycaine Hydrochloride, Pro ate, pentigetide, Pentisomicin, Pentizidone Sodium, Pento poxyphene Hydrochloride, Propranolol Hydrochloride, Pro barbital, Pentomone, Pentopril, pentosan, pentostatin, Pen 65 pulsid, propyl bis-acridone, Propylhexedrine, Propyliodone, toxifylline, Pentrinitrol, pentrozole, Peplomycin Sulfate, Propylthiouracil, ProquaZone, Prorenoate Potassium, Pepstatin, perflubron, perfofamide, Perfosfamide, pergolide, Proroxan Hydrochloride, Proscillaridin, Prostalene, prostra US 8,268,352 B2 21 22 tin, Protamine Sulfate, protegrin, Protirelin, protosufloxacin, Zene, Simvastatin, Sincalide, Sinefungin, sinitrodil, Protriptyline Hydrochloride, Proxazole, Proxazole Citrate, sinnabidol, Sipatrigine, Sirolimus, Sisomicin, Sitogluside, Proxicromil, Proxorphan Tartrate, prulifloxacin, Pseu sizofiran, sobuzoxane, Sodium Amylosulfate, Sodium Iodide doephedrine Hydrochloride, Puromycin, purpurins, I 123, Sodium Nitroprusside, Sodium Oxybate, sodium phe Pyrabrom, Pyrantel Pamoate, Pyrazinamide, Pyrazofurin, nylacetate, Sodium Salicylate, solverol, Solypertine Tartrate, pyrazoloacridine, Pyridostigmine Bromide, Pyrilamine 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 Maleate, Pyr-rocaine, Pyrroliphene Hydrochloride, Pyrrolni Hydrochloride, Sparfloxacin, Sparfosate Sodium, sparfosic trin, Pyrvinium Pamoate, Quadazocine Mesylate, Quazepam, 10 acid, Sparsomycin, Sparteine Sulfate, Spectinomycin Hydro Quazinone, QuaZodine, QuaZolast, quetiapine, quiflapon, chloride, spicamycin D. Spiperone, Spiradoline Mesylate, quinagolide, Quinaldine Blue, quinapril, Quinaprilat, Spiramycin, Spirapril Hydrochloride, Spiraprilat, Spiroger Quinazosin Hydrochloride, Quinbolone, Quinctolate, Quin manium Hydrochloride, Spiromustine, Spironolactone, decamine Acetate, Quindonium Bromide, Quinelorane Spiroplatin, SpiroXasone, splenopentin, spongistatin 1, Hydrochloride, Quinestrol, Quinfamide, Quingestanol 15 Sprodiamide, squalamine, Stallimycin Hydrochloride, Stan Acetate, Quingestrone, Quinidine Gluconate, Quinielorane nous Pyrophosphate, Stannous Sulfur Colloid, Stanozolol, Hydrochloride, Quinine Sulfate, Quinpirole Hydrochloride, Statolon, staurosporine, stavudine, Steffimycin, Stenbolone Quinterenol Sulfate, Quinuclium Bromide, Quinupristin, Acetate, stepronin, Stilbazium Iodide, Stilonium Iodide, Quipazine Maleate, Rabeprazole Sodium, Racephenicol, stipiamide, Stiripentol, stobadine, Streptomycin Sulfate, Racepinephrine, rafantagonists, Rafoxanide, Ralitoline, ral Streptonicozid, Streptonigrin, Streptozocin, Stromelysin oxifene, raltitrexed, ramatroban, Ramipril, Ramoplanin, inhibitors, Strontium Chloride Sr 89, succibun, Succimer, ramosetron, ranelic acid, Ranimycin, Ranitidine, ranolazine, Succinylcholine Chloride. Sucralfate. Sucrosofate Potas Rauwolfia Serpentina, recainam, Recainam Hydrochloride, sium, Sudoxicam, Sufentanil, Sufotidine, Sulazepam, Sul Reclazepam, regavirumab, RegramoStim, Relaxin, Relomy bactam Pivoxil, Sulconazole Nitrate, Sulfabenz, Sulfabenza cin, Remacemide Hydrochloride, Remifentanil Hydrochlo 25 mide, Sulfacetamide, Sulfacytine, Sulfadiazine, Sulfadoxine, ride, Remiprostol, Remoxipride, Repirinast, Repromicin, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sul Reproterol Hydrochloride, Reserpine, resinferatoxin, Resor famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sul cinol, retelliptine demethylated, reticulon, reviparin Sodium, famoxole, Sulfanilate Zinc, Sulfanitran, sulfasalazine, Sulfa revizinone, rhenium Re 186 etidronate, rhizoxin, Ribaminol, somizole, Sulfazamet, Sulfinalol Hydrochloride, sulfinosine, Ribavirin, Riboprine, ribozymes, ricasetron, Ridogrel, 30 Sulfinpyrazone, Sulfisoxazole, Sulfomyxin, Sulfonterol Rifabutin, Rifametane, Rifamexil, Rifamide, Rifampin, Rifa Hydrochloride, sulfoxamine, Sulinldac, Sulmarin, Sulnida pentine, Rifaximin, RII retinamide, rilopirox, Riluzole, Zole, Suloctidil, Sulofemur, Sulopenem, Suloxifen Oxalate, rimantadine, Rimcazole Hydrochloride, Rimexolone, Rimit Sulpiride, Sulprostone, Sultamicillin, Sulthiame, sultopride, erol Hydrobromide, rimoprogin, riodipine, Rioprostil, Sulukast, Sumarotene, Sumatriptan, Suncillin Sodium, Supro Ripazepam, ripisartan, Risedronate Sodium, risedronic acid, 35 clone, Suprofen, Suradista, Suramin, Surfomer, Suricainide Risocaine, Risotilide Hydrochloride, rispenzepine, Risper Maleate, Suritozole, Suronacrine Maleate, Suxemerid Sul dal, Risperidone, Ritanserin, ritipenem, Ritodrine, fate, Swainsonine, Symakalim, Symclosene, Symetine Ritolukast, ritonavir, rizatriptan benzoate, Rocastine Hydro Hydrochloride, synthetic glycosaminoglycans, Taciamine chloride, Rocuronium Bromide, Rodocaine, Roflurane, Hydrochloride, Tacrine Hydrochloride, Tacrolimus, Talampi Rogletimide, rohitukine, rokitamycin, Roletamicide, Rolga 40 cillin Hydrochloride, Taleranol, Talisomycin, tallimustine, midine, Rolicyprine, Rolipram, Rolitetracycline, Rolodine, Talmetacin, Talniflumate, Talopram Hydrochloride, Talos RomaZarit, romurtide, Ronidazole, ropinirole, Ropitoin alate, Tametraline Hydrochloride, Tamoxifen, Tampramine Hydrochloride, ropivacaine, Ropizine, roquinimex, Rosa Fumarate, Tamsulosin Hydrochloride, Tandamine Hydro ramicin, Rosoxacin, Rotoxamine, roXaitidine, Roxarsone, chloride, tandospirone, tapgen, taprostene, Tasosartan, tauro roXindole, roXithromycin, rubiginone B1, ruboxyl, rufloxa 45 mustine, Taxane, Taxoid, Tazadolene Succinate, taZanolast, cin, rupatidine, Rutamycin, ruzadolane, Sabeluzole, Safingol. tazarotene, Tazifylline Hydrochloride, Tazobactam, safironil, Saintopin, Salbutamol, R-, Salcolex, Salethamide Tazofelone, Tazolol Hydrochloride, Tebufelone, Tebuquine, Maleate, Salicyl Alcohol, Salicylamide, Salicylate Meglu Technetium Tc 99 m Bicisate, Teclozan, Tecogalan Sodium, mine, Salicylic Acid, Salmeterol, Salnacedin, Salsalate, Teecleukin, Teflurane, Tegafur, Tegretol, Teicoplanin, telen sameridine, Sampatrilat, Sancycline, Sanfetrinem, Sangui 50 Zepine, tellurapyrylium, telmesteine, telmisartan, telomerase narium Chloride, Saperconazole, saprisartan, sapropterin, inhibitors, Teloxantrone Hydrochloride, Teludipine Hydro saquinavir, Sarafloxacin Hydrochloride, Saralasin Acetate, chloride, Temafloxacin Hydrochloride, Tematropium Methyl 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 55 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, 60 Tetracaine, tetrachlorodecaoxide, Tetracycline, Tetrahydro Sepazonium Chloride, Seperidol Hydrochloride, Seprilose, Zoline Hydrochloride, Tetramisole Hydrochloride, Tetrazo Seproxetine Hydrochloride, Seractide Acetate, Sergolexole 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 65 Thiamphenicol. Thiamylal. Thiazesim Hydrochloride. Thi mine Hydrochloride, signal transduction inhibitors, Silan azinamium Chloride. Thiethylperazine. Thimerfonate drone, silipide, silteplase, Silver Nitrate, simendan, Simtra Sodium, Thimerosal, thiocoraline, thiofedrine. Thioguanine, US 8,268,352 B2 23 24 thiomarinol, Thiopental Sodium, thioperamide. Thior velaresol, Velnacrine Maleate, Venlafaxine, Veradoline idazine. Thiotepa, Thiothixene. Thiphenamil Hydrochloride, Hydrochloride, Veramine, Verapamil Hydrochloride, verdins, Thiphencillin Potassium, Thiram, Thozalinone. Threonine, Verilopam Hydrochloride, Verlukast, Verofylline, Veroxan, Thrombin, thrombopoietin, thrombopoietin mimetic, thy verteporfin, Vesnarinone, vexibinol, Vidarabine, vigabatrin, malfasin, thymopoietin receptor agonist, thymotrinan, Thy Viloxazine Hydrochloride, Vinblastine Sulfate, vinburnine romedan Hydrochloride, Thyroxine 1 125, Thyroxine 1 131, citrate, Vincofos, Vinconate, Vincristine Sulfate, Vindesine, Tiacrilast, Tiacrilast Sodium, tiagabine, Tiamenidine, tianep Vindesine Sulfate, Vinepidine Sulfate, Vinglycinate Sulfate, tine, tiapafant, Tiapamil Hydrochloride, Tiaramide Hydro Vinleurosine Sulfate, vinorelbine, vinpocetine, Vintoperol, chloride, Tiazofurin, Tibenelast Sodium, Tibolone, Tilbric vinxaltine, Vinzolidine Sulfate, Viprostol, Virginiamycin, Acid, Ticabesone Propionate, Ticarbodine, Ticarcillin Cresyl 10 Viridofulvin, Viroxime, vitaxin, Volazocine, Voriconazole, Sodium, Ticlatone, ticlopidine, Ticrynafen, tienoxolol, Tifu Vorozole, voxergolide, Warfarin Sodium, Xamoterol, rac Sodium, Tigemonam Dicholine, Tigestol, Tiletamine Xanomeline, Xanoxate Sodium, Xanthinol Niacinate, Hydrochloride, Tilidine Hydrochloride, tilisolol, tilnoprofen Xemilofiban, Xenalipin, Xenbucin, Xilobam, Ximoprofen, arbamel, Tilorone Hydrochloride, Tiludronate Disodium, Xipamide, Xorphanol Mesylate, Xylamidine Tosylate, Xyla tiludronic acid, Timefurone, Timobesone Acetate, Timolol, 15 zine Hydrochloride, Xylometazoline Hydrochloride, Xylose, tin ethyl etiopurpurin, Tinabinol, Tinidazole, Tinzaparin yangambin, Zabicipril, Zacopride, Zafirlukast, Zalcitabine, Sodium, Tioconazole, TiodaZosin, Tiodonium Chloride, Tio Zaleplon, Zalospirone, Zaltidine Hydrochloride, Zaltoprofen, peridone Hydrochloride, Tiopinac, Tiospirone Hydrochlo Zanamivir, Zankiren, Zanoterone, Zantac, Zarirlukast, Zate ride, Tiotidine, tiotropium bromide, Tioxidazole, Tipentosin bradine, Zatosetron, Zatosetron Maleate, Zenarestat, ZenaZo Hydrochloride, Tipredane, Tiprenolol Hydrochloride, Tipri cine Mesylate, Zeniplatin, Zeranol, Zidometacin, Zidovu nast Meglumine, Tipropidil Hydrochloride, Tiqueside, dine, Zifrosilone, Zilantel, Zilascorb, Zileuton, Zimeldine Tiquinamide Hydrochloride, tirandalydigin, Tirapazamine, Hydrochloride, Zinc Undecylenate, Zindotrine, Zinocona tirilazad, tirofiban, tiropramide, titanocene dichloride, Tix Zole Hydrochloride, Zinostatin, Zinterol Hydrochloride, Zin anox, Tixocortol Pivalate, Tizanidine Hydrochloride, Tobra viroxime, ziprasidone, Zobolt, Zofenopril Calcium, Zofeno mycin, Tocainide, Tocamphyl, Tofenacin Hydrochloride, 25 prilat, Zolamine Hydrochloride, Zolazepam Hydrochloride, Tolamolol, Tolazamide, Tolazoline Hydrochloride, Tolbuta Zoledronie acid, Zollertine Hydrochloride, Zolmitriptan, mide, Tolcapone, Tolciclate, Tolfamide, Tolgabide, lamot Zolpidem, Zomepirac Sodium, Zometapine, ZonicleZole rigine, Tolimidone, Tolindate, Tolmetin, Tolnaftate, Tolpovi Hydrochloride, Zonisamide, Zopiclone, Zopolrestat, Zorba done 1 131, Tolpyrramide, Tolrestat, Tomelukast, mycin, Zorubicin Hydrochloride, Zotepine, Zucapsaicin or Tomoxetine Hydrochloride, Tonazocine Mesylate, Topira 30 its pharmaceutically acceptable salts thereof. mate, topotecan, Topotecan Hydrochloride, top sentin, As indicated above this portion may comprise auxiliary Topterone, Toquizine, torasemide, toremifene, Torsemide, excipients such as for example diluents, binders, lubricants, Tosifen, Tosufloxacin, totipotent stem cell factor, Traca Surfactants, disintegrants, plasticisers, anti-tack agents, Zolate, trafermin, Tralonide, Tramadol Hydrochloride, Tra opacifying agents, pigments, and Such like. As will be appre mazoline Hydrochloride, trandolapril, Tranexamic Acid, Tra 35 ciated by those skilled in the art, the exact choice of excipient nilast, Transcainide, translation inhibitors, traXanox, and their relative amounts will depend to some extent on the Trazodone Hydrochloride, Trazodone-HCL, Trebenzomine final oral dosage form. Hydrochloride, Trefentanil Hydrochloride, Treloxinate, Suitable diluents include for example pharmaceutically Trepipam Maleate, Trestolone Acetate, tretinoin, Triacetin, acceptable inert fillers such as microcrystalline cellulose, lac triacetyluridine, Triafungin, Triamcinolone, TriampyZine 40 tose, starch, dibasic calcium phosphate, Saccharides, and/or Sulfate, Triamterene, Triazolam, Tribenoside, tricaprilin, mixtures of the foregoing. Examples of diluents include Tricetamide, Trichlormethiazide, trichohyalin, triciribine, microcrystalline celluloses such as those sold under the Trade Tricitrates, Triclofenol piperazine, Triclofos Sodium, Tri Mark Avicel PH 101, Avicel PH 102, Avicel PH 112, Avicel clonide, trientine, Trifenagrel, triflavin, Triflocin, Trifluba PH 200, Avicel PH301 and Avicel PH 302; lactose such as Zam, Triflumidate, Trifluoperazine Hydrochloride, Triflu 45 lactose monohydrate, lactose anhydrous and Pharmatose peridol, Triflupromazine, Triflupromazine Hydrochloride, DCL21 (Pharmatose is a Trade Mark), including anhydrous, Trifluridine, Trihexyphenidyl Hydrochloride, Trilostane, Tri monohydrate and spray dried forms; dibasic calcium phos maZosin Hydrochloride, trimegestone, Trimeprazine Tar phate Such as Emcompress (Emcompress is a Trade Mark); trate, Trimethadione, Trimethaphan Camsylate, Tri mannitol; Pearlitol SD200 (Pearlitol SD200 is a trade mark); methobenzamide Hydrochloride, Trimethoprim, 50 starch; Sorbitol; Sucrose; and glucose. Trimetozine, Trimetrexate, Trimipramine, Trimoprostil, Tri Suitable binders include for example starch, povidone, moxamine Hydrochloride, Triolein 1 125, Triolein 1 131, hydroxypropylmethylcellulose, pregelatinised starch, Trioxifene Mesylate, Tripamide, Tripelennamine Hydrochlo hydroxypropylcellulose and/or mixtures of the foregoing. ride, Triprolidine Hydrochloride, Triptorelin, Trisulfapyrim Suitable lubricants, including agents that act on the idines, Troclosene Potassium, troglitaZone, Trolamine, Trole 55 flowability of the powder to be compressed are, for example, andomycin, trombodipine, trometamol, Tropanserin colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a Hydrochloride, Tropicamide, tropine ester, tropisetron, tros Trade Mark); talc, Stearic acid, magnesium Stearate, calcium pectomycin, trovafloxacin, troVirdine, Tryptophan, Tubercu Stearate and sodium Stearyl fumarate. lin, Tubocurarine Chloride, Tubulozole Hydrochloride, Suitable disintegrants include for example lightly tucarcsol, tulobuterol, turosteride, Tybamate, tylogenin, 60 crosslinked polyvinyl pyrrolidone, corn starch, potato starch, Tyropanoate Sodium, Tyrosine, Tyrothricin, tyrphostins, ube maize starch and modified starches, croScarmellose Sodium, nimex, Uldazepam, Undecylenic Acid, Uracil Mustard, ura cross-povidone, Sodium starch glycolate and combinations pidil, Urea, Uredepa, uridine triphosphate, Urofollitropin, and mixtures thereof. Urokinase, Ursodiol, Valaciclovir, Valine, Valnoctamide, Val The amount of release controlling agent(s) to be used in proate Sodium, Valproic Acid, Valsartan, Vamicamide, Vana 65 will be determined based on drug release rate etc. deine, Vancomycin, Vaninolol, Vapiprost Hydrochloride, The release controlling agents(s) are selected from alkyl Vapreotide, variolin B. Vasopressin, Vecuronium Bromide, celluloses, hydroxyalkyl celluloses, cellulose ethers, cellu US 8,268,352 B2 25 26 lose esters, nitro celluloses, polymers of acrylic and meth tem. Alternatively the coating of the micro matrix particles acrylic acids and esters thereof, polyamides, polycarbonates, with one or more rate controlling agents can be done by hot polyalkylenes, polyalkylene glycols, polyalkylene terephtha melt process using a granulator or fluidized bed coated (pref lates, polyvinyl esters, polyvinylpyrrolidone, polyglycolides, erably Wurster coating), or in a pan coating system. The polysiloxanes and polyurethanes and co-polymers thereof. compression of tablets is carried out on usual compression The high water soluble?permeable release controlling machines (e.g. machines of the Manesty, Cadmach or Kilian). agents is Suitably polyvinyl alcohol, polyvinylpyrrolidone, The tablets can be made of various sizes and shapes. methylcellulose, hydroxypropylcellulose, hydroxypropylm Process for manufacturing combination dosage form as per ethyl cellulose or polyethylene glycol, alginates, polyacrylic instant invention comprising highly soluble drug as modified acids, Xanthun gum or a mixture thereof. 