US 20040185097A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0185097 A1 Kannan et al. (43) Pub. Date: Sep. 23, 2004

(54) CONTROLLED RELEASE MODIFYING (30) Foreign Application Priority Data COMPLEX AND PHARMACEUTICAL COMPOSITIONS THEREOF Jan. 31, 2003 (IN)...... 130/MUM/2003 (75) Inventors: Muthaiyyan Esakki Kannan, Mumbai Publication Classification (IN); Anandi Krishnan, Mumbai (IN); Beena Amol Sapre, Mumbai (IN); (51) Int. Cl...... A61K 9/22 Chitra Siddharth Shah, Mumbai (IN); (52) U.S. Cl...... 424/468 Atul Vishvanath Patil, Mumbai (IN) Correspondence Address: LERNER, DAVID, LITTENBERG, (57) ABSTRACT KRUMHOLZ & MENTLIK 600 SOUTHAVENUE WEST Disclosed is a controlled release modifying complex for WESTFIELD, NJ 07090 (US) Solid oral controlled release pharmaceutical compositions (73) Assignee: Glenmark Pharmaceuticals Ltd., Prin Suitable for once-a-day administration. The composition ceton, NJ comprises an active pharmaceutical ingredient, a release modifying complex and other required pharmaceutically (21) Appl. No.: 10/762,180 acceptable excipients. The release modifying complex com prises a primary release modifying agent, a Secondary (22) Filed: Jan. 21, 2004 release modifying agent and an auxiliary release modifying Related U.S. Application Data agent or varying combinations thereof, wherein Said pri mary, Secondary and auxiliary release modifying agents are (60) Provisional application No. 60/517,589, filed on Nov. present in amounts that Synergistically effect and extend the 5, 2003. release of active pharmaceutical ingredient.

Plasma Concentration of Clarithr mycin 500 mg Extended R lase tablets

0.9

Time (h) Patent Application Publication Sep. 23, 2004 US 2004/0185097 A1

Plasma Concentration of Clarithr mycin 500 mg Extended R lase tablets

0.9

0. 8

0. 7

0. 6

0. 5

0. 4.

0. 3.

O. 2

Time (h)

