US 20060018934A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2006/0018934 A1 Vaya et al. (43) Pub. Date: Jan. 26, 2006

(54) NOVEL DRUG DELIVERY SYSTEM (30) Foreign Application Priority Data

(76) Inventors; Navin Vaya, Gujarat (IN); Rajesh Aug. 5, 2002 (IN) ...... 698/MUM/2002 Singh Karan, Gujarat (IN); Suni] Aug. 5, 2002 (IN) ...... 696/MUM/2003 Sadanand Nadkarni, Gujarat (IN); Jan. 22, 2003 (IN) ...... 81/MUM/2003 Vinod Kumar Gupta, Gujarat (IN) Publication Classi?cation Correspondence Address: HEDMAN & COSTIGAN RC. (51) Int. Cl. 1185 AVENUE OF THE AMERICAS A61K 9/00 (2006.01) NEW YORK, NY 10036 (US) A61K 9/24 (2006.01) (52) US. Cl...... 424/400; 424/472 (57) ABSTRACT (21) Appl. No.: 11/134,632 A novel modi?ed release dosage form comprising of a high (22) Filed: May 19, 2005 solubility active ingredient, Which utilizes dual retard tech nique to effectively reduce the quantity of release controlling Related US. Application Data agents. Present invention can optionally comprise addition ally another active ingredient as an immediate release form (63) Continuation-in-part of application No. 10/630,348, or modi?ed release form. Present invention also relates to a ?led on Jul. 29, 2003. process for preparing the said formulation. Patent Application Publication Jan. 26, 2006 Sheet 1 0f 5 US 2006/0018934 A1

FIGURE 1 (a)

FIGURE 1 (b) Patent Application Publication Jan. 26, 2006 Sheet 2 0f 5 US 2006/0018934 A1

FIGURE 2

120 — (95) 100

80

60

ActiveIngredientRelease 4O -

2O -

0 2 4 6 8 10 12 14 16 18 2O 22 24 Q 26 Time (hour) Patent Application Publication Jan. 26, 2006 Sheet 3 0f 5 US 2006/0018934 A1

120 -

(%) 100.

80 - IngredientReleaseActive 60 — 4O -

20

O 2 4 6 8 10 l2 14 16 18 2O 22 24 26 Time (hour) Patent Application Publication Jan. 26, 2006 Sheet 4 0f 5 US 2006/0018934 A1

FIGURE 4

120 -

14

100 15

' so_ / 16 13 ReleaseActiveIngredient 60 40

20

0 2 4 6 8 - 1O 12 14 Time (hour) Patent Application Publication Jan. 26, 2006 Sheet 5 0f 5 US 2006/0018934 A1

FIGURE 5

1600

1400

1200 - :E\@5co?umupcmucoomEwmHm 1000 2846 0O O0

Time [Hours] US 2006/0018934 A1 Jan. 26, 2006

NOVEL DRUG DELIVERY SYSTEM [0006] One method of prolonging the release of a highly Water-soluble drug is disclosed PCT Patent application no. [0001] This application is a continuation-in-part of WO99/47128. Abiphasic controlled release delivery system 10/630,348, ?led Jul. 29, 2003. for metformin hydrochloride, Which has prolonged gastric residence and that sWells folloWing hydration. The ratio of FIELD OF INVENTION inner solid phase to outer continuous phase is 0.5 :1 to about [0002] This invention relates to a modi?ed release dosage 4:1. The major limitation of this invention is that it provides form comprising of a high solubility active ingredient, a very bulky formulation for higher doses of the metformin Which utiliZes dual retard technique to effectively reduce the hydrochloride that is very inconvenient for human consump quantity of release controlling agents. Present invention can tion. For instance, example cited provides formulation of optionally comprise additionally another active ingredient as 500 mg metformin hydrochloride With tablet Weight of 1.0 an immediate release form or modi?ed release form. Present gm. Hence restricting to the loW dose sustained release invention also relates to a process for preparing the said tablets of 500 mg or slightly more and making it obligatory formulation. to take tWo tablets of 500 mg each time to provide sustain action. The cited example teaches use of combination of BACKGROUND OF THE INVENTION atleast one hydrophilic polymer and Which is a essential part for sWelling. Non sWellable or nonerodeble formulations are [0003] It is Well knoWn to those skilled in the art that the not included in the invention. blood levels of drugs need to be maintained above a mini mum effective level and beloW its minimum toxic level in [0007] PCT application No. WO 02/28181 A1 describes a order to obtain the desired therapeutic effects and to mini monolithic sustained release formulation of metformin miZe side effects. Unfortunately, the pharmacokinetic prop hydrochloride. The method of making the formulation erties (absorption, elimination and metabolism) of most involves hot melt granulation folloWed by Wet granulation drugs are such that they need to be administered three to four With binders or extrusion. The formulation essentially times a day. This kind of a dosing regimen is very incon requires binder and auxiliary pharmaceutically acceptable venient and leads to reduction in patient compliance. Reduc excipients. The formulation consists of metformin hydro tion of dosing regimen from three times a day (t.i.d.) to tWice chloride polymer and or hydrophobic material. The dosage daily (bid) to once a day results in increased convenience form release more than 90% of the drug Within 8 hours. and comfort and therefore increased patient compliance. Drugs that are administered in the form of conventional [0008] Similarly US. Pat. No. 6,340,475 B2 assigned to tablets of capsules become available to body ?uids at a rate Depomed Inc. describes monolithic controlled release for that is initially very high, folloWed by a rapid decline. For mulation of highly Water soluble drugs including metformin many drugs, this delivery pattern results in a transient hydrochloride. The formulation sWells When ingested thus overdose, folloWed by a long period of under dosing. This is prolonging its residence time in the stomach. The formula a pattern of limited clinical usefulness. The delivery pattern tions are made of hydrophilic polymers, Which results in Was improved in the 1970’s With the introduction of a sWellable and erodible matrix. variety of modi?ed delivery systems. Modi?ed release for [0009] Another method of prolonging the release of a mulations, Which are effective in maintaining the therapeutic highly Water-soluble drug is disclosed in International Patent blood levels over, extended periods of time result in optimal application publication no. WO 96/26718, published Sep. 6, therapy. They not only reduce the frequency of dosing, but 1996. The method of this publication is the incorporation of they also reduce the severity and frequency of side effects, the drug into a polymeric matrix to form a tablet that is as they maintain substantially constant blood levels and administered orally. The polymer is Water-sWellable yet avoid the ?uctuations associated With the conventional erodible in gastric ?uids. immediate release formulations administered three to four times a day. [0010] Similarly Chih-Ming Chen in international patent application number WO 02/36100 describes a once a for [0004] There are a number of different modi?ed release mulation of metformin hydrochloride Which is based on dosage forms available commercially. HoWever, some of osmotically controlled technique and that is non expandable these are expensive to manufacture and can be dif?cult to in nature and has a passage in the coating membrane for sWalloW, particularly in elderly patients. Many of these release of drug. modi?ed delivery systems utiliZe hydrophilic, polymeric matrices that provide useful levels of control to the delivery [0011] Kim et al. in US. Pat. No. 6,337,091 describes a of sparingly soluble drugs. For soluble drugs, hoWever, and matrix based controlled release formulation for highly particularly for highly soluble drugs, such matrices do not soluble drugs over long periods of time. The release con provide adequate control over the release rate, instead result trolling agent is a sWellable gum Which encapsulates or ing in a release that approximates ?rst-order kinetics and make granules of drug, Which is then disposed in more may have a problem of dose dumping or burst release. sWellable erodible polymers such as HPMC or poly(ethyl HoWever, since many modi?ed release dosage forms contain eneoxide). comparatively large amounts of active ingredient it is often [0012] These systems can provide for modi?ed release for necessary to include large amounts of suitable excipients to achieve appropriate controlled release pro?les. Clearly, this selected active ingredients like active ingredients With loW dose or loW Water solubility. HoWever, When a highly Will tend to increase the siZe of the dosage form. soluble or high dose active ingredient is used, most of these [0005] The various techniques to make modi?ed release systems have the disadvantages such as comparatively loW dosage form of drugs as described in prior art are as payload of active ingredient thus making dosage form bulky folloWs— and expensive or lead to burst effect or prolonged release of US 2006/0018934 A1 Jan. 26, 2006

active ingredient for a shorter duration or use of complex [0024] The present invention also provides a novel process manufacturing procedure and/or equipment. for preparing the novel formulations of the invention. [0013] There exists a need for compositions and process [0025] The present invention further provides a method of for making orally deliverable dosage form containing highly treating an animal, particularly a human in need of treatment soluble active ingredient as modi?ed release that overcomes utiliZing the active agents, comprising administering a thera the problems discussed above. This invention addresses the peutically effective amount of composition or solid oral need. dosage form according to the invention to provide admin istration of active ingredients. [0014] Therefore, it Would be of considerable clinical bene?t to design a dosage form With high pay load of highly DETAILED DESCRIPTION OF THE soluble active ingredient that Would be much easier for the INVENTION patient to sWalloW. This type of technology could also be used to reduce the siZe of many existing drug formulations. [0026] This invention relates to a modi?ed release dosage form comprising of a high solubility active ingredient pre [0015] Therefore an object of the present invention is a pared by using dual retard technique to control the release of modi?ed release dosage form of high solubility active the high solubility active ingredient and to increase the ingredient. payload of high solubility active ingredient [0016] The second object of the present invention is a [0027] The term “modi?ed release” as used herein in modi?ed release dosage form With high payload of active relation to the composition according to the invention or a ingredient, Which is suitable for sWalloWing for humans. rate controlling polymer or used in any other context means [0017] Yet another object of the present invention is to release, Which is not immediate release and is taken to provide a dosage form, Which uses dual retard technique to encompass controlled release, sustained release, prolonged control the release of the high solubility active ingredient release, timed release, retarded release, extended release and and signi?cantly reduce the amount of release controlling delayed release. The term “modi?ed release dosage form” as agents Which are otherWise required in very high quantity used herein can be described as dosage forms Whose drug and make the dosage form very bulky and therefore pose release characteristics of time course and/or location are dif?culty in sWalloWing. chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution [0018] A further object of the present invention is to or an immediate release dosage form. Modi?ed release solid provide a dosage form, Which gives accurate dosing and is oral dosage forms include both delayed and extended release simple to prepare. drug products (as per US FDA guideline for ‘SUPAC-MR: Modi?ed Release Solid Oral Dosage Forms’). [0019] A further object of the present invention is to provide a dosage form, Which can be given tWice a day or [0028] The term “dosage form” denotes any form of the more preferably can be given once a day. formulation that contains an amount suf?cient to achieve a therapeutic effect With a single administration. [0020] A further object of the present invention is to provide a dosage form, Which can optionally comprise [0029] The term “active ingredient” refers to an agent, additionally another active ingredient as an immediate active ingredient compound or other substance, or compo sitions and mixture thereof that provide some pharmaco release form or modi?ed release form. logical, often bene?cial, effect. Reference to a speci?c active ingredient shall include Where appropriate the active ingre SUMMARY OF THE INVENTION dient and it’s pharmaceutically acceptable salts. [0021] The above objects are realiZed by a dosage form, [0030] The term “high solubility” as used herein in rela Which comprises of a) Micro matrix particles containing tion to active agent means that from less than 1 part to 300 high solubility active ingredient and one or more hydropho parts of Water or less than 1 part to 30 parts of Water Will be bic release controlling agent, b) Coating of Micro matrix required to dissolve 1 part of active ingredient. particles With one or more hydrophobic release controlling agents. It may optionally also include one or more com [0031] The invention provides a novel modi?ed release monly used excipients in oral pharmaceutical formulations. dosage form of high solubility active ingredient, Which The present invention also provides solid oral dosage form utiliZes dual retard technique to effectively reduce the quan comprising a composition according to the invention. tity of release controlling agents and a process for preparing Optionally, it may also comprise additionally another active the dosage form. ingredient as an immediate release form or modi?ed release [0032] The dosage form comprises of a) Micro matrix form. particles containing, high solubility active ingredient and [0022] The present invention also teaches the use of dual one or more hydrophobic release controlling agent, b) Coat retard technique to effectively control the release rate of ing of Micro matrix particles With one or more hydrophobic modi?ed release active ingredient by using small quantity of release controlling agents. It may optionally also include one release controlling agents. This dual retard technique thus or more commonly used excipients in oral pharmaceutical sufficiently reduces the siZe of the dosage form, Which is formulations. The release of high solubility active ingredient convenient for sWalloWing. is controlled through dual retard technique. The dual retard technique is a combination of matrix formulations and [0023] The present invention further teaches the use of reservoir formulations. First the micromatrix particles of hydrophobic release controlling agents. high solubility dose active ingredient and one or more US 2006/0018934 A1 Jan. 26, 2006