10 release and another active ingredient as immediate release or The low water soluble/permeable release controlling modified release: agents is Suitably ethylcellulose, cellulose acetate, cellulose Part (A)—Granules comprising highly soluble drug: as propionate (lower, medium or higher molecular weight), cel described above. lulose acetate propionate, cellulose acetate butyrate, cellulose Part (B)—It may have following options for manufacturing of acetate phthalate, cellulose triacetate, poly(methyl methacry 15 formulation for another active ingredient. late), poly(ethyl methacrylate), poly(butyl methacrylate), i) Granules for multilayered or compression coated tablets— poly(isobutyl methacrylate), and poly (hexyl methacrylate). It be manufactured in accordance with usual techniques in Poly(isodecyl methacrylate), poly (lauryl methacrylate), poly which the active ingredient(s) and other excipients are (phenyl methacrylate), poly (methyl acrylate), poly (isopro mixed and granulated by adding Solution of binder in a low pyl acrylate), poly (isobutyl actylate), poly (octadecyl acry or high shear mixer or by fluidized bed granulation. The late), waxes such as beeswax, carnauba wax, microcrystalline granulate is dried, preferably in a fluidized bed dryer. The wax, and OZokerite; fatty alcohols such as cetostearyl alcohol, dried granulate is sieved and mixed with lubricants and Stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty disintegrants. Alternatively the manufacture of granules of acid esters such as glyceryl monostearate, glyceryl distearate, inner portion can be made by direct mixing of the directly glycerol monooleate, acetylated monoglycerides, tristearin, 25 compressible excipients or by roller compaction. tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyc ii) Solution or Suspension of active ingredient(s) for drug eryl behenate, and hydrogenated castor oil or a mixture layering on compact part—Active ingredient(s) can be dis thereof. solved or suspended in solution of suitable binder(s) This The non-biodegradable materials are selected from but are Solution or Suspension can be sprayed or layered over the not limited to Ammonio methacrylate copolymers type A and 30 dosage form prepared as per the invention. Spraying can be B as described in USP, Polyacrylate dispersion 30% as carried out using a fluidized bedcoated, or in a pan coating described in Ph. Eur, Polyvinyl acetate dispersion, cellulose system. derivatives such as ethylcellulose, cellulose acetate waxes C) Tablet Compression Such as beeswax, carnauba wax, microcrystalline wax, and Suitable tablet presses can be used for single layered tab oZokerite; fatty alcohols such as cetostearyl alcohol, Stearyl 35 lets, multilayered tablets or compression coated tablets using alcohol; cetyl alcohol and myristyl alcohol; and fatty acid granules prepared in part A and part B. esters such as glyceryl monostearate, glyceryl distearate, D) Capsule Filling glycerol monooleate, acetylated monoglycerides, tristearin, Compact tablets of highly soluble active ingredient and tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyc tablets or granules of another active ingredient can be filled in eryl behenate, and hydrogenated castor oil. 40 hard gelatin capsule shells by using Suitable machines. The mucoadhesive release controlling agents are selected from but are not limited to carbopol, sodium carboxymethyl BRIEF DESCRIPTION OF THE DRAWINGS cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium FIG. 1 (a) is a cross section of coated micro matrix particles hyaluronate, gaur gum, Sodium alginate, polycabophil. 45 prepared by spheronization and coating for the purpose of starch, dextran or chitosan. illustration only. Active ingredients especially the poorly soluble active FIG.1 (b) is a cross section of coated micro matrix particles ingredients mentioned above can be micronized to increase prepared by granulation and coating for the purpose of illus solubility and/or bioavialability. tration only. The novel modified release dosage form of the present 50 FIG. 2 is a plot of % active ingredient versus time for invention can be manufactured by the following procedure: modified release active agent prepared using dual retard tech The micro matrix particles can be manufactured in accor nique as described in the present invention and prepared dance with usual techniques in which the active ingredient without retard release technique as per examples 1 and 3; and one or more hydrophobic release controlling agents are FIG. 3 is a plot of % active ingredient versus time for mixed and granulated by adding solvent in a low or high shear 55 modified release active agent prepared using dual retard tech mixer or by fluidized bed granulator. The granulate is dried, nique as described in the present invention and prepared preferably in a fluidized bed dryer. The dried granulate is without retard release technique as per examples 2 and 4. sized. The sizing of the micromatrix particles can be done FIG. 4 is a plot of % active ingredient versus time for using oscillating granulator, comminuting mill or any other modified release active agent prepared using dual retard tech conventional method. The sieve used for the sizing can have 60 nique as described in the present invention and prepared openings from 0.25 mm to 5 mm. Alternatively the micro without retard release technique as per examples 8 and 11 matrix particles can be made by extrusion, spheronization or respectively. by roller compaction. The micro matrix particles can be FIG. 5 is a plot of metformin plasma concentration versus coated by a solution of one or more hydrophobic release time for formulation prepared as per the invention; controlling agents by any known method, including spray 65 FIGS. 1 (a) and 1(b) show the cross section of the coated application. Spraying can be carried out using a fluidized bed micro matrix particles 1 as described in the present invention coated (preferably Wurster coating), or in a pan coating sys and having a high solubility active ingredient 2, hydrophobic US 8,268,352 B2 27 28 release controlling agent 3 and a coating of hydrophobic mately 4 to 6 hours. The minimum plasma concentration (at release controlling agent 4. FIGS. 2 and 3 show release of 24 hours) of the said dosage form ranges between 0 and 450 high solubility active agent 5 & 6 and 9 & 10 as per example ng/ml after oral administration. 1 & 2 respectively from a dosage form prepared using dual Conclusion: retard technique and release of high solubility active agent 7 & 8 and 11 & 12 as per example 3 & 4 respectively The composition of the micromatrix particles and coated from a dosage form prepared without using dual retard micromatrix particles of the dosage form comprising niacin is release technique. The total quantity of the hydrophobic as follows— release controlling agent is same in all the dosage forms inspite of that the figures clearly shows that dual retard tech 10 nology significantly reduces the burst effect and effectively controls the release rate of the high solubility active ingredi Micro matrix particles ent for prolonged period. FIG. 4 shows release of high solu bility active agent 13 & 14 as per example 8 from a dosage Niacin 75% Wiw to 99% Wiw form prepared using dual retard technique and release of high 15 Eudragit RS 1% Wiw to 25% Wiw solubility active agent 15 & 16 as per example 11 from a Coated micro matrix particles dosage form prepared without using dual retard release tech nique. The total quantity of the hydrophobic release control Micro matrix particles 70% Wiw to 99% Wiw ling agent is same in all the dosage forms. Inspite of that the Hydrogenated castor oil 1% Wiw to 30% Wiw figures clearly show that dual retard technology significantly Magnesium stearate O% Wiw to 2% Wiw reduces the burst effect and effectively controls the release rate of the high solubility antidiabetic active ingredient for prolonged period. The composition of the micromatrix particles and coated 25 DESCRIPTION OF PREFERRED micromatrix particles of the dosage form comprising met EMBODIMENTS formin hydrochloride is as follows— The following examples further illustrate but by no means limit the present invention. Micro matrix particles The dissolution of novel dosage form of the present inven 30 tion was determined by following method. Metformin hydrochloride 75% Wiw to 99% Wiw Eudragit RS 1% Wiw to 25% Wiw Coated micro matrix particles Micro matrix particles 70% Wiw to 99% Wiw For sodium valproate 35 Hydrogenated castor oil 1% Wiw to 30% Wiw Magnesium stearate O% Wiw to 2% Wiw instrument Apparatus I, USP (basket) Revolution 60 min. Temperature 37 - O.S. C. Dissolution medium 1000 ml pH 6.8 buffer For niacin 40 Description Preferred Embodiments instrument Apparatus I, USP (Basket) Revolution 100/min. Temperature 37 - O.S. C. EXAMPLES Dissolution medium 900 in O.1 NHC For venlafaxine hydrochloride 45 Example 1 instrument Apparatus II, USP (Paddle) Revolution 100/min. Temperature 37 - O.S. C. A) Micro matrix particles—90.91% w/w of sodium val Dissolution medium 500 ml water For metformin hydrochloride proate is mixed with 9.09% w/w of Eudragit RS (Ammonio 50 Methacrylate Copolymer type B USP) and the mixture is instrument Apparatus II, USP (Paddle) granulated with a solvent mixture of acetone and methylene Revolution 50/min. chloride and then dried. The granules are sized. Temperature 37 - O.S. C. Dissolution medium 900 in O.1 NHC B) Coating of Micro matrix particles 85.54% w/w of 55 micro matrix particles is charged in fluidized bed processor. The dissolution of high solubility ingredient of the formu 13.61% w/w of hydrogenated castor oil is dissolved in lation of the present invention is achieved not more than 50% acetone and this coating solution is sprayed to coat the micro in 1 hour and from 25 to 90% in six hours. matrix particles. The coated micro matrix particles are sieved The dissolution of metformin hydrochloride is achieved and mixed with 0.86% w/w magnesium stearate. not more than 50% in 1 hour, and from 30 to 90% is in four 60 C) Compression of tablets hours and not less than 65% in 12 hours. After oral administration of a dosage form of the present Tablet (1)—1286 mg granules are pressed to tablet (equiva invention the maximum plasma concentration can be lent to 1000 mg sodium valproate) using 20.3x9.8 mm oval achieved between 700 ng/ml and 2500 ng/ml, preferably from punches. 900 ng/ml to 2400 ng/ml and more preferably from 1000 65 Tablet (2)—0.643 mg granules are pressed to tablet (equiva ng/ml to 2350 ng/ml. The invivo mean dissolution time lent to 500 mg sodium valproate) using 14.95x8.35 mm (MDT) of the dosage form of the present invention is approxi oblong punches. US 8,268,352 B2 29 30 The dissolution rate of the novel dosage form was deter USP) and the mixture is granulated with a solvent mixture of mined (Table 1) acetone and methylene chloride and then dried. The granules are sized and mixed with 13.6% w/w of hydrogenated castor TABLE 1. oil and 0.86% w/w of magnesium stearate. 5 Compression of tablets Dissolution profile Tablet (1)—1286 mg granules are pressed to tablet (equiva % Released lent to 1000 mg sodium valproate) using 20.3x9.8 mm oval punches. Tablet (1) Tablet (2) Tablet (2)—643 mg granules are pressed to tablet (equivalent 1 18.2 23.4 10 to 500 mg sodium valproate) using 14.95x8.35 mm oblong 2 27.8 35.1 4 42.5 51.5 punches. 6 52.8 62.9 The dissolution rate of the novel dosage form was deter 8 61.6 72.1 mined (Table 3) 10 68.3 79.2 12 74.2 84.1 15 14 79.2 88.3 TABLE 3 24 94.4 102.0 Dissolution profile % Released Example 2 Tablet (1) Tablet (2) A) Micro matrix particles—90.91% w/w of niacin is mixed 1 63.4 SO.2 with 9.09% w/w of Eudragit RS (Ammonio Methacrylate 2 85.1 69.1 Copolymer type BUSP) and the mixture is granulated with a 4 101.6 92.0 6 103.1 102.5 solvent mixture of acetone and methylene chloride and then 25 dried. The granules are sized. B) Coating of Micro matrix particles 85.54% w/w of micro matrix particles is charged in fluidized bed processor. Example 4 13.61% w/w of hydrogenated castor oil is dissolved in acetone and this coating solution is sprayed to coat the micro 77.76% w/w of niacin is mixed with 7.78% w/w of matrix particles. The coated micro matrix particles are sieved 30 Eudragit RS (Ammonio Methacrylate Copolymer type B and mixed with 0.86% w/w magnesium stearate. USP) and the mixture is granulated with a solvent mixture of C) Compression of tablets acetone and methylene chloride and then dried. The granules Tablet (1)—1286 mg granules are pressed to tablet (equiva are sized and mixed with 13.6% w/w of hydrogenated castor lent to 1000 mg niacin) using 20.3x9.8 mm oval punches. oil and 0.86% w/w of magnesium stearate. Tablet (2)—643 mg granules are pressed to tablet (equivalent 35 Compression of tablets to 500 mg niacin) using 14.95x8.35 mm oblong punches. Tablet (1) The granules are pressed to 1286 mg (equivalent The dissolution rate of the novel dosage form was deter to 1000 mg niacin) are compressed using 20.3x9.8 mm mined (Table 2) oval punches. 