FIG. 1 US 2004/0185097 A1 Sep. 23, 2004

CONTROLLED RELEASE MODIFYING COMPLEX grade hydroxypropyl methylcellulose. A carrier base mate AND PHARMACEUTICAL COMPOSITIONS rial combined with a therapeutically active medicament and THEREOF shaped and compressed to a Solid unit dosage form having a controlled and prolonged release pattern upon administra CROSS REFERENCE TO RELATED tion. APPLICATIONS 0008 U.S. Pat. No. 5,393,765 describes an erodible phar 0001. This patent application claims the benefit of the maceutical composition providing a unique Zero order con filing date of the U.S. Provisional Application No. 60/517, trolled release profile. The erodible composition contains a 589, filed Nov. 5, 2003, and the priority from the filing date therapeutically active Substance having Solubility not greater of the Indian Provisional Application No. 132/Mum/2003, than 80 mg/mL, a hydroxypropyl methylcellulose derivative filed Jan. 31, 2003, the disclosures of both of which are and erosion modifiers depending on drug Solubility and drug hereby incorporated by reference in their entirety. loading, Such as lactose and polyoxyalkylene derivatives of propylene glycol, as well as other inert materials. Such as BACKGROUND OF THE INVENTION binders and lubricants. 0002 Traditionally, solid oral pharmaceutical dosage 0009 U.S. Pat. No. 6,010,718 discloses an extended forms (drug delivery Systems) are comprised of immediate release formulation of erythromycin derivatives. The for release (IR) dosages in the form of tablets or capsules. These mulation comprises an erythromycin derivative and a phar IR dosage forms release the active drug Substance into the maceutically acceptable polymer So that, when ingested body of a subject at a rate that is initially very high followed orally, the composition induces Significantly lower Cmax in by a rapid decline. One potential result of an IR dosage form the plasma than an immediate release composition of the is that the Subject may have varying degrees of blood level erythromycin derivative while maintaining bioavailability fluctuation, which may result in transient therapeutic over and minimum concentration Substantially equivalent to that dose, followed by a period of therapeutic under dosing. of the immediate release composition of the erythromycin These blood level fluctuations are known as “peaks and derivative upon multiple dosing. The compositions of the Valleys' or Similarly as "peaks and troughs.' invention have an improved taste profile and reduced gas trointestinal Side effects as compared to those for the imme 0003. One of the most frequently utilized methods to diate release composition. extend the duration of drug action in the body and/or control blood level fluctuations is modification of the pharmaceuti 0010 U.S. Pat. No. 5,705,190 is directed to a controlled cal dosage form. This is usually achieved with Single or release, oral, Solid, pharmaceutical composition for a multi-component matrix Systems. Such as granules, pellets, reduced daily dosage regimen, where the therapeutic ingre tablets or a combination of the above where the drug dient is a poorly Soluble basic drug. The formulation com delivery is mainly controlled by a diffusion, osmotic or prises the use of a water-Soluble alginate Salt, a complex Salt erosion mechanism. of alginic acid and an organic carboxylic acid in admixture with the therapeutic drug. 0004 Controlled-release (CR) formulations have the advantage that the active drug is gradually released over a 0011 U.S. Pat. No. 4,808,411 describes compositions, relatively long period So that the drug is maintained in the which comprise a complex of carbomer (acrylic acid poly blood Stream for a longer time and at a more uniform mers) and erythromycin or a derivative thereof Such as concentration than would otherwise be the case. This allows 6-O-methylerythromycin. The compositions provide non administration only once or twice daily for drugs that would toxic, palatable dry and liquid dosage forms for oral admin otherwise have to be taken more frequently to maintain istration. required blood levels. Many different types of controlled 0012. The drug delivery systems disclosed in these pat release oral dosage forms have been developed, but each has ents provide for Solid, oral controlled release dosage forms disadvantages, which affect its Suitability to a particular drug of Active Pharmaceutical Ingredients (API). However, these and therapeutic objective. Systems contain additional disadvantages Such as relatively 0005 The most common Immediate Release (IR) oral fast drug release profiles, dose dumping, lack of Stability, dosage forms are administered more than once a day. These variation in drug release profile between the units and IR dosage forms may lead to a peak and trough blood level difficult or expensive manufacturing methods. fluctuations. The more than once daily dosing can also result 0013 Therefore, there still exists a need for developing in a poor compliance due to its multiple dosing regimen. The an efficient controlled release pharmaceutical composition most effective approach to overcome the above mentioned of an API that is capable of controlled drug delivery in order non-compliance causes have been to develop a controlled to prevent and improve upon these problems. release oral Solid pharmaceutical composition of clarithro mycin. SUMMARY OF THE INVENTION 0006 U.S. Pat. No. 4,389,393 discloses a sustained 0014. The present invention relates to a controlled release release therapeutic compositions based on high molecular modifying complex for Solid oral controlled release phar weight hydroxypropyl methylcellulose. A carrier base mate maceutical compositions Suitable for once-a-day adminis rial combined with a therapeutically active medicament and tration. More particularly, the pharmaceutical composition shaped and compressed to a Solid unit dosage form having comprises an API, a release modifying complex and other a regular and prolonged release pattern upon administration. required pharmaceutically acceptable excipients. The 0007 U.S. Pat. No. 4,540,566 discloses a prolonged release modifying complex of the invention comprises a release drug dosage forms based on modified low Viscosity primary, Secondary and auxiliary release modifying agent or US 2004/0185097 A1 Sep. 23, 2004 combination thereof, wherein Said primary, Secondary and provide a therapeutic effective level and plasma concentra auxiliary release modifying agents are present in amounts tion of Said penicillin antibiotic that is Suitable for once-a- that Synergistically effect and extend the release of the day dosing. erythromycin derivative. 0022. In another aspect, the present invention relates to a 0.015. It has been discovered that the controlled-release CR pharmaceutical composition comprising a high Soluble (CR) formulations of the present invention which comprises high dose API or their pharmaceutically acceptable Salts, an active pharmaceutical ingredient ("API) and a controlled ester or hydrates and a controlled release modifying com release modifying complex, wherein Said release modifying pleX, So that when ingested orally, the complex slowly complex Synergistically effects and extends the release of the releases Said API over an extended period of time So as to API and thereby prevents dose dumping and unwanted provide a therapeutic effective level and plasma concentra plasma level fluctuations. tion of Said API that is Suitable for once-a-day dosing. 0016. In one aspect, the present invention relates to a CR 0023. In another aspect, the present invention relates to a pharmaceutical composition of an API or their pharmaceu CR pharmaceutical composition comprising a high Soluble tically acceptable Salts, ester or hydrates, compressible to a low dose API or their pharmaceutically acceptable Salts, Size Suitable for oral administration to humans, comprising ester or hydrates and a controlled release modifying com an API and a controlled release modifying complex, So that pleX, So that when ingested orally, the complex slowly when ingested orally, the API is released into the gastrointes releases Said API over an extended period of time So as to tinal tract predominantly in Solution phase rather than a Solid provide a therapeutic effective level and plasma concentra phase thus avoiding any chances of dose dumping and tion of Said API that is Suitable for once-a-day dosing. thereby reduce the drug release variation between dosage units to a minimum. 0024. In another aspect, the present invention relates to a CR pharmaceutical composition comprising a low Soluble 0.017. In another aspect, the present invention relates to a high dose API or their pharmaceutically acceptable Salts, CR pharmaceutical composition comprising an API or their ester or hydrates and a controlled release modifying com pharmaceutically acceptable Salts, ester or hydrates and a pleX, So that when ingested orally, the complex slowly controlled release modifying hydrophilic complex, So that releases Said API over an extended period of time So as to when ingested orally, the complex slowly releases the API provide a therapeutic effective level and plasma concentra over an extended period of time So as to provide a thera tion of Said API that is Suitable for once-a-day dosing. peutic effective level and plasma concentration of the API that is Suitable for once-a-day dosing. 0025. In another aspect, the present invention relates to a CR pharmaceutical composition comprising a low Soluble 0.018. In another aspect, the present invention relates to a low dose API or their pharmaceutically acceptable Salts, CR pharmaceutical composition comprising a macrollide or ester or hydrates and a controlled release modifying com azalide antibiotic or their pharmaceutically acceptable Salts, pleX, So that when ingested orally, the complex slowly ester or hydrates and a controlled release modifying com releases Said API over an extended period of time So as to pleX, So that when ingested orally, the complex slowly provide a therapeutic effective level and plasma concentra releases said macrollide or azalide over an extended period of time So as to provide a therapeutic effective level and plasma tion of Said API that is Suitable for once-a-day dosing. concentration of Said macrollide or azalide that is Suitable for 0026. In yet another aspect, the present invention relates once-a-day dosing. to a CR pharmaceutical composition comprising an API and a controlled release modifying complex, So that when 0019. In another aspect, the present invention relates to a ingested orally, the composition provides a convenient, CR pharmaceutical composition comprising a quinolone generally Self-administered dosage form that yields a con antibiotic or its pharmaceutically acceptable Salts, ester or Stant infusion of the drug. Advantages of the controlled hydrates and a controlled release modifying complex, So that release drug delivery System of the present invention when ingested orally, the complex slowly releases Said include, but are not limited to: (1) Reduction in drug blood quinolone over an extended period of time So as to provide level fluctuations. For example, by controlling the rate of a therapeutic effective level and plasma concentration of drug release, “peaks and Valleys' of drug-blood or Serum Said quinolone that is Suitable for once-a-day dosing. levels are eliminated. (2) Reduction in dosing frequency. For 0020. In another aspect, the present invention relates to a example, rate-controlled products deliver more than a Single CR pharmaceutical composition comprising a cephalosporin dose of medication and thus are taken less often than antibiotic or its pharmaceutically acceptable Salts, ester or conventional forms. (3) Enhanced patient convenience and hydrates and a controlled release modifying complex, So that compliance. For example, with less frequency of dose when ingested orally, the complex slowly releases Said administration, the patient is leSS apt to neglect taking a cephalosporin antibiotic over an extended period of time So dose. There is also greater patient convenience with daytime as to provide a therapeutic effective level and plasma con and nighttime medication, and control of chronic illness. (4) centration of Said cephalosporin antibiotic that is Suitable for Reduction in adverse side effects. Because there are Seldom once-a-day dosing. drug blood level peaks above the drugs therapeutic range, 0021. In another aspect, the present invention relates to a and into the toxic range, adverse side effects are leSS CR pharmaceutical composition comprising a penicillin frequently encountered. antibiotic or its pharmaceutically acceptable Salts, ester or 0027. In another aspect, the present invention relates to a hydrates and a controlled release modifying complex, So that controlled release pharmaceutical composition of an API when ingested orally, the complex slowly releases Said comprising an API and a Synergistic release modifying penicillin antibiotic over an extended period of time So as to complex wherein said complex comprises, (a) a primary US 2004/0185097 A1 Sep. 23, 2004 release modifying agent, (b) a secondary release modifying disorder or condition developing in a mammal that may be agent, and (c) an auxiliary release modifying agent, so that afflicted with or predisposed to the State, disorder or condi when ingested orally, Said complex Synergistically effects tion but does not yet experience or display clinical or and extends release of the API. Subclinical Symptoms of the State, disorder or condition, (2) 0028. In another aspect, the present invention relates to a inhibiting the State, disorder or condition, i.e., arresting or controlled release pharmaceutical composition of an API reducing the development of the disease or at least one comprising an API and a Synergistic release modifying clinical or Subclinical Symptom thereof, or (3) relieving the complex wherein said complex comprises, (a) a primary disease, i.e., causing regression of the State, disorder or release modifying agent, or (b) a secondary release modi condition or at least one of its clinical or Subclinical Symp fying agent, and (c) an auxiliary release modifying agent, So toms. The benefit to a subject to be treated is either statis that when ingested orally, Said complex Synergistically tically significant or at least perceptible to the patient or to effects and extends release of the API. the physician 0029. In yet still another aspect, the present invention 0037. The term “therapeutically effective amount” as relates to a controlled release pharmaceutical composition of used herein means the amount of a compound that, when an API comprising an API and a Synergistic release modi administered to a mammal for treating a State, disorder or fying complex, wherein said complex comprises, (a) a condition, is Sufficient to effect Such treatment. The “thera primary release modifying agent Selected from low molecu peutically effective amount' will vary depending on the lar weight hydrophilic polymers, (b) a Secondary release compound, the disease and its Severity and the age, weight, modifying agent Selected from high molecular weight physical condition and responsiveness of the mammal to be hydrophilic polymers, and (c) an auxiliary release modifying treated. agent Selected from Starch derivatives. 0038. The term “delivering” as used herein means pro 0.030. In yet still another aspect, the present invention Viding a therapeutically effective amount of an active ingre relates to a controlled release pharmaceutical composition of dient to a particular location within a host causing a thera an API comprising an API and a Synergistic release modi peutically effective blood concentration of the active fying complex, wherein said complex comprises, (a) a ingredient at the particular location. This can be accom primary release modifying agent Selected from low molecu plished, e.g., by local or by Systemic administration of the lar weight hydrophilic polymers, or (b) a Secondary release active ingredient to the host. modifying agent selected from high molecular weight 0039. By “pharmaceutically acceptable' is meant those hydrophilic polymers, and (c) an auxiliary release modifying Salts and esters which are, within the Scope of Sound medical agent Selected from Starch derivatives. judgment, Suitable for use in contact with the tissues of 0031. The pharmaceutical composition of the invention humans and lower animals without undue toxicity, irritation, also relates to a wide variety of APIs suitable for use in allergic response and the like, commensurate with a reason controlled release formulations. able benefit/risk ratio, and effective for their intended use. Representative acid additions Salts include the hydrochlo 0.032 The present invention also relates to a process, for ride, hydrobromide, Sulphate, bisulphate, acetate, oxalate, the preparation of a controlled release composition of an API Valerate, oleate, palmitate, Stearate, laurate, borate, ben Suitable for once-a-day administration, comprising a wet Zoate, lactate, phosphate, tosylate, meSylate, citrate, maleate, granulation, dry granulation, Slugging, roll compaction, fumarare, Succinate, tartrate, ascorbate, glucoheptonate, lac direct compression or any other technique known in the tobionate, lauryl Sulphate Salts and the like. Representative pharmaceutical art. alkali or alkaline earth metal Salts include the Sodium, calcium, potassium and magnesium Salts, and the like. BRIEF DESCRIPTION OF THE DRAWINGS 0040. The term “subject” or “a patient” or “a host” as 0.033 FIG. 1: illustrates a plasma concentration profile of used herein refers to mammalian animals, preferably human. clarithromycin 500 mg extended release tablets of Example 13. 0041) The term “high soluble API” as used herein will mean that leSS than 30 parts of water is required to com DEFINITIONS pletely dissolve 1 part of the API. 0034. The term “controlled release” as used herein means 0042. The term “low soluble API” as used herein will a drug dosage System in which the rate of the API release is mean that greater than 30 parts of water is required to more precisely controlled compared to that of immediate or completely dissolve 1 part of the API. sustained release products, wherein the API is delivered 0043. The term “high dose API” as used herein will mean from the dosage System at a predictable and predetermined that the individual unit dose of the API is 50 mg or greater. rate within the body of a patient Such that a therapeutically effective blood level, devoid of peak and trough fluctuations, 0044) The term “low dose API” as used herein will mean is maintained over an extended period of time. that the individual unit dose is less than 50 mg. 0035. The term “drug delivery systems” as used herein 0045. The term “high soluble high dose API” as used means the technology utilized to present the drug to the herein will mean that less than 30 parts of water is required desired body Site for drug release and absorption. to completely dissolve 1 part of the API and that the 0036) The term “treating” or “treatment” of a state, individual unit dose of the API is 50 mg or greater. disorder or condition as used herein means: (1) preventing or 0046) The term “high soluble low dose API” as used delaying the appearance of clinical Symptoms of the State, herein will mean that less than 30 parts of water is required US 2004/0185097 A1 Sep. 23, 2004