hydrophobic release controlling agents are formed and then agonist; mood regulator; mucolytic; mydriatic; nasal decon these are further coated With one or more release controlling gestant; neuromuscular blocking agent; neuroprotective; agents. Thus the dual retard release technique presents the NMDA antagonist; non-hormonal sterol derivative; plasmi double barriers and effectively controls the diffusion of the nogen activator; platelet activating factor antagonist; platelet high solubility active ingredients from the present invention aggregation inhibitor; psychotropic; radioactive agent; in predictable manner and also signi?cantly reduces the scabicide; sclerosing agent; sedative; sedative-hypnotic; amount of release controlling agents Which are otherWise selective adenosine Al antagonist; serotonin antagonist; required in very high quantity and make the dosage form serotonin inhibitor; serotonin receptor antagonist; steroid; very bulky and therefore pose dif?culty in sWalloWing. The thyroid hormone; thyroid inhibitor; thyromimetic; tranquil other advantages of the present invention are such as it iZer; amyotrophic lateral sclerosis agent; cerebral ischemia reduces the chances of dose dumping, unnecessary burst agent; Paget’s disease agent; unstable angina agent; vaso effects and failure of the system, Which are otherWise usually constrictor; vasodilator; Wound healing agent; xanthine oxi associated With simple matrix or reservoir systems. dase inhibitor. [0033] Optionally, it may also contain another active [0037] Examples of high solubility active ingredients ingredient as an immediate release form or modi?ed release comprises of but not limited to Abacavir sulfate; Aminoca form. proic acid; Alendronate sodium; Amitriptyline hydrochlo ride; Amphetamine; Acetaminophen; Atropine sulfate; Bal [0034] The high solubility active ingredient can be present salaZide; BenZepril hydrochloride; Bisoprolol fumarate; in the form of a free base or in the form of pharmaceutically Bupropion hydrochloride; Buformin; Captopril; CetriZine acceptable salts. Pharmaceutically acceptable salts forming hydrochloride; Cipro?oxacin; Clindamycin; Chlorphe part of this invention are intended to de?ne but not limited niramine maleate; ChlorpromaZine hydrochloride; Clomi to salts of the carboxylic acid moiety such as alkali metal pramine hydrochloride; Clonidine hydrochloride; Clopi salts like Li, Na and K salts; alkaline earth metal salts like dogrel bisulfate; Cloxacillin Sodium; Codeine phosphate; Ca and Mg salts; salts of organic bases such as lysine, Colchicines; Cyclophosphamide; DiethylcarbamaZine cit arginine, guanidine, diethanolamine, choline, and the like; rate; DL-methionine; Eprosartan; Ethembutol hydrochlo ammonium or substituted ammonium salts and aluminium ride; Ethosuximide; Erythromycin; Ferrous sulfate; Fluox salts. Salts may be acid addition salts Which de?nes but not etine hydrochloride; Fosinopril sodium; Gabapentin; limited to sulfates, nitrates, phosphates, perchlorates, HydralaZine hydrochloride; Hydrocodone bitartrate; borates, hydrohalides, acetates, tartrates, maleates, citrates, HydroxyZine hydrochloride; Hydroxyurea; Indinavir sul succinates, palmoates, methanesulfonates, benZoates, sali fate; IsoniaZid; Isosorbide moninitrate; Lactobionate; Lami cylates, hydroxynaphthoates, benZensulfonates, ascorbates, vudine; Levamisole hydrochloride; Levo?oxacin; Lisino glycerophosphates, ketoglutarates and the like. pril; Losartan potassium; Metformin hydrochloride; [0035] Further, high solubility active ingredient, Where Methylphenidate hydrochloride; Metoprolol tartrate; applicable, may be present either in the form of one sub Minocycline hydrochloride; Montelukast sodium; Naproxen stantially optically pure enantiomer or as a mixture of sodium; Neostigmine bromide; Nicotinamide; Niacin; enantiomers or polymorphs thereof. Nifurtimox; Nortriptyline hydrochloride; OlanZepine; Oxy bytynin chloride; Penicillamine; Penicillin V potassium; [0036] The high solubility active ingredients comprises of Phenyloin sodium; Phenformin; Pravastatin sodium; Potas the folloWing therapeutic classes but not limited to adren sium chloride; Primaquine phosphate; PromethaZine; ergic agent; adrenocortical steroid; adrenocortical suppres PromethaZine hydrochloride; Proponolol hydrochloride; sant; aldosterone antagonist; amino acid; anabolic; analep Propoxyphene hydrochloride; Pseudophedrine hydrochlo tic; analgesic; anesthetic; anorectic; anti-acne agent; anti ride; Pyridostigmine bromide; Pyridoxine hydrochloride; adrenergic; anti-allergic; anti-amebic; anti-anemic; anti Quinapril hydrochloride; Quetiapine; Ramipril; Ranitidine anginal; anti-arthritic; anti-asthmatic; anti-atherosclerotic; hydrochloride; Risedronate sodium; RosiglitaZone maleate; antibacterial; anticholinergic; anticoagulant; anticonvulsant; Sodium valproate; Salbutamol sulfate; Stavudine; Sumatrip antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti tan succinate; TeraZosin hydrochloride; Tetracycline hydro emetic; anti-epileptic; anti?brinolytic; antifungal; antihem chloride; Timolol meleate; Tramodol hydrochloride; Vala orrhagic; antihistamine; antihyperlipidemia; antihyperten cyclovir hydrochloride; Vancomycin; Venlafaxine sive; antihypotensive; anti-infective; anti-in?ammatory; hydrochloride; Verapamil hydrochloride; Wafarin sodium antimicrobial; antimigraine; antimitotic; antimycotic, antin and the active ingredients described in US. Pat. Nos. auseant, antineoplastic, antineutropenic, antiparasitic; anti 2,968,158, 3,097,242, 3,454,635, 3,654,357, 3,668,215, proliferative; antipsychotic; antirheumatic; antiseborrheic; 3,669,966, 3,708,486, 3,801,495, 5,104,888, 5,232,945, antisecretory; antispasmodic; antithrombotic; anti-ulcer 5,264,451, 5,478,852, 6,296,874, 3,957,853, 4,080,472, ative; antiviral; appetite suppressant; blood glucose regula 3,174,901, 4,835,184, 6,031,004 and European patent pub tor; bone resorption inhibitor; bronchodilator; cardiovascu lication numbers EP0008203, EP0032128, EP0139421, lar agent; cholinergic; depressant; diagnostic aid; diuretic; EP0155845, EP0177353, EP0208420, EP0257881, dopaminergic agent; estrogen receptor agonist; ?brinolytic; EP0306228, EP0319189, EP0332331, EP0332332, ?uorescent agent; free oxygen radical scavenger; gastric EP0428312, EP0489663, EP0508740, EP0528734, acid supressant; gastrointestinal motility effector; glucocor EP0533933, EP0833933, EP87112480.6 and Japanese ticoid; hair groWth stimulant; hemostatic; histamine H2 patent number 05271204 and United Kingdom patent num receptor antagonists; hormone; hypocholesterolemic; bers 5504078, GB2088365A and PCT patent application hypoglycemic; hypolipidemic; hypotensive; imaging agent; numbers WO91/19702, WO92/03425, WO92/18501, immuniZing agent; immunomodulator; immunoregulator; WO93/02079, WO93/21166, WO93/22445, WO94/01420, immunostimulant; immunosuppressant; keratolytic; LHRH WO94/05659. US 2006/0018934 A1 Jan. 26, 2006

[0038] The quantity of the high solubility active ingredient [0048] According to an especially preferred embodiment for eg as mentioned above can be less than or equal to 1500 the release controlling agent contains ammonio methacry mg. late co-polymers and fatty acid esters as hereinafter described. [0039] Adosage form of the present invention may option ally contain more than one high solubility active ingredient. [0049] The suitable hydrophobic agents are polymers sold under the Trade Mark Eudragit RS (Ammonio Methacrylate [0040] Adosage form of the present invention may option Copolymer type B USP), Eudragit NE 30D (Polyacrylate ally contain more than one antidiabetic active ingredient. dispersion 30% Ph., Eur.), Eudragit RL (Ammonio Meth [0041] As indicated above the outer portion of the present acrylate Copolymer type AUSP) and Kollicoat SR 30 D and invention may comprise auxiliary excipients such as for fatty acid esters such as glyceryl behenate, and hydrogenated example lubricants, plasticisers, anti-tack agents, opacifying castor oil. Eudragit polymers are polymeric lacquer sub agents, pigments, and such like. As Will be appreciated by stances based on acrylate and/or methacrylates. those skilled in the art, the exact choice of excipient and their [0050] The dosage form can also include one or more relative amounts Will depend to some extent on the ?nal oral commonly used excipients in oral pharmaceutical formula dosage form. tions. [0042] Suitable lubricants, including agents that act on the [0051] Representative commonly used excipients in oral ?oWability of the poWder to be compressed are, for example, pharmaceutical formulations include talc, fumed silica, colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a glyceryl monostearate, magnesium stearate, calcium stear Trade Mark); talc; stearic acid, magnesium stearate, calcium ate, kaolin, colloidal silica, gypsum, TWeen 80, Geleol stearate and sodium stearyl fumarate. pastiles (trade mark), micronised silica and magnesium trisilicate. [0043] In micro matrix particles, the active ingredient and one or more hydrophobic release controlling agents are [0052] The quantity of commonly used excipients in oral preferably present in a ratio of from 100:1 to 100175, more pharmaceutical formulations used is from about 2% to about particularly from 10012.5 to 100150, still more preferably 500% by Weight, preferably from 2 to 100% more particu from 10012.5 to 100130 and most preferably from 10012.5 to larly 10 to 60% based on the total dry Weight of the polymer. 100120. [0053] The dosage form can also include a material that [0044] Micro matrix particles and coating of one or more improves the processing of the release controlling agents. hydrophobic release controlling agents are preferably Such materials are generally referred to as “plasticisers” and present in a ratio of from 10010.5 to 100175, more particu include, for example, adipates, aZelates, benZoates, citrates, larly from 10012.5 to 100150, still more preferably from isoebucaes, phthalates, sebacates, stearates, tartrates, poly 10012.5 to 100130 and most preferably from 10012.5 to hydric alcohols and glycols. 100120. [0054] Representative plasticisers include acetylated [0045] According to one embodiment the release control monoglycerides; butyl phthalyl butyl gylcolate; dibutyl tar ling agents are pharmaceutically excipients, Which are trate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl hydrophobic in nature. ethyl glycolate; glycerin; ethylene glycol, propylene glycol; Triethyl citrate; triacetin; tripropinoin; diacetin; dibutyl [0046] The polymers that can be used to form the rate phthalate; acetyl monoglyceride; polyethylene glycols; cas controlling membrane or micromatrix are described in tor oil; triethyl citrate; polyhydric alcohols, acetate esters, greater detail herein beloW. glycerol triacetate, acetyl triethyl citrate, dibenZyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phtha [0047] The hydrophobic release controlling agents are late, butyl octyl phthalate, dioctyl aZelate, epoxidised tallate, selected from but are not limited to Ammonio methacrylate triisoctyl trimellitate, diethylexyl phthalate, di-n-octyl copolymers type A and B as described in USP, methacrylic phthalate, di-1-octyl phthalate, di-1-decyl phthalate, di-n acid copolymer type A, B and C as described in USP, undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylexyl Polyacrylate dispersion 30% as described in Ph. Eur., Poly trimellitate, di-2-ethylexyl adipate, di-2-ethylhexyl seba vinyl acetate dispersion, ethylcellulose, cellulose acetate, cate, di-2-ethylhexyl aZelate, dibutyl sebacate, glyceryl cellulose propionate (loWer, medium or higher molecular monocaprylate, glycerol distearate, glyceryl monocaprate, Weight), cellulose acetate propionate, cellulose acetate nicotine, oxybutamine chloride, perinodopril erbumine, butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly pilocorpine, poldine methyl sulfate and Zalcitane. (butyl methacrylate), poly(isobutyl methacrylate), and poly [0055] The amount of plasticiser to be used is from about (hexyl methacrylate). Poly(isodecyl methacrylate), poly 1% to 50% based on the Weight of the dry release controlling (lauryl methacrylate), poly(phenyl methacrylate), poly agent(s). (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl [0056] The amount of release controlling agent(s) to be actylate), poly (octadecyl acrylate), Waxes such as beesWax, used in forming the outer portion Will be determined based carnauba Wax, microcrystalline Wax, and oZokerite; fatty on various parameters such as the desired delivery proper alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl ties, including the amount of active ingredient to be deliv alcohol and myristyl alcohol; and fatty acid esters such as glyceryl monostearate, glyceryl distearate, glycerol ered, the active ingredient release rate desired, and the siZe monooleate, acetylated monoglycerides, tristearin, tripalm of the micro matrix particles. itin, cetyl esters Wax, glyceryl palmitostearate, glyceryl [0057] Part comprising another active ingredient—It com behenate, and hydrogenated castor oil. prises of active ingredient(s) and includes one or more US 2006/0018934 A1 Jan. 26, 2006