40 Tablet (2) The granules are pressed to 643 mg (equivalent to TABLE 2 500 mg niacin) are compressed using 14.95x8.35 mm Dissolution profile oblong punches. The dissolution rate of the novel dosage form was deter % Released mined (Table 4) Tablet (1) Tablet (2) 45 TABLE 4 1 9.1 12.0 2 14.6 18.2 Dissolution profile 4 23.8 28.6 6 27.5 35.2 % Released 8 30.6 39.5 50 10 34.7 44.8 Tablet (1) Tablet (2) 12 37.6 49.5 14 43.8 52.5 1 31.9 29.6 24 S.O.3 64.5 2 44.8 34.9 4 60.3 51.7 6 71.7 62.1 Dosage forms described in the examples 3 and 4 are pre 55 8 81.4 67.7 pared by not coating the micro matrix particles but the hydro 10 88.2 74.7 phobic release controlling agent is mixed with the micro 12 94.7 82.3 matrix particles. The sole purpose of these examples is to 24 98.6 98.1 demonstrate the usefulness of the present invention as described earlier. The examples clearly show that the rate of 60 release of the modified release active ingredient is signifi Example 5 cantly faster than the present invention. A) Micro matrix particles 80.93% w/w of Venlafaxine Example 3 hydrochloride is mixed with 19.07% w/w of Eudragit RS 65 (Ammonio Methacrylate Copolymer type B USP) and the 77.76% w/w of sodium valproate is mixed 7.78% w/w of mixture is granulated with a solvent mixture of acetone and Eudragit RS (Ammonio Methacrylate Copolymer type B methylene chloride and then dried. The granules are sized. US 8,268,352 B2 31 32 B) Coating of Micro matrix particles 70.13% w/w of C) Compression of tablets—1161 mg granules are pressed micro matrix particles is charged in fluidized bed processor. to tablet (equivalent to 1000 mg niacin) using 20.3x9.8 mm 28.37% w/w of hydrogenated castor oil is dissolved in oval punches. acetone and this coating solution is sprayed to coat the micro The dissolution rate of the novel dosage form was deter matrix particles. The coated micro matrix particles are sieved mined (Table 7) and mixed with 1.0% w/w magnesium stearate and 0.50% w/w colloidal silicon dioxide. TABLE 7 C) Compression of tablets 299.09 mg granules are pressed to tablet (equivalent to 150 mg venlafaxine) 9.53 mm Dissolution profile 10 round, concave punches. Time (hour) % Released The dissolution rate of the novel dosage form was deter 24.35 mined (Table 5) 36.41 43.86 TABLE 5 SO.63 15 57.43 Dissolution profile 63.82 71.20 Time (hour) % Released 2 32.1 4 4.1.8 Example 8 6 S.O.3 8 62.5 12 68.4 A) Micro matrix particles—90.91% w/w of metformin hydrochloride is mixed with 9.09% w/w of Eudragit RS (Am monio Methacrylate Copolymer type BUSP) and the mixture 25 Example 6 is granulated with a solvent mixture of acetone and methylene chloride and then dried. The granules are sized. B) Coating of Micro matrix particles 85.54% w/w of A) Micro matrix particles—95.24% w/w of niacin is mixed micro matrix particles is charged in fluidized bed processor. with 4.76% w/w of Eudragit RS (Ammonio Methacrylate 13.61% w/w of hydrogenated castor oil is dissolved in Copolymer type BUSP) and the mixture is granulated with a 30 acetone and this coating solution is sprayed to coat the micro solvent mixture of acetone and methylene chloride and then matrix particles. The coated micro matrix particles are sieved dried. The granules are sized. and mixed with 0.86% w/w magnesium stearate. B) Coating of Micro matrix particles—92.43% w/w of C) Compression of tablets micro matrix particles is charged in fluidized bed processor. Tablet (1)—1286 mg granules are pressed to tablet (equiva 6.60% w/w of hydrogenated castor oil is dissolved in acetone 35 lent to 1000 mg metforminhydrochloride) are compressed and this coating solution is sprayed to coat the micro matrix using 20.3x9.8 mm oval punches. particles. The coated micro matrix particles are sieved and Tablet (2)—643 mg granules are pressed to tablet (equivalent mixed with 0.97% w/w magnesium stearate. to 500 mg metforminhydrochloride) are compressed using C) Compression of tablets—1136 mg granules are pressed 14.95x8.35 mm oblong punches. to tablet (equivalent to 1000 mg niacin) using 20.3x9.8 mm 40 The dissolution rate of the novel dosage form was deter oval punches. mined (Table 8) The dissolution rate of the novel dosage form was deter mined (Table 6) TABLE 8 45 Dissolution profile TABLE 6 % Released Dissolution profile Tablet (1) Tablet (2) Time (hour) % Released 50 1 37.1 36.5 24.87 2 49.5 S1.O 35.25 4 65.3 63.6 48.71 6 76.2 77.5 57.80 8 84.O 87.8 64.61 10 91.7 91.9 72.22 12 98.9 95.8 77.20 55

Example 9 Example 7 60 A) Micro matrix particles—90.91% w/w of metformin A) Micro matrix particles—Same as example 6. hydrochloride is mixed with 9.09% w/w of Eudragit RS (Am B) Coating of Micro matrix particles—90.44% w/w of monio Methacrylate Copolymer type BUSP) and the mixture micro matrix particles is charged in fluidized bed processor. is granulated with a solvent mixture of acetone and methylene 8.61% w/w of hydrogenated castor oil is dissolved in acetone chloride and then dried. The granules are sized. and this coating solution is sprayed to coat the micro matrix 65 B) Coating of Micro matrix particles 83.91% w/w of particles. The coated micro matrix particles are sieved and micro matrix particles is charged in fluidized bed processor. mixed with 0.95% w/w magnesium stearate. 15.26% w/w of hydrogenated castor oil is dissolved in US 8,268,352 B2 33 34 acetone and this coating solution is sprayed to coat the micro Example 11 matrix particles. The coated micro matrix particles are sieved and mixed with 0.84% w/w magnesium stearate. 77.76% w/w of metformin hydrochloride is mixed with C) Compression of tablets 7.78% w/w of Eudragit RS (Ammonio Methacrylate Copoly 1311 mg granules are pressed to tablet (equivalent to 1000 mer type BUSP) and the mixture is granulated with a solvent mg metformin hydrochloride) using 20.3x9.8 mm oval mixture of acetone and methylene chloride and then dried. punches. The granules are sized and mixed with 13.6% w/w of hydro The dissolution rate of the novel dosage form was deter genated castor oil and 0.86% w/w of magnesium Stearate. mined (Table 9) 10 Compression of Tablets Tablet (1)—1286 mg granules are pressed to tablet (equiva TABLE 9 lent to 1000 mg metformin hydrochloride) using 20.3x9.8 Dissolution profile mm oval punches. Tablet (2)—643 mg granules are pressed to tablet (equivalent Time 15 (hour)Ol %o ReleasedRee8Se. to 500 mg metformin hydrochloride) using 14.95x8.35 mm oblong punches. 1 3344 2 45.79 The dissolution rate of the novel dosage form was deter 4 55.28 mined (Table 11) 6 6O45 8 66.10 10 69.87 TABLE 11 12 73.88 24 86.97 Dissolution profile % Released 25 Example 10 Tablet (1) Tablet (2) 1 S.O.3 52.5 2 70.5 74.2 A) Micro matrix particles—90.91% w/w of metformin 4 88.0 89.4 hydrochloride is mixed with 9.09% w/w of Eudragit RS (Am 6 100.9 100.7 monio Methacrylate Copolymer type BUSP) and the mixture 30 is granulated with a solvent mixture of acetone and methylene chloride and then dried. The granules are sized. B) Coating of Micro matrix particles 87.23% w/w of Example 12 micro matrix particles is charged in fluidized bed processor. 11.90% w/w of hydrogenated castor oil is dissolved in A) Micro matrix particles—93.02% w/w of metformin acetone and this coating solution is sprayed to coat the micro hydrochloride is mixed with 6.98% w/w of Eudragit RS (Am matrix particles. The coated micro matrix particles are sieved monio Methacrylate Copolymer type BUSP) and the mixture and mixed with 0.87% w/w magnesium stearate. is granulated with a solvent mixture of acetone and methylene C) Compression of tablets 40 chloride and then dried. The granules are sized. 1261 mg granules are pressed to tablet (equivalent to 1000 B) Coating of Micro matrix particles—90.56% w/w of mg metformin hydrochloride) using 20.3x9.8 mm oval micro matrix particles is charged in fluidized bed processor. punches. 8.42% w/w of hydrogenated castor oil is dissolved in acetone The dissolution rate of the novel dosage form was deter and this coating solution is sprayed to coat the micro matrix mined (Table 10) 45 particles. The coated micro matrix particles are sieved and mixed with 1.01% w/w magnesium stearate. TABLE 10 C) Compression of tablets Dissolution profile 1187 mg granules are pressed to tablet (equivalent to 1000 mg metformin hydrochloride) using 20.3x9.8 mm oval Time 50 punches. (hour) % Released The dissolution rate of the novel dosage form was deter 42.1 51.30 mined (Table 12) 66.60 78.8O 55 TABLE 12 84.60 91.OO Dissolution profile 99.70 Time (hour) % Released Dosage forms described in the example 11 are prepared by 60 37.59 not coating the micro matrix particles but the hydrophobic 48.91 release controlling agent is mixed with the micro matrix 59.24 particles. The Sole purpose of these examples is to demon 74-85 86.15 strate the usefulness of the present invention as described 88.48 earlier. The examples clearly show that the rate of release of 65 93.30 the modified release antidiabetic active ingredient is signifi cantly faster than the present invention. US 8,268,352 B2 35 36 Example 13 particles. The coated micro matrix particles are sieved and mixed with 1.02% w/w magnesium stearate. A) Micro matrix particles—Same as of example 12. C) Compression of tablets B) Coating of Micro matrix particles 88.70% w/w of 1177 mg granules are pressed to tablet (equivalent to 1000 micro matrix particles is charged in fluidized bed processor. 5 mg metformin hydrochloride) using 20.3x9.8 mm oval 10.31% w/w of hydrogenated castor oil is dissolved in punches. acetone and this coating solution is sprayed to coat the micro The dissolution rate of the novel dosage form was deter matrix particles. The coated micro matrix particles are sieved mined (Table 15) and mixed with 0.99% w/w magnesium stearate. C) Compression of tablets 10 TABLE 1.5 1212 mg granules are pressed to tablet (equivalent to 1000 mg metformin hydrochloride) using 20.3x9.8 mm oval Dissolution profile punches. Time (hour) % Released The dissolution rate of the novel dosage form was deter 15 mined (Table 13) 44.OO 58.80 TABLE 13 71.30 84.10 Dissolution profile 91.93 95.34 Time 98.59 (hour) % Released 31.84 44.66 Example 16 50.55 25 65.29 73.29 Establishing the Pharmacokinetic Profile of 79.8O Metformin Sustained Release Formulation 85.90 The study was carried out to evaluate the pharmacokinetic 30 parameters of the Sustained release metformin formulation Example 14 prepared as per the examples described above. Methodology: A) Micro matrix particles—Same as of example 12. The biostudy had an open label, single period, single treat B) Coating of Micro matrix particles—92.51% w/w of ment, single dose study design. micro matrix particles is charged in fluidized bed processor. 35 Non-compartmental Pharmacokinetic assessment was 6.45% w/w of hydrogenated castor oil is dissolved in acetone based on the plasma levels of metformin. Blood samples were and this coating solution is sprayed to coat the micro matrix obtained before dosing and at the following times after particles. The coated micro matrix particles are sieved and administration of test formulation; mixed with 1.03% w/w magnesium stearate. Pre-dose, 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, C) Compression of tablets 40 10.0, 12.0, 15.0, 18.0, and 24.0 hours. 1162 mg granules are pressed to tablet (equivalent to 1000 Study Population: mg metformin hydrochloride) using 20.3x9.8 mm oval Healthy male volunteers aged between 18 to 45 years. punches. Number of Subjects: The dissolution rate of the novel dosage form was deter Four (04) volunteers were enrolled and all of them com 45 pleted the study. All 04 volunteers were included in the Phar mined (Table 14) macokinetic and safety analyses. TABLE 1.4 Test Formulation, Dose and Mode of Administration: Test Formulation: 1000 mg Metformin sustained release Dissolution profile (SR) formulation prepared as per the invention disclosed. 50 Volunteers received a single oral dose of the above product Time with 200 ml of water 30 minutes after a following high calorie (hour) % Released breakfast (-800 Kcal). 45.90 Pharmacokinetics: 60.10 77.00 The following Pharmacokinetic parameters were calcu 89.70 55 lated using non compartments methods: the area under the 96.72 drug plasma concentration curve from time of dosing to the 98.57 time of last sampling point (AUCo.); the area under the drug 104.33 plasma concentration versus time curve extrapolated to infin ity (AUCo.); the maximum measured concentration of 60 the drug in the plasma (C) and the time at which this Example 15 concentration was measured (t); the concentration at 24 hours (C); the time taken for drug plasma concentration to A) Micro matrix particles—Same as of example 12. decrease by 50% (t); and the terminal first-order elimina B) Coating of Micro matrix particles—91.33% w/w of tion rate constant (K). micro matrix particles is charged in fluidized bed processor. 65 Area Under the curve (AUC) is the integral part of drug 7.65% w/w of hydrogenated castor oil is dissolved in acetone blood level over time from Zero to infinity and is a measure of and this coating solution is sprayed to coat the micro matrix quantity of drug absorbed and in the body. US 8,268,352 B2 37 38 AUC(0-t) represents area under the curve from Zero to time granulated with a solvent mixture of acetone and methylene t, where t represents the time at which last blood sample was chloride and then dried. The granules are sized through 1.0 taken. SCC. AUCo. represents area under the curve from Zero to B) Coating of Micro matrix particles—92.67% w/w of infinity. micro matrix particles is charged in fluidized bed processor. Elimination halflife of a drug is the time in hours necessary 6.47% w/w of hydrogenated castor oil is dissolved in acetone to reduce the drug concentration in the blood, plasma or and this coating solution is sprayed to coat the micro matrix serum to /2 after equilibrium is reached. particles. The coated micro matrix particles are sieved and C is the peak plasma concentration achieved after the mixed with 0.86% w/w magnesium stearate. administration of the drug. 10 T is the time to reach peak plasma concentration. 