to completely dissolve 1 part of the API and that the Cefinenoxime, Cefodizime Sodium, Cefotaxime, Ce?pimi individual unit dose of the API is less than 50 mg. Zole, Cefpiramide, Ceftazidime, Ceftiolene, CeftizOXime, Ceftriaxone, Cefepime, Cefetecol, Cefpirome, Cefauinome, 0047. The term “low soluble high dose API” as used Cefalosporin C, Cefozopran Hydrochloride, Cefaclor, herein will mean that greater than 30 parts of water is Cefadroxil, Cefalexin, Cefaloglycine, Cefatrizine, Cefdinir, required to completely dissolve 1 part of the API and that the Cefetamet Pivoxil, Cefixime, Ceforanide, Cefotiam, Ce?po individual unit dose of the API is 50 mg or greater. doxime, Cefpodoxime Proxetil, Cefprozil, Cefradine, 0048. The term “low soluble low dose API” as used Cefroxadine, Cefteram Pivoxil, Ceftibuten, Cefuroxime herein will mean that greater than 30 parts of water is Axetil, and their pharmaceutically acceptable hydrates, Salts required to completely dissolve 1 part of the API and that the and esters. individual unit dose of the API is less than 50 mg. 0054. In still yet another embodiment of the present invention, a preferred API is a quinolone class antibiotic or DETAILED DESCRIPTION OF THE derivative thereof. Preferably, the API is a quinolone INVENTION Selected from the group consisting of Nalidixic Acid, Cino 0049. The present invention relates to a solid oral con Xacin, OXolinic Acid, Flumequine, Pipemidic Acid, RoSOXa trolled release modifying complex and pharmaceutical com cin, Norfloxacin, Lomefloxacin, Ofloxacin, Enrofloxacin, positions thereof for once-a-day administration to a Subject Ciprofloxacin, Enoxacin, Amifloxacin, Fleroxacin, Gati in need thereof. More particularly, the pharmaceutical com floxacin, Gemifloxacin, Pefloxacin, Rufloxacin, Sparfloxa position comprises an API, a controlled release modifying cin, Temafloxacin, ToSufloxacin, Grepafloxacin, Levofloxa complex and other required pharmaceutically acceptable cin, Moxifloxacin, Trovafloxacin, and their excipients. The controlled release modifying complex of the pharmaceutically acceptable hydrates, Salts and esters. invention comprises a primary, Secondary and/or auxiliary 0055. In still yet another embodiment of the present release modifying agent or varying combination thereof, invention, a preferred API is a high soluble high dose API or wherein Said primary, Secondary and auxiliary release modi derivative thereof. Preferably, the API is a high soluble high fying agents are present in amounts that Synergistically dose API Selected from the group consisting of Acebutolol effect and extend the release of the API. hydrochloride, Amantadine hydrochloride, Aminocaproic 0050. The pharmaceutical composition of the present acid, Aminophylline, Amodiaquine hydrochloride, AScorbic invention shows a predictable and predetermined controlled acid, CarbenoXolone Sodium, Cefuroxime Sodium, Chloro drug release, So that the API is available over a period up to quine phosphate, Chloroquine Sulphate, Chlorpromazine 24 hours. The release period is dependent on the precise hydrochloride, Ciprofloxacin hydrochloride, Cloxacillin tablet Size, the identity of the active ingredient, aqueous Sodium, Cycloserine, Diltiazem hydrochloride, Diethyl car Solubility of the active ingredient, hardneSS and particular bamazine citrate, Doxycycline hydrochloride, EthosuXim composition of the release modifying complex. The com ide, Ferrous gluconate, Isoniazid, Levamisole hydrochlo position prepared in accordance with the present invention is ride, Lincomycin hydrochloride, Mebeverine hydrochloride, hard, has low friability and provides controlled release over Mepyramine maleate, Metformin hydrochloride, Metoprolol an extended period. Moreover, the drug release profile of tartrate, Nicotinamide, Nicotinic acid, Oxprenolol hydro each dosage unit is uniform and without any significant chloride, Oxytetracycline hydrochloride, Penicillamine, variation. Pentobarbitone sodium, Phenoxy Methyl Penicillin K, Phe nyloin Sodium, piperazine adipate, Procainamide hydrochlo 0051. According to the present invention, a preferred API ride, Pseudoephedrine hydrochloride, Quinalbarbitone is a macrollide or azalide antibiotic. Preferably, the API is an erythromycin derivative Selected from the group consisting Sodium, Quinine bisulphate, Ranitidine hydrochloride, ofjosamycin, midecamycin, kitamycin, roXithromycin, roki Sodium amino Salicylate, Sodium fusidate, Sodium Val tamycin, oleandomycin, miocamycin, flurithromycin, rosa proate, Streptomycin Sulphate, Tetracycline hydrochloride, ramicin, azithromycin, and clarithromycin, and their phar Troxidone, Verapamil hydrochloride and the like and their maceutically acceptable hydrates, Salts and esters. pharmaceutically acceptable Salts, ester and hydrates. 0056. In still yet another embodiment of the present 0.052 In another embodiment of the present invention, a invention, a preferred API is a high soluble low dose API or preferred API is a penicillin class antibiotic or derivative derivative thereof. Preferably, the API is a high soluble low thereof. Preferably, the API is a penicillin selected from the dose API Selected from the group consisting of Amitriptyl group consisting of Amoxicillin, Ampicillin, Ampicillin line hydrochloride, captopril, Clonidine hydrochloride, Sodium, Apalcillin, ASpoxicillin, AZlocillin, Aztreonam, Colchicin, Cyclophosphamide, Diphenhydramine hydro Bacampicillin, Cabenicillin, Carfecillin, Carindacillin, chloride, Dothiepen hydrochloride, Doxepin hydrochloride Ciclacillin, Cloxacillin, Dicloxacillin, and their pharmaceu Ephedrine hydrochloride, Ergometrine maleate, Ergo tically acceptable hydrates, Salts and esters. metrine tartrate, Fenfluramine hydrochloride, Folic acid, 0053. In yet another embodiment of the present inven Glyceryl trinitrate, Hyoscine hydrobromide, Hyoscine tion, a preferred API is a cephalosporin class antibiotic or buytlbromide, Imipramine hydrochloride, Isoprenaline Sul derivative thereof. Preferably, the API is a cephalosporin phate, ISOSorbide dinitrate, ISOSorbide-5-mononitrate, Selected from the group consisting of Cefacetrile, Methadone hydrochloride, Methdilazine hydrochloride, Cefadroxil, Cefaloridine, Cefalothin Sodium, Cefapirin, Metoclopramide hydrochloride, Neostigmine bromide, Cefazaflur, Cefazedone, Cefazolin, Cefradine, Ceftezole, Oxybutynin hydrochloride, Pethidine hydrochloride, Phen Cefsulodin Sodium, Cefamandole, Cefonicid, Cefopera formin hydrochloride, Pheniramine maleate, Phenobarbi Zone, Cefuroxime, CefuZonam, CefbuperaZone, Cefoxitin, tone Sodium, Primaquine phosphate, Promethazine hydro Cefnminox, Cefinetazole, Cefotetan, Loracarbef, chloride, Propantheline bromide, Propranolol US 2004/0185097 A1 Sep. 23, 2004