commonly used eXcipients in oral immediate release or 16-epiestriol, 17 alpha dihydroequilenin, 17 alpha estradiol, modi?ed release pharmaceutical formulations. 17 beta estradiol, 17 hydroXy progesterone, lalpha-hydrox [0058] The active ingredient(s) can be present in the form yvitamin D2, l-dodecpyrrolidinone, 20-epi-1,25 dihydroX of a free base or in the form of pharmaceutically acceptable yvitamin D3,22-oXacalcitriol, 2CVV, 2‘-nor-cGMP, 3-isobu salts. Pharmaceutically acceptable salts forming part of this tyl GABA, S-ethynyluracil, 6-FUDCA, 7-methoXytacrine, invention are intended to de?ne but not limited to salts of the Abamectin, abanoquil, abecarnil, abiraterone, Ablukast, carboXylic acid moiety such as alkali metal salts like Li, Na Ablukast Sodium, Acadesine, acamprosate, Acarbose, Ace and K salts; alkaline earth metal salts like Ca and Mg salts; butolol, Acecainide Hydrochloride, Aceclidine, aceclofenae, salts of organic bases such as lysine, arginine, guanidine, Acedapsone, Aceglutamide Aluminum, Acemannan, diethanolamine, choline, and the like; ammonium or substi Acetaminophen, AcetaZolamide, AcetoheXamide, Acetohy tuted ammonium salts and aluminium salts. Salts may be droXamic Acid, acetomepregenol, AcetophenaZine Maleate, acid addition salts Which de?nes but not limited to sulfates, Acetosulfone Sodium, Acetylcholine Chloride, Acetylcys nitrates, phosphates, perchlorates, borates, hydrohalides, teine, acetyl-L-carnitine, acetylmethadol,Acifran, acipimoX, acetates, tartrates, maleates, citrates, succinates, palmoates, acitemate, Acitretin, Acivicin, Aclarubicin, aclatonium, methanesulfonates, benZoates, salicylates, hydroXynaph AcodaZole Hydrochloride, aconiaZide, Acrisorcin, Acrivas thoates, benZensulfonates, ascorbates, glycerophosphates, tine, Acronine, Actisomide, Actodigin, Acyclovir, acylful ketoglutarates and the like. vene, adafenoXate, adapalene, Adapalene, adatanserin, Ada [0059] Further, active ingredient(s), Where applicable, tanserin Hydrochloride, adecypenol, adecypenol, Adefovir, may be present either in the form of one substantially adelmidrol, ademetionine, Adenosine, AdinaZolam, optically pure enantiomer or as a miXture of enantiomers or Adipheinine Hydrochloride, adiposin, AdoZelesin, adra?nil, polymorphs thereof. Adrenalone, airbutamine, alacepril, Alamecin, Alanine, Ala proclate, alaptide, AlbendaZole, albolabrin, Albuterol, Albu [0060] The active ingredient(s) comprises of the folloWing toin, Alclofenae, Alclometasone Dipropionate, AlcloXa, therapeutic classes but not limited to adrenergic agent; aldecalmycin, Aldesleukin, AldioXa, Alendronate Sodium, adrenocortical steroid; adrenocortical suppressant; aldoster alendronic acid, alentemol, Alentemol Hydrobromide, Ale one antagonist; amino acid; anabolic; analeptic; analgesic; tamine Hydrochloride, Aleuronium Chloride, AleXidine, anesthetic; anorectic; anti-acne agent; anti-adrenergic; anti alfacalcidol, Alfentanil Hydrochloride, alfuZosin, Algestone allergic; anti-amebic; anti-anemic; anti-anginal; anti-ar Acetonide, alglucerase, Ali?urane, alinastine, Alipamide, thritic; anti-asthmatic; anti-atherosclerotic; antibacterial; Allantoin, Allobarbital, Allopurinol, ALL-TK antagonists, anticholinergic; anticoagulant; anticonvulsant; antidepres Alonimid, alosetron, Alosetron Hydrochloride, Alovudine, sant; antidiabetic; antidiarrheal; antidiuretic; anti-emetic; Alpertine, Alpha Amylase, alpha idosone, Alpidem, Alpra anti-epileptic; anti?brinolytic; antifungal; antihemorrhagic; Zolam, Alprenolol Hydrochloride, AlprenoXime Hydrochlo antihistamine; antihyperlipidemia; antihypertensive; antihy ride, Alprostadil, Alrestatin Sodium, Altanserin Tartrate, potensive; anti-infective; anti-in?ammatory; antimicrobial; Alteplase, AlthiaZide, Altretamine, altromycin B, Alverinc antimigraine; antimitotic; antimycotic, antinauseant, antine Citrate, Alvircept SudotoX, Amadinone Acetate, Amantadine oplastic, antineutropenic, antiparasitic; antiproliferative; Hydrochloride, ambamustine, Ambomycin, Ambruticin, antipsychotic; antirheumatic; antiseborrheic; antisecretory; Ambuphylline, Ambuside, Amcinafal, Amcinonide, Amdi antispasmodic; antithrombotic; anti-ulcerative; antiviral; nocillin, Amdinocillin PivoXil, Amedalin Hydrochloride, appetite suppressant; blood glucose regulator; bone resorp amelometasone, Ameltolide, Amesergide, Ametantrone tion inhibitor; bronchodilator; cardiovascular agent; cholin Acetate, ameZinium metilsulfate, amfebutamone, Amfenac ergic; depressant; diagnostic aid; diuretic; dopaminergic Sodium, Am?utiZole, Amicycline, Amidephrine Mesylate, agent; estrogen receptor agonist; ?brinolytic; ?uorescent amidoX, Ami?oXacin, amifostine, Amikacin, Amiloride agent; free oXygen radical scavenger; gastric acid supres Hydrochloride, Aminacrine Hydrochloride, AminobenZoate sant; gastrointestinal motility effector; glucocorticoid; hair Potassium, AminobenZoate Sodium, Aminocaproic Acid, groWth stimulant; hemostatic; histamine H2 receptor Aminoglutethimide, Aminohippurate Sodium, aminole antagonists; hormone; hypocholesterolemic; hypoglycemic; vulinic acid, Aminophylline, A minoreX, Aminosalicylate hypolipidemic; hypotensive; imaging agent; immuniZing sodium, Aminosalicylic acid, Amiodarone, Amiprilose agent; immunomodulator; immunoregulator; immunostimu Hydrochloride, Amiquinsin Hydrochloride, amisulpride, lant; immunosuppressant; keratolytic; LHRH agonist; mood AmitraZ, Amitriptyline Hydrochloride, AmleXanoX, amlo regulator; mucolytic; mydriatic; nasal decongestant; neuro dipine, Amobarbital Sodium, Amodiaquine, Amodiaquine muscular blocking agent; neuroprotective; NMDA antago Hydrochloride, Amorol?ne, AmoXapine, AmoXicillin, nist; non-hormonal sterol derivative; plasminogen activator; Amphecloral, Amphetamine Sulfate, Amphomycin, Ampho platelet activating factor antagonist; platelet aggregation tericin B, Ampicillin, ampiroXicam, AmpyZine Sulfate, inhibitor; psychotropic; radioactive agent; scabicide; scle Amquinate, Amrinone, amrinone, amrubicin, Amsacrine, rosing agent; sedative; sedative-hypnotic; selective adenos amylin, amythiamicin, Anagestone Acetate, anagrelide, ine Al antagonist; serotonin antagonist; serotonin inhibitor; Anakinra, ananain, anaritide, Anaritide Acetate, Anastro serotonin receptor antagonist; steroid; thyroid hormone; Zole, AnaZolene Sodium, Ancrod, andrographolide, Andros thyroid inhibitor; thyromimetic; tranquiliZer; amyotrophic tenedione, angiogenesis inhibitors, Angiotensin Amide, Ani lateral sclerosis agent; cerebral ischemia agent; Paget’s doXime, Anileridine, Anilopam Hydrochloride, Aniracetam, disease agent; unstable angina agent; vasoconstrictor; Anirolac, Anisotropine Methylbromide, Anistreplase, Ani vasodilator; Wound healing agent; Xanthine oXidase inhibi traZafen, anordrin, antagonist D, antagonist G, antareliX, tor. AntaZoline Phosphate, Anthelmycin, Anthralin, Anthramy [0061] Examples of active ingredient comprises of but not cin, antiandrogen, Acedapsone, Felbamate, antiestrogen, limited to—16-alpha ?uorocstradiol, 16alpha-gitoXin, antineoplaston, Antipyrine, antisense oligonucleotides, apa US 2006/0018934 A1 Jan. 26, 2006

doline, apafant, Apalcillin Sodium, apaXifylline, ApaZone, Dipropionate, Bolasterone, Boldenone Undecylenate, bol aphidicolin glycinate, ApiXifylline, Apomorphine Hydro dine, Bolenol, Bolmantalate, bopindolol, Bosentan, BoXi chloride, apraclonidine, Apraclonidine Hydrochloride, dine, brefeldin, bre?ate, Brequinar Sodium, BretaZenil, Apramycin, Aprindine, Aprindine Hydrochloride, aprosulate Bretylium Tosylate, Brifentanil Hydrochloride, brimoni sodium, Aprotinin, AptaZapine Maleate, aptiganel, apurinic dine, Brinolase, Brocresine, Brocrinat, BrofoXine, Broma acid, apurinic acid, aranidipine, Aranotin, Arbaprostil, doline Maleate, BromaZepam, Bromchlorenone, Brome arbekicin, arbidol, Arbutamine Hydrochloride, Arclofenin, lains, bromfenac, Brominidione, Bromocriptine, Ardeparin Sodium, argatroban, Arginine, Argipressin Tan Bromodiphenhydramine Hydrochloride, BromoXanide, Bro nate, Arildone, aripipraZol, arotinolol, Arpinocid, Arte?ene, mperidol, Bromperidol Decanoate, Brompheniramine Male Artilide Fumarate, asimadoline, aspalatone, Asparaginase, ate, Broperamole, Bropirimine, BrotiZolam, Bucainide Aspartic Acid, Aspartocin, asperfuran, Aspirin, aspoXicillin, Maleate, bucindolol, BucliZine Hydrochloride, Bucromar Asprelin, AstemiZole, Astromicin Sulfate, asulacrine, ata one, Budesonide, budipine, budotitane, Buformin, Bumeta mestane, Atenolol, atevirdine, AtipameZole, Atiprosin Male mide, Bunaprolast, bunaZosin, Bunolol Hydrochloride, ate, Atolide, Atorvastatin Calcium, Atosiban, Atovaquone, Bupicomide, Bupivacaine Hydrochloride, Buprenorphine atpenin B, Atracurium Besylate, atrimustine, atrinositol, Hydrochloride, Bupropion Hydrochloride, Buramate, Atropine, Aurano?n, aureobasidin A, Aurothioglucose, Buserelin Acetate, Buspirone Hydrochloride, Busulfan, But Avilamycin, Avoparcin, Avridine, Axid, aXinastatin 1, aXin abarbital, Butacetin, Butaclamol Hydrochloride, Butalbital, astatin 2, aXinastatin 3, AZabon, AZacitidinie, AZaclorZine Butamben, Butamirate Citrate, ButaperaZine, Butaprost, Hydrochloride, AZaconaZole, aZadirachtine, AZalanstat Butedronate Tetrasodium, butena?ne, ButeriZine, buthion Dihydrochloride, AZaloXan Fumarate, AZanator Maleate, ine sulfoXimine, Butikacin, Butilfenin, Butirosin Sulfate, AZanidaZole, AZaperone, AZaribine, AZaserine, aZasetron, ButiXirate, butiXocort propionate, ButoconaZole Nitrate, AZatadine Maleate, AZathioprine, AZathioprine Sodium, Butonate, Butopamine, ButoproZine Hydrochloride, Butor aZatoXin, aZatyrosine, aZelaic acid, aZelastine, aZelnidipine, phanol, ButoXamine Hydrochloride, Butriptyline Hydro AZepindole, AZetepa, aZimilide, AZithromycin, AZlocillin, chloride, Cactinomycin, CadeXomer Iodine, Caffeine, cal AZolimine, AZosemide, AZotomycin, AZtreonam, anolide A, Calcifediol, Calcipotriene, calcipotriol, AZumolene Sodium, Bacampicillin Hydrochloride, baccatin Calcitonin, Calcitriol, Calcium Undecylenate, calphostin C, III, Bacitracin, Baclofen, bacoside A, bacoside B, bactobo Calusterone, CambendaZole, camonagrel, camptothecin lamine, balanol, balaZipone, balhimycin, balo?oXacin, bal derivatives, canarypoX IL-2, candesartan, Candicidin, can salaZide, Bambermycins, bambuterol, Bamethan Sulfate, doXatril, candoXatrilat, Caniglibose, Canrenoate Potassium, Bamifylline Hydrochloride, BamidaZole, baohuoside 1, Bar Canrenone, capecitabine, Capobenate Sodium, Capobenic mastine, barnidipine, Basifungin, Batanopride Hydrochlo Acid, Capreomycin Sulfate, capromab, capsaicin, Captopril, ride, batebulast, Batelapine Maleate, Batimastat, beauveri Capuride, Caracemide, Carbachol, CarbadoX, Carbam cin, Becanthone Hydrochloride, becaplermin, aZepine, Carbamide Peroxide, Carbantel Lauryl Sulfate, becliconaZole, Beclomethasone Dipropionate, be?oXatone, Carbaspirin Calcium, CarbaZeran, carbaZomycin C, Carbe BeinseraZide, Belfosdil, Belladonna, BeloXamide, nicillin Potassium, CarbenoXolone Sodium, Carbetimer, car Bemesetron, Bemitradine, Bemoradan, BenapryZine Hydro betocin, Carbidopa, Carbidopa-Levodopa, CarbinoXamine chloride, BenaZepril Hydrochloride, BenaZeprilat, Benda Maleate, Carbiphene Hydrochloride, Carbocloral, Car calol Mesylate, BendaZac, Bendro?umethiaZide, ben?ume bocysteine, Carbol-Fuchsin, Carboplatin, Carboprost, car tol, benidipine, Benorterone, BenoXaprofen, BenoXaprofen, bovir, carboXamide-amino-triaZo-le, carboXyamidotriaZole, BenoXinate Hydrochloride, Benperidol, BentaZepam, Ben carboXymethylated beta-1,3-glucan, Carbuterol Hydrochlo tiromide, Benurestat, BenZbromarone, BenZethonium Chlo ride, CaRest M3, Carfentanil Citrate, Carisoprodol, Carman ride, BenZetimide Hydrochloride, BenZilonium Bromide, tadine, Carmustine, CARN 700, CamidaZole, CaroXaZone, BenZindopyrine Hydrochloride, benZisoXaZole, BenZocaine, carperitide, CarphenaZine Maleate, Carprofen, Carsatrin benZochlorins, BenZoctamine Hydrochloride, BenZodepa, Succinate, CartaZolate, carteolol, Carteolol Hydrochloride, benZoidaZoXan, BenZonatate, BenZoyl Peroxide, Ben cartilage derived inhibitor, Carubicin Hydrochloride, Caru Zoylpas Calcium, benZoylstaurosporine, BenZquinamide, monam Sodium, carvedilol, carvotroline, Carvotroline BenZthiaZide, benZtropine, BenZtropine Mesylate, BenZy Hydrochloride, carZelesin, casein kinase inhibitors (ICOS), damine Hydrochloride, BenZylpenicilloyl Polylysine, bepri castanospermine, caurumonam, cebaracetam, cecropin B, dil, Bepridil Hydrochloride, Beractant, Beraprost, Berefrine, Cede?ngol, Cefaclor, CefadroXil, Cefamandole, Cefaparole, berlafenone, bertosamil, Berythromycin, besipirdine, beta CefatriZine, CefaZa?ur Sodium, CefaZolin, CefbuperaZone, alethine, betaclamycin B, Betamethasone, betamipron, cefcapene pivoXil, cefdaloXime penteXil tosilate, Cefdinir, betaXolol, BetaXolol Hydrochloride, Bethanechol Chloride, cefditoren pivoXil, Cefepime, cefetamet, Cefetecol, Bethanidine Sulfate, betulinic acid, bevantolol, Bevantolol ce?Xime, ce?uprenam, Ce?nenoXime Hydrochloride, Ce?n Hydrochloride, BeZa?brate, bFGF inhibitor, Bialamicol etaZole, cefminloX, cefodiZime, Cefonicid Sodium, Cefop Hydrochloride, Biapenem, Bicalutamide, Bicifadine Hydro eraZone Sodium, Ceforamide, cefoselis, CefotaXime chloride, Biclodil Hydrochloride, Bidisomide, bifemelane, Sodium, Cefotetan, cefotiam, CefoXitin, cefoZopran, cefpi BifonaZole, bimakalim, bimithil, Bindarit, Biniramycin, miZole, Cefpiramide, cefpirome, cefpodoXime proXetil, cef binospirone, bioXalomycin alpha2, Bipenamol Hydrochlo proZil, CefroXadine, cefsulodin, CeftaZidime, cefteram, cef ride, Biperiden, Biphenamine Hydrochloride, biriperone, tibuten, CeftiZoXime Sodium, ceftriaXone, CefuroXime, bisantrene, bisaramil, bisaZiridinylspermine, bis-benZimida celastrol, celikalim, celiprolol, cepacidiine A, Cephacetrile Zole A, bis-benZimidaZole B, bisna?de, Bisobrin Lactate, Sodium, CephaleXin, Cephaloglycin, Cephaloridine, Cepha Bisoprolol, Bispyrithione MagsulfeX, bistramide D, bistra lothin Sodium, Cephapirin Sodium, Cephradine, cer mide K, bistratene A, Bithionolate Sodium, Bitolterol Mesy iclamine, cerivastatin, Ceronapril, certoparin sodium, Ceru late, Bivalirudin, BiZelesin, Bleomycin Sulfate, Bolandiol letide, Cetaben Sodium, Cetalkonium Chloride, Cetamolol US 2006/0018934 A1 Jan. 26, 2006