3) Compression of Bilayered Tablets Statistical Methods: Descriptive statistics of relevant Pharmacokinetic param 483.17 mg granules of inner portion (equal to 325.0 mg eters were performed. aspirin) and 1160 mg granules of outer portion (equal to 1000 Methods used for analysis of Metformin in plasma 15 mg nicotinic acid) are compressed into bilayered tablets using samples: Estimation of Metformin in plasma samples was 20.3x9.8 mm oblong shaped punches. carried out by High Performance Liquid Chromatography What is claimed is: and UV detection at 234 nm. Briefly 0.5 ml of plasma sample 1. A modified release dosage form comprising of a high was precipitated with 2.0 ml acetonitrile. Samples were cen solubility active ingredient prepared by using dual retard trifuged and Supernatant aliquot was washed with dichlo technique to control the release of the high solubility active romethane. After centrifugation, aqueous layer was injected ingredient, wherein the said dual retard technique is a com On HPLC. bination of matrix formulation and reservoir formulation said Pharmacokinetic Results: dosage form consists of a) micro matrix particles which con The Summary of the Pharmacokinetic parameters is con tain a high solubility active ingredient and one or more hydro tained in Table 16. The mean plasma concentration versus 25 phobic release controlling agents, and b) a coating of one or time curve is depicted in FIG. 5. more hydrophobic release controlling agents on said micro matrix particles to form a double barrier to control the diffu TABLE 16 sion of the high solubility active ingredient, wherein the hydrophobic release controlling agents are selected from the Pharmacokinetic Parameters - 30 group consisting of poly(ethyl acrylate, methyl methacrylate, Metformin SR (1000 mg trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly (ethyl acrylate, methyl methacrylate, trimethylamonioethyl Parameters Unit Test (Mean + SD) methacrylate chloride) 1:2:0.2 and poly(ethyl acrylate, AUCo. if ng *hriml 18776, 4672 methyl methacrylate) 1:1, polyvinyl acetate dispersion, eth AUCo 24 ng *hriml 15424 3428 Cmax ng ml 1348 116 35 ylcellulose, cellulose acetate, lower molecular weight cellu C2A, ng ml 245 90 lose propionate, medium molecular weight cellulose propi Tmax hir 4.88 - 1.03 onate, higher molecular weight cellulose proprionate, T1/2 hir 9.28, 173 cellulose acetate propionate, cellulose acetate butyrate, cel lulose acetate phthalate, cellulose triacetate, poly(methyl Conclusion: 40 methacrylate), poly(ethyl methacrylate), poly(butyl meth Metformin has shown Sustained release characteristics acrylate), poly(isobutyl methacrylate), poly (hexyl methacry with following Pharmacokinetic profile; late), poly(isodecyl methacrylate), poly (lauryl methacry The AUC ranged from 12395 to 20345 nghr/ml. late), poly(phenyl methacrylate), poly(methyl acrylate), poly The AUCorranged from 15791 to 25727 nghr/ml. (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl The C ranged from 1227 to 1452 ng/ml. 45 acrylate), beeswax, carnauba wax, microcrystalline wax, and The C- ranged from 165 to 373 ng/ml. oZokerite; cetostearyl alcohol, Stearyl alcohol, cetyl alcohol The T ranged from 3.50 to 6.00 hours. and myristyl alcohol; glyceryl monostearate; glycerol The Tranged from 7.13 to 11.19 hours. monooleate, acetylated monoglycerides, tristearin, tripalm itin, cetyl esters wax, glyceryl palmitostearate, glyceryl Example 17 50 behenate and hydrogenated castor oil, wherein the active ingredient can be less than or equal to 1500 mg. 1) Production of Inner Portion 2. A dosage form as claimed in claim 1, is in the form of tablet. 69.61% w/w of Aspirin coated granules (Aspirin 96% w/w, 3. A dosage form according to claim 1, wherein in said 2.0% w/w hydrogenated castor oil & 2.0% w/w citric acid 55 micro matrix particles, the active ingredient and the one or anhydrous coated) mixed with the mixture of 11.56% w/w of more hydrophobic release controlling agents are present in a microcrystalline cellulose (PH1 12, dried), 7.17% w/w weight ratio of from 100:2.5 to 100:30. sodium starch Glycolate (dried), 2.24% w/w citric acid anhy 4. A dosage form according to claim 1, wherein micro drous, 4.48% w/w talc, 1.79% w/w colloidal silicon dioxide, matrix particles and coating of one or more hydrophobic 1.79% w/w stearic acid and 1.35% w/w hydrogenated veg 60 release controlling agents are present in a weight ratio of from etable oil. 100:25 to 100:30. 5. A dosage form according to claim 1, wherein the high 2) Production of Outer Portion solubility active ingredient is selected from the group con sisting of adrenergic agent; adrenocortical steroid; adreno A) Micro matrix particles—93.02% w/w of nicotinic acid 65 cortical Suppressant; aldosterone antagonist; amino acid; ana is mixed with 6.98% w/w of Eudragit RS PO (Ammonio bolic; analeptic; analgesic; anesthetic; anorectic; anti-acne Methacrylate Copolymer type B USP) and the mixture is agent; anti-adrenergic; anti-allergic; anti-amebic; anti-ane US 8,268,352 B2 39 40 mic; anti-anginal; anti-arthritic; anti-asthmatic; anti-athero Timolol meleate; Tramodol hydrochloride; Valacyclovir Sclerotic; antibacterial; anticholinergic; anticoagulant; anti hydrochloride: Vancomycin; Venlafaxine hydrochloride; convulsant; antidepressant; antidiabetic; antidiarrheal; Verapamil hydrochloride: Wafarin sodium or pharmaceuti antidiuretic; anti-emetic; anti-epileptic; antifibrinolytic; anti cally acceptable salts thereof. fungal; antihemorrhagic; antihistamine; antihyperlipidemia; 7. A process for the preparation of a modified release antihypertensive; antihypotensive; anti-infective; anti-in dosage form comprising a) preparing a micro matrix particles flammatory; antimicrobial; antimigraine; antimitotic; anti consisting of high solubility active ingredient and one or more mycotic, antinauseant, antineoplastic, antineutropenic, anti hydrophobic release controlling agent and b) coating the said parasitic; antiproliferative; antipsychotic; antirheumatic; micromatrix particles consisting of high solubility active antiseborrheic; antisecretory; antispasmodic; antithrombotic; 10 ingredient and one or more hydrophobic release controlling anti-ulcerative; antiviral; appetite Suppressant, blood glucose agent. regulator; bone resorption inhibitor; bronchodilator; cardio 8. A dosage form as claimed in claim 1, wherein said vascular agent; cholinergic; depressant; diagnostic aid; dosage form can optionally comprise another active ingredi diuretic; dopaminergic agent; estrogen receptor agonist; ent as immediate release form or modified release form. fibrinolytic; fluorescentagent, free oxygen radical Scavenger, 15 9. A dosage form as claimed in claim 8, wherein another gastric acid Supressant; gastrointestinal motility effector; glu active ingredient is selected from the group consisting of cocorticoid; hair growth stimulant; hemostatic; histamine H2 adrenergic agent, adrenocortical steroid; adrenocortical Sup receptor antagonists; hormone; hypocholesterolemic; pressant; aldosterone antagonist; amino acid; anabolic; ana hypoglycemic; hypolipidemic; hypotensive; imaging agent; leptic; analgesic; anesthetic; anorectic; anti-acne agent; anti immunizing agent; immunomodulator; immunoregulator; adrenergic; anti-allergic; anti-amebic; anti-anemic; anti immunostimulant; immunosuppressant; keratolytic; LHRH anginal; anti-arthritic; anti-asthmatic; anti-atherosclerotic; agonist; mood regulator, mucolytic, mydriatic; nasal decon antibacterial; anticholinergic; anticoagulant; anticonvulsant; gestant; neuromuscular blocking agent; neuroprotective; antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti NMDA antagonist; non-hormonal sterol derivative; plasmi emetic; anti-epileptic; antifibrinolytic; antifungal; antihem nogen activator, platelet activating factor antagonist, platelet 25 orrhagic; antihistamine; antihyperlipidemia; antihyperten aggregation inhibitor, psychotropic; radioactive agent; scabi sive; antihypotensive; anti-infective; anti-inflammatory; cide; sclerosing agent; sedative; sedative-hypnotic; selective antimicrobial; antimigraine; antimitotic; antimycotic, antin adenosine Al antagonist, serotonin antagonist; serotonin auseant, antineoplastic, antineutropenic, antiparasitic; anti inhibitor, serotonin receptor antagonist; Steroid; thyroid hor proliferative; antipsychotic; antirheumatic; antiseborrheic; mone; thyroid inhibitor, thyromimetic; tranquilizer; amyo 30 antisecretory; antispasmodic; antithrombotic; anti-ulcer trophic lateral Sclerosis agent; cerebral ischemia agent; Pag ative; antiviral; appetite Suppressant, blood glucose regulator; et's disease agent; unstable angina agent; vasoconstrictor; bone resorption inhibitor; bronchodilator; cardiovascular vasodilator, wound healing agent and Xanthine oxidase agent; cholinergic; depressant; diagnostic aid; diuretic; inhibitor. dopaminergic agent; estrogen receptor agonist; fibrinolytic; 6. A dosage form according to claim 1, wherein the high 35 fluorescent agent; free oxygen radical Scavenger, gastric acid solubility active ingredient is selected from the group com Supressant; gastrointestinal motility effector, glucocorticoid: prising of Abacavir Sulfate; Aminocaproic acid; Alendronate hair growth stimulant; hemostatic; histamine H2 receptor Sodium; Amitriptyline hydrochloride; Amphetamine; antagonists; hormone; hypocholesterolemic; hypoglycemic; Acetaminophen; Atropine sulfate; Balsalazide; Benzepril hypolipidemic; hypotensive; imaging agent; immunizing hydrochloride; Bisoprolol fumarate; Bupropion hydrochlo 40 agent; immunomodulator, immunoregulator, immunostimu ride; Buformin; Captopril; Cetrizine hydrochloride: Ciprof lant; immunosuppressant; keratolytic; LHRH agonist; mood loxacin; Clindamycin; Chlorpheniramine maleate; Chlorpro regulator, mucolytic; mydriatic; nasal decongestant; neuro mazine hydrochloride; Clomipramine hydrochloride; muscular blocking agent; neuroprotective; NMDA antago Clonidine hydrochloride; Clopidogrel bisulfate; Cloxacillin nist; non-hormonal sterol derivative; plasminogen activator; Sodium; Codeine phosphate; Colchicines; Cyclophospha 45 platelet activating factor antagonist; platelet aggregation mide; Diethylcarbamazine citrate; DL-methionine: Eprosar inhibitor, psychotropic; radioactive agent; Scabicide; Scleros tan; Ethembutol hydrochloride; Ethosuximide; Erythromy ing agent; sedative; sedative-hypnotic; selective adenosine Al cin: Ferrous sulfate: Fluoxetine hydrochloride; Fosinopril antagonist; serotonin antagonist, serotonin inhibitor, seroto sodium; Gabapentin: Hydralazine hydrochloride; Hydroc nin receptor antagonist; Steroid; thyroid hormone; thyroid odone bitartrate; Hydroxyzine hydrochloride; Hydroxyurea; 50 inhibitor; thyromimetic; tranquilizer, amyotrophic lateral Indinavir Sulfate; Isoniazid; Isosorbide moninitrate; Lacto Sclerosis agent; cerebral ischemia agent; Paget’s disease bionate; Lamivudine; Levamisole hydrochloride; Levofloxa agent; unstable angina agent; vasoconstrictor; vasodilator; cin; Lisinopril; Losartan potassium; Metformin hydrochlo wound healing agent; and Xanthine oxidase inhibitor. ride; Methylphenidate hydrochloride; Metoprolol tartrate; 10. A dosage form as claimed in claim 8, wherein another Minocycline hydrochloride; Montelukast sodium; Naproxen 55 active ingredient is selected from the group comprising of sodium; Neostigmine bromide; Nicotinamide; Niacin; Nifur 16-alpha fluoroestradiol 16-alpha-gitoxin, 16-epiestriol, timox: Nortriptyline hydrochloride; Olanzepine: Oxybytynin 17-alpha-dihydroequilenin, 17-alphaestradiol, 17-betaestra chloride; Penicillamine; Penicillin V potassium; Phenyloin diol, 17-hydroxy progesterone, 1-alpha-hydroxyvitamin D2, sodium; Phenformin; Pravastatin sodium; Potassium chlo 20-epi-1,25-dihydroxyvitamin D3, 22-oxacalcitriol. 2'-nor ride; Primaquine phosphate: Promethazine: Promethazine 60 cGMP 3-isobutyl GABA, 5-ethynyluracil, 6-FUDCA, hydrochloride: Proponolol hydrochloride: Propoxyphene 7-methoxytacrine, Abamectin, abanoquil, abecarnil, abirater hydrochloride: Pseudophedrine hydrochloride: Pyridostig one, Ablukast, Acadesine, Acamprosate, Acarbose, Acebu mine bromide: Pyridoxine hydrochloride; Quinapril hydro tolol, Acecainide Hydrochloride, Aceclidine, Aceclofenae, chloride; Quetiapine: Ramipril; Ranitidine hydrochloride: Acedapsone, Aceglutamide Aluminum, Acemannan, Risedronate Sodium; RosiglitaZone maleate; Sodium Val 65 Acetaminophen, Acetazolamide, Acetohexamide, Acetohy proate: Salbutamol sulfate; Stavudine: Sumatriptan succi droxamic Acid, Acetomepregenol, Acetophenazine Maleate, nate; Terazosin hydrochloride; Tetracycline hydrochloride; Acetosulfone Sodium, Acetylcholine Chloride, Acetylcys US 8,268,352 B2 41 42 teine, acetyl-L-carnitine, Acetylmethadol, Acifran, acipi azadirachtine, AZalanstatDihydrochloride, AZaloxan Fuma moX, acitemate, Acitretin, Acivicin, Aclarubicin, aclatonium, rate, AZanator Maleate, AZanidazole, AZaperone, AZaribine, Acodazole Hydrochloride, aconiazide, Acrisorcin, Acrivas AZaserine, aZasetron, AZatadine Maleate, AZathioprine, AZa tine, Acronine, Actisomide, Actodigin, Acyclovir, acylful thioprine Sodium, azatoxin, azatyrosine, azelaic acid, azelas Vene, adafenoxate, adapalene, Adapalene, adatanserin, Ada tine, azelnidipine, AZepindole, AZetepa, azimilide, Azithro tanserin Hydrochloride, adecypenol, Adefovir, adelmidrol, mycin, AZlocillin, AZolimine, AZosemide, AZotomycin, ademetionine, Adenosine, Adinazolam, Adipheinine Hydro Aztreonam, AZumolene Sodium, Bacampicillin Hydrochlo chloride, adiposin, Adozelesin, adrafinil, Adrenalone, airb ride, baccatin III, Bacitracin, Baclofen, bacoside A, bacoside utamine, alacepril, Alamecin, Alanine, Alaproclate, alaptide, B, bactobolamine, balanol, balazipone, balhimycin, balof Albendazole, albolabrin, Albuterol, Albutoin, Alclofenac, 10 loxacin, balsalazide, Bambermycins, bambuterol, Bamethan Alclometasone Dipropionate, Alcloxa, aldecalmycin, Sulfate, Bamifylline Hydrochloride, Bamidazole, baohuo Aldesleukin, Aldioxa, Alendronate Sodium, alendronic acid, side 1, Barmastine, barnidipine, Basifungin, Batanopride alentemol, Alentemol Hydrobromide, Aletamine Hydrochlo Hydrochloride, batebulast, Batelapine Maleate, Batimastat, ride, Aleuronium Chloride, Alexidine, alfacalcidol, Alfenta beauvericin, Becanthone Hydrochloride, becaplermin, becli nil Hydrochloride, alfuzosin, Algestone Acetonide, algluc 15 conazole, Beclomethasone Dipropionate, befloxatone, Bein erase, Aliflurane, alinastine, Alipamide, Allantoin, serazide, Belfosdil, Belladonna, Beloxamide, Bemesetron, Allobarbital, Allopurinol, Alonimid, alosetron, Alovudine, Bemitradine, Bemoradan, Benapryzine Hydrochloride, Alpertine, Alpha Amylase, Alpidem, Alprazolam, Alprenolol Benazepril Hydrochloride, Benazeprilat, Bendacalol Mesy Hydrochloride, Alprenoxime Hydrochloride, Alprostadil, late, Bendazac, Bendroflumethiazide, benflumetol, benid