hydrochloride, Pyridoxine hydrochloride, Salbutamol Sul include antibacterial, antacids, analgesic and anti-inflamma phate, Terbutaline Sulphate, Thiamine hydrochloride, tory agents, anti-arrhythmic agents, antiprotozoal agents, Timolol maleate, Trifluoperazine hydrochloride, Triflupro anti-coagulants, antidepressants, anti-diabetic agents, anti mazine hydrochloride, Triprolidine hydrochloride, Warfarin epileptic agents, antifungal agents, antihistamines, anti-hy Sodium and the like and their pharmaceutically acceptable pertensive agents, anti-muscarnic agents, antineoplastic Salts, ester and hydrates. agents, antimetabolites, anti-migraine agents, anti-Parkinso 0057. In still yet another embodiment of the present nian agents, antipsychotic, hypnotic and Sedating agents, invention, a preferred API is a low soluble high dose API or anti-Stroke agents, antituSSive, antivirals, cardiac inotropic derivative thereof. Preferably, the API is a low soluble high agents, corticosteroids, disinfectants, diuretics, enzymes, dose API Selected from the group consisting of Acetazola essential oils, gastro-intestinal agents, haemoStatics, lipid mide, Allopurinol, Atenolol, Carbamazepine, Cefadroxil, regulating agents, local anesthetics, opioid analgesics, para Cephalexin, Chloramphenicol, Cefuroxime Axetil, Chlo Sympathomimetics and anti-dementia drugs, peptides and rthalidone, Cimetidine, Clarithromycin, ClofaZemine, Dap proteins, SeX hormones, Stimulating agents, vasodilators or Sone, Diclofenac Sodium, Diiodohydroxy quinolone, Dilox mixtures thereof. anide furoate, Disulfiram, Erythromycin, Erythromycin 0060. The amount of active pharmaceutical ingredient in eStolate, Erythromycin Stearate, Ethacrynic cid, Ethiona the composition generally varies from about 0.1% to about mide, Ethopropazine hydrochloride, Ferrous fumarate, Flu 90% by weight of the composition. Preferably, the amount conazole, Flurbiprofen, Furazolidone, Griseofulvin, Hydro of active pharmaceutical ingredient varies from about 0.1% chlorthiazide, Ibuprofen, Ketoconazole, Ketoprofen, to about 80% by weight of the composition. Labetalol hydrochloride, Levodopa, LineZolid, Lithium car bonate, Magaldrate, Mebendazole, Mefenamic acid, Mege 0061 The immediate object of the present invention is to Strol acetate, Mercaptopurine, Nalidixic acid, Niclosamide, develop an efficient controlled release pharmaceutical com Nitrofurantoin, Norfloxacin, Oxyphenbutazone, Paraceta position that is capable of controlled drug delivery of active mol, Phenindione, Phenobarbitone, Phenylbutazone, Phe pharmaceutical ingredient, in order to provide Sustained/ nylsulphathiazole, piperazine phosphate, Proguanil hydro extended therapeutic effects up to 24 hours without dose chloride, Promethazine theoclate, Propylthiouracil, dumping. The present invention is directed to an extended Quinidine Sulphate, Quinine Sulphate, Quinidochlor, release pharmaceutical composition of active pharmaceuti Rifampicin, Spironolactone, Succinylsulphathiazole, Sul cal ingredient, Said composition comprising a pharmaceuti phadiazine, Sulphadimethoxine, Sulphadimidine, Sul cally effective amount of the API, a release modifying phafurazole, Sulphaphenazole, Thiabendazole, Tinidazole, complex and the other required pharmaceutically acceptable Tolbutamide, Triamterene, Sulphamethoxazole and the like additives. The Said release modifying complex essentially and their pharmaceutically acceptable Salts, ester and comprises, a primary release modifying agent Selected from hydrates. a low molecular weight polyethylene oxide, a Secondary release modifying agent Selected from a high molecular 0.058. In still yet another embodiment of the present weight polyethylene oxide, and an auxiliary release modi invention, a preferred API is a low soluble low dose API or fying agent Selected from a Starch derivative. The Said derivative thereof. Preferably, the API is a low soluble low release modifying complex when present in a Synergistic dose API Selected from the group consisting of Alprazolam, effective amount is Sufficient to extend the release of the Amiloride hydrochloride, Astemizole, Benzhexol hydro active pharmaceutical ingredient. chloride, Betamethasone, Bromhexine hydrochloride, Bro mocryptine meSylate, Buprenorphine hydrochloride, carbi 0062) The release modifying complex of the invention mazole, Chlordiazepoxide, Cortisone acetate, comprises a low molecular weight polyethylene oxide, a cyproheptadine hydrochloride, diazepam, Dexamethasone high molecular weight polyethylene oxide and a Starch hydrochloride, Dextromethorphan hydrochloride, dicyclom derivative. The amount of release modifying complex in the ine hydrochloride, Dienoestrol, Digitoxin, Digoxin, composition of the present invention generally varies from Dydrogesterone, enalapril maleate, Ethinyloestradiol, Ethy about 1% to about 90% by weight of the composition. loestrenol, Fludrocortisone acetate, Frusemide, glibencla Preferably, the amount of said complex varies from about mide, haloperidol, Indomethacin, ISOXSuprine hydrochlo 5% to about 85% by weight of the composition. Most ride, Lanatoside C, Lercanidipine hydrochloride, preferably the amount of Said complex varies from about LevonorgeSrtel, Lomustine, isoxuprine hydrochloride, 10% to about 80% by weight of the composition. methotrexate, Mecizine hydrochloride, Melphalan, Methotr 0063 Polyethylene oxide is a non ionic homopolymer of exate, Methylergometrine maleate, Methylprednisolone, oxyethylene groups (molecular weight of about 2000 to over Mianserin hydrochloride, Nicoumalone, Nifedipine, 100,000) and they are water soluble. They are thermoplastic Nitrazepam, Norethisterone, nortriptyline hydrochloride, agents that are readily calendared, extruded, injection Omeprazole, Ormeloxifene hydrochloride, Pentazocine molded or cast. Higher molecular weight polyethylene hydrochloride, Phenindamine tartrate, piroXicam, prazosin oxides provide extended release via the hydrophilic matrix hydrochloride, Prednisolone, Prednisone, Prochlorperazine approach. Polyethylene oxides on exposure to water or maleate, Riboflavinee, Stilbostrol, Tamoxifen citrate, Thy gastric juices hydrate and Swell rapidly to form hydrogels roxine Sodium, triamcinilone, Trimethoprim and the like and with properties ideally Suited for controlled release formu their pharmaceutically acceptable Salts, ester and hydrates. lations. The Polyethylene oxides are non-ionic, So no inter 0059. In still yet another embodiment of the present action between the drug and the polymer is to be expected. invention, the pharmaceutical composition of the invention 0064. The primary release modifying agent of the present also relates to a wide variety of APIs suitable for use in invention is Selected from the low molecular weight poly controlled release formulations. Representative API's may ethylene oxides, having a molecular weight of at least US 2004/0185097 A1 Sep. 23, 2004