Hydrochloride, cetiedil, cetiriZine, Cetophenicol, CetraXate Cyclophospharnide, cycloplatarn, Cyclopropane, Cyclos Hydrochloride, cetroreliX, Cetylpyridiniurn Chloride, erine, cyclosin, Cyclosporine, cyclothialidine, CyclothiaZ Chenodiol, Chlophedianol Hydrochloride, Chloral Betaine, ide, cyclothiaZornycin, Cyheptarnide, cypernycin, Cype Chlorarnbucil, Chlorarnphenicol, Chlordantoin, ChlordiaZ narnine Hydrochloride, CypraZeparn, Cyproheptadine epoXide, ChlorheXidine Gluconate, chlorins, Chlorrnadinone Hydrochloride, Cyprolidol Hydrochloride, cyproterone, Acetate, chloroorienticin A, Chloroprocaine Hydrochloride, CyproXirnide, Cystearnine, Cysteine Hydrochloride, Cys Chloroproparnide, Chloroquine, chloroquinoXaline sulfona tine, Cytarabine, Cytarabine Hydrochloride, cytarabine rnide, ChlorothiaZide, Chlorotrianisene, ChloroXine, ocfosfate, cytochalasin B, cytolytic factor, cytostatin, Dac ChloroXylenol, Chlorphenesin Carbarnate, Chlorphe arbaZine, dacliXirnab, dactirnicin, Dactinornycin, daidZein, nirarnine Maleate, ChlorprornaZine, Chlorproparnide, Chlo Daledalin Tosylate, dalfopristin, Dalteparin Sodiurn, Dal rprothiXene, Chlortetracycline Bisulfate, Chlorthalidone, troban, Dalvastatin, danaparoid, DanaZol, Dantrolene, ChlorZoXaZone, Cholestyrarnine Resin, Chrornonar Hydro daphlnodorin A, dapipraZole, dapitant, DapoXetine Hydro chloride, cibenZoline, cicaprost, Ciclafrine Hydrochloride, chloride, Dapsone, Daptornycin, DarglitaZone Sodiurn, CiclaZindol, ciclesonide, cicletanine, CiclopiroX, Ciclopro darifenacin, darlucin A, Darodipine, darsidornine, Daunoru fen, cicloprolol, Cidofovir, CidoXepin Hydrochloride, bicin Hydrochloride, DaZadrol Maleate, DaZepinil Hydro Cifenline, CiglitaZone, Ciladopa Hydrochloride, cilansetron, chloride, DaZrnegrel, DaZopride Furnarate, DaZoXiben Cilastatin Sodium, CilaZapril, cilnidipine, Cilobarnine Hydrochloride, Debrisoquin Sulfate, Decitabine, defer Mesylate, cilobradine, Cilofungin, cilostaZol, Cirnaterol, iprone, de?aZacort, Dehydrocholic Acid, dehydrodidernnin Cirnetidine, cirnetropiurn brornide, Cinalukast, Cinanserin B, Dehydroepiandrosterone, delapril, Delapril Hydrochlo Hydrochloride, CinepaZet Maleate, Cin?urnide, Cingestol, ride, Delavirdine Mesylate, delequarnine, delfapraZine, Del cinitapride, Cinnarnedrine, CinnariZine, cinolaZeparn, Cino rnadinone Acetate, delrnopinol, delphinidin, Dernecariurn Xacin, Cinperene, Cinrornide, CintaZone, Cintriarnide, Ciot Brornide, Derneclocycline, Dernecycline, DernoXeparn, eronel, Ciparnfylline, Ciprefadol Succinate, Ciprocinonide, Denofungin, deoXypyridinoline, Depakote, deprodone, Cipro?brate, Cipro?oXacin, ciprostene, Cirarnadol, Cirole Deprostil, depsidornycin, derarnciclane, derrnatan sulfate, rnycin, cisapride, cisatracuriurn besilate, CisconaZole, Cis Desciclovir, Descinolone Acetonide, Des?urane, platin, cis-porphyrin, cistineXine, citaloprarn, Citenarnide, Desiprarnine Hydrochloride, desirudin, Deslanoside, citicoline, citrearnicin alpha, cladribine, ClarnoXyquin deslorelin, desrnopressin, desogestrel, Desonide, Des Hydrochloride, Clarithrornycin, clausenarnide, Clavulanate oXirnetasone, desoXoarniodarone, DesoXycorticosterone Potassium, ClaZolam, ClaZolimine, clebopride, Clemastine, Acetate, detajmium bitartrate, Deterenol Hydrochloride, ClentiaZern Maleate, Clidiniurn Brornide, clina?oXacin, DetireliX Acetate, DevaZepide, DeXarnethasone, DeXarni Clindarnycin, Clioquinol, ClioXanide, Cliprofen, clobaZarn, sole, DeXbrornphenirarnine Maleate, DeXchlorphenirarnine Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Maleate, DeXclarnol Hydrochloride, DeXetirnide, DeXfen Acetate, Clodanolene, ClodaZon Hydrochloride, clodronic ?urarnine Hydrochloride, deXifosfarnide, DeXirnafen, DeXi acid, ClofaZirnine, Clo?brate, Clo?liurn Phosphate, Cloge vacaine, dexketoprofen, deXloXiglurnide, DeXrnedetorni stone Acetate, Clornacran Phosphate, Clornegestone dine, DeXorrnaplatin, DeXoXadrol Hydrochloride, Acetate, Clornetherone, clornethiaZole, clornifene ana DeXpanthenol, DeXpernedolac, DeXpropranolol Hydrochlo logues, ClorninoreX, Clorniphene, Clorniprarnine Hydro ride, DeXraZoXane, deXsotalol, deXtrin 2-sulphate, Dextro chloride, ClonaZeparn, Clonidine, Clonitrate, CloniXeril, arnphetarnine, DeXtrornethorphan, DeXtrorphan Hydrochlo CloniXin, Cloparnide, ClopenthiXol, Cloperidone Hydro ride, DeXtrothyroXine Sodiurn, deXveraparnil, DeZaguanine, chloride, clopidogrel, ClopirnoZide, ClopipaZan Mesylate, deZinarnide, deZocine, Diacetolol Hydrochloride, Clopirac, Cloprednol, Cloprostenol Sodiurn, CloraZepate Diarnocaine Cyclarnate, Diaparnide, DiatriZoate Meglu Dipotassiurn, Clorethate, CloreXolone, Cloroperone Hydro rnine, DiatriZoic Acid, Diaveridine, DiaZeparn, DiaZiquone, chloride, Clorprenaline Hydrochloride, Clorsulon, Clorter DiaZoXide, DibenZepin Hydrochloride, DibenZothiophene, rnine Hydrochloride, Closantel, Closirarnine Aceturate, Dibucaine, Dichliorvos, DichloralphenaZone, Dichlorphe Clothiapine, ClothiXarnide Maleate Cloticasone Propionate, narnide, Dicirenone, Diclofenac Sodiurn, DicloXacillin, dic ClotrirnaZole, CloXacillin BenZathine, CloXyquin, CloZap ranin, Dicurnarol, Dicyclornine Hydrochloride, Didanosine, ine, Cocaine, Coccidioidin, Codeine, CodoXirne, Colchicine, didernnin B, didoX, Dienestrol, dienogest, Diethylcarbarn colestirnide, Colestipol Hydrochloride, Colestolone, Col aZine Citrate, diethylhornosperrnine, diethylnorsperrnine, forsin, Colfosceril Palrnitate, Colistirnethate Sodiurn, Colis Diethylpropion Hydrochloride, Diethylstilbestrol, DifenoX tin Sulfate, collisrnycin A, collisrnycin B, Colterol Mesylate, irnide Hydrochloride, DifenoXin, Di?orasone Diacetate, cornbretastatin A4, cornbretastatin analogue, cornplestatin, Di?oXacin Hydrochloride, Di?uanine Hydrochloride, Di?u conagenin, Conorphone Hydrochloride, contignasterol, con cortolone, Di?urnidone Sodiurn, Di?unisal, Di?uprednate, tortrostatin, Corrnethasone Acetate, Corticorelin Ovine Tri Diftalone, Digitalis, DigitoXin, DigoXin, DiheXyverine ?utate, Corticotropin, Cortisone Acetate, CortivaZol, Corto Hydrochloride, dihydreXidine, dihydro-S-azacytidine, Dihy doXone, cosalane, costatolide, Cosyntropin, cotinine, drocodeine Bitartrate, Dihydroergotarnine Mesylate, Dihy Cournadin, Cournerrnycin, crarnbescidin 816, Crilvastatin, droestosterone, Dihydrostreptornycin Sulfate, Dihydrotach crisnatol, Crornitrile Sodiurn, Crornolyn Sodiurn, Crotarni ysterol, dihydrotaXol, 9-, Dilantin, Dilevalol Hydrochloride, ton, cryptophycin 8, cucurnariosid, CuprirnyXin, curacin A, DiltiaZern Hydrochloride, Dirnefadane, Dirne?ine Hydro curdlan sulfate, curiosin, Cyclacillin, CyclaZocine, cycla chloride, Dirnenhydrinate, Dirnercaprol, Dirnethadione, Zosin, cyclic HPMPC, Cyclindole, Cyclirarnine Maleate, Dirnethindene Maleate, Dirnethisterone, dirnethyl prostag CycliZine, CyclobendaZole, cyclobenZaprine, cyclobut A, landin A1, Dirnethyl SulfoXide, dirnethylhornosperrnine, cyclobut G, cyclocapron, Cycloguanil Parnoate, CycloheX dirniracetarn, DirnoXarnine Hydrochloride, Dinoprost, Dino irnide, cyclopentanthraquinones, CyclopenthiaZide, Cyclo prostone, DioXadrol Hydrochloride, dioXarnycin, Diphenhy pentolate Hydrochloride, CyclophenaZine Hydrochloride, drarnine Citrate, Diphenidol, DiphenoXylate Hydrochloride, US 2006/0018934 A1 Jan. 26, 2006