Alrestatin Sodium, Altanserin Tartrate. Alteplase. Althiazide, ipine, Benorterone, Benoxaprofen, Benoxaprofen, Benoxi Altretamine, altromycin B, Alverinc Citrate, Alvircept nate Hydrochloride, Benperidol, Bentazepam, Bentiromide, Sudotox, Amadinone Acetate, Amantadine Hydrochloride, Benurestat, Benzbromarone, Benzethonium Chloride, Ben ambamustine, Ambomycin, Ambruticin, Ambuphylline, Zetimide Hydrochloride, Benzilonium Bromide, Benzin Ambuside, Amcinafal, Amcinonide, Amdinocillin, Amdi dopyrine Hydrochloride, benzisoxazole, Benzocaine, ben nocillin Pivoxil, Amedalin Hydrochloride, amelometasone, 25 Zochlorins, Benzoctamine Hydrochloride, Benzodepa, Ameltolide, Amesergide, Ametantrone Acetate, amezinium benzoidazoxan, BenZonatate, Benzoyl Peroxide, Benzoylpas metilsulfate, amfebutamone, Amfenac Sodium, Amflutizole, Calcium, benzoylstaurosporine, BenZquinamide, Benzthiaz Amicycline, Amidephrine Mesylate, amidox, Amifloxacin, ide, benztropine, Benztropine Mesylate, Benzydamine amifostine, Amikacin, Amiloride Hydrochloride, Amina Hydrochloride, Benzylpenicilloyl Polylysine, bepridil, crine Hydrochloride, Aminobenzoate Potassium, Aminoben 30 Bepridil Hydrochloride, Beractant, Beraprost, Berefrine, ber Zoate Sodium, Aminocaproic Acid, Aminoglutethimide, lafenone, bertosamil, Berythromycin, besipirdine, beta Aminohippurate Sodium, aminolevulinic acid, Aminophyl alethine, betaclamycin B. Betamethasone, betamipron, line. A minorex, Aminosalicylate Sodium, Aminosalicylic betaxolol, Betaxolol Hydrochloride, Bethanechol Chloride, acid, Amiodarone, Amiprilose Hydrochloride, Amiquinsin Bethanidine Sulfate, betulinic acid, bevantolol, Bevantolol Hydrochloride, amisulpride, Amitraz, Amitriptyline Hydro 35 Hydrochloride, Bezafibrate, Bialamicol Hydrochloride, Bia chloride, Amlexanox, amlodipine. Amobarbital Sodium, penem, Bicalutamide, Biciifadine Hydrochloride, Biclodil Amodiaquine. Amodiaquine Hydrochloride, Amorolfine, Hydrochloride, Bidisomide, bifemelane, Bifonazole, Amoxapine, Amoxicillin, Amphecloral, Amphetamine Sul bimakalim, bimithil, Bindarit, Biniramycin, binospirone, fate, Amphomycin, Amphotericin B, Ampicillin, ampiroxi bioxalomycin alpha2, Bipenamol Hydrochloride, Biperiden, cam, AmpyZine Sulfate, Amquinate, Amrinone, Amrinone, 40 Biphenamine Hydrochloride, biriperone, bisantrene, bisa amrubicin, Amsacrine, amylin, amythiamicin, Anagestone ramil, bisaziridinylspermine, bis-benzimidazole A, bis-ben Acetate, anagrelide, Anakinra, ananain, anaritide, Anaritide Zimidazole B, bisnafide, Bisobrin Lactate, Bisoprolol, Bispy Acetate, Anastrozole, Anazolene Sodium, Ancrod, androgra rithione Magsulfex, bistramide D, bistramide K, bistratene A, pholide, Androstenedione, Angiotensin Amide, Anidoxime, Bithionolate Sodium, Bitolterol Mesylate, Bivalirudin, Bize Anileridine, Anilopam Hydrochloride, Aniracetam, Anirolac, 45 lesin, Bleomycin Sulfate, Bolandiol Dipropionate, Bolaster Anisotropine Methylbromide, Anistreplase, Anitrazafen, one, Boldenone Undecylenate, boldine, Bolenol, Bolmanta anordrin, antarelix, Antazoline Phosphate, Anthelmycin, late, bopindolol, Bosentan, Boxidine, brefeldin, breflate, Anthralin, Anthramycin, antiandrogen, Acedapsone, Fel Brequinar Sodium, Bretazenil, Bretylium Tosylate, Brifenta bamate, antiestrogen, antineoplaston, Antipyrine, apadoline, nil Hydrochloride, brimonidine, Brinolase, Brocresine, Bro apafant, Apalcillin Sodium, apaxifylline, ApaZone, aphidi 50 crinat, Brofoxine, Bromadoline Maleate, Bromazepam, Bro colin glycinate, Apixifylline, Apomorphine Hydrochloride, mchlorenone, Bromelains, bromfenac, Brominidine, apraclonidine, Apraclonidine Hydrochloride, Apramycin, Bromocriptine, Bromodiphenhydramine Hydrochloride, Aprindine, Aprindine Hydrochloride, aprosulate Sodium, Bromoxanide, Bromperidol, Bromperidol Decanoate, Bro Aprotinin, Aptazapine Maleate, aptiganel, apurinic acid, mpheniramine Maleate, Broperamole, Bropirimine, Broti aranidipine, Aranotin, Arbaprostil, arbekicin, arbidol, Arb 55 Zolam, Bucainide Maleate, bucindolol, Buclizine Hydrochlo utamine Hydrochloride, Arclofenin, Ardeparin Sodium, arga ride, Bucromarone, Budesonide, budipine, budotitane, troban, Arginine, Argipressin Tannate, Arildone, aripiprazol. Buformin, Bumetanide, Bunaprolast, bunazosin, Bunolol arotinolol, Arpinocid, Arteflene, Artilide Fumarate, asimado Hydrochloride, Bupicomide, Bupivacaine Hydrochloride, line, aspalatone, Asparaginase, Aspartic Acid, Aspartocin, Buprenorphine Hydrochloride, Bupropion Hydrochloride, asperfuran, Aspirin, aspoxicillin, Asprelin, Astemizole, 60 Buramate, Buserelin Acetate, Buspirone Hydrochloride, Astromicin Sulfate, asulacrine, atameStane, Atenolol, atevir Busulfan, Butabarbital, Butacetin, Butaclamol Hydrochlo dine, Atipamezole, Atiprosin Maleate, Atolide, Atorvastatin ride, Butalbital, Butamben, Butamirate Citrate. Butapera Calcium, Atosiban, Atovaquone, atpenin B, Atracurium zine. Butaprost, Butedronate Tetrasodium, butenafine. Buter Besylate, atrimustine, atrinositol, Atropine, Auranofin, aure izine, buthionine sulfoximine, Butikacin, Butilfenin, obasidin A, Aurothioglucose, Avilamycin, Avoparcin, AVri 65 Butirosin Sulfate. Butixirate, butixocort propionate. Buto dine, axinastatin 1, axinastatin 2, axinastatin 3, AZabon, AZa conazole Nitrate. Butonate. Butopamine. Butoprozine citidinie, AZaclorzine Hydrochloride, AZaconazole, Hydrochloride. Butorphanol, Butoxamine Hydrochloride, US 8,268,352 B2 43 44 Butriptyline Hydrochloride, Cactinomycin, Cadexomer mide, Clavulanate Potassium, Clazolam, Clazolimine, clebo Iodine, Caffeine, calanolide A, Calcifediol, Calcipotriene, pride, Clemastine, Clentiazem Maleate, Clidinium Bromide, calcipotriol, Calcitonin, Calcitriol, Calcium Undecylenate, clinafloxacin, Clindamycin, Clioquinol, Clioxanide, Clipro calphostin C, Calusterone, Cambendazole, camonagrel, fen, clobazam, Clobetasol Propionate, Clobetasone Butyrate, camptothecin derivatives, canarypox, candesartan, Candici Clocortolone Acetate, Clodanolene, Clodazon Hydrochlo din, candoxatril, candoXatrilat, Caniglibose, Canrenoate ride, clodronic acid, Clofazimine, Clofibrate, Clofilium Phos Potassium, Canrenone, capecitabine, Capobenate Sodium, phate, Clogestone Acetate, Clomacran Phosphate, Clomege Capobenic Acid, Capreomycin Sulfate, capromab, capsaicin, stone Acetate, Clometherone, clomethiazole, Clominorex, Captopril, Capuride, Caracemide, Carbachol, Carbadox, Car Clomiphene, Clomipramine Hydrochloride, Clonazepam, bamazepine, Carbamide Peroxide, Carbantel Lauryl Sulfate, 10 Clonidine, Clonitrate, Clonixeril, Clonixin, Clopamide, Clo Carbaspirin Calcium, Carbazeran, carbazomycin C, Carbe penthixol, Cloperidone Hydrochloride, clopidogrel, Clopi nicillin Potassium, Carbenoxolone Sodium, Carbetimer, car mozide, Clopipazan Mesylate, Clopirac, Cloprednol, Clo betocin, Carbidopa, Carbidopa-Levodopa, Carbinoxamine prostenol Sodium, Clorazepate Dipotassium, Clorethate, Maleate, Carbiphene Hydrochloride, Carbocloral, Carbocys Clorexolone, Cloroperone Hydrochloride, Clorprenaline teine, Carbol-Fuchsin, Carboplatin, Carboprost, carbovir, 15 Hydrochloride, Clorsulon, Clortermine Hydrochloride, Clos carboxamide-amino-triazole, carboxyamidotriazole, car antel, Closiramine Aceturate, Clothiapine, Clothixamide boxymethylated beta-1,3-glucan, Carbuterol Hydrochloride, Maleate Cloticasone Propionate, Clotrimazole, Cloxacillin Carfentanil Citrate, Carisoprodol, Carmantadine, Carmus BenZathine, Cloxyquin, Clozapine, Cocaine, Coccidioidin, tine, Camidazole, CaroXaZone, carperitide, Carphenazine Codeine, Codoxime, Colchicine, colestimide, Colestipol Maleate, Carprofen, Carsatirin Succinate, Cartazolate, car Hydrochloride, Colestolone, Colforsin, Colfosceril Palmi teolol, Carteolol Hydrochloride, Carubicin Hydrochloride, tate, Colistimethate Sodium, Colistin Sulfate, collismycin A, Carumonam Sodium, carvedilol, carvotroline, Carvotroline collismycin B, Colterol Mesylate, combretastatin A4, com Hydrochloride, carZelesin, castanospermine, caurumonam, plestatin, conagenin, Conorphone Hydrochloride, contignas cebaracetam, cecropin B, Cedefingol, Cefaclor, Cefadroxil, terol, contortrostatin, Cormethasone Acetate, Corticorelin Cefamandole, Cefaparole, Cefatrizine, Cefazaflur Sodium, 25 Ovine Triflutate, Corticotropin, Cortisone Acetate, Cortiva Cefazolin, Cefbuperazone, cefcapene pivoxil, cefdaloxime Zol, Cortodoxone, cosalane, costatolide, Cosyntropin, coti pentexil tosilate, Cefdinir, cefditoren pivoxil, Cefepime, nine, Coumadin, Coumermycin, crambescidin 816, Crilvas cefetamet, Cefetecol, cefixime, cefluprenam, Cefinenoxime tatin, crisinatol, Cromitrile Sodium, Cromolyn Sodium, Hydrochloride, Cefinetazole, cefiminlox, cefodizime, Crotamiton, cryptophycin 8, cucumariosid Cuprimyxin, Cefonicid Sodium, CefoperaZone Sodium, Ceforanide, 30 curacinA, curdlan Sulfate, curiosin, Cyclacillin, Cyclazocine, cefoselis, Cefotaxime Sodium, Cefotetan, cefotiam, Cefox cyclazosin, cyclic HPMPC, Cyclindole, Cycliramine Male itin, cefoZopran, cefpimizole, Cefniramide, cefpirome, cef ate, Cyclizine, Cyclobendazole, cyclobenzaprine, cyclobut podoxime proxetil, cefprozil, Cefroxadine, cefsulodin, A cyclobut G, cyclocapron, Cycloguanil Pamoate, Cyclo Ceftazidime, cefteram, ceftibuten, Ceftizoxime Sodium, heximide, cyclopentanthraquinones, Cyclopenthiazide, ceftriaxone, Cefuroxime, celastrol, celikalim, celiprolol. 35 Cyclopentolate Hydrochloride, Cyclophenazine Hydrochlo cepacidine A, Cephacetrile Sodium, Cephalexin, Cepha ride, Cyclophosphamide, cycloplatam, Cyclopropane, loglycin, Cephaloridine, Cephalothin Sodium, Cephapirin Cycloserine, cyclosin, Cyclosporine, cyclothialidine, Sodium, Cephradine, cericlamine, cerivastatin, Ceronapril, Cyclothiazide, cyclothiazomycin, Cyheptamide, cypemycin, certoparin sodium, Ceruletide, Cetaben Sodium, Cetalko Cypenamine Hydrochloride, Cyprazepam, Cyproheptadine nium Chloride, Cetamolol Hydrochloride, cetiedil, cetirizine, 40 Hydrochloride, Cyprolidol Hydrochloride, cyproterone, Cetophenicol, Cetraxate Hydrochloride, cetrorelix, Cetylpy Cyproximide, Cysteamine, Cysteine Hydrochloride, Cystine, ridinium Chloride, Chenodiol, Chlophedianol Hydrochlo Cytarabine, Cytarabine Hydrochloride, cytarabine ocfosfate, ride, Chloral Betaine, Chlorambucil, Chloramphenicol, cytochalasin B, cytostatin, Dacarbazine, dacliximab, dac Chlordantoin, Chlordiazepoxide, Chlorhexidine Gluconate, timicin, Dactinomycin, daidzein, Daledalin Tosylate, dalfo chlorins, Chlormadinone Acetate, chloroorienticin A, Chlo 45 pristin, Dalteparin Sodium, Daltroban, Dalvastatin, danap roprocaine Hydrochloride, Chloropropamide, Chloroquine, aroid, DanaZol, Dantrolene, daphlnodorin A, dapiprazole, chloroquinoxaline sulfonamide, Chlorothiazide, Chlorotria dapitant, Dapoxetine Hydrochloride, Dapsone, Daptomycin, nisene, Chloroxine, Chloroxylenol, Chlorphenesin Carbam DarglitaZone Sodium, darifenacin, darlucin A, Darodipine, ate, Chlorpheniramine Maleate, Chlorpromazine, Chlorpro darsidomine, Daunorubicin Hydrochloride, Dazadrol Male pamide, Chlorprothixene, Chlortetracycline Bisulfate, 50 ate, Dazepinil Hydrochloride, Dazmegrel, Dazopride Fuma Chlorthalidone, ChlorZoxazone, Cholestyramine Resin, rate, Dazoxiben Hydrochloride, Debrisoquin Sulfate, Decit Chromonar Hydrochloride, cibenzoline, cicaprost, Ciclafrine abine, deferiprone, deflazacort, Dehydrocholic Acid, Hydrochloride, Ciclazindol, ciclesonide, cicletanine, Ciclo dehydrodidemnin B, Dehydroepiandrosterone, delapril, pirox, Cicloprofen, cicloprolol, Cidofovir, Cidoxepin Hydro Delapril Hydrochloride, Delavirdine Mesylate, delequamine, chloride, Cifenline, Ciglitazone, Ciladopa Hydrochloride, 55 delfaprazine, Delmadinone Acetate, delmopinol, delphini cilansetron, Cilastatin Sodium, Cilazapril, cilnidipine, Cilo din, Demecarium Bromide, Demeclocycline, Demecycline, bamine Mesylate, cilobradine, Cillofungin, ciloStaZol. Demoxepam, Denofungin, deoxypyridinoline, Depakote, Cimaterol, Cimetidine, cimetropium bromide, Cinalukast, deprodone, Deprostil, depsidomycin, deramciclane, derma Cinanserin Hydrochloride, Cinepazet Maleate, Cinflumide, tan sulfate, Desciclovir, Descinolone Acetonide, Desflurane, Cingestol, cinitapride, Cinnamedrine, Cinnarizine, cino 60 Desipramine Hydrochloride, desirudin, Deslanoside, lazepam, Cinoxacin, Cinperene, Cinromide, CintaZone, Cin deslorelin, desmopressin, desogestrel, Desonide. Des triamide, Cioteronel, Cipamfylline, Ciprefadol Succinate, Oximetasone, desoxoamiodarone, Desoxycorticosterone Ciprocinonide, Ciprofibrate, Ciprofloxacin, ciprostene, Cira Acetate, detajmium bitartrate, Deterenol Hydrochloride, madol, Cirolemycin, cisapride, cisatracurium besilate, Detirelix Acetate, Devazepide, Dexamethasone, Dexamisole, Cisconazole, Cisplatin, cis-porphyrin, cistinexine, citalo 65 Dexbrompheniramine Maleate, Dexchlorpheniramine Male pram, Citenamide, citicoline, citreamicin alpha, cladribine, ate, Dexclamol Hydrochloride, Dexetimide, Dexfenflu Clamoxyquin Hydrochloride, Clarithromycin, clausena ramine Hydrochloride, dexifosfamide, Deximafen, Dexi US 8,268,352 B2 45 46 vacaine, dexketoprofen, dexloxiglumide, Dexmedetomidine, Ethacrynate Sodium, Ethacrynic Acid, Ethambutol Hydro Dexormaplatin, Dexoxadrol Hydrochloride, Dexpanthenol, chloride, Ethamivan, Ethanolamine Oleate, Ethchlorvynol, Dexpemedolac, Dexpropranolol Hydrochloride, Dexrazox Ether, Ethinyl estradiol, Ethiodized Oil, Ethionamide, Etho ane, dexSotalol, dextrin 2-sulphate, Dextroamphetamine, nam Nitrate, Ethopropazine Hydrochloride, Ethosuximide, Dextromethorphan, Dextrorphan Hydrochloride, Dextrothy Ethotoin, Ethoxazene Hydrochloride, Ethybenztropine, roxine Sodium, dexVerapamil, DeZaguanine, dezinamide, Ethyl Chloride, Ethyl Dibunate, Ethylestrenol, Ethyndiol, dezocine, Diacetolol Hydrochloride, Diamocaine Cycla Ethynerone, Ethynodiol Diacetate, Etibendazole, Etidocaine, mate, Diapamide, Diatrizoate Meglumine, Diatrizoic Acid, Etidronate Disodium, Etidronic Acid, Etifenin, Etintidine Diaveridine, Diazepam, Diaziquone, Diazoxide, Dibenzepin Hydrochloride, etizolam, Etodolac, Etofenamate, Etoformin Hydrochloride, Dibenzothiophene, Dibucaine, Dichliorvos, 10 Hydrochloride, Etomidate, Etonogestrel, Etoperidone Dichloralphenazone, Dichlorphenamide, Dicirenone, Hydrochloride, Etoposide, Etoprine, Etoxadrol Hydrochlo Diclofenac Sodium, Dicloxacillin, dicranin, Dicumarol, ride, EtoZolin, etrabamine, Etretinate, Etryptamine Acetate, Dicyclomine Hydrochloride, Didanosine, didemnin B, Eucatropine Hydrochloride, Eugenol, Euprocin Hydrochlo didox, Dienestrol, dienogest, Diethylcarbamazine Citrate, ride, eveninomicin, Exametazime, examorelin, Exaprolol diethylhomospermine, diethylnorspermine, Diethylpropion 15 Hydrochloride, exemestane, fadrozole, faerieflungin, Famci Hydrochloride, Diethylstilbestrol. Difenoximide Hydrochlo clovir, Famotidine, Fampridine, fantofarone, Fantridone ride. Difenoxin, Diflorasone Diacetate. Difloxacin Hydro Hydrochloride, faropenem, fasidotril, fasudil, fazarabine, chloride, Difluanine Hydrochloride, Diflucortolone, Diflu fedotozine, felbamate, Felbinac, Felodipine, Fely pressin, midone Sodium, Diflunisal, Difluprednate. Diftalone, Fenalamide, Fenamole, Fenbendazole, Fenbufen, Fenci Digitalis, Digitoxin, Digoxin, Dihexyverine Hydrochloride, butirol, Fenclofenac, Fenclonine, Fenclorac, Fendosal, dihydrexidine, dihydro-5-azacytidine, Dihydrocodeine Fenestrel, Fenethylline Hydrochloride, Fenfluramine Hydro Bitartrate, Dihydroergotamine Mesylate, Dihydroestoster chloride, Fengabine, Fenimide, Fenisorex, Fenmetozole one, Dihydrostreptomycin Sulfate, Dihydrotachysterol, dihy Hydrochloride, Fenmetramide, Fenobam, Fenoctimine Sul drotaxol. 