100,000 and the molecular weight range from 100,000 to (retrogradation) and washing with ethanol. The retrograded 900,000. Low molecular weight Polyethylene oxides are pregelatinized Starch is a linear oligosaccharide and is commercially available in various grades, under Several characterized by a high Specific Surface area. The pharma trade names including Polyox WSRN-10, WSR N-80, WSR ceutical composition of the present invention may contain N-750, WSR-705, and WSR1105 from The Dow Chemical either one of the above Starch derivatives alone or a com Co. USA. The different grades under the given trade name bination of the above starch derivatives as the auxiliary represent the differences in oxyethylene contents as well as release modifying agents. All the above Starch derivatives molecular weight. The pharmaceutical composition of the are contemplated to be used in the present invention. For present invention may contain one low molecular weight example, the pharmaceutical composition contemplates the polyethylene oxide grade alone or a combination of different use of retrograded pregelatinized Starch. The retrograded grades of low molecular weight polyethylene oxides. All the pregelatinized Starch is commercially available as Prejel PA various grades of polyethylene oxides mentioned above are 5 PH from Avebe Inc. (The Netherlands). contemplated to be used in this present invention. 0070 The amount of the auxiliary release modifying 0065. The amount of the primary release modifying agent agent in the release modifying complex generally varies in the release modifying complex generally varies from from about 1% to about 95% by weight of the complex. about 1% to about 90% by weight of the complex. Prefer Preferably, the amount of auxiliary release modifying agent ably, the amount of primary release modifying agent varies varies from about 9% to about 95% by weight of the complex. from about 5% to about 80% by weight of the complex. Most preferably, the amount of auxiliary release modifying Most preferably, the amount of primary release modifying agent varies from about 10% to about 95% by weight of the agent varies from about 5% to about 70% by weight of the complex. complex. 0071. The presence of synergistic effective amounts of 0.066 The secondary release modifying agent of the the low molecular weight polyethylene oxide and/or the high present invention is Selected from the high molecular weight molecular weight polyethylene oxide in combination with polyethylene oxides, having a molecular weight of at least the retrograded Starch provides a better controlled drug 1,000,000 and the molecular weight range from 1,000,000 to release profile without dose dumping. When used in the 9,000,000. High molecular weight Polyethylene oxides are amounts provided, the drug release profile is Substantially commercially available in various grades, under Several better than the drug release profile using either low molecu trade names including Polyox WSR N-12K, WSR N-60K, lar weight polyethylene oxide or high molecular weight WSR-301, WSR coagulant and WSR-303 from The Dow polyethylene oxide or retrograded Starch alone. Chemical Co. USA. The different grades under the given trade name represent the differences in oxyethylene contents 0072 The low molecular weight polyethylene oxide i.e. as well as molecular weight. The pharmaceutical composi the primary release modifying agent, the high molecular tion of the present invention may contain one high molecular weight polyethylene oxide i.e., the Secondary release modi weight polyethylene oxide grade alone or a combination of fying agent and the retrograded Starch i.e., the auxiliary different grades of high molecular weight polyethylene release modifying agent are present in the pharmaceutical oxides. All the various grades of polyethylene oxides men composition of the invention in Synergistic effective tioned above are contemplated to be used in this present amounts. When the high molecular weight polyethylene invention. oxide, low molecular weight polyethylene oxide and the retrograded Starch are present together as the release modi 0067. The amount of the secondary release modifying fying complex in the pharmaceutical composition of the agent in the release modifying complex generally varies invention, the controlled release ability of the composition is from about 1% to about 95% by weight of the complex. better than just an additive effect. More specifically, the Preferably, the amount of Secondary release modifying agent pharmaceutical composition of the present invention exhib varies from about 5% to about 90% by weight of the its a better drug release profile when the release modifying complex. complex comprises the above mentioned components, in the 0068 The other essential component of the release modi prescribed amounts, than any one by themselves. In another fying complex is the auxiliary release modifying agent, embodiment, the present invention may exhibit a better drug Selected from the Starch derivatives. Examples of Starch release profile, which is devoid of any dose dumping and derivatives include pregelatinized Starch, partially pregela also ensures the release of the complete amount of the drug tinized Starch and retrograded Starch. Pregelatinized Starch is over a period of about 12 to 24 hours depending on the a Starch that has been chemically and/or mechanically requirement for a particular API. AS used herein, the term processed to rupture all or a part of the Starch granules and Synergistic effective combination of the above mentioned So as to render the Starch flowable and directly compressible. components when used in combination to effect a better drug Partially pregelatinized Starch is a physically modified Starch release profile or other improved result in the pharmaceuti having the benefit of a soluble functionality and an insoluble cal composition of the present invention relative to the functionality. Partial pregelatinization breaks the bond formulation containing one or the other of the three com between the amylase and amylopectin, which are the two ponents used individually or formulations containing any polymers, tightly bound in a Specific spherocrystalline Struc other rate controlling, release modifying polymers. ture in Starch. The partial pregelatinization proceSS results in partial Solubility, increased particle size, improved flow 0073. It is very well within the scope of the present invention to achieve a controlled release composition com properties and compactability. prising a pharmaceutically active ingredient, release modi 0069. Retrograded starch is a new pregelatinized starch, fying complex and other required pharmaceutically accept which is prepared by enzymatic degradation, precipitation able additives, where the release modifying complex US 2004/0185097 A1 Sep. 23, 2004 comprises a primary release modifying agent and an auxil also typically used in pharmaceuticals. Such as coloring iary release modifying agent only. It is also very well within agents, preservatives, flavorings, and the like. The amount of the Scope of the present invention to achieve a controlled optional ingredients generally varies from about 0.1% to release composition comprising of the pharmaceutically about 5.0% by weight of the composition. active ingredient, release modifying complex and other 0081. Another embodiment of the present invention pro required pharmaceutically acceptable additives, where the vides methods of making a controlled release formulation of release modifying complex comprises a Secondary release an active pharmaceutical ingredient by wet granulation, dry modifying agent and an auxiliary release modifying agent granulation, Slugging, roll compaction, direct compression only. or any other technique known in the pharmaceutical art, 0.074 The pharmaceutical composition of the present wherein Said formulation Synergistically effects and extends invention also contains other required pharmaceutically the release of the API. acceptable excipients. The amount of additional pharmaceu 0082 The wet granulation process comprises the follow tically acceptable excipients generally varies from about ing steps. (1) Dry blending the mixture of API, primary 10% to about 90% by weight of the composition. release modifying agent, Secondary release modifying agent, 0075. The pharmaceutically acceptable excipients used in auxiliary release modifying agent and other required phar the present invention are Selected from the fillers, glidants maceutically acceptable additives to make a uniform and lubricants that are typically used in the pharmaceutical homogenous blend. (2) Wet granulating the uniform blend. arts for oral solid dosage forms. The filler used herein is inert (3) Diminuting the wet mass. (4) Drying and sizing the filler, may be water soluble or water insoluble and selected granules to an optimum size Suitable for compression. (5) from those typically used in the pharmaceutical art for oral Blending the sized granules with the required pharmaceuti Solid dosage forms. Examples include calcium carbonate, cally acceptable additives/lubricants. (6) Compressing the dicalcium phosphate, tricalcium phosphate, microcrystalline blended granules into tablets. cellulose, monosaccharide, disaccharides, polyhydric alco hols, Sucrose, dextrose, lactose, fructose, mannitol, Sorbitol, 0083. In another aspect of the invention, the homogenous alone or mixtures thereof and the like and mixtures thereof. blend of the active ingredient, the primary release modifying agent, the Secondary release modifying agent, the auxiliary 0.076 The amount of fillers generally varies from about release modifying agent and the other required pharmaceu 1% to about 90% by weight of the composition. All the tically acceptable additives is compacted into Slugs or rib various fillers mentioned above are contemplated to be used bons using a compression machine or roller compactor. The in the present invention. Slugs or ribbons are reduced to the desired size, then 0077. The glidants of the present invention are selected lubricated and compressed into tablets. from those glidants typically used in the pharmaceutical art 0084. In a further aspect of the invention, the homog for oral Solid dosage forms. For example, colloidal Silicon enous blend of the active ingredient, the primary release dioxide, talc alone or mixtures and equivalents thereof. The modifying agent, the Secondary release modifying agent, the amount of glidants generally varies from about 0.1% to auxiliary release modifying agent and the other required about 5.0% by weight of the composition. pharmaceutically acceptable additives is directly com 0078. The lubricants of the present invention are selected pressed into tablets. The pharmaceutical composition of the from those lubricants typically used in the pharmaceutical present invention can be prepared by any other technique art for oral Solid dosage forms. For example, Stearate Salts known in the pharmaceutical art. Such as calcium Stearate, magnesium Stearate, Zinc Stearate, Stearic acid, talc, hydrogenated vegetable oil, vegetable oil 0085. In the processes illustrated above, the pharmaceu derivatives, Silica, Silicones, high molecular weight poly tical composition is preferably compressed into a tablet alkylelene glycol and Saturated fatty acids alone or mixtures form, which has hardness in the order of 25 N to 350 N and and equivalents thereof. The amount of lubricants generally more preferably 40 N to 300 N as determined by a Schle varies from about 0.1% to about 5.0% by weight of the uniger hardneSS tester. The compressed tablets can be composition. optionally coated with a coating, using the polymers or other coating agents which may or may not be intended or 0079 The pharmaceutical composition of the present designed for the modification of drug release. invention can be optionally coated with a coating, using the polymers or other coating agents which may or may not be 0086 The following examples are provided to enable one intended or designed for the modification of drug release. skilled in the art to practice the invention and are merely Examples include cellulose etherS Such as ethyl cellulose, illustrative of the invention. The examples should not be hydroxypropyl methyl cellulose, hydroxypropyl cellulose, read as limiting the Scope of the invention as defined in the otherS Such as polyvinyl alcohol, polyvinyl pyrrolidone, claims. methacrylic acid derivatives, resins, clays, long chain hydro carbons, long chain carboxylic acids, long chain carboxylic EXAMPLE 1. acid esters, long chain alcohols and the like or mixtures 0087 Nicotinic acid, which is a high soluble high dose thereof. The coating composition comprises of the coating API was mixed with high molecular weight polyethylene polymer and the other required additives like plasticizer, oxide (Secondary release modifying agent), retrograded opacifier, colorant, preservatives and the like. The weight Starch (auxiliary release modifying agent) and lactose mono gain of the coating generally varies from about 0.1% to hydrate. The mixture was sifted through ASTM mesh no. 40, about 25.0% by weight of the composition. blended together in a blender to get a homogenous blend. 0080. The pharmaceutical composition of the present The homogenous blend was granulated with water, the invention may contain other optional ingredients that are granules were dried in a fluid bed drier. The dried granules US 2004/0185097 A1 Sep. 23, 2004