diphenyl spiromustine, Dipive?n Hydrochloride, Dipivefrin, retinide, fenspiride, Fentanyl Citrate, FentiaZac, Fenticlor, dipliencyprone, diprafenone, dipropylnorspermine, Dipy fenticonaZole, Fenyripol Hydrochloride, fepradinol, ferpifo ridamole, Dipyrithione, Dipyrone, dirithromycin, discoder sate sodium, ferristene, ferriXan, Ferrous Sulfate, Dried, molide, Disobutamide, Disofenin, Disopyramide, DisoXaril, FerumoXides, ferumoXsil, FetoXylate Hydrochloride, feX disul?ram, Ditekiren, DivalproeX Sodium, DiZocilpine ofenadine, FeZolamine Fumarate, Fiacitabine, Fialuridine, Maleate, Dobutamine, docarpamine, Docebenone, Doc Fibrinogen 1 125, ?lgrastim, Filipin, ?nasteride, Flavodilol etaXel, DoconaZole, docosanol, dofetilide, dolasetron, Ebas Maleate, ?avopiridol, FlavoXate Hydrochloride, FlaZalone, tine, ebiratide, ebrotidine, ebselen, ecabapide, ecabet, eca ?ecainide, ?erobuterol, FleroXacin, ?esinoXan, Flestolol dotril, ecdisteron, echicetin, echistatin, Echothiophate Sulfate, FletaZepam, ?eZelastine, ?obufen, Floctafenine, ?o Iodide, Eclanamine Maleate, EclaZolast, ecomustine, Econa moXef, Flordipine, ?orfenicol, ?orifenine, ?osatidil, Flose Zole, ecteinascidin 722, edaravone, EdatreXate, edelfosine, quinan, FloXacillin, FloXuridine, ?uasterone, FluaZacort, Edifolone Acetate, edobacomab, EdoXudine, edrecolomab, Flubanilate Hydrochloride, FlubendaZole, Flucindole, Flu Edrophonium Chloride, edroXyprogesteone Acetate, efegat cloronide, FluconaZole, Flucytosine, Fludalanine, Fludara ran, e?ornithine, efonidipine, egualcen, Elantrine, eleatonin, bine Phosphate, FludaZonium Chloride, FludeoXyglucose F elemene, eletriptan, elgodipine, eliprodil, Elsamitrucin, elte 18, FludoreX, Fludrocortisone Acetate, Flufenamic Acid, nae, Elucaine, emalkalim, emedastine, Emetine Hydrochlo Flufenisal, FlumaZenil, ?umecinol, Flumequine, Flumeri ride, emiglitate, Emilium Tosylate, emitefur, emoctakin, done, Flumethasone, Flumetramide, FlumeZapine, Flumi Enadoline Hydrochloride, enalapril, Enalaprilat, Enalkiren, noreX, FlumiZole, FlumoXonide, ?unariZine, FlunidaZole, enaZadrem, Encyprate, EndralaZine Mesylate, Endrysone, Flunisolide, FlunitraZepam, FluniXin, ?uocalcitriol, Fluoci En?urane, englitaZone, EnilconaZole, Enisoprost, Enlimo nolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocor mab, Enloplatin, Enofelast, Enolicam Sodium, EnoXacin, tolone, Fluorescein, ?uorodaunorunicin hydrochloride, enoXacin, enoXaparin sodium, EnoXaparin Sodium, EnoXi Fluorodopa F 18, Fluorometholone, Fluorouracil, Flu mone, Enpiroline Phosphate, Enprofylline, Enpromate, enta otracen Hydrochloride, FluoXetine, FluoXymesterone, ?up capone, enterostatin, Enviradene, EnviroXime, Ephedrine, aroXan, Fluperamide, Fluperolone Acetate, FluphenaZine Epicillin, Epimestrol, Epinephrine, Epinephryl Borate, Decanoate, ?upirtine, Fluprednisolone, FluproquaZone, Flu Epipropidine, EpiriZole, epirubicin, Epitetracycline Hydro prostenol Sodium, FluquaZone, Fluradoline Hydrochloride, chloride, EpithiaZide, Epoetin Alfa, Epoetin Beta, Epopros Flurandrenolide, FluraZepam Hydrochloride, Flurbiprofen, tenol, Epoprostenol Sodium, epoXymeXrenone, epristeride, Fluretofen, ?urithromycin, Flurocitabine, Flurofamide, Eprosartan, eptastigmine, equilenin, Equilin, ErbuloZole, Flurogestone Acetate, Flurothyl, FluroXene, Fluspiperone, erdosteine, Ergoloid Mesylates, Ergonovine Maleate, Fluspirilene, Fluticasone Propionate, ?utrimaZole, Flutro Ergotamine Tartrate, ersentilide, Ersofermin, erythritol, line, ?uvastatin, Fluvastatin Sodium, ?uvoXamine, FluZina Erythrityl Tetranitrate, Erythromycin, Esmolol Hydrochlo mide, Folic Acid, Follicle regulatory protein, Folliculostatin, ride, Esorubicin Hydrochloride, Esproquin Hydrochloride, FomepiZole, FonaZine Mesylate, forasartan, forfenimeX, for EstaZolam, Estradiol, Estramustine, estramustine analogue, fenirmeX, formestane, Formocortal, formoterol, Fosarilate, EstraZinol Hydrobromide, Estriol, Estrofurate, estrogen ago FosaZepam, Foscarnet Sodium, fosfomycin, Fosfonet nists, estrogen antagonists, Estrogens, Conjugated, Estro Sodium, fosinopril, Fosinoprilat, fosphenyloin, Fosquidone, gens, Esteri?ed, Estrone, Estropipate, esuprone, Etafedrine Fostedil, fostriecin, fotemustine, Fuchsin, Basic, FumoXicil Hydrochloride, EtanidaZole, etanterol, Etarotene, EtaZolate lin, Fungimycin, Furaprofen, FuraZolidone, FuraZolium Hydrochloride, Eterobarb, ethaciZin, Ethacrynate Sodium, Chloride, Furegrelate Sodium, Furobufen, FurodaZole, Ethacrynic Acid, Ethambutol Hydrochloride, Ethamivan, Furosemide, Fusidate Sodium, Fusidic Acid, gabapentin, Ethanolamine Oleate, Ethehlorvynol, Ether, Ethinyl estra Gadobenate Dimeglumine, gadobenic acid, gadobutrol, diol, EthiodiZed Oil, Ethionamide, Ethonam Nitrate, Etho Gadodiamide, gadolinium teXaphyrin, Gadopentetate propaZine Hydrochloride, EthosuXimide, Ethotoin, EthoXa Dimegiumine, gadoteric acid, Gadoteridol, Gadoverseta Zene Hydrochloride, EthybenZtropine, Ethyl Chloride, Ethyl mide, galantamine, galdansetron, Galdansetron Hydrochlo Dibunate, Ethylestrenol, Ethyndiol, Ethynerone, Ethynodiol ride, Gallamine Triethiodide, gallium nitrate, gallopamil, Diacetate, EtibendaZole, Etidocaine, Etidronate Disodium, galocitabine, GamfeXine, gamolenic acid, Ganciclovir, Etidronic Acid, Etifenin, Etintidine Hydrochloride, eti ganireliX, gelatinase inhibitors, Gemcadiol, Gemcitabine, Zolam, Etodolac, Etofenamate, Etoformin Hydrochloride, Gemeprost, Gem?broZil, Gentamicin Sulfate, Gentian Vio Etomidate, Etonogestrel, Etoperidone Hydrochloride, Eto let, gepirone, Gestaclone, Gestodene, Gestonorone poside, Etoprine, EtoXadrol Hydrochloride, EtoZolin, etra Caproate, Gestrinone, Gevotroline Hydrochloride, giriso bamine, Etretinate, Etryptamine Acetate, Eucatropine pam, glaspimod, glaucocalyXin A, Glemanserin, Gliamilide, Hydrochloride, Eugenol, Euprocin Hydrochloride, evemi Glibornuride, Glicetanile Sodium, Gli?umide, Glimepiride, nomicin, EXametaZime, eXamorelin, EXaprolol Hydrochlo GlipiZide, GloXimonam, Glucagon, glutapyrone, glutathione ride, eXemestane, fadroZole, faeriefungin, Famciclovir, inhibitors, Glutethimide, Glyburide, glycopine, glycopril, Famotidine, Fampridine, fantofarone, Fantridone Hydro Glycopyrrolate, GlyheXamide, Glymidine Sodium, Glyoc chloride, faropenem, fasidotril, fasudil, faZarabine, fedot tamide, Glyparamide, Gold Au 198, Gonadoctrinins, Gona oZine, felbamate, Felbinac, Felodipine, Felypressin, Fenala dorelin, Gonadotropins, Goserelin, Gramicidin, Granisetron, mide, Fenamole, FenbendaZole, Fenbufen, Fencibutirol, grepa?oXacin, Griseofulvin, Guaiapate, Guaithylline, Gua Fenclofenac, Fenclonine, Fenclorac, Fendosal, Fenestrel, nabenZ, GuanabenZ Acetate, Guanadrel Sulfate, Guancy Fenethylline Hydrochloride, Fen?uramine Hydrochloride, dine, Guanethidine Monosulfate, Guanfacine Hydrochlo Fengabine, Fenimide, FenisoreX, FenmetoZole Hydrochlo ride, Guanisoquin Sulfate, Guanoclor Sulfate, Guanoctine ride, Fenmetramide, Fenobam, Fenoctimine Sulfate, feno? Hydrochloride, GuanoXabenZ, GuanoXan Sulfate, GuanoXy brate, fenoldopam, Fenoprofen, Fenoterol, Fenpipalone, fen Sulfate, Gusperimus Trihydrochloride, HalaZepam, Hal Fenprinast Hydrochloride, Fenprostalene, FenquiZone, fen cinonide, halichondrin B, Halobetasol Propionate, halofan US 2006/0018934 A1 Jan. 26, 2006

trine, Halofantrine Hydrochloride, Halofenate, orbide Mononitrate, Isotiquimide, Isotretinoin, IsoXepac, Halofuginone Hydrobromide, halomon, Halopemide, Halo IsoXicam, IsoXsuprine Hydrochloride, isradipine, itameline, peridol, halopredone, Haloprogesterone, Haloprogin, Hal itasetron, ItaZigrel, itopride, ItraconaZole, Ivermectin, jas othane, Halquinols, Hamycin, Han memopausal gonadotro plakinolide, Josamycin, kahalalide F, Kalafungin, Kanamy pins, hatomamicin, hatomarubigin A, hatomarubigin B, cin Sulfate, Ketamine Hydrochloride, Ketanserin, KetaZo hatomarubigin C, hatomarubigin D, Heparin Sodium, hep cine, KetaZolam, KethoXal, Ketipramine Fumarate, sulfam, heregulin, Hetacillin, Heteronium Bromide, KetoconaZole, Ketoprofen, Ketorfanol, ketorolac, Ketotifen HexachlorophenezHydrogen Peroxide, HeXa?uorenium Fumarate, Kitasamycin, Labetalol Hydrochloride, Lacid Bromide, heXamethylene bisacetamide, HeXedine, HeX ipine, lacidipine, lactitol, lactivicin, laennec, lafutidine, obendine, HeXoprenaline Sulfate, HeXylresorcinol, Hista lamellarin-N triacetate, lami?ban, Lamivudine, Lamot mine Phosphate, Histidine, Histoplasmin, Histrelin, Homa rigine, lanoconaZole, LanoXin, lanperisone, lanreotide, Lan tropine Hydrobromide, HoquiZil Hydrochloride, Human sopraZole, latanoprost, lateritin, laurocapram, Lauryl Iso chorionic gonadotropin, Hycanthone, HydralaZine Hydro quinolinium Bromide, Lavoltidine Succinate, laZabemide, chloride, HydralaZine PolistireX, HydrochlorothiaZide, Lecimibide, leinamycin, lemildipine, leminopraZole, lener Hydrocodone Bitartrate, Hydrocortisone, Hydro?umethiaZ cept, Leniquinsin, lenograstim, Lenperone, lentinan sulfate, ide, Hydromorphone Hydrochloride, HydroXyamphetamine leptin, leptolstatin, lercanidipine, Lergotrile, lerisetron, Hydrobromide, HydroXychloroquine Sulfate, HydroXyphe Letimide Hydrochloride, letraZuril, letroZole, Leucine, leu namate, HydroXyprogesterone Caproate, HydroXyurca, comyZin, Leuprolide Acetate, leuprolide+estrogen+proges HydroXyZine Hydrochloride, Hymecromone, Hyoscyamine, terone, leuprorelin, Levamfetamine Succinate, levamisole, hypericin, Iba?oXacin, ibandronic acid, ibogaine, Ibopam Levdobutamine Lactobionate, Leveromakalim, levetirac ine, ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icati etam, Leveycloserine, levobetaXolol, levobunolol, levobupi bant Acetate, Ichthammol, Icotidine, idarubicin, idoXifene, vacaine, levocabastine, levocarnitine, Levodopa, levodro IdoXuridine, idramantone, Ieme?oXacin, Iesopitron, propiZine, levo?oXacin, Levofuraltadone, Levoleucovorin Ifetroban, Ifosfamide, Ilepeimide, illimaquinone, ilmofos Calcium, Levomethadyl Acetate, Levomethadyl Acetate ine, ilomastat, Ilonidap, iloperidone, iloprost, Imafen Hydro Hydrochloride, levomoprolol, Levonantradol Hydrochlo chloride, ImaZodan Hydrochloride, imidapril, imidaZenil, ride, Levonordefrin, Levonorgestrel, LevopropoXyphene imidaZoacridones, Imidecyl Iodine, Imidocarb Hydrochlo Napsylate, Levopropylcillin Potassium, levormeloXifene, ride, Imidoline Hydrochloride, Imidurea, ImiloXan Hydro Levorphanol Tartrate, levosimendan, levosulpiride, chloride, Imipenem, Imipramine Hydrochloride, imiqui LevothyroXine Sodium, Levoxadrol Hydrochloride, Lexi mod, immunostimulant peptides, Impromidine pafant, LeXithromycin, liaroZole, LibenZapril, Lidamidine Hydrochloride, Indacrinone, Indapamide, Indecainide Hydrochloride, Lidocaine, Lidofenin, Lido?aZine, LifariZ Hydrochloride, IndeloXaZine Hydrochloride, Indigotindisul ine, Li?brate, Li?brol, Linarotene, Lincomycin, linear fonate Sodium, indinavir, Indocyanine Green, Indolapril polyamine analogue, Linogliride, Linopirdine, linotroban, Hydrochloride, Indolidan, indometacin, Indomethacin linsidomine, lintitript, lintopride, Liothyronine I 125, liothy Sodium, Indoprofen, indoramin, Indorenate Hydrochloride, ronine sodium, LiotriX, lireXapride, lisinopril, lissoclinamide IndoXole, Indriline Hydrochloride, inocoterone, inogatran, 7, LiXaZinone Sulfate, lobaplatin, LobenZarit Sodium, Lobu inolimomab, Inositol Niacinate, Insulin, interferons, inter cavir, Lodelaben, IodoXamide, LofemiZole Hydrochloride, leukins, IntraZole, Intriptyline Hydrochloride, iobenguane, Lofentanil Oxalate, Lofepramine Hydrochloride, LofeXidine IobenZamic Acid, iobitridol, Iocarmate Meglumine, Iocar Hydrochloride, lombricine, Lome?oXacin, lomeriZine, mic Acid, Iocetamic Acid, Iodamide, Iodine, Iodipamide Lometraline Hydrochloride, lometreXol, Lomofungin, Meglumine, IodiXanol, iodoamiloride, Iodoantipyrine 1131, LomoXicam, Lomustine, Lonapalene, lonaZolac, Iodocholesterol 1131, iododoXorubicin, Iodohippurate lonidamine, Loperamide Hydrochloride, loracarbef, Sodium 1131, Iodopyracet 1125, Iodoquinol, IodoXamate Lorajmine Hydrochloride, loratadine, LoraZepam, Lorbam Meglumine, IodoXamie Acid, Ioglicic Acid, Iofetamine ate, Lorcainide Hydrochloride, LorecleZole, Loreinadol, lor Hydrochloride 1123, iofratol, Ioglucol, Ioglucomide, Iogly glumide, LormetaZepam, LornoXicam, lornoXicam, Lorta camic Acid, Iogulamide, IoheXol, iomeprol, Iomethin 1125, lamine, LorZafone, losartan, losigamone, losoXantrone, Iopamidol, Iopanoic Acid, iopentol, lophendylate, Ioproce LosulaZine Hydrochloride, loteprednol, lovastatin, loviride, mic Acid, iopromide, Iopronic Acid, Iopydol, Iopydone, LoXapine, LoXoribine, lubeluZole, Lucanthone Hydrochlo iopyrol, Iosefamic Acid, Ioseric Acid, Iosulamide Meglu ride, Lu?ronil, Lurosetron Mesylate, lurtotecan, luteiniZing mine, Iosumetic Acid, Iotasul, Iotetric Acid, Iothalamate hormone, lutetium, Lutrelin Acetate, luZindole, Lyapolate Sodium, Iothalamic Acid, iotriside, Iotrolan, IotroXic Acid, Sodium, Lycetamine, lydicamycin, Lydimycin, Lynestrenol, Iotyrosine 1 131, Ioversol, IoXagiate Sodium, IoXaglate Lypressin, Lysine, lysofylline, lysostaphin, lytic peptides, Meglumine, IoXaglic Acid, ioXilan, IoXotriZoic Acid, ipaZil Maduramicin, Mafenide, magainin 2 amide, Magnesium ide, ipenoXaZone, ipidacrine, Ipodate Calcium, ipomeanol, Salicylate, Magnesium Sulfate, magnolol, maitansine, Male 4-, Ipratropium Bromide, ipri?avone, Iprindole, Iprofenin, thamer, mallotochromene, mallotojaponin, Malotilate, IpronidaZole, Iproplatin, IproXamine Hydrochloride, ipsa malotilate, mangafodipir, manidipine, maniWamycin A, pirone, irbesartan, irinotecan, irloXacin, iroplact, irsoglad Mannitol, mannostatin A, manumycin E, manumycin F, ine, IrtemaZole, isalsteine, IsamoXole, isbogrel, Isepamicin, mapinastine, Maprotiline, marimastat, Martek 8708, Martek isobengaZole, Isobutamben, IsocarboXaZid, IsoconaZole, 92211, Masoprocol, maspin, massetolide, matrilysin inhibi Isoetharine, iso?oXythepin, Iso?upredone Acetate, Iso?u tors, Maytansine, MaZapertine Succiniate, MaZindol, rane, Iso?urophate, isohomohalicondrin B, Isoleucine, Iso MebendaZole, Mebeverine Hydrochloride, Mebrofenin, maZole Hydrochloride, Isomylamine Hydrochloride, Iso Mebutamate, Mecamylamine Hydrochloride, Mechlore niaZid, Isopropamide Iodide, Isopropyl Alcohol, isopropyl thamine Hydrochloride, Meclocycline, Meclofenamate unoprostone, Isoproterenol Hydrochloride, Isosorbide, Isos Sodium, Mecloqualone, Meclorisone Dibutyrate, US 2006/0018934 A1 Jan. 26, 2006