9-, Dilantin, Dilevalol Hydrochloride, Diltiazem fate, fenofibrate, fenoldopam, Fenoprofen, Fenoterol, Fenpi Hydrochloride, Dimefadane, Dimefline Hydrochloride, 25 palone, Fenprinast Hydrochloride, Fenprostalene, Fen Dimenhydrinate, Dimercaprol, Dimethadione, Dimethin quizone, fenretinide, fenspiride, Fentanyl Citrate, Fentiazac, dene Maleate, Dimethisterone, dimethyl prostaglandin A1, Fenticlor, fenticonazole, Fenyripol Hydrochloride, fepradi Dimethyl Sulfoxide, dimethylhomospermine, dimiracetam, nol, ferpifosate sodium, ferristene, ferrixan, Ferrous Sulfate, Dimoxamine Hydrochloride, Dinoprost, Dinoprostone, Ferumoxides, ferumoxsil, Fetoxylate Hydrochloride, fex Dioxadrol Hydrochloride, dioxamycin, Diphenhydramine 30 ofenadine, Fezolamine Fumarate, Fiacitabine, Fialuridine, Citrate, Diphenidol, Diphenoxylate Hydrochloride, diphenyl Fibrinogen 125, filgrastim, Filipin, finasteride, Flavodilol spiromustine, Dipivefin Hydrochloride, Dipivefrin, diphen Maleate, flavopiridol, Flavoxate Hydrochloride, Flazalone, cyprone, diprafenone, dipropylnorspermine, Dipyridamole, flecainide, flerobuterol, Fleroxacin, flesinoxan, Flestolol Sul Dipyrithione, Dipyrone, dirithromycin, discodermolide, Dis fate, Fletazepam, flezelastine, flobufen, Floctafenine, flo obutamide, Disofenin, Disopyramide, Disoxaril, disulfiram, 35 moxef, Flordipine, florfenicol, florifenine, flosatidil, Flose Ditekiren, Divalproex Sodium, Dizocilpine Maleate, Dob quinan, Floxacillin, Floxuridine, fluasterone, Fluazacort, utamine, docarpamine, Docebenone, Docetaxel, Docona Flubanilate Hydrochloride, Flubendazole, Flucindole, Flu Zole, docosanol, dolfetilide, dolasetron, Ebastine, ebiratide, cloronide, Fluconazole, Flucytosine, Fludalanine, Fludara ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdysteron, bine Phosphate, Fludazonium Chloride, Fludeoxyglucose F echicetin, echistatin, Echothiophate Iodide, Eclanamine 40 18, Fludorex, Fludrocortisone Acetate, Flufenamic Acid, Maleate, EclaZolast, ecomustine, Econazole, ecteinascidin Flufenisal, Flumazenil, flumecinol, Flumequine, Flumeri 722, edaravone, Edatrexate, edelfosine, Edifolone Acetate, done, Flumethasone, Flumetramide, Flumezapine, Flumi edobacomab, Edoxudine, edrecolomab, Edrophonium Chlo norex, Flumizole, Flumoxonide, flunarizine, Flunidazole, ride, edroxyprogesteone Acetate, efegatran, eflornithine, Flunisolide, Flunitrazepam, Flunixin, fluocalcitriol, Fluoci efonidipine, Elantrine, eleatonin, elemene, eletriptan, elgo 45 nolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocor dipine, eliprodil, Elsamitrucin, Elucaine, emalkalim, eme tolone, Fluorescein, Fluorodopa F 18, Fluorometholone, dastine, Emetine Hydrochloride, emiglitate, Emilium Tosy Fluorouracil, Fluotracen Hydrochloride, Fluoxetine, Flu late, emitefur, emoctakin, Enadoline Hydrochloride, oxymesterone, fluparoxan, Fluperamide, Fluperolone enalapril, Enalaprilat, Enalkiren, enaZadrem, Encyprate, Acetate, Fluphenazine Decanoate, flupirtine, Flupredniso Endralazine Mesylate, Endrysone, Enflurane, englitaZone, 50 lone, FluproduaZone, Fluprostenol Sodium, FluquaZone, Flu Enilconazole, Enisoprost, Enlimomab, Enloplatin, Enofelast, radoline Hydrochloride, Flurandrenolide, Flurazepam Enolicam Sodium, Enoxacin, Enoxaparin Sodium, Enoxi Hydrochloride, Flurbiprofen, Fluretofen, flurithromycin, mone, Enpiroline Phosphate, Enprofylline, Enpromate, enta Flurocitabine, Flurofamide, Flurogestone Acetate, Flurothyl, capone, enterostatin, Enviradene, Enviroxime, Ephedrine, Fluroxene, Fluspiperone, Fluspirilene, Fluticasone Propi Epicillin, Epimestrol, Epinephrine, Epinephryl Borate, 55 onate, flutrimazole, Flutroline, fluvastatin, Fluvastatin Epipropidine, Epirizole, epirubicin, Epitetracycline Hydro Sodium, fluvoxamine, Fluzinamide, Folic Acid, Follicle chloride, Epithiazide, Epoetin Alfa, Epoetin Beta, Epopros regulatory protein, Folliculostatin, Fomepizole, Fonazine tenol, Epoprostenol Sodium, epoxymexrenone, epristeride, Mesylate, forasartan, forfenimex, formestane, Formocortal, Eprosartan, eptastigmine, equilenin, Equilin, ErbuloZole, formoterol, Fosarilate, Fosazepam, Foscarnet Sodium, fosfo erdosteine, Ergoloid Mesylates, Ergonovine Maleate, Ergota 60 mycin, Fosfonet Sodium, fosinopril, Fosinoprilat, fospheny mine Tartrate, ersentilide, Ersofermin, erythritol, Erythrityl loin, Fosquidone, Fostedil, fostriecin, fotemustine, Fumox Tetranitrate, Erythromycin, Esmolol Hydrochloride, Esoru icillin, Fungimycin, Furaprofen, Furazolidone. Furazolium bicin Hydrochloride, Esproquin Hydrochloride, Estazolam, Chloride. Furegrelate Sodium, Furobufen, Furodazole. Furo Estradiol, Estramustine, EstraZinol Hydrobromide, Estriol, semide, Fusidate Sodium, Fusidic Acid, gabapentin, Gado Estrofurate, Estrogen, Estcrifica, Estrone, Estropipate, esu 65 benate Dimeglumine, gadobenic acid, gadobutrol, Gadodia prone, Etafedrine Hydrochloride, Etanidazole, etanterol, mide, gadolinium texaphyrin, Gadopentetate Dimeglumine, Etarotene, Etazolate Hydrochloride, Eterobarb, ethacizin, gadoteric acid, Gadoteridol, Gadoversetamide, galantamine, US 8,268,352 B2 47 48 galdansetron, Galdansetron Hydrochloride, Gallamine Tri Acid, iotriside, Iotrolan, Iotroxic Acid, Iotyrosine I 131, ethiodide, gallium nitrate, gallopamil, galocitabine, Gamfex Ioversol, Ioxagiate Sodium, Ioxaglate Meglumine, Ioxaglic ine, gamolenic acid, Ganciclovir, ganirelix, Gemcadiol. Acid, ioxilan, Ioxotrizoic Acid, ipazilide, ipenoxazone, ipi Gemcitabine, Gemeprost, Gemfibrozil, Gentamicin Sulfate, dacrine, Ipodate Calcium, ipomeanol, Ipratropium Bromide, gepirone, Gestaclone, Gestodene, Gestonorone Caproate, ipriflavone, Iprindole, Iprofenin, Ipronidazole, Iproplatin, Gestrinone, GeVotroline Hydrochloride, girisopam, glaspi Iproxamine Hydrochloride, ipsapirone, irbesartan, irinote mod, glaucocalyxin A, Glemanserin, Gliamilide, Glibornu can, irloxacin, iroplact, irsogladine, Irtemazole, isalsteine, ride, Glicetanile Sodium, Gliflumide, Glimepiride, Glipizide, Isamoxole, isbogrel, Isepamicin, isobengaZole, Isobutamben, GloXimonam, Glucagon, glutapyrone, Glutethimide, Gly Isocarboxazid, Isoconazole, Isoetharine, isofloxythepin, buride, glycopine, glycopril, Glycopyrrolate, Glyhexamide, 10 Isoflupredone Acetate, Isoflurane, Isoflurophate, isohomo Glymidine Sodium, Glyoctamide, Glyparamide, Gonadoctri halicondrin B, Isoleucine, Isomazole Hydrochloride, Isomy nins, Gonadorelin, Gonadotropins, Goserelin, Gramicidin, lamine Hydrochloride, Isoniazid, Isopropamide Iodide, Iso Granisetron, grepafloxacin, Griseofulvin, Guaiapate, Guaith propyl Alcohol, isopropyl unoprostone, Isoproterenol yline, Guanabenz, Guanabenz. Acetate, Guanadrel Sulfate, Hydrochloride, Isosorbide, Isosorbide Mononitrate, Iso Guancydine, Guanethidine Monosulfate, Guanfacine Hydro 15 tiquimide, Isotretinoin, Isoxepac, Isoxicam, ISOXSuprine chloride, Guanisoquin Sulfate, Guanoclor Sulfate, Guanoc Hydrochloride, isradipine, itameline, itasetron, ItaZigrel, ito tine Hydrochloride, Guanoxabenz, Guanoxan Sulfate, Gua pride, Itraconazole, Ivermectin, jasplakinolide, Josamycin, noxyfen Sulfate, Gusperimus Trihydrochloride, Halazepam, kahalalide F, Kalafungin, Kanamycin Sulfate, Ketamine Halcinonide, halichondrin B. Halobetasol Propionate, halo Hydrochloride, Ketanserin, Ketazocine, Ketazolam, fantrine, Halofantrine Hydrochloride, Halofenate, Halofugi Kethoxal, Ketipramine Fumarate, Ketoconazole, Ketoprofen, none Hydrobromide, halomon, Halopemide, Haloperidol, Ketorfanol, ketorolac, Ketotifen Fumarate, Kitasamycin, halopredone, Haloprogesterone, Haloprogin, Halothane, Labetalol Hydrochloride, Lacidipine, lactitol, lactivicin, lafu Halduinols, Hamycin, hatomamicin, hatomarubigin A, tidine, lamellarin-N triacetate, lamifiban, Lamivudine, Lam hatomarubigin B, hatomarubigin C, hatomarubigin D. Hep otrigine, lanoconazole, Lanoxin, lanperisone, lanreotide, arin Sodium, hepsulfam, heregulin, Hetacillin, Heteronium 25 Lansoprazole, latanoprost, lateritin, laurocapram, Lauryl Iso Bromide, Hexachlorophene:Hydrogen Peroxide, Hexafluo quinolinium Bromide, LaVoltidine Succinate, lazabemide, renium Bromide, hexamethylene bisacetamide, Hexedine, Lecimibide, leinamycin, lemildipine, leminoprazole, lener Hexobendine, Hexoprenaline Sulfate, Hexylresorcinol, His cept, Leniquinsin, lenograstim, Lemperone, lentinan Sulfate, tamine Phosphate. Histidine, Histoplasmin, Histrelin, Homa leptin, leptolstatin, lercanidipine, Lergotrile, lerisetron, tropine Hydrobromide, Hoquizil Hydrochloride, Human 30 Letimide Hydrochloride, letraZuril, letrozole, Leucine, leu chorionic gonadotropin, Hycanthone, Hydralazine Hydro comyzin, Leuprolide Acetate, leuprorelin, Levamfetamine chloride, Hydralazine Polistirex, Hydrochlorothiazide, Succinate, levamisole, Levdobutamine Lactobionate, Hydrocodone Bitartrate, Hydrocortisone, Hydroflumethiaz Leveromakalim, levetiracetam, Levey closerine, levobetax ide, Hydromorphone Hydrochloride, Hydroxyamphetamine olol, levobunolol, levobupivacaine, levocabastine, levocar Hydrobromide, Hydroxychloroquine Sulfate, Hydroxyphe 35 nitine, Levodopa, levodropropizine, levofloxacin, Levofural namate, Hydroxyprogesterone Caproate, Hydroxyurea, tadone, Levoleucovorin Calcium, Levomethadyl Acetate, Hydroxyzine Hydrochloride, Hymecromone, Hyoscyamine, Levomethadyl Acetate Hydrochloride, levomoprolol, Levo hypericin, Ibafloxacin, ibandronic acid, ibogaine, Ibopamine, nantradol Hydrochloride, Levonordefrin, Levonorgestrel, ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icatibant Levopropoxyphene Napsylate, Levopropylcillin Potassium, Acetate, Ichthammol. Icotidine, idarubicin, idoxifene, Idoxu 40 levormeloxifene, Levorphanol Tartrate, levosimendan, levo ridine, idramantone, Iemefloxacin, Iesopitron, Ifetroban, Sulpiride, Levothyroxine Sodium, Levoxadrol Hydrochlo Ifosfamide, Ilepeimide, illimaquinone, ilmofosine, illomastat, ride, Lexipafant, Lexithromycin, liarozole, LibenZapril, Ilonidap, illoperidone, iloprost, Imafen Hydrochloride, Ima Lidamidine Hydrochloride, Lidocaine, Lidofenin, Lidofla Zodan Hydrochloride, imidapril, imidazenil, imidazoacri Zine, Lifarizine, Lifibrate, Lifibrol, Linarotene, Lincomycin, dones, Imidecyl Iodine, Imidocarb Hydrochloride, Imidoline 45 Linogliride, Linopirdine, linotroban, linsidomine, lintitript, Hydrochloride. Imidurea, Imiloxan Hydrochloride, Imi lintopride, Liothyronine I 125, liothyronine sodium, Liotrix, penem, Imipramine Hydrochloride, imiquimod, Impromi lirexapride, lisinopril, lissoclinamide 7. Lixazinone Sulfate, dine Hydrochloride, Indacrinone, Indapamide, Indecainide lobaplatin, Lobenzarit Sodium, Lobucavir, Lodelaben, Hydrochloride, Indeloxazine Hydrochloride, Indigotindisul Lodoxamide, Lofemizole Hydrochloride, Lofentanil fonate Sodium, indinavir, Indocyanine Green, Indolapril 50 Oxalate, Lofepramine Hydrochloride, Lofexidine Hydro Hydrochloride, Indolidan, indometacin, Indomethacin chloride, lombricine, Lomefloxacin, lomerizine, Lometraline Sodium, Indoprofen, indoramin, Indorenate Hydrochloride, Hydrochloride, lometrexol, Lomofungin, Lomoxicam, Indoxole, Indriline Hydrochloride, inocoterone, inogatran, Lomustine, Lonapalene, lonazolac, lonidamine, Loperamide inolimomab, Inositol Niacinate, Insulin, interferons, interleu Hydrochloride, loracarbef, Lorajmine Hydrochloride, lorata kins, Intrazole, Intriptyline Hydrochloride, iobenguane, 55 dine, Lorazepam, Lorbamate, Lorcainide Hydrochloride, Iobenzamic Acid, iobitridol, Iocarmate Meglumine, Iocarmic LorecleZole, Loreinadol, lorglumide, Lorimetazepam, Lor Acid, Iocetamic Acid, Iodamide, Iodine, Iodipamide Meglu noxicam, Lortalamine, LorZafone, losartan, losigamone, mine, Iodixanol, iodoamiloride, Iodoantipyrine 1131, Iodoc losoxantrone, Losulazine Hydrochloride, loteprednol, lovas holesterol I 131, iododoxorubicin, Iodohippurate Sodium I tatin, loviride, Loxapine, Loxoribine, lubeluzole, Lucanthone 131. Iodopyriacet I 125. Iodoquinol, Iodoxamate Meglumine, 60 Hydrochloride, Lufironil, Lurosetron Mesylate, lurtotecan, Iodoxamie Acid, Ioglicic Acid, Iofetamine Hydrochloride I luteinizing hormone, lutetium, Lutrelin Acetate, luZindole, 123, iofratol, Ioglucol, Ioglucomide, Ioglycamic Acid, Iogu Lyapolate Sodium, Lycetamine, lydicamycin, Lydimycin, lamide, Iohexol, iomeprol, Iomethin I 125, Iopamidol, Lynestrenol, Lypressin, Lysine, lysofylline, lysostaphin, lytic Iopanoic Acid, iopentol, Iophendylate, Ioprocemic Acid, peptides, Maduramicin, Mafenide, magainin 2 amide, Mag iopromide, Iopronic Acid, Iopydol, Iopy done, iopyrol, Iose 65 nesium Salicylate, Magnesium Sulfate, magnolol. famic Acid, Ioseric Acid, IoSulamide Meglumine, IoSumetic maitansine, Malethamer, mallotochromene, mallotojaponin, Acid, Iotasul, Iotetric Acid, Iothalamate Sodium, Iothalamic Malotilate, malotilate, mangafodipir, manidipine, maniwa US 8,268,352 B2 49 50 mycin A. Mannitol, mannostatin A, manumycin E, manumy Motretinide, Moxalactam Disodium, Moxazocine, moxira cin F. mapinastine, Maprotiline, marimastat, Masoprocol, prine, Moxinidazole, moxonidine, Muzolimine, mycaperoX maspin, massetolide, Maytansine, Mazapertine Succiniate, ide B, Mycophenolic Acid, myriaporone, Nabazenil, Mazindol, Mebendazole, Mebeverine Hydrochloride, Nabilone, Nabitan Hydrochloride, Naboctate Hydrochloride, Mebrofenin, Mebutamate, Mecamylamine