were reduced and sized to ASTM mesh no. 16 granules and acid in USP Dissolution Apparatus Type II at 50 RPM and then lubricated with talc and magnesium Stearate. the results are tabulated below. The results showed a con trolled release of the drug from the dosage form of the TABLE 1-1 Example 2. The drug release from the dosage form men Qty.f tioned in example 2 was extended up to 24 h as shown in Sr. unit % w/w of unit Table 2-2. No. Ingredient (mg) dosage form 1. Nicotinic acid SOOOO 66.66 TABLE 2-2 2. Polyethylene Oxide 17O.OO 22.66 (Mol. Wit.: 4,000,000) % Cumulative 3. Retrograded Starch 40.OO 5.33 Time (h) Drug Released 4. Lactose Monohydrate 3O.OO 4.OO 5. Talc S.OO O.66 1. 9 6. Magnesium Stearate S.OO O.66 4 24 7. Purified Water C.S C.S 8 41 12 55 16 66 0088. The drug release profile from the dosage form of 24 78 the invention was studied in 900 ml of purified water in USP Dissolution Apparatus Type I at 100 RPM and the results are tabulated below. The results showed a controlled release of EXAMPLE 3 the drug from the dosage form of the Example 1. The drug release from the dosage form mentioned in example 1 was 0091. Oxybutynin hydrochloride, which is a high soluble extended up to 24 h as shown in table 1-2. low dose API was mixed with high molecular weight polyethylene oxides (secondary release modifying agents), TABLE 1-2 retrograded Starch (auxiliary release modifying agent) and % Cumulative lactose monohydrate. The mixture was Sifted through an Time (h) Drug Released ASTM mesh no. 40 and then blended together in a blender to get a homogenous blend. The homogenous blend was 1. 8.86 2 14.45 compacted into Slugs or ribbons using a roller compactor. 4 24.66 The Slugs or ribbons are reduced to the desired size, then 8 42.59 lubricated and compressed into tablets. 12 62.50 16 8O.32 24 98.OO TABLE 3-1 Qty.f Sr. unit % w/w of unit EXAMPLE 3 No. Ingredient (mg) dosage form 0089. Oxybutynin hydrochloride, which is a high soluble 1. Oxybutynin hydrochloride 15.OO 3.33 2. Polyethylene Oxide 15.OO 3.33 low dose API was mixed with high molecular weight (Mol. Wit.: 2,000,000) polyethylene oxides (secondary release modifying agents), 3. Polyethylene Oxide 24OOO 53.33 retrograded Starch (auxiliary release modifying agent) and (Mol. Wit.: 4,000,000) lactose monohydrate. The mixture was Sifted through an 3. Retrograded Starch 45.OO 1O.OO 4. Lactose Monohydrate 126.OO 28.00 ASTM mesh no. 40 and then blended together in a blender 5. Aerosil 4.50 1.OO to get a homogenous blend. The homogenous blend was 6. Magnesium Stearate 4.50 1.OO compacted into Slugs or ribbons using a roller compactor. The Slugs or ribbons are reduced to the desired size, then lubricated and compressed into tablets. 0092. The drug release profile from the dosage form of the invention was studied in 500 ml of 0.1N Hydrochloric TABLE 2-1 acid in USP Dissolution Apparatus Type II at 50 RPM and Qty.f the results are tabulated below. The results showed a con Sr. unit % w/w of unit trolled release of the drug from the dosage form of the No. Ingredient (mg) dosage form Example 3. The drug release from the dosage form men 1. Oxybutynin hydrochloride 15.OO 3.33 tioned in example 3 was extended up to 24 h as shown in 2. Polyethylene Oxide 15.OO 3.33 Table 3-2. (Mol. Wit.: 2,000,000) 3. Polyethylene Oxide 3OOOO 66.66 (Mol. Wit.: 4,000,000) TABLE 3-2 3. Retrograded Starch 45.OO 1O.OO 4. Lactose Monohydrate 66.OO 14.66 % Cumulative 5. Aerosil 4.50 1.OO Time (h) Drug Released 6. Magnesium Stearate 4.50 1.OO 1. 1O 4 31 8 51 0090 The drug release profile from the dosage form of 12 67 the invention was studied in 500 ml of 0.1N Hydrochloric US 2004/0185097 A1 Sep. 23, 2004