MedaZeparn Hydrochloride, Medorinone, Medrogestone, rnoxonidine, Mumps Skin Test Antigen, rnustard anticancer Medroxalol, Medroxyprogesterone, Medrysone, MeeliZine agent, MuZolirnine, rnycaperoxide B, Mycophenolic Acid, Hydrochloride, Mefenarnic Acid, Mefenidil, Mefenorex rnyriaporone, NabaZenil, Nabilone, Nabitan Hydrochloride, Hydrochloride, Mefexarnide, Me?oquine Hydrochloride, Naboctate Hydrochloride, Naburnetone, N-acetyldinaline, Mefruside, Megalornicin Potassium Phosphate, Megestrol Nadide, nadi?oxacin, Nadolol, nadroparin calciurn, nafadot Acetate, Meglurnine, Meglutol, Melengestrol Acetate, Meli ride, nafarnostat, nafarelin, Nafcillin Sodiurn, Nafenopin, tracen Hydrochloride, Melphalan, Mernotine Hydrochlo Na?rnidone Hydrochloride, Na?ocort, Nafornine Malate, ride, Menabitan Hydrochloride, Menoctone, rnenogaril, Nafoxidine Hydrochloride, Nafronyl Oxalate, Nafti?ne Menotropins, Meobentine Sulfate, Mepartricin, Mepen Hydrochloride, naftopidil, naglivan, nagrestip, Nalbuphine Zolate Brornide, Meperidine Hydrochloride, Mephenterrnine Hydrochloride, Nalidixate Sodiurn, Nalidixic Acid, Sulfate, Mephenyloin, Mephobarbital, Mepivacaine Hydro nalrnefene, Nalrnexone Hydrochloride, naloxone+pentaZo chloride, Meprobarnate, MeptaZinol Hydrochloride, Mequi cine, Naltrexone, Narnoxyrate, Nandrolone Phenpropionate, dox, Meralein Sodiurn, rnerbarone, Mercaptopurine, Mer Nantradol Hydrochloride, Napactadine Hydrochloride, cufenol Chloride, Mercury, Arnrnoniated, Merisoprol Hg napadisilate, NaparneZole Hydrochloride, napaviin, Nap 197, Meropenern, Mesalarnine, MeseclaZone, MesoridaZine, haZoline Hydrochloride, naphterpin, Naproxen, Naproxol, Mesterolone, Mestranol, Mesuprine Hydrochloride, Metalol napsagatran, Naranol Hydrochloride, Narasin, naratriptan, Hydrochloride, Metaproterenol Polistirex, Metararninol nartograstirn, nasaruplase, Natarnycin, nateplase, Nax Bitartrate, Metaxalone, Meteneprost, rneterelin, Metforrnin, agolide Hydrochloride, Nebivolol, Nebrarnycin, nedaplatin, Methacholine Chloride, Methacycline, Methadone Hydro Nedocrornil, NefaZodone Hydrochloride, Ne?urnoZide chloride, Methadyl Acetate, MethalthiaZide, Metharnphet Hydrochloride, Nefoparn Hydrochloride, NeleZaprine Male arnine Hydrochloride, Methaqualone, MethaZolarnide, ate, NernaZoline Hydrochloride, nernorubicin, Neornycin MethdilaZine, Methenarnine, Methenolone Acetate, Meth Palrnitate, Neostigrnine Brornide, neridronic acid, Netilrni etoin, Methicillin Sodiurn, MethirnaZole, rnethioninase, cin Sulfate, neutral endopeptidase, Neutrarnycin, Nevirap Methionine, MethisaZone, Methixene Hydrochloride, ine, Nexeridine Hydrochloride, Niacin, Nibroxane, Nicar Methocarbarnol, Methohexital Sodiurn, Methopholine, dipine Hydrochloride, Nicergoline, Niclosarnide, Methotrexate, MethotrirnepraZine, rnethoxatone, Methoxy Nicorandil, Nicotinyl Alcohol, Nifedipine, Ni?rrnerone, ?urane, Methsuxirnide, MethyclothiaZide, Methyl Palrnox Ni?uridide, Nifuradene, NifuraldeZone, Nifuratel, Nifura irate, Methylatropine Nitrate, MethylbenZethoniurn Chlo trone, NifurdaZil, Nifurirnide, Nifurpirinol, NifurquinaZol, ride, Methyldopa, Methyldopate Hydrochloride, Methylene NifurthiaZole, nilutamide, Nilvadipine, NimaZone, Nimo Blue, Methylergonovine Maleate, rnethylhistarnine, R-al dipine, niperotidine, niravoline, NiridaZole, nisarnycin, Nis pha, rnethylinosine rnonophosphate, Methylphenidate buterol Mesylate, nisin, Nisobarnate, Nisoldipine, Nisoxet Hydrochloride, Methylprednisolone, Methyltestosterone, ine, Nisterirne Acetate, Nitarsone, nitaZoxanide, nitecapone, Methynodiol Diacelate, Methysergide, Methysergide Male Nitrafudarn Hydrochloride, Nitralarnine Hydrochloride, Nit ate, Metiarnide, Metiapine, Metioprirn, rnetiparnide, rarnisole Hydrochloride, NitraZeparn, Nitrendipine, Nitrocy Metipranolol, MetiZoline Hydrochloride, Metkepharnid cline, Nitrodan, Nitrofurantoin, NitrofuraZone, Nitroglyc Acetate, rnetocloprarnide, Metocurine Iodide, Metogest, erin, Nitrornersol, Nitrornide, Nitrornifene Citrate, Nitrous MetolaZone, MetopirnaZine, Metoprine, Metoprolol, Meto Oxide, nitroxide antioxidant, nitrullyn, NivaZol, Nivirne quiZine, rnetrifonate, MetriZarnide, MetriZoate Sodiurn, done Sodiurn, NiZatidine, Noberastine, NocodaZole, MetronidaZole, Meturedepa, Metyrapone, Metyrosine, Nogalarnycin, Noliniurn Brornide, Nornifensine Maleate, Mexiletine Hydrochloride, Mexrenoate Potassiurn, Noracyrnethadol Hydrochloride, Norbolethone, Norepi MeZlocillin, rnfonelic Acid, Mianserin Hydrochloride, nephrine Bitartrate, Norethindrone, Norethynodrel, Nor rnibefradil, Mibefradil Dihydrochloride, Mibolerone, rnich ?oxacin, Nor?urane, Norgestirnate, Norgestornet, Norg ellarnine B, MiconaZole, rnicrocolin A, Mida?ur, Mida estrel, Nortriptyline Hydrochloride, Noscapine, Novobiocin Zolarn Hydrochloride, rnidodrine, rnifepristone, Mifobate, Sodiurn, N-substituted benZairnides, Nufenoxole, rniglitol, rnilacernide, rnilarneline, rnildronate, Milenperone, Nylestriol, Nystatin, O6-benZylguanine, Obidoxirne Chlo Milipertine, rnilnacipran, Milrinone, rniltefosine, Mirnbane ride, Ocaperidone, Ocfentanil Hydrochloride, Ocinaplon, Hydrochloride, rninaprine, Minaxolone, Minocrornil, Octanoic Acid, OctaZarnide, Octenidine Hydrochloride, Minocycline, Minoxidil, Mio?aZine Hydrochloride, rnioka Octodrine, Octreotide, Octriptyline Phosphate, O?oxacin, rnycin, rnipragoside, rnirfentanil, rnirirnostirn, Mirincarny Oforrnine, okicenone, OlanZapine, oligonucleotides, olo cin Hydrochloride, Mirisetron Maleate, MirtaZapine, rnis patadine, olprinone, olsalaZine, OlsalaZine Sodiurn, Olvanil, rnatched double stranded RNA, MisonidaZole, Misoprostol, ornepraZole, onapristone, ondansetron, OntaZolast, Oocyte Mitindornide, Mitocarcin, Mitocrornin, Mitogillin, rnitogua rnaturation inhibitor, Opiprarnol Hydrochloride, oracin, Zone, rnitolactol, Mitornalcin, Mitornycin, rnitona?de, Mito OrconaZole Nitrate, Orgotein, Orlislat, Orrnaplatin, Orrne sper, Mitotane, rnitoxantrone, rnivacuriurn chloride, rnivaZ toprirn, OrnidaZole, Orpanoxin, Orphenadrine Citrate, erol, rnixanpril, Mixidine, rniZolastine, rniZoribine, osaterone, otenZepad, Oxacillin Sodiurn, Oxagrelate, oxali Moclobernide, rnoda?nil, Modaline Sulfate, Modecainide, platin, Oxarnarin Hydrochloride, oxarnisole, Oxarnniquine, rnoexipril, rnofarotene, Mofegiline Hydrochloride, rnof oxandrolone, Oxantel Parnoate, Oxaprotiline Hydrochlo eZolac, rnolgrarnostirn, MolinaZone, Molindone Hydrochlo ride, OxaproZin, OxarbaZole, Oxatornide, oxaunornycin, ride, Molsidornine, rnornetasone, Monatepil Maleate, Mon OxaZeparn, oxcarbaZepine, Oxendolone, OxethaZaine, ensin, Monoctanoin, Montelukast Sodiurn, rnontirelin, Oxetorone Furnarate, OxfendaZole, Oxfenicine, Oxibenda rnopidarnol, rnoraciZine, Morantel Tartrate, MoriciZine, Zole, oxiconaZole, Oxidoparnine, Oxidronic Acid, Oxifungin Morni?urnate, Morphine Sulfate, Morrhuate Sodiurn, Hydrochloride, Oxilorphan, Oxirnonarn, Oxirnonarn rnosaprarnine, rnosapride, rnotilide, Motretinide, Moxalac Sodiurn, Oxiperornide, oxiracetarn, Oxirarnide, Oxisuran, tarn Disodiurn, MoxaZocine, rnoxiraprine, MoxnidaZole, Oxrnetidine Hydrochloride, oxodipine, Oxogestone Phen US 2006/0018934 A1 Jan. 26, 2006