Hydrochloride, Nabumetone, N-acetyldinaline, Nadide, nadifloxacin, Nad Mechlorethamine Hydrochloride, Meclocycline, Meclofe olol, nadroparin calcium, nafadotride, nafamo.stat, nafarelin, namate Sodium, Mecloqualone, Meclorisone Dibutyrate, Nafcillin Sodium, Nafenopin, Nafimidone Hydrochloride, Medazepam Hydrochloride, Medorinone, Medrogestone, Naflocort, Nafomine Malate, Nafoxidine Hydrochloride, Medroxalol, Medroxyprogesterone, Medrysone, Meelizine Nafronyl Oxalate, Naftifine Hydrochloride, naftopidil, nagli Hydrochloride, Mefenamic Acid, Mefenidil, Mefenorex 10 van, nagrestip, Nalbuphine Hydrochloride, Nalidixate Hydrochloride, Mefexamide, Mefloquine Hydrochloride, Sodium, Nalidixic Acid, nalmefene, Nalmexone Hydrochlo Mefruside, Megalomicin Potassium Phosphate, Megestrol ride, naloxone-pentazocine, Naltrexone, NamoXyrate, Nan Acetate, Meglumine, Meglutol, Melengestrol Acetate, Meli drolone Phenpropionate, Nantradol Hydrochloride, Napacta tracen Hydrochloride, Melphalan, Memotine Hydrochloride, dine Hydrochloride, napadisilate, Napamezole Menabitan Hydrochloride, Menoctone, menogaril, Menotro 15 Hydrochloride, Naphazoline Hydrochloride, naphterpin, pins, Meobentine Sulfate, Mepartricin, Mepenzolate Bro Naproxen, NaproXol, napsagatran, Naranol Hydrochloride, mide, Meperidine Hydrochloride, Mephentermine Sulfate, Narasin, naratriptan, nartograstim, nasaruplase, Natamycin, Mephenyloin, Mephobarbital, Mepivacaine Hydrochloride, nateplase, Naxagolide Hydrochloride, Nebivolol, Nebramy Meprobamate, Meptazinol Hydrochloride, Mequidox, Mera cin, nedaplatin, Nedocromil, Nefazodone Hydrochloride, lein Sodium, merbarone, Mercaptopurine, Mercufenol Chlo Neflumozide Hydrochloride, Nefopam Hydrochloride, ride, Mercury, Meropenem, Mesalamine, MeseclaZone, NeleZaprine Maleate, Nemazoline Hydrochloride, nemoru Mesoridazine, Mesterolone, Mestranol, Mesuprine Hydro bicin, Neomycin Palmitate, Neostigmine Bromide, chloride, Metalol Hydrochloride, Metaproterenol Polistirex, neridronic acid, Netilmicin Sulfate, Neutramycin, Nevirap Metaraminol Bitartrate, Metaxalone, Meteneprost, meter ine. Nexeridine Hydrochloride, Niacin, Nibroxane, Nicar elin, Metformin, Methacholine Chloride, Methacycline, 25 dipine Hydrochloride, Nicergoline, Niclosamide, Nicorandil, Methadone Hydrochloride, Methadyl Acetate, Methalthiaz Nicotinyl Alcohol, Nifedipine, Nifirmerone, Nifluridide, ide, Methamphetamine Hydrochloride, Methaqualone, Met Nifuradene, Nifuraldezone, Nifuratel, Nifuratrone, Nifurda hazolamide, Methdilazine, Methenamine, Methenolone zil, Nifurimide, Nifurpirinol, Nifurcquinazol, Nifurthiazole, Acetate, Methetoin, Methicillin Sodium, Methimazole, nilutamide, Nilvadipine, Nimazone, Nimodipine, niperoti methioninase, Methionine, Methisazone, Methixene Hydro 30 dine, niravoline, Niridazole, nisamycin, Nisbuterol Mesylate, chloride, Methocarbamol, Methohexital Sodium, Methopho nisin, Nisobamate, Nisoldipine, Nisoxetine, Nisterime line, Methotrexate, Methotrimeprazine, methoxatone, Meth Acetate, Nitarsone, nitazoxanide, nitecapone, Nitrafudam oxyflurane, Methsuximide, Methyclothiazide, Methyl Hydrochloride, Nitralamine Hydrochloride, Nitramisole Palmoxirate, Methylatropine Nitrate, Methylbenzethonium Hydrochloride, Nitrazepam, Nitrendipine, Nitrocycline, Chloride, Methyldopa, Methyldopate Hydrochloride, Meth 35 Nitrodan, Nitrofurantoin, Nitrofurazone, Nitroglycerin, ylene Blue, Methylergonovine Maleate, methylhistamine, Nitromersol, Nitromide, Nitromifene Citrate, Nitrous Oxide, methylinosine monophosphate, Methylphenidate Hydro nitroxide antioxidant, nitrullyn, Nivazol, Nivinedone chloride, Methylprednisolone, Methyltestosterone, Meth Sodium, Nizatidine, Noberastine, Nocodazole, Nogalamy ynodiol Diacetate, Methysergide, Methysergide Maleate, cin, Nolinium Bromide, Nomifensine Maleate, Noracymeth Metiamide, Metiapine, Metioprim, metipamide, Metipra 40 adol Hydrochloride, Norbolethone, Norepinephrine Bitar nolol, Metizoline Hydrochloride, Metkephamid Acetate, trate, Norethindrone, Norethynodrel, Norfloxacin, metoclopramide, Metocurine Iodide, Metogest, Metolazone, Norflurane, Norgestimate, Norgestomet, Norgestrel, Nortrip Metopimazine, Metoprine, Metoprolol, Metoquizine, metri tyline Hydrochloride, Noscapine, Novobiocin Sodium, fonate, Metrizamide, Metrizoate Sodium, Metronidazole, Nufenoxole, Nylestriol, Nystatin, O6-benzylguanine, Obi Meturedepa, Metyrapone, Metyrosine, Mexiletine Hydro 45 doxime Chloride, Ocaperidone, Ocfentanil Hydrochloride, chloride, Mexrenoate Potassium, Mezlocillin, Amfonelic Ocinaplon, Octanoic Acid, Octazamide, Octenidine Hydro Acid, Mianserin Hydrochloride, mibefradil, Mibefradil chloride, Octodrine, Octreotide, Octriptyline Phosphate, Dihydrochloride, Mibolerone, michellamine B, Miconazole, Ofloxacin, Oformine, okicenone, Olanzapine, oligonucle microcolin A, Midaflur, Midazolam Hydrochloride, mido otides, olopatadine, olprinone, olSalazine, Olsalazine drine, mifepristone, Mifobate, miglitol, millacemide, milame 50 Sodium, Olvanil, omeprazole, onapristone, ondansetron, line, mildronate, Milenperone, Milipertine, milnacipran, Mil Ontazolast, Opipramol Hydrochloride, oracin, Orconazole rinone, miltefosine, Mimbane Hydrochloride, minaprine, Nitrate, Orgotein, Orlislat, Ormaplatin, Ormetoprim, Ornida Minaxolone, Minocromil, Minocycline, Minoxidil, Miofla Zole, Orpanoxin, Orphenadrine Citrate, osaterone, otenZe Zine Hydrochloride, miokamycin, mipragoside, mirfentanil, pad, Oxacillin Sodium, Oxagrelate, Oxaliplatin, OXamarin mirimostim, Mirincamycin Hydrochloride, Mirisetron Male 55 Hydrochloride, oxamisole, Oxamniquine, Oxandrolone, ate, Mirtazapine, Misonidazole, Misoprostol, Mitindomide, Oxantel Pamoate, Oxaprotiline Hydrochloride, Oxaprozin, Mitocarcin, Mitocromin, Mitogillin, mitoguaZone, mitolac Oxarbazole, Oxatomide, oxaunomycin, Oxazepam, oXcarba tol, Mitomalcin, Mitomycin, mitonafide, Mitosper, Mitotane, Zepine, Oxendolone, Oxethazaine, Oxetorone Fumarate, mitoxantrone, mivacurium chloride, mivaZerol, mixanpril, Oxfendazole, Oxfenicine, Oxibendazole, oxiconazole, Oxi Mixidine, mizolastine, mizoribine, Moclobemide, modafinil, 60 dopamine, Oxidronic Acid, Oxifungin Hydrochloride, Modaline Sulfate, Modecainide, moexipril, mofarotene, Oxilorphan, Oximonam, Oximonam Sodium, Oxiperomide, Mofegiline Hydrochloride, mofezolac, molgramostim, Moli oxiracetam, Oxiramide, Oxisuran, Oxmetidine Hydrochlo naZone, Molindone Hydrochloride, Molsidomine, mometa ride, oxodipine, Oxogestone Phenpropionate, Oxolinic Acid, sone, Monatepil Maleate, Monensin, Monoctanoin, Mon Oxprenolol Hydrochloride, oxtriphylline, Oxybutynin Chlo telukast Sodium, montirelin, mopidamol, moracizine, 65 ride, Oxychlorosene, Oxycodone, Oxymetazoline Hydro Morantel Tartrate, Moricizine, Morniflumate, Morphine Sul chloride, Oxymetholone, Oxymorphone Hydrochloride, fate, Morrhuate Sodium, mosapramine, mosapride, motilide, Oxypertine, Oxyphenbutazone, Oxypurinol, Oxytetracy US 8,268,352 B2 51 52 cline, Oxytocin, oZagrel, Ozolinone, Paclitaxel, palauamine, Pranolium Chloride, Pravadoline Maleate, Pravastatin, Paldimycin, palinavir, palmitoylrhizoxin, Palmoxirate Prazepam, Prazosin, Prazosin Hydrochloride, Prednazate, Sodium, pamaqueside, Pamatolol Sulfate, pamicogrel, Pam Prednicarbate, Prednimustine, Prednisolone, Prednisone, idronate Disodium, pamidronic acid, Panadiplon, pan Prednival, Pregnenolone Succiniate, Prenalterol Hydrochlo amesine, panaxytriol, Pancopride, Pancuronium Bromide, ride, Pridefine Hydrochloride, Prifelone, Prilocalne Hydro panipenem, pannorin, panomifene, pantethine, pantoprazole, chloride, Primaquine Phosphate, Primidolol, Primidone, Papaverine Hydrochloride, parabactin, Parachlorophenol, Prinivil, Prinomide Tromethamine, Prinoxodan, Prizidilol Paraldehyde, Paramethasone Acetate, Paranyline Hydrochlo Hydrochloride, Proadifen Hydrochloride, Probenecid, Probi ride, Parapenzolate Bromide, Pararosaniline Pamoate, Par cromil Calcium, Probucol, Procainamide Hydrochloride, bendazole, Parconazole Hydrochloride, Paregoric, Pareptide 10 Procaine Hydrochloride, Procarbazine Hydrochloride, Pro Sulfate, Pargyline Hydrochloride, parnaparin sodium, Paro caterol Hydrochloride, Prochlorperazine, Procinonide, Pro momycin Sulfate, Paroxetine, parthenolide, Partricin, Paulo clonol, Procyclidine Hydrochloride, Prodilidine Hydrochlo mycin, paZelliptine, PaZinaclone, Pazoxide, paZufloxacin, ride, Prodolic Acid, Profadol Hydrochloride, Progabide, pefloxacin, pegaspargase, Pegorgotein, Pelanserin Hydro Progesterone, Proglumide, Proinsulin Human, Proline, Pro chloride, peldesine, Peliomycin, Pelretin, Pelrinone Hydro 15 lintane Hydrochloride, Promazine Hydrochloride, Promet chloride, Pemedolac, Pemerid Nitrate, pemirolast, Pemoline, hazine Hydrochloride, Propafenone Hydrochloride, Penamecillin, Penbutolol Sulfate, Penciclovir, Penfluridol, propagermanium, Propanidid, Propantheline Bromide, Pro Penicillin G BenZathine, Penicillin G Potassium, Penicillin G paracaine Hydrochloride, Propatyl Nitrate, propentofylline, Procaine, Penicillin G Sodium, PenicillinV, Penicillin V Ben Propenzolate Hydrochloride, Propikacin, Propiomazine, Zathine, Penicillin V Hydrabamine, Penicillin V Potassium, Propionic Acid, propionylcarnitine, propiram, propiverine, Pentabamate, Pentaerythritol Tetranitrate, pentafuside, pen Propofol, Propoxycaine Hydrochloride, Propoxyphene tamidine, pentamorphone, Pentamustine, Pentapiperium Hydrochloride, Propranolol Hydrochloride, Propulsid, pro Methylsulfate, Pentazocine, Pentetic Acid, Pentiapine Male pyl bis-acridone, Propylhexedrine, Propyliodone, Propylth ate, pentigetide, Pentisomicin, Pentizidone Sodium, Pento iouracil, ProquaZone, Prorenoate Potassium, Proroxan barbital, Pentomone, Pentopril, pentosan, pentostatin, Pen 25 Hydrochloride, Proscillaridin, Prostalene, prostratin, Prota toxifylline, Pentrinitrol, pentrozole, Peplomycin Sulfate, mine Sulfate, protegrin, Protirelin, protosufloxacin, Protrip Pepstatin, perflubron, perfofamide, Perfosfamide, pergolide, tyline Hydrochloride, Proxazole, Proxazole Citrate, Proxi Perhexiline Maleate, perillyl alcohol, Perindopril, perindop cromil, Proxorphan Tartrate, prulifloxacin, Pseudoephedrine rilat, Perlapine, Permethrin, perospirone, Perphenazine, Hydrochloride, Puromycin, purpurin, Pyrabrom, Pyrantel Phenacemide, phenaridine, phenazinomycin, Phenazopyri 30 Pamoate, Pyrazinamide, Pyrazofurin, pyrazoloacridine, Pyri dine Hydrochloride, Phenbutazone Sodium Glycerate, Phen dostigmine Bromide, Pyrilamine Maleate, Pyrimethamine, carbamide, Phencyclidine Hydrochloride, Phendimetrazine Pyrinoline, Pyrithione Sodium, Pyrithione Zinc, Pyrovale Tartrate, Phenelzine Sulfate, Phenmetrazine Hydrochloride, rone Hydrochloride, Pyroxamine Maleate, Pyrrocaine, Pyr Phenobarbital, Phenoxybenzamine Hydrochloride, Phen roliphene Hydrochloride, Pyrrolnitrin, Pyrvinium Pamoate, procoumon, phenserine, phensuccinal, PhenSuximide, Phen 35 Quadazocine Mesylate, Quazepam, Quazinone, QuaZodine, termine, Phentermine Hydrochloride, phentolamine mesi QuaZolast, quetiapine, quiflapon, quinagolide, Quinaldine late, Phentoxifylline, Phenyl Aminosalicylate, phenylacetate, Blue, quinapril, Quinaprilat, Quinazosin Hydrochloride, Phenylalanine, phenylalanyl ketoconazole, Phenylbutazone, Quinbolone, Quinctolate, Quindecamine Acetate, Quindo Phenylephrine Hydrochloride, Phenylpropanolamine Hydro nium Bromide, Quinelorane Hydrochloride, Quinestrol, chloride, Phenylpropanolamine Polistirex, Phenyramidol 40 Quinfamide, Quingestanol Acetate, Quingestrone, Quinidine Hydrochloride, Phenyloin, Physostigmine, picenadol, Gluconate, Quinielorane Hydrochloride, Quinine Sulfate, picibanil, Picotrin Diolamine, picroliv, picumeterol, pidoti Quinpirole Hydrochloride, Quinterenol Sulfate, Quinuclium mod, Pifamine, Pilocarpine, pilsicainide, pimagedine, Pimet Bromide, Quinupristin, Quipazine Maleate, Rabeprazole ine Hydrochloride, pimilprost, Pimobendan, Pimozide, Pina Sodium, Racephenicol, Racepinephrine, Rafoxanide, Ralito cidil, Pinadoline, Pindolol, pinnenol, pinocebrin, Pinoxepin 45 line, raloxifene, raltitrexed, ramatroban, Ramipril, Ramopla Hydrochloride, pioglitaZone, Pipamperone, Pipazethate, nin, ramosetron, ranelic acid, Ranimycin, Ranitidine, ranola pipecuronium bromide, Piperacetazine, Piperacillin Sodium, Zine, Rauwolfia Serpentina, recainam, Recainam Piperamide Maleate, piperazine, Pipobroman, Piposulfan, Hydrochloride, Reclazepam, regavirumab, RegramoStim, Pipotiazine Palmitate, Pipoxolan Hydrochloride, Piprozolin, Relaxin, Relomycin, Remacemide Hydrochloride, Remifen Piquindone Hydrochloride, Piquizil Hydrochloride, Pirac 50 tanil Hydrochloride, Remiprostol, Remoxipride, Repirinast, etam, Pirandamine Hydrochloride, pirarubicin, PiraZmonam Repromicin, Reproterol Hydrochloride, Reserpine, resin Sodium, Pirazolac, Pirbenicillin Sodium, Pirbuterol Acetate, feratoxin, Resorcinol, retelliptine demethylated, reticulon, Pirenperone, Pirenzepine Hydrochloride, piretanide, Pirfeni reviparin sodium, revizinone, rhenium Re-186 etidronate, done, Piridicillin Sodium, Piridronate Sodium, Piriprost, piri rhizoxin, Ribaminol, Ribavirin, Riboprine, ribozymes, trexim, Pirlimycin Hydrochloride, pirlindole, pirmagrel, Pir 55 ricasetron, Ridogrel, Rifabutin, Rifametane, Rifamexil, Rifa menol Hydrochloride, Pirnabine, Piroctone, Pirodavir, mide, Rifampin, Rifapentine, Rifaximin, retinamide, pirodomast, Pirogliride Tartrate, Pirolate, Pirolazamide, rilopirox, Riluzole, rimantadine, Rimcazole Hydrochloride, Piroxantrone Hydrochloride, Piroxicam, Piroximone, Pirpro Rimexolone, Rimiterol Hydrobromide, rimoprogin, rio fen, Pirquinozol, Pirsidomine, Prenylamine, Pivampicillin dipine, Rioprostil, Ripazepam, ripisartan, Risedronate Hydrochloride, Pivopril, Pizotyline, placetin A, platinum 60 Sodium, risedronic acid, Risocaine, Risotilide Hydrochlo triamine complex, Plicamycin, Plomestane, Pobilukast ride, rispenzepine, Risperdal, Risperidone, Ritanserin, riti Edamine, Podofilox, Poisonoak Extract, Poldine Methylsul penem, Ritodrine, Ritolukast, ritonavir, rizatriptan benzoate, fate, Poliglusam, Polignate Sodium, Polymyxin B Sulfate, Rocastine Hydrochloride, Rocuronium Bromide, Rodocaine, Polythiazide, Ponalrestat, Porfimer Sodium, Porfiromycin, Roflurane, Rogletimide, rohitukine, rokitamycin, Roletami Potassium Chloride, Potassium Iodide, Potassium Perman 65 cide, Rolgamidine, Rolicyprine, Rolipram, Rolitetracycline, ganate, Povidone-Iodine, Practolol, Pralidoxime