TABLE 3-2-continued TABLE 4-2

% Cumulative % Cumulative Time (h) Drug Released Time (h) Drug Released 16 78 13 24 91 26 58 90 92 EXAMPLE 3A 92 0093. The tablets of Example 3 were coated with an aqueous dispersion of ethyl cellulose to a weight gain of 4 EXAMPLE 5 percent weight by weight of the dosage form. The aqueous dispersion of ethyl cellulose is commercially available as 0097 Lercanidipine hydrochloride, which is a low Surelease (E 719010) from Colorcon Pvt. Ltd. soluble low dose API was mixed with low molecular weight polyethylene oxide (primary release modifying agent), high 0094. The drug release profile from the coated dosage molecular weight polyethylene oxide (secondary release form of the invention was studied in 500 ml of 0.1N modifying agent), retrograded Starch (auxiliary release Hydrochloric acid in USP Dissolution Apparatus Type II at modifying agent) and lactose monohydrate. The mixture 50 RPM and the results are tabulated below. The results was sifted through ASTM mesh no. 40 and then blended showed a controlled release of the drug from the dosage together in a blender to get a homogenous blend. The form of the Example 3A. The drug release from the dosage homogenous blend was compacted into Slugs or ribbons form mentioned in example 3A was extended up to 24 h. In using a roller compactor. The Slugs or ribbons are reduced to the dosage form of example 3A, there was no drug release the desired size, then lubricated and compressed into tablets. until the end of 4 hours and the drug release profile was extended up to 24 hours. TABLE 5-1 Qty.f % w/w of EXAMPLE 4 Sr. unit unit dosage No. Ingredient (mg) form 0.095 Lercanidipine hydrochloride, which is a low 1. Lercanidipine hydrochloride 2O.OO 13.33 soluble low dose API was mixed with low molecular weight 2. Polyethylene Oxide S.OO 3.33 polyethylene oxide (primary release modifying agent), high (Mol. Wit.: 2,00,000) molecular weight polyethylene oxide (secondary release 3. Polyethylene Oxide 1O.OO 6.66 modifying agent), retrograded Starch (auxiliary release (Mol. Wit.: 2,000,000) 3. Retrograded Starch 1O.OO 6.66 modifying agent) and lactose monohydrate. The mixture 4. Lactose Monohydrate 101.50 67.66 was sifted through ASTM mesh no. 40 and then blended 5. Aerosil O.8O O.533 together in a blender to get a homogenous blend. The 6. Magnesium Stearate 2.70 18O homogenous blend was compacted into Slugs or ribbons using a roller compactor. The Slugs or ribbons are reduced to the desired size, then lubricated and compressed into tablets. 0098. The drug release profile from the dosage form of the invention was studied in 900 ml of 0.1N Hydrochloric TABLE 4-1 acid with 1% sodium lauryl Sulfate in USP Dissolution Apparatus Type II at 75 RPM and the results are tabulated Qty.f % w/w of Sr. unit unit dosage below. The results showed a controlled release of the drug No. Ingredient (mg) form from the dosage form of the Example 5. As shown in table 5-2, the drug release from the dosage form mentioned in 1. Lercanidipine hydrochloride 2O.OO 13.33 2. Polyethylene Oxide 1O.OO 6.66 example 5 was extended up to 12 h. (Mol. Wit.: 2,00,000) 3. Polyethylene Oxide 2O.OO 13.33 TABLE 5-2 (Mol. Wit.: 2,000,000) 3. Retrograded Starch 15.OO 1O.OO % Cumulative 4. Lactose Monohydrate 81.50 54.33 Time (h) Drug Released 5. Aerosil O.80 O.533 6. Magnesium Stearate 2.70 18O 22 37 72 79 0096. The drug release profile from the dosage form of 8O the invention was studied in 900 ml of 0.1N Hydrochloric 81 acid with 1% sodium lauryl Sulfate in USP Dissolution Apparatus Type II at 75 RPM and the results are tabulated below. The results showed a controlled release of the drug EXAMPLE 6 from the dosage form of the Example 4. The drug release from the dosage form mentioned in example 4 was extended 0099 Clarithromycin, which is a low soluble high dose up to 12 has shown in table 4-2. API, was mixed with a low molecular weight polyethylene US 2004/0185097 A1 Sep. 23, 2004 oxide (primary release modifying agent) and/or high molecular weight polyethylene oxide (secondary release TABLE 7-1-continued modifying agent), retrograded Starch (auxiliary release Qty.f modifying agent) and lactose monohydrate. The resulting Sr. unit % w/w of unit mixture was sifted through ASTM mesh no. 40, blended No. Ingredient (mg) dosage form together in a blender to get a homogenous blend. The homogenous blend was granulated with water, the granules 5. Lactose Monohydrate 135.OO 13.50 6. Talc 3O.OO 3.OO were dried in a fluid bed drier. The dried granules were 7. Magnesium Stearate 15.OO 1.50 reduced and sized to ASTM mesh no. 16 granules and then 8. Purified Water C.S C.S lubricated with talc and magnesium Stearate. The lubricated granules were compressed to tablets using the desired Spe cific punches. The tablets were optionally coated with a 0102) The drug release profile from the dosage form of polymer coating, using the polymers or coating agents not the invention was studied in 900 ml of pH 5.0 acetate buffer Specifically designed for modification of drug release. in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled TABLE 6-1 release of the drug from the dosage form of the Example 7. Qty.f The drug release from the dosage form mentioned in Sr. unit % w/w of unit example 7 was extended up to 12 h, as shown in table 7-2. No. Ingredient (mg) dosage form TABLE 7-2 1. Clarithromycin SOOOO SO.OO 2. Polyethylene Oxide 1SO.OO 15.OO % Cumulative (Mol. Wit.: 200,000) Time (h) Drug Released 3. Polyethylene Oxide (Mol. SO.OO S.OO Wit.: 2,000,000) 1. 8 4. Retrograded Starch 1SO.OO 15.OO 2 17 5. Lactose Monohydrate 12O.OO 12.00 4 37 6. Talc 15.OO 1.50 6 56 7. Magnesium Stearate 15.OO 1.50 8 72 8. Purified Water C.S C.S 1O 88 12 95 0100. The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer EXAMPLE 8 in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled 0103) release of the drug from the dosage form of the Example 6. The drug release from the dosage form mentioned in TABLE 8-1 example 6 was extended up to 12 has shown in table 6-2. Qty.f Sr. unit % w/w of unit TABLE 6-2 No. Ingredient (mg) dosage form % Cumulative 1. Clarithromycin SOOOO SO.OO Time (h) Drug Released 2. Polyethylene Oxide 87.50 8.75 (Mol. Wit.: 200,000) 1. 7 3. Polyethylene Oxide 62.50 6.25 2 16 (Mol. Wit.: 2,000,000) 4 36 4. Retrograded Starch 1OOOO 1O.OO 6 57 5. Lactose Monohydrate 2O5.OO 2OSO 8 78 6. Talc 3O.OO 3.OO 1O 96 7. Magnesium Stearate 15.OO 1.50 12 1OO 8. Purified Water C.S C.S

EXAMPLE 7 0104. The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer 01.01 in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled TABLE 7-1 release of the drug from the dosage form of the Example 8. The drug release from the dosage form mentioned in Qty.f Sr. unit % w/w of unit example 8 was extended up to 12 h, as shown in table 8-2. No. Ingredient (mg) dosage form TABLE 8-2 1. Clarithromycin SOO.O SO.OO 2. Polyethylene Oxide 14O.OO 14.OO % Cumulative (Mol. Wit.: 200,000) Time (h) Drug Released 3. Polyethylene Oxide 40.OO 4.OO (Mol. Wit.: 2,000,000) 1. 9 4. Retrograded Starch 14O.OO 14.OO 2 2O US 2004/0185097 A1 Sep. 23, 2004 11

TABLE 8-2-continued TABLE 10-1-continued

% Cumulative Qty.f Time (h) Drug Released Sr. unit % w/w of unit No. Ingredient (mg) dosage form 4 42 6 63 5. Lactose Monohydrate 125.OO 12.50 8 81 6. Talc 3O.OO 3.OO 1O 93 7. Magnesium Stearate 15.OO 1.50 12 97 8. Purified Water C.S C.S

EXAMPLE 9 0108. The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer 01.05 in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled TABLE 9-1 release of the drug from the dosage form of the Example 10. The drug release from the dosage form mentioned in Qty.f Sr. unit % w/w of unit example 10 was extended up to 12 h, as shown in table 10-2. No. Ingredient (mg) dosage form TABLE 10-2 1. Clarithromycin SOO.OO SO.OO 2. Polyethylene Oxide 247.50 24.75 % Cumulative (Mol. Wit.: 200,000) Time (h) Drug Released 3. Polyethylene Oxide 36.OO 3.60 (Mol. Wit.: 2,000,000) 1. 7 4. Retrograded Starch 166.50 16.65 2 14 5. Lactose Monohydrate S.OO O.SO 4 29 6. Talc 3O.OO 3.OO 6 44 7. Magnesium Stearate 15.OO 1.50 8 59 8. Purified Water C.S C.S 1O 72 12 84 0106 The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer EXAMPLE 11 in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled 01.09) release of the drug from the dosage form of the Example 9. The drug release from the dosage form mentioned in TABLE 11-1 example 9 was extended up to 12 h, as shown in table 9-2. Qty.f Sr. unit % w/w of unit TABLE 9-2 No. Ingredient (mg) dosage form % Cumulative 1. Clarithromycin SOO.OO SO.OO Time (h) Drug Released 2. Polyethylene Oxide 17O.OO 17.OO (Mol. Wit.: 200,000) 1. 8 3. Polyethylene Oxide 7O.OO 7.00 2 17 (Mol. Wit.: 2,000,000) 4 35 4. Retrograded Starch 7O.OO 7.00 6 53 5. Lactose Monohydrate 145.00 14.50 8 69 6. Talc 3O.OO 3.00 1O 83 7. Magnesium Stearate 15.OO 1.50 12 94 8. Purified Water C.S C.S

EXAMPLE 10 0110. The drug release profil from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in 01.07 USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled TABLE 10-1 release of the drug from the dosage form of the Example 11. The drug release from the dosage form mentioned in Qty.f Sr. unit % w/w of unit example 11 was extended up to 12 h, as shown in table 11-2. No. Ingredient (mg) dosage form TABLE 11-2 1. Clarithromycin SOO.OO SO.OO 2. Polyethylene Oxide 16O.OO 16.OO % Cumulative (Mol. Wit.: 200,000) Time (h) Drug Released 3. Polyethylene Oxide 7O.OO 7.00 (Mol. Wit.: 2,000,000) 1. 7 4. Retrograded Starch 1OO.OO 1O.OO 2 13 US 2004/0185097 A1 Sep. 23, 2004

TABLE 11-2-continued TABLE 13-1-continued

% Cumulative Qty.f Time (h) Drug Released Sr. unit % w/w of unit No. Ingredient (mg) dosage form 4 27 6 44 5. Lactose Monohydrate 140.00 14.00 8 58 6. Talc 3O.OO 3.00 1O 72 7. Magnesium Stearate 15.OO 1.50 12 84 8. Purified Water C.S C.S