propionate, OXolinic Acid, OXprenolol Hydrochloride, OXt ZOl, Pirsidomine, Prenylamine, Pituitary, Posterior, Pivampi riphylline, OXybutynin Chloride, OXychlorosene, Oxyc cillin Hydrochloride, Pivopril, PiZotyline, placetin A, plati odone, OXymetaZoline Hydrochloride, OXymetholone, num compounds, platinum-triamine complex, Plicamycin, OXymorphone Hydrochloride, OXypertine, OXyphenbuta Plomestane, Pobilukast Edamine, Podo?loX, Poisonoak Zone, OXypurinol, OXytetracycline, OXytocin, oZagrel, OZo Extract, Poldine Methylsulfate, Poliglusam, Polignate linone, PaclitaXel, palauamine, Paldimycin, palinavir, palmi Sodium, PolymyXin B Sulfate, PolythiaZide, Ponalrestat, toylrhiZoXin, PalmoXirate Sodium, pamaqueside, Pamatolol Por?mer Sodium, Por?romycin, Potassium Chloride, Potas Sulfate, pamicogrel, Pamidronate Disodium, pamidronic sium Iodide, Potassium Permanganate, Povidone-Iodine, acid, Panadiplon, panamesine, panaXytriol, Pancopride, Practolol, PralidoXime Chloride, Pramiracetam Hydrochlo Pancuronium Bromide, panipenem, pannorin, panomifene, ride, PramoXine Hydrochloride, Pranolium Chloride, Prava pantethine, pantopraZole, Papaverine Hydrochloride, para doline Maleate, Pravastatin (Pravachol), PraZepam, Pra bactin, Parachlorophenol, Paraldehyde, Paramethasone Zosin, PraZosin Hydrochloride, PrednaZate, Prednicarbate, Acetate, Paranyline Hydrochloride, ParapenZolate Bromide, Prednimustine, Prednisolone, Prednisone, Prednival, Preg Pararosaniline Pamoate, ParbendaZole, ParconaZole Hydro nenolone Succiniate, Prenalterol Hydrochloride, Pride?ne chloride, Paregoric, Pareptide Sulfate, Pargyline Hydrochlo Hydrochloride, Prifelone, Prilocalne Hydrochloride, ride, parnaparin sodium, Paromomycin Sulfate, ParoXetine, Prilosec, Primaquine Phosphate, Primidolol, Primidone, parthenolide, Partricin, Paulomycin, paZelliptine, PaZina Prinivil, Prinomide Tromethamine, PrinoXodan, PriZidilol clone, PaZoXide, paZu?oXacin, pe?oXacin, pegaspargase, Hydrochloride, Proadifen Hydrochloride, Probenecid, Pro Pegorgotein, Pelanserin Hydrochloride, peldesine, Peliomy bicromil Calcium, Probucol, Procainamide Hydrochloride, cin, Pelretin, Pelrinone Hydrochloride, Pemedolac, Pemerid Procaine Hydrochloride, ProcarbaZine Hydrochloride, Pro Nitrate, pemirolast, Pemoline, Penamecillin, Penbutolol Sul caterol Hydrochloride, ProchlorperaZine, Procinonide, Pro fate, Penciclovir, Pen?uridol, Penicillin G BenZathine, Peni clonol, Procyclidine Hydrochloride, Prodilidine Hydrochlo cillin G Potassium, Penicillin G Procaine, Penicillin G ride, Prodolic Acid, Profadol Hydrochloride, Progabide, Sodium, Penicillin V, Penicillin V BenZathine, Penicillin V Progesterone, Proglumide, Proinsulin Human, Proline, Pro Hydrabamine, Penicillin V Potassium, Pentabamate, Pen lintane Hydrochloride, PromaZine Hydrochloride, Promet taerythritol Tetranitrate, pentafuside, pentamidine, pentam haZine Hydrochloride, Propafenone Hydrochloride, orphone, Pentamustine, Pentapiperium Methylsulfate, Pen propagermanium, Propanidid, Propantheline Bromide, Pro taZocine, Pentetic Acid, Pentiapine Maleate, pentigetide, paracaine Hydrochloride, Propatyl Nitrate, propentofylline, Pentisomicin, PentiZidone Sodium, Pentobarbital, Pento PropenZolate Hydrochloride, Propikacin, PropiomaZine, mone, Pentopril, pentosan, pentostatin, PentoXifylline, Pen Propionic Acid, propionylcarnitine, L-, propiram, propiram+ trinitrol, pentroZole, Peplomycin Sulfate, Pepstatin, per?u paracetamol, propiverine, Propofol, PropoXycaine Hydro bron, perfofamide, Perfosfamide, pergolide, PerheXiline chloride, PropoXyphene Hydrochloride, Propranolol Hydro Maleate, perillyl alcohol, Perindopril, perindoprilat, Perlap chloride, Propulsid, propyl bis-acridone, PropylheXedrine, ine, Permethrin, perospirone, PerphenaZine, Phenacemide, Propyliodone, Propylthiouracil, ProquaZone, Prorenoate phenaridine, phenaZinomycin, PhenaZopyridine Hydrochlo Potassium, ProroXan Hydrochloride, Proscillaridin, Prostal ride, PhenbutaZone Sodium Glycerate, Phencarbamide, ene, prostratin, Protamine Sulfate, protegrin, Protirelin, pro Phencyclidine Hydrochloride, PhendimetraZine Tartrate, tosu?oXacin, Protriptyline Hydrochloride, ProXaZole, ProX PhenelZine Sulfate, PhenmetraZine Hydrochloride, Phe aZole Citrate, ProXicromil, ProXorphan Tartrate, nobarbital, PhenoXybenZamine Hydrochloride, Phenprocou pruli?oXacin, Pseudoephedrine Hydrochloride, Puromycin, mon, phenserine, phensuccinal, PhensuXimide, Phenter purpurins, Pyrabrom, Pyrantel Pamoate, PyraZinamide, mine, Phentermine Hydrochloride, phentolamine mesilate, PyraZofurin, pyraZoloacridine, Pyridostigmine Bromide, PhentoXifylline, Phenyl Aminosalicylate, phenylacetate, Pyrilamine Maleate, Pyrimethamine, Pyrinoline, Pyrithione Phenylalanine, phenylalanyl ketoconaZole, PhenylbutaZone, Sodium, Pyrithione Zinc, Pyrovalerone Hydrochloride, Phenylephrine Hydrochloride, Phenylpropanolamine PyroXamine Maleate, Pyr-rocaine, Pyrroliphene Hydrochlo Hydrochloride, Phenylpropanolamine PolistireX, Phenyra ride, PyrroInitrin, Pyrvinium Pamoate, QuadaZocine Mesy midol Hydrochloride, Phenyloin, phosphatase inhibitors, late, QuaZepam, QuaZinone, QuaZodine, QuaZolast, quetiap Physostigmine, picenadol, picibanil, Picotrin Diolamine, ine, qui?apon, quinagolide, Quinaldine Blue, quinapril, picroliv, picumeterol, pidotimod, Pifamine, Pilocarpine, pil Quinaprilat, QuinaZosin Hydrochloride, Quinbolone, Quinc sicainide, pimagedine, Pimetine Hydrochloride, pimilprost, tolate, Quindecamine Acetate, Quindonium Bromide, Pimobendan, PimoZide, Pinacidil, Pinadoline, Pindolol, pin Quinelorane Hydrochloride, Quinestrol, Quinfamide, nenol, pinocebrin, PinoXepin Hydrochloride, pioglitaZone, Quingestanol Acetate, Quingestrone, Quinidine Gluconate, Pipamperone, PipaZethate, pipecuronium bromide, Piperac Quinielorane Hydrochloride, Quinine Sulfate, Quinpirole etaZine, Piperacillin Sodium, Piperamide Maleate, pipera Hydrochloride, Quinterenol Sulfate, Quinuclium Bromide, Zine, Pipobroman, Piposulfan, PipotiaZine Palmitate, Quinupristin, QuipaZine Maleate, RabepraZole Sodium, PipoXolan Hydrochloride, PiproZolin, Piquindone Hydro Racephenicol, Racepinephrine, raf antagonists, RafoXanide, chloride, PiquiZil Hydrochloride, Piracetam, Pirandamine Ralitoline, raloXifene, raltitreXed, ramatroban, Ramipril, Hydrochloride, pirarubicin, PiraZmonam Sodium, PiraZolac, Ramoplanin, ramosetron, ranelic acid, Ranimycin, Raniti Pirbenicillin Sodium, Pirbuterol Acetate, Pirenperone, dine, ranolaZine, RauWol?a Serpentina, recainam, Recainam PirenZepine Hydrochloride, piretanide, Pirfenidone, Piridi Hydrochloride, ReclaZepam, regavirumab, Regramostim, cillin Sodium, Piridronate Sodium, Piriprost, piritreXim, RelaXin, Relomycin, Remacemide Hydrochloride, Remifen Pirlimycin Hydrochloride, pirlindole, pirmagrel, Pirmenol tanil Hydrochloride, Remiprostol, RemoXipride, Repirinast, Hydrochloride, Pirnabine, Piroctone, Pirodavir, pirodomast, Repromicin, Reproterol Hydrochloride, Reserpine, resin Pirogliride Tartrate, Pirolate, PirolaZamide, PiroXantrone feratoXin, Resorcinol, retelliptine demethylated, reticulon, Hydrochloride, PiroXicam, PiroXimone, Pirprofen, Pirquino reviparin sodium, reviZinone, rhenium Re 186 etidronate, US 2006/0018934 A1 Jan. 26, 2006

rhiZoXin, Ribaminol, Ribavirin, Riboprine, riboZymes, SulfameraZine, Sulfameter, SulfamethaZine, SulfamethiZole, ricasetron, Ridogrel, Rifabutin, Rifametane, RifameXil, SulfamethoXaZole, SulfamonomethoXine, SulfamoXole, Sul Rifamide, Rifampin, Rifapentine, RifaXimin, RII retina fanilate Zinc, Sulfanitran, sulfasalaZine, SulfasomiZole, Sul mide, rilopiroX, RiluZole, rimantadine, RimcaZole Hydro faZamet, Sul?nalol Hydrochloride, sul?nosine, Sul?npyra chloride, RimeXolone, Rimiterol Hydrobromide, rimopro Zone, Sul?soXaZole, SulfomyXin, Sulfonterol gin, riodipine, Rioprostil, RipaZepam, ripisartan, Hydrochloride, sulfoXamine, Sulinldac, Sulmarin, Sulnida Risedronate Sodium, risedronic acid, Risocaine, Risotilide Zole, Suloctidil, Sulofenur, sulopenem, SuloXifen Oxalate, Hydrochloride, rispenZepine, Risperdal, Risperidone, Sulpiride, Sulprostone, sultamicillin, Sulthiame, sultopride, Ritanserin, ritipenem, Ritodrine, Ritolukast, ritonavir, riZa sulukast, Sumarotene, sumatriptan, Suncillin Sodium, triptan benZoate, Rocastine Hydrochloride, Rocuronium Suproclone, Suprofen, suradista, suramin, Surfomer, Suric Bromide, Rodocaine, Ro?urane, Rogletimide, rohitukine, ainide Maleate, SuritoZole, Suronacrine Maleate, SuXemerid rokitamycin, Roletamicide, Rolgamidine, Rolicyprine, Sulfate, sWainsonine, symakalim, Symclosene, Symetine Rolipram, Rolitetracycline, Rolodine, RomaZarit, romurtide, Hydrochloride, synthetic glycosaminoglycans, Taciamine RonidaZole, ropinirole, Ropitoin Hydrochloride, ropiv Hydrochloride, Tacrine Hydrochloride, Tacrolimus, acaine, RopiZine, roquinimeX, Rosaramicin, RosoXacin, Talampicillin Hydrochloride, Taleranol, Talisomycin, talli RotoXamine, roXaitidine, RoXarsone, roXindole, roXithromy mustine, Talmetacin, Talni?umate, Talopram Hydrochlo cin, rubiginone B1, ruboXyl, ru?oXacin, rupatidine, Ruta ride, Talosalate, Tametraline Hydrochloride, Tamoxifen, mycin, ruZadolane, SabeluZole, sa?ngol, sa?ronil, saintopin, Tampramine Fumarate, Tamsulosin Hydrochloride, Tan salbutamol, R-, SalcoleX, Salethamide Maleate, Salicyl damine Hydrochloride, tandospirone, tapgen, taprostene, Alcohol, Salicylamide, Salicylate Meglumine, Salicylic Tasosartan, tauromustine, TaXane, TaXoid, TaZadolene Suc Acid, Salmeterol, Salnacediin, Salsalate, sameridine, sam cinate, taZanolast, taZarotene, TaZifylline Hydrochloride, patrilat, Sancycline, sanfetrinem, Sanguinarium Chloride, TaZobactam, TaZofelone, TaZolol Hydrochloride, SaperconaZole, saprisartan, sapropterin, saquinavir, Sara Tebufelone, Tebuquine, Technetium Tc 99 m Bicisate, Teclo ?oXacin Hydrochloride, Saralasin Acetate, SarCNU, sarco Zan, Tecogalan Sodium, Teecleukin, Te?urane, Tegafur, phytol A, sargramostim, SarmoXicillin, Sarpicillin, sar Tegretol, Teicoplanin, telenZepine, tellurapyrylium, telm pogrelate, saruplase, saterinone, satigrel, satumomab esteine, telmisartan, telomerase inhibitors, TeloXantrone pendetide, Schick Test Control, Scopafungin, Scopolamine Hydrochloride, Teludipine Hydrochloride, Tema?oXacin Hydrobromide, ScraZaipine Hydrochloride, Sdi 1 mimetics, Hydrochloride, Tematropium Methyl sulfate, TemaZepam, Secalciferol, Secobarbital, SeelZone, Seglitide Acetate, sel Temelastine, temocapril, Temocillin, temopor?n, temoZolo egiline, Selegiline Hydrochloride, Selenium Sul?de, Sele mide, Tenidap, Teniposide, tenosal, tenoXicam, tepirindole, nomethionine Se 75, Selfotel, sematilide, semduramicin, TepoXalin, Teprotide, teraZosin, Terbina?ne, Terbutaline semotiadil, semustine, sense oligonucleotides, SepaZonium Sulfate, TerconaZole, terfenadine, ter?avoXate, terguride, Chloride, Seperidol Hydrochloride, Seprilose, SeproXetine Teriparatide Acetate, terlakiren, terlipressin, terodiline, Hydrochloride, Seractide Acetate, SergoleXole Maleate, TeroXalene Hydrochloride, TeroXirone, tertatolol, Tesicam, Serine, Sermetacin, Sermorelin Acetate, sertaconaZole, Tesimide, Testolactone, Testosterone, Tetracaine, tetrachlo sertindole, sertraline, setiptiline, Setoperone, sevirumab, rodecaoXide, Tetracycline, TetrahydroZoline Hydrochloride, sevo?urane, seZolamide, Sibopirdine, Sibutramine Hydro Tetramisole Hydrochloride, TetraZolast Meglumine, tetra chloride, signal transduction inhibitors, Silandrone, silipide, Zomine, Tetrofosmin, Tetroquinone, TetroXoprim, Tetry silteplase, Silver Nitrate, simendan, SimtraZene, Simvasta damine, thaliblastine, Thalidomide, Theo?brate, Theophyl tin, Sincalide, Sinefungin, sinitrodil, sinnabidol, sipatrigine, line, ThiabendaZole, Thiamiprine, Thiamphenicol, sirolimus, Sisomicin, Sitogluside, siZo?ran, sobuZoXane, Thiamylal, ThiaZesim Hydrochloride, ThiaZinamium Chlo Sodium Amylosulfate, Sodium Iodide I 123, Sodium Nitro ride, ThiethylperaZine, Thimerfonate Sodium, Thimerosal, prusside, Sodium OXybate, sodium phenylacetate, Sodium thiocoraline, thiofedrine, Thioguanine, thiomarinol, Thio Salicylate, solverol, Solypertine Tartrate, Somalapor, pental Sodium, thioperamide, ThioridaZine, Thiotepa, Thio Somantadine Hydrochloride, somatomedin B, somatomedin thiXene, Thiphenamil Hydrochloride, Thiphencillin Potas C, somatrem, somatropin, Somenopor, Somidobove, soner sium, Thiram, ThoZalinone, Threonine, Thrombin, min, Sorbinil, Sorivudine, sotalol, Soterenol Hydrochloride, thrombopoietin, thrombopoietin mimetic, thymalfasin, thy Spar?oXacin, Sparfosate Sodium, sparfosic acid, Sparsomy mopoietin receptor agonist, thymotrinan, Thyromedan cin, Sparteine Sulfate, Spectinomycin Hydrochloride, spi Hydrochloride, ThyroXine 1 125, ThyroXine 1 131, Tiac camycin D, Spiperone, Spiradoline Mesylate, Spiramycin, rilast, Tiacrilast Sodium, tiagabine, Tiamenidine, tianeptine, Spirapril Hydrochloride, Spiraprilat, Spirogermanium tiapafant, Tiapamil Hydrochloride, Tiaramide Hydrochlo Hydrochloride, Spiromustine, Spironolactone, Spiroplatin, ride, TiaZofurin, Tibenelast Sodium, Tibolone, Tibric Acid, SpiroXasone, splenopentin, spongistatin 1, Sprodiamide, Ticabesone Propionate, Ticarbodine, Ticarcillin Cresyl squalamine, Stallimycin Hydrochloride, Stannous Pyro Sodium, Ticlatone, ticlopidine, Ticrynafen, tienoXolol, Tifu phosphate, Stannous Sulfur Colloid, StanoZolol, Statolon, rac Sodium, Tigemonam Dicholine, Tigestol, Tiletamine staurosporine, stavudine, Stef?mycin, Stenbolone Acetate, Hydrochloride, Tilidine Hydrochloride, tilisolol, tilnoprofen stepronin, StilbaZium Iodide, Stilonium Iodide, stipiamide, arbamel, Tilorone Hydrochloride, Tiludronate Disodium, Stiripentol, stobadine, Streptomycin Sulfate, StreptonicoZid, tiludronic acid, Timefurone, Timobesone Acetate, Timolol, Streptonigrin, StreptoZocin, stromelysin inhibitors, Stron tin ethyl etiopurpurin, Tinabinol, TinidaZole, TinZaparin tium Chloride Sr 89, succibun, Succimer, Succinylcholine Sodium, TioconaZole, TiodaZosin, Tiodonium Chloride, Tio Chloride, Sucralfate, Sucrosofate Potassium, SudoXicam, peridone Hydrochloride, Tiopinac, Tiospirone Hydrochlo Sufentanil, Sufotidine, SulaZepam, Sulbactam PivoXil, Sul ride, Tiotidine, tiotropium bromide, TioXidaZole, Tipentosin conaZole Nitrate, SulfabenZ, SulfabenZamide, Sulfaceta Hydrochloride, Tipredane, Tiprenolol Hydrochloride, Tipri mide, Sulfacytine, SulfadiaZine, SulfadoXine, Sulfalene, nast Meglumine, Tipropidil Hydrochloride, Tiqueside, US 2006/0018934 A1 Jan. 26, 2006