Chloride, Rolodine, Romazarit, romurtide, Ronidazole, ropinirole, Pramiracetam Hydrochloride, Pramoxine Hydrochloride, Ropitoin Hydrochloride, ropivacaine, Ropizine, roquinimex, US 8,268,352 B2 53 54 Rosaramicin, Rosoxacin, Rotoxamine, roXaitidine, Roxar fylline Hydrochloride, Tazobactam, Tazofelone, Tazolol Sone, roXindole, roXithromycin, rubiginone B1, ruboxyl, Hydrochloride, Tebufelone, Tebuquine, Technetium Tc 99 m rufloxacin, rupatidine, Rutamycin, ruzadolane, Sabeluzole, Bicisate, Teclozan, Tecogalan Sodium, Teceleukin, Teflu Safingol, Safironil, Saintopin, Salbutamol-R, Salcolex, Sale rane, Tegafur, Tegretol, Teicoplanin, telenZepine, tellurapy thamide Maleate, Salicyl Alcohol, Salicylamide, Salicylate rylium, telmesteine, telmisartan, Teloxantrone Hydrochlo Meglumine, Salicylic Acid, Salmeterol, Salnacedin, Sal ride, Teludipine Hydrochloride, Temafloxacin salate, Sameridine, Sampatrilat, Sancycline, Sanfetrinem, Hydrochloride, Tematropium Methyl sulfate, Temazepam, Sanguinarium Chloride, Saperconazole, Saprisartan, saprop Temelastine, temocapril, Temocillin, temoporfin, temozolo terin, saquinavir, Sarafloxacin Hydrochloride, Saralasin mide, Tenidap, Teniposide, tenosal, tenoxicam, tepirindole, Acetate, SarCNU, sarcophytol A, SargramoStim, Sarmoxicil 10 Tepoxalin, Teprotide, terazosin, Terbinafine, Terbutaline Sul lin, Sarpicillin, Sarpogrelate, Saruplase, Saterinone, satigrel, fate, Terconazole, terfenadine, terflavoxate, terguride, Teri Satumomab pendetide, Scopafungin, Scopolamine, Hydro paratide Acetate, terlakiren, terlipressin, terodiline, TeroX bromide, Scrazaipine Hydrochloride, Secalciferol, Secobar alene Hydrochloride, Teroxirone, tertatolol, Tesicam, bital, Seelzone, Seglitide Acetate, selegiline, Selegiline Tesimide, Testolactone, Testosterone, Tetracaine, tetrachlo Hydrochloride, Selenium Sulfide, Selenomethionine Se 75, 15 rodecaoxide, Tetracycline, Tetrahydrozoline Hydrochloride, Selfotel, sematilide, semduramicin, semotiadil, Semustine, Tetramisole Hydrochloride, Tetrazolast Meglumine, tetra Sepazonium Chloride, Seperidol Hydrochloride, Seprilose, Zomine, Tetrofosmin, Tetroquinone, TetroXoprim, Tetry Seproxetine Hydrochloride, Seractide Acetate, Sergolexole damine, thaliblastine, Thalidomide. Theofibrate. Theophyl Maleate, Serine, Sermetacin, Sermorelin Acetate, sertacona line. Thiabendazole. Thiamiprine. Thiamphenicol, Zole, sertindole, Sertraline, Setiptiline, Setoperone, Thiamylal. Thiazesim Hydrochloride. Thiazinamium Chlo sevirumab, sevoflurane, sezolamide, Sibopirdine, Sibutra ride. Thiethylperazine. Thimerfonate Sodium, Thimerosal, mine Hydrochloride, Silandrone, silipide, silteplase, Silver thiocoraline, thiofedrine. Thioguanine, thiomarinol, Thio Nitrate, simendan, SimtraZene, Simvastatin, Sincalide, Sine pental Sodium, thioperamide. Thioridazine. Thiotepa, Thio fungin, Sinitrodil, sinnabidol, sipatrigine, sirolimus, Sisomi thixene. Thiphenamil Hydrochloride. Thiphencillin Potas cin, Sitogluside, sizofuran, Sobuzoxane, Sodium Amylosul 25 sium, Thiram, Thozalinone, Threonine, Thrombin, fate, Sodium Iodide I 123, Sodium Nitroprusside, Sodium thrombopoietin, thrombopoietin mimetic, thymalfasin, thy Oxybate, sodium phenylacetate, Sodium Salicylate, solverol, motrinan, Thyromedan Hydrochloride, Thyroxine I 125, Solypertine Tartrate. Somalapor. Somantadine Hydrochlo Thyroxine I 131, Tiacrilast, Tiacrilast Sodium, tiagabine, Tia ride, Somatomedin B, Somatomedin C. Somatrem, somatro menidine, tianeptine, tiapafant, Tiapamil Hydrochloride, pin, Somenopor. Somidobove, sonermin, Sorbinil, Sorivu 30 Tiaramide Hydrochloride, Tiazofurin, Tibenelast Sodium, dine, so talol, Soterenol Hydrochloride, Sparfloxacin, Tibolone, Tilbric Acid, Ticabesone Propionate, Ticarbodine, Sparfosate Sodium, sparfosic acid, Sparsomycin, Sparteine Ticarcillin Cresyl Sodium, Ticlatone, ticlopidine, Ticrynafen, Sulfate, Spectinomycin Hydrochloride, spicamycin D. Spip tienoXolol, Tifurac Sodium, Tigemonam Dicholine, Tigestol, erone, Spiradoline Mesylate, Spiramycin, Spirapril Hydro Tiletamine Hydrochloride, Tilidine Hydrochloride, tilisolol, chloride, Spiraprilat, Spirogermanium Hydrochloride, Spiro 35 tilnoprofen arbamel, Tilorone Hydrochloride, Tiludronate mustine, Spironolactone, Spiroplatin, SpiroXasone, Disodium, tiludronic acid, Timefurone, Timobesone Acetate, splenopentin, spongistatin 1, Sprodiamide, squalamine, Stal Timolol, tin ethyl etiopurpurin, Tinabinol, Tinidazole, Tinza limycin Hydrochloride, Stannous Pyrophosphate, Stannous parin Sodium, Tioconazole, TiodaZosin, Tiodonium Chlo Sulfur Colloid, Stanozolol, Statolon, staurosporine, stavu ride, Tioperidone Hydrochloride, Tiopinac, Tiospirone dine, Steffimycin, Stenbolone Acetate, stepronin, Stilbazium 40 Hydrochloride, Tiotidine, tiotropium bromide, Tioxidazole, Iodide, Stilonium Iodide, stipiamide, Stiripentol, stobadine, Tipentosin Hydrochloride, Tipredane, Tiprenolol Hydrochlo Streptomycin Sulfate, Streptonicozid, Streptonigrin, Strepto ride, Tiprinast Meglumine, Tipropidil Hydrochloride, Tique Zocin, Strontium Chloride Sr 89, succibun, Succimer, Succi side, Tiquinamide Hydrochloride, tirandalydigin, Tira nylcholine Chloride. Sucralfate. Sucrosofate Potassium, paZamine, tirilazad, tirofiban, tiropramide, titanocene Sudoxicam, Sufentanil, Sufotidine, Sulazepam, Sulbactam 45 dichloride, Tixanox, Tixocortol Pivalate, Tizanidine Hydro Pivoxil, Sulconazole Nitrate, Sulfabenz, Sulfabenzamide, chloride, Tobramycin, Tocainide, Tocamphyl, Tofenacin Sulfacetamide, Sulfacytine, Sulfadiazine, Sulfadoxine, Sul Hydrochloride, Tolamolol, Tolazamide, Tolazoline Hydro falene, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfame chloride, Tolbutamide, Tolcapone, Tolciclate, Tolfamide, Tol thizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfamox gabide, Tolimidone, Tolindate, Tolimetin, Tolnaftate, Tolpovi ole, Sulfanilate Zinc, Sulfanitran, sulfasalazine, 50 done I 131, Tolpyrramide, Tolrestat, Tomelukast, Tomoxetine Sulfasomizole, Sulfazamet, Sulfinalol Hydrochloride, sulfi Hydrochloride, Tonazocine Mesylate, Topiramate, topote nosine, Sulfinpyrazone, Sulfisoxazole, Sulfomyxin, Sul can, Topotecan Hydrochloride, top sentin, Topterone, fonterol Hydrochloride, sulfoxamine, Sulinldac, Sulmarin, Toquizine, torasemide, toremifene, Torsemide, Tosifen, Sulnidazole, Suloctidil, Sulofenur, Sulopenem, Suloxifen ToSufloxacin, Tracazolate, trafermin, Tralonide, Tramadol Oxalate, Sulpiride, Sulprostone, Sultamicillin, Sulthiame, 55 Hydrochloride, Tramazoline Hydrochloride, trandolapril, Sultopride, Sulukast, Sumarotene, Sumatriptan, Suncillin Tranexamic Acid, Tranilast, Transcainide, traxanox, TraZ Sodium, Suproclone, Suprofen, Suradista, Suramin, Surfo odone Hydrochloride, Trazodone-HCL, Trebenzomine mer, Suricainide Maleate, Suritozole, Suronacrine Maleate, Hydrochloride, Trefentanil Hydrochloride, Treloxinate, SuXemerid Sulfate, Swainsonine, Symakalim, Symclosene, Trepipam Maleate, Trestolone Acetate, tretinoin, Triacetin, Symetine Hydrochloride, Taciamine Hydrochloride, Tacrine 60 triacetyluridine, Triafungin, Triamcinolone, TriampyZine Hydrochloride, Tacrolimus, Talampicillin Hydrochloride, Sulfate, Triamterene, Triazolam, Tribenoside, tricaprilin, Taleranol, Talisomycin, tallimustine, Talmetacin, Talniflu Tricetamide, Trichlormethiazide, trichohyalin, triciribine, mate, Talopram Hydrochloride, Talosalate, Tametraline Tricitrates, Triclofenol piperazine, Triclofos Sodium, Tri Hydrochloride, Tamoxifen, Tampramine Fumarate, Tamsu clonide, trientine, Trifenagrel, triflavin, Triflocin, Trifluba losin Hydrochloride, Tandamine Hydrochloride, tan 65 Zam, Triflumidate, Trifluoperazine Hydrochloride, Triflu dospirone, taprostene, Tasosartan, tauromustine, Taxane, peridol, Triflupromazine, Triflupromazine Hydrochloride, Taxoid, Tazadolene Succinate, taZanolast, tazarotene, Tazi Trifluridine, Trihexyphenidyl Hydrochloride, Trilostane, Tri US 8,268,352 B2 55 56 maZosin Hydrochloride, trimegestone, Trimeprazine Tar of one or more hydrophobic release controlling agents on said trate, Trimethadione, Trimethaphan Camsylate, Tri micro matrix particles particles to form a double barrier to methobenzamide Hydrochloride, Trimethoprim, control the diffusion of the high soluble active ingredient, Trimetozine, Trimetrexate, Trimipramine, Trimoprostil, Tri wherein the hydrophobic release controlling agents are moxamine Hydrochloride, Triolein I 125, Triolein I 125, Tri selected from the group consisting of poly(ethyl acrylate, oxifene Mesylate, Tripamide, Tripelennamine Hydrochlo methyl methacrylate, trimethylammonioethyl methacrylate ride, Triprolidine Hydrochloride, Triptorelin, chloride) 1:2:0.1; poly(ethyl acrylate, methyl methacrylate, Trisulfapyrimidines, Troclosene Potassium, troglitaZone, trimethylamonioethyl methacrylate chloride) 1:2:0.2 and Trolamine, Troleandomycin, trombodipine, trometamol. poly(ethyl acrylate, methyl methacrylate) 1:1, polyvinyl Tropanserin Hydrochloride, Tropicamide, tropine ester, tro 10 acetate dispersion, ethylcellulose, cellulose acetate, cellulose pisetron, trospectomycin, trovafloxacin, troVirdine, Tryp propionate (lower, medium or higher molecular weight), cel tophan, Tuberculin, Tubocurarine Chloride, Tubulozole lulose acetate propionate, cellulose acetate butyrate, cellulose Hydrochloride, tucaresol, tulobuterol, turosteride, Tybamate, acetate phthalate, cellulose triacetate, poly(methyl methacry tylogenin, Tyropanoate Sodium, Tyrosine, Tyrothricin, tyr late), poly(ethyl methacrylate), poly(butyl methacrylate), 15 poly(isobutyl methacrylate), poly (hexyl methacrylate), poly phostins, ubenimex, Uldazepam, Undecylenic Acid, Uracil (isodecyl methacrylate), poly (lauryl methacrylate), poly Mustard, urapidil, Urea, Uredepa, uridine triphosphate, Uro (phenyl methacrylate), poly (methyl acrylate), poly (isopro follitropin, Urokinase, Ursodiol, Valaciclovir, Valine, Valnoc pyl acrylate), poly (isobutyl actylate), poly (octadecyl tamide, Valproate Sodium, Valproic Acid, Valsartan, Vamica acrylate), waxes selected from the group consisting of bees mide, Vanadeine, Vancomycin, Vaninolol, Vapiprost wax, carnauba wax, microcrystalline wax, and oZokerite; Hydrochloride, Vapreotide, variolin B. Vasopressin, Vecuro fatty alcohols selected from the group consisting of ceto nium Bromide, velaresol, Velnacrine Maleate, Venlafaxine, Stearyl alcohol, Stearyl alcohol, cetyl alcohol and myristyl Veradoline Hydrochloride, Veramine, Verapamil Hydrochlo alcohol; and fatty acid esters selected from the group consist ride, verdins, Verilopam Hydrochloride, Verlukast, Verofyl ing of glyceryl monostearate; glycerol monooleate, acety line, Veroxan, verteporfin, Vesnarinone, vexibinol, Vidara 25 lated monoglycerides, tristearin, tripalmitin, cetyl esters wax, bine, vigabatrin, Viloxazine Hydrochloride, Vinblastine glyceryl palmitostearate, glyceryl behenate and hydroge Sulfate, vinburnine citrate, Vincofos, Vinconate, Vincristine Sulfate, Vindesine, Vindesine Sulfate, Vinepidine Sulfate, nated castor oil wherein the metformin hydrochloride can be Vinglycinate Sulfate, Vinleurosine Sulfate, vinorelbine, vin less than or equal to 1500 mg. pocetine, vintoperol, vinxaltine, Vinzolidine Sulfate, Vipros 13. A dosage form as claimed in claim 12, is in the form of tol, Virginiamycin, Viridofulvin, Viroxime, vitaxin, Volazo 30 tablet. cine, Voriconazole, Vorozole, Voxergolide, Warfarin Sodium, 14. A dosage form according to claim 12, wherein in said Xamoterol, Xanomeline, Xanoxate Sodium, Xanthinol micro matrix particles, metformin hydrochloride and one or Niacinate, xemilofiban, Xenalipin, Xenbucin, Xilobam, more hydrophobic release controlling agents are present in a ximoprofen, Xipamide, Xorphanol Mesylate, Xylamidine weight ratio of from 100:2.5 to 100:30. Tosylate, Xylazine Hydrochloride, Xylometazoline Hydro 35 15. A dosage form according to claim 12, wherein said chloride, Xylose, yangambin, Zabicipril, Zacopride, micro matrix particles and the coating of one or more hydro Zafirlukast, Zalcitabine, Zaleplon, Zalospirone, Zaltidine phobic release controlling agents are present in a weight ratio Hydrochloride, Zaltoprofen, Zanamivir, Zankiren, Zanoterone, of from 100:2.5 to 100:30. Zarirlukast, Zatebradine, Zatosetron, Zatosetron Maleate, 16. A dosage form according to claim 12, wherein the Zenarestat, Zenazocine Mesylate, Zeniplatin, Zeranol, 40 dissolution of metforminhydrochloride is not more than 50% Zidometacin, Zidovudine, Zifrosilone, Zilantel, Zilascorb, in 1 hour, from 30 to 90% in four hours and not less than 65% zileuton, Zimeldine Hydrochloride, Zinc Undecylenate, Zin in twelve hours. dotrine, Zinoconazole Hydrochloride, Zinostatin, Zinterol 17. A dosage form according to claim 12, wherein the Hydrochloride, Zinviroxime, ziprasidone, Zobolt, Zofenopril modified release metformin formulation for once daily Calcium, Zofenoprilat, Zolamine Hydrochloride, Zolazepam 45 administration exhibit in vivo mean dissolution time (MDT) Hydrochloride, Zoledronic acid, Zolertine Hydrochloride, of approximately 4 hours to 6 hours. Zolmitriptan, Zolpidem, Zomepirac Sodium, Zometapine, 18. A dosage form as claimed in claim 12, wherein the said Zoniclezole Hydrochloride, Zonisamide, Zopiclone, Zopolr dosage form may optionally contain more than one antidia estat, Zorbamycin, Zorubicin Hydrochloride, Zotepine, betic active ingredient. Zucapsaicin and pharmaceutically acceptable salts thereof. 50 19. A process for the preparation of a modified release 11. A dosage form as claimed in claim 8, wherein said dosage form comprising a) preparing a micro matrix particles dosage form is in the form of a multilayered tablet or a coated consisting of metformin hydrochloride and one or more tablet or a tablet in tablet or a capsule. hydrophobic release controlling agent and b) coating the said 12. A modified release dosage form comprising metformin micro matrix particles consisting of metforminhydrochloride hydrochloride prepared by using dual retard technique to 55 and one or more hydrophobic release controlling agent. control the release of metformin, wherein the said dual retard 20. A dosage form according to claim 1, for once a day technique is a combination of matrix formulation and rservoir administration. formulation, said dosage form consist of a) micro matrix 21. A dosage form according to claim 12, for once a day particles containing metformin hydrochloride and one or administration. more hydrophobic release controlling agents and b) coating