Tiquinamide Hydrochloride, tirandalydigin, TirapaZamine, amivir, Zankiren, Zanoterone, Zantac, Zarirlukast, Zatebra tirilaZad, tiro?ban, tiropramide, titanocene dichloride, Tix dine, Zatosetron, Zatosetron Maleate, Zenarestat, ZenaZocine anox, Tixocortol Pivalate, TiZanidine Hydrochloride, Tobra Mesylate, Zeniplatin, Zeranol, Zidometacin, Zidovudine, mycin, Tocainide, Tocamphyl, Tofenacin Hydrochloride, Zifrosilone, Zilantel, Zilascorb, Zileuton, Zimeldine Hydro Tolamolol, TolaZamide, TolaZoline Hydrochloride, Tolbuta chloride, Zinc Undecylenate, Zindotrine, ZinoconaZole mide, Tolcapone, Tolciclate, Tolfamide, Tolgabide, lamot Hydrochloride, Zinostatin, Zinterol Hydrochloride, Zin rigine, Tolimidone, Tolindate, Tolmetin, Tolnaftate, Tolpovi viroxime, Ziprasidone, Zobolt, Zofenopril Calcium, Zofeno done 1 131, Tolpyrramide, Tolrestat, Tomelukast, prilat, Zolamine Hydrochloride, ZolaZepam Hydrochloride, Tomoxetine Hydrochloride, TonaZocine Mesylate, Topira Zoledronie acid, Zolertine Hydrochloride, Zolmitriptan, mate, topotecan, Topotecan Hydrochloride, topsentin, Zolpidem, Zomepirac Sodium, Zometapine, ZonicleZole Hydrochloride, Zonisamide, Zopiclone, Zopolrestat, Zorba Topterone, ToquiZine, torasemide, toremifene, Torsemide, myciin, Zorubicin Hydrochloride, Zotepine, Zucapsaicin or Tosifen, Tosu?oxacin, totipotent stem cell factor, Traca its pharmaceutically acceptable salts thereof. Zolate, trafermin, Tralonide, Tramadol Hydrochloride, Tra maZoline Hydrochloride, trandolapril, Tranexamic Acid, [0062] As indicated above this portion may comprise Tranilast, Transcainide, translation inhibitors, traxanox, Tra auxiliary excipients such as for example diluents, binders, Zodone Hydrochloride, TraZodone-HCL, TrebenZomine lubricants, surfactants, disintegrants, plasticisers, anti-tack Hydrochloride, Trefentanil Hydrochloride, Treloxinate, agents, opacifying agents, pigments, and such like. As Will Trepipam Maleate, Trestolone Acetate, tretinoin, Triacetin, be appreciated by those skilled in the art, the exact choice of triacetyluridine, Triafungin, Triamcinolone, TriampyZine excipient and their relative amounts Will depend to some Sulfate, Triamterene, TriaZolam, Tribenoside, tricaprilin, extent on the ?nal oral dosage form. Tricetamide, TrichlormethiaZide, trichohyalin, triciribine, Tricitrates, Triclofenol piperaZine, Triclofos Sodium, Tri [0063] Suitable diluents include for example pharmaceu clonide, trientine, Trifenagrel, tri?avin, Tri?ocin, Tri?uba tically acceptable inert ?llers such as microcrystalline cel Zam, Tri?umidate, Tri?uoperaZine Hydrochloride, Tri?u lulose, lactose, starch, dibasic calcium phosphate, saccha peridol, Tri?upromaZine, Tri?upromaZine Hydrochloride, rides, and/or mixtures of the foregoing. Examples of diluents Tri?uridine, Trihexyphenidyl Hydrochloride, Trilostane, include microcrystalline celluloses such as those sold under TrimaZosin Hydrochloride, trimegestone, TrimepraZine Tar the Trade Mark Avicel PH 101, Avicel PH 102, Avicel PH trate, Trimethadione, Trimethaphan Camsylate, Tri 112, Avicel PH 200, Avicel PH301 and Avicel PH 302; methobenZamide Hydrochloride, Trimethoprim, Trime lactose such as lactose monohydrate, lactose anhydrous and toZine, Trimetrexate, Trimipramine, Trimoprostil, Pharmatose DCL21 (Pharmatose is a Trade Mark), including Trimoxamine Hydrochloride, Triolein 1 125, Triolein 1 131, anhydrous, monohydrate and spray dried forms; dibasic Trioxifene Mesylate, Tripamide, Tripelennamine Hydro calcium phosphate such as Emcompress (Emcompress is a chloride, Triprolidine Hydrochloride, Triptorelin, Trisul Trade Mark); mannitol; Pearlitol SD 200 (Pearlitol SD 200 fapyrimidines, Troclosene Potassium, troglitaZone, Trola is a trade mark); starch; sorbitol; sucrose; and glucose. mine, Troleandomycin, trombodipine, trometamol, [0064] Suitable binders include for example starch, povi Tropanserin Hydrochloride, Tropicamide, tropine ester, tro done, hydroxypropylmethylcellulose, pregelatinised starch, pisetron, trospectomycin, trova?oxacin, trovirdine, Tryp hydroxypropylcellulose and/or mixtures of the foregoing. tophan, Tuberculin, Tubocurarine Chloride, TubuloZole Hydrochloride, tucarcsol, tulobuterol, turosteride, Tybam [0065] Suitable lubricants, including agents that act on the ate, tylogenin, Tyropanoate Sodium, Tyrosine, Tyrothricin, ?oWability of the poWder to be compressed are, for example, tyrphostins, ubenimex, UldaZepam, Undecylenic Acid, colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a Uracil Mustard, urapidil, Urea, Uredepa, uridine triphos Trade Mark); talc; stearic acid, magnesium stearate, calcium phate, Urofollitropin, Urokinase, Ursodiol, valaciclovir, stearate and sodium stearyl fumarate. Valine, Valnoctamide, Valproate Sodium, Valproic Acid, valsartan, vamicamide, vanadeine, Vancomycin, vaninolol, [0066] Suitable disintegrants include for example lightly Vapiprost Hydrochloride, Vapreotide, variolin B, Vaso crosslinked polyvinyl pyrrolidone, corn starch, potato pressin, Vecuronium Bromide, velaresol, Velnacrine Male starch, maiZe starch and modi?ed starches, croscarmellose ate, venlafaxine, Veradoline Hydrochloride, veramine, Vera sodium, cross-povidone, sodium starch glycolate and com pamil Hydrochloride, verdins, Verilopam Hydrochloride, binations and mixtures thereof. Verlukast, Verofylline, veroxan, vertepor?n, Vesnarinone, vexibinol, Vidarabine, vigabatrin, ViloxaZine Hydrochlo [0067] The amount of release controlling agent(s) to be ride, Vinblastine Sulfate, vinburnine citrate, Vincofos, vin used in Will be determined based on drug release rate etc. conate, Vincristine Sulfate, Vindesine, Vindesine Sulfate, [0068] The release controlling agents(s) are selected from Vinepidine Sulfate, Vinglycinate Sulfate, Vinleurosine Sul alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, fate, vinorelbine, vinpocetine, vintoperol, vinxaltine, VinZo cellulose esters, nitro celluloses, polymers of acrylic and lidine Sulfate, Viprostol, Virginiamycin, Viridofulvin, methacrylic acids and esters thereof, polyamides, polycar Viroxime, vitaxin, VolaZocine, voriconaZole, voroZole, vox bonates, polyalkylenes, polyalkylene glycols, polyalkylene ergolide, Warfarin Sodium, Xamoterol, Xanomeline, Xan terephthalates, polyvinyl esters, polyvinylpyrrolidone, oxate Sodium, Xanthinol Niacinate, xemilo?ban, Xenalipin, polyglycolides, polysiloxanes and polyurethanes and co Xenbucin, Xilobam, ximoprofen, Xipamide, Xorphanol polymers thereof. Mesylate, Xylamidine Tosylate, XylaZine Hydrochloride, XylometaZoline Hydrochloride, Xylose, yangambin, Zab [0069] The high Water soluble/permeable release control icipril, Zacopride, Za?rlukast, Zalcitabine, Zaleplon, ling agents is suitably polyvinyl alcohol, polyvinylpyrroli Zalospirone, Zaltidine Hydrochloride, Zaltoprofen, Zan done, methylcellulose, hydroxypropylcellulose, hydrox US 2006/0018934 A1 Jan. 26, 2006

ypropylmethyl cellulose or polyethylene glycol, alginates, ?uidized bed coated (preferably Wurster coating), or in a pan polyacrylic acids, xanthun gum or a mixture thereof. coating system. The compression of tablets is carried out on usual compression machines (e.g. machines of the Manesty, [0070] The loW Water soluble/permeable release control Cadmach or Kilian). The tablets can be made of various ling agents is suitably ethylcellulose, cellulose acetate, cel sizes and shapes. lulose propionate (loWer, medium or higher molecular Weight), cellulose acetate propionate, cellulose acetate [0075] Process for manufacturing combination dosage butyrate, cellulose acetate phthalate, cellulose triacetate, form as per instant invention comprising highly soluble drug poly(methyl methacrylate), poly(ethyl methacrylate), poly as modi?ed release and another active ingredient as imme (butyl methacrylate), poly(isobutyl methacrylate), and poly diate release or modi?ed release: (hexyl methacrylate). Poly(isodecyl methacrylate), poly (lauryl methacrylate), poly(phenyl methacrylate), poly [0076] Part (A)—Granules comprising highly soluble (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl drug: as described above. actylate), poly (octadecyl acrylate), Waxes such as beesWax, [0077] Part (B)—It may have folloWing options for manu carnauba Wax, microcrystalline Wax, and ozokerite; fatty facturing of formulation for another active ingredient. alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as [0078] i) Granules for multilayered or compression coated glyceryl monostearate, glyceryl distearate, glycerol tablets—It be manufactured in accordance With usual monooleate, acetylated monoglycerides, tristearin, tripalm techniques in Which the active ingredient(s) and other itin, cetyl esters Wax, glyceryl palmitostearate, glyceryl excipients are mixed and granulated by adding solution of behenate, and hydrogenated castor oil or a mixture thereof. binder in a loW or high shear mixer or by ?uidized bed [0071] The non-biodegradable materials are selected from granulation. The granulate is dried, preferably in a ?uid but are not limited to Ammonio methacrylate copolymers ized bed dryer. The dried granulate is sieved and mixed type A and B as described in USP, Polyacrylate dispersion With lubricants and disintegrants. Alternatively the manu 30% as described in Ph. Eur., Polyvinyl acetate dispersion, facture of granules of inner portion can be made by direct cellulose derivatives such as ethylcellulose, cellulose acetate mixing of the directly compressible excipients or by roller Waxes such as beesWax, carnauba Wax, microcrystalline compaction. Wax, and ozokerite; fatty alcohols such as cetostearyl alco [0079] ii) Solution or suspension of active ingredient(s) hol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and for drug layering on compact part—Active ingredient(s) fatty acid esters such as glyceryl monostearate, glyceryl can be dissolved or suspended in solution of suitable distearate, glycerol monooleate, acetylated monoglycerides, binder(s) This solution or suspension can be sprayed or tristearin, tripalmitin, cetyl esters Wax, glyceryl palmito layered over the dosage form prepared as per the inven stearate, glyceryl behenate, and hydrogenated castor oil. tion. Spraying can be carried out using a ?uidized bed [0072] The mucoadhesive release controlling agents are coated, or in a pan coating system. selected from but are not limited to carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydrox C) Tablet Compression ypropylmethyl cellulose, hydroxyethyl cellulose, methyl [0080] Suitable tablet presses can be used for single lay cellulose, sodium hyaluronate, gaur gum, sodium alginate, ered tablets, multilayered tablets or compression coated polycabophil, starch, dextran or chitosan. tablets using granules prepared in part A and part B. [0073] Active ingredients especially the poorly soluble D) Capsule Filling active ingredients mentioned above can be micronized to increase solubility and/or bioavialabiity. [0081] Compact tablets of highly soluble active ingredient and tablets or granules of another active ingredient can be [0074] The novel modi?ed release dosage form of the ?lled in hard gelatin capsule shells by using suitable present invention can be manufactured by the folloWing machines. procedure: The micro matrix particles can be manufactured in accordance With usual techniques in Which the active BRIEF DESCRIPTION OF THE DRAWINGS ingredient and one or more hydrophobic release controlling agents are mixed and granulated by adding solvent in a loW [0082] FIG. 1 (a) is a cross section of coated micro matrix or high shear mixer or by ?uidized bed granulator. The particles prepared by spheronization and coating for the granulate is dried, preferably in a ?uidized bed dryer. The purpose of illustration only. dried granulate is sized. The sizing of the micromatrix particles can be done using oscillating granulator, commi [0083] FIG. 1 (b) is a cross section of coated micro matrix nuting mill or any other conventional method. The sieve particles prepared by granulation and coating for the purpose used for the sizing can have openings from 0.25 mm to 5 of illustration only. mm. Alternatively the micro matrix particles can be made by [0084] FIG. 2 is a plot of % active ingredient versus time extrusion, spheronization or by roller compaction. The for modi?ed release active agent prepared using dual retard micro matrix particles can be coated by a solution of one or technique as described in the present invention and prepared more hydrophobic release controlling agents by any knoWn Without retard release technique as per examples 1 and 3; method, including spray application. Spraying can be carried out using a ?uidized bed coated (preferably Wurster coat [0085] FIG. 3 is a plot of % active ingredient versus time ing), or in a pan coating system. Alternatively the coating of for modi?ed release active agent prepared using dual retard the micro matrix particles With one or more rate controlling technique as described in the present invention and prepared agents can be done by hot melt process using a granulator or Without retard release technique as per examples 2 and 4.