EXAMPLE 12 0114. The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer 0111 in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled TABLE 12-1 release release from the dosage form of the Example 13. The drug release from the dosage form mentioned in example 13 Qty.f Sr. unit % w/w of unit was extended up to 12 h, as shown in table 13-2. No. Ingredient (mg) dosage form TABLE 13-2 1. Clarithromycin SOOOO SO.OO 2. Polyethylene Oxide 18O.OO 18.00 % Cumulative (Mol. Wit.: 200,000) Time (h) Drug Released 3. Polyethylene Oxide 65.OO 6.50 (Mol. Wit.: 2,000,000) 1. 9 4. Retrograded Starch 7OOO 7.00 2 18 5. Lactose Monohydrate 140.OO 14.00 4 35 6. Talc 3OOO 3.OO 6 52 7. Magnesium Stearate 15.OO 1.50 8 66 8. Purified Water C.S C.S 1O 79 12 89 0112 The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer EXAMPLE 1.4 in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled 0115) release of the drug from the dosage form of the Example 12. The drug release from the dosage form mentioned in TABLE 14-1 example 12 was extended up to 12 h, as shown in table 12-2. Qty.f Sr. unit % w/w of unit TABLE 12-2 No. Ingredient (mg) dosage form % Cumulative 1. Clarithromycin SOO.OO SO.OO Time (h) Drug Released 2. Polyethylene Oxide 240.00 22.OO (Mol. Wit.: 200,000) 1. 7 3. Retrograded Starch 12O.OO 1O.OO 2 17 4. Lactose Monohydrate 135.00 13.50 4 36 5. Talc 3O.OO 3.00 6 55 6. Magnesium Stearate 15.OO 1.50 8 70 7. Purified Water C.S C.S 1O 78 12 86 0116. The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer EXAMPLE 13 in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled 0113) release of the drug from the dosage form of the Example 14. The drug release from the dosage form mentioned in TABLE 13-1 example 14 was extended up to 12 h, as shown in table 14-2. Qty.f unit % w/w of unit TABLE 14-2 Ingredient (mg) dosage form % Cumulative Clarithromycin SOOOO SO.OO Time (h) Drug Released Polyethylene Oxide 185.OO 18.50 (Mol. Wit.: 200,000) 1. 2O Polyethylene Oxide 6O.OO 6.OO 2 35 (Mol. Wit.: 2,000,000) 4 65 Retrograded Starch 7OOO 7.00 6 8O US 2004/0185097 A1 Sep. 23, 2004 13

TABLE 14-2-continued TABLE 16-1-continued % Cumulative Qty.f % w/w of Time (h) Drug Released Sr. unit unit dosage No. Ingredient (mg) form 8 90 1O 95 3. Retrograded Starch 65.OO 65.OO 12 97 4. Lactose Monohydrate 29.OO 29.OO 5. Magnesium Stearate OSO OSO

EXAMPLE 1.5 0117) 0120) The drug release profil from the dosage form of the invention was studied in 500 ml of pH 6.8 phosphate buffer TABLE 1.5-1 in USP Dissolution Apparatus Type I at 100 RPM and the results are tabulated below. The results showed a controlled Qty.f release of the drug from the dosage form of the Example 16. Sr. unit % w/w of unit AS shown in table 16-2, the drug release from the dosage No. Ingredient (mg) dosage form form mentioned in example 16 was extended up to 12 h, as 1. Clarithromycin SOOOO SO.OO shown in table 16-2. 2. Polyethylene Oxide 55.00 7.50 (Mol. Wit.: 2,000,000) 3. Retrograded Starch 12O.OO 12.00 TABLE 16-2 4. Lactose Monohydrate 26O.OO 26.00 5. Talc 3OOO 3.OO % Cumulative 6. Magnesium Stearate 15.OO 1.50 Time (h) Drug Released 7. Purified Water C.S C.S 11 29 52 0118. The dosage release profile from the dosage form of 70 the invention was studied in 900 ml of pH 5.0 acetate buffer 84 in USP Dissolution Apparatus Type II at 50 RPM and the 96 results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 15. The drug release from the dosage form mentioned in 0121 The pharmaceutical compostions of the present example 15 was extended up to 12 h, as shown in table 15-2. invention mentioned in the above examples shows a pre dictable and predetermined controlled drug release profile TABLE 1.5-2 devoid of dose dumping and the drug release was almost complete over an extended duration of about 12 to 24 hours % Cumulative depending on the requirement for a particular API. The Time (h) Drug Released difference between the drug release from the individual unit 1O dosage forms is insignificant. 2O 35 0.122 One skilled in the art would recognize that the 40 Specifically recited drugs Nicotinic Acid, Oxybutynin hydro 50 chloride, Lercanidipine hydrochloride, Clarithromycin, and 60 Alprazolam, their respective dosing and Solubility ranges are 8O only representative examples of the present invention and are not meant to limit the Scope of the invention to the Specific drugs or drug profiles recited herein. One of skill in EXAMPLE 16 the art would also recognize that a wide range of drug 0119) Alprazolam which is a low soluble low dose API compositions would be determined from the Scope of the was mixed with low molecular weight polyethylene oxide (primary release modifying agent), retrograded Starch (aux invention, as well as their desired profiles. iliary release modifying agent), lactose monohydrate and 0123 Pharmacokinetic Study: The pharmaceutical com magnesium stearate. The mixture was sifted through ASTM position of the invention as described in Example 13 was mesh no. 40 and then blended together in a blender to get a Subjected to a bioavailability Study against the commercially homogenous blend. The homogenous blend was compressed available Clarithromycin 500 mg Extended Release Tablets into tablets. (Biaxin XL Filmtab, 500 mg). 0.124. An open label, randomized, two-treatment, two TABLE 16-1 period, two-Sequence, Single dose, croSSOver oral bioavail Qty.f % w/w of ability Study in healthy, adult male Subjects was conducted Sr. unit unit dosage on the composition of Example 13 of the present invention No. Ingredient (mg) form administered once daily with Biaxin XL Filmtab, 500 mg 1. Alprazolam OSO OSO tablet of Abbott Laboratories. 2. Polyethylene Oxide S.OO S.OO (Mol. Wit.: 2,00,000) 0.125 The mean plasma concentration-time profiles for the single-dose study are illustrated in FIG. 1. US 2004/0185097 A1 Sep. 23, 2004 14

0.126 The log transformed pharmacokinetic parameters 2. A Solid oral controlled release pharmaceutical compo for the two clarithromycin extended release compositions Sition for administration to a Subject in need thereof com are tabulated in Table 13-3. prising: (a) a therapeutically effective amount of a pharmaceuti TABLE 13-3 cally active ingredient; and Formula Composition (b) a controlled release modifying complex wherein said Comparison Cmax (ug.fml) AUCo (ug.hr/ml) complex comprises: Biaxin XL Filmtab, 1.01 13.61 500 mg (i) a primary release modifying agent; or (Reference) Clarithromycin 1.06 13.72 (ii) a secondary release modifying agent; and Extended Release Composition of (iii) an auxiliary release modifying agent wherein said Example 8 primary, Secondary and auxiliary release modifying (Test) agents are present in amounts that Synergistically extend the release of the pharmaceutically active ingredient. 0127 Point estimates of the relative bioavailability and 3. A Solid oral controlled release pharmaceutical compo 90% confidence intervals from the log transformed values Sition for administration to a Subject in need thereof com are tabulated in Table 13-4. prising: TABLE 13-4 (a) a therapeutically effective amount of a pharmaceuti cally active ingredient; and Formula Composition Comparison Cmax (ug.fml) AUCo (ug.hr/ml) (b) a controlled release modifying complex Ratio (%) 104.19 100.75 wherein Said complex comprises: Test/Reference 90%. Confidence 84.41-128.61 81.63-124.36 (i) a primary release modifying agent Selected from low Interval molecular weight hydrophilic polymers, (ii) a secondary release modifying agent Selected from 0128. Although the invention herein has been described high molecular weight hydrophilic polymers, and with reference to particular embodiments, it is to be under stood that these embodiments are merely illustrative of the (iii) an auxiliary release modifying agent Selected from principles and applications of the present invention. It is the starch derivatives therefore to be understood that numerous modifications may wherein Said primary, Secondary and auxiliary release be made- to the illustrative embodiments and that other modifying agents are present in amounts that Synergis arrangements may be devised without departing from the tically extend the release of the pharmaceutically active Spirit and Scope of the present invention as defined by the ingredient. above descriptions, examples and the claims. 4. A Solid oral controlled release pharmaceutical compo 0129. All patent and non-patent publications cited in this Sition for administration to a Subject in need thereof com specification are indicative of the level of skill of those prising: skilled in the art to which this invention pertains. All these publications and patent applications are herein incorporated (a) a therapeutically effective amount of a pharmaceuti by reference to the same extent as if each individual publi cally active ingredient; and cation or patent application was specifically and individually (b) a controlled release modifying complex indicated to be incorporated herein by reference. wherein Said complex comprises: 1. A Solid oral controlled release pharmaceutical compo (i) a primary release modifying agent Selected from low Sition for administration to a Subject in need thereof com molecular weight hydrophilic polymers, or prising: (ii) a secondary release modifying agent Selected from (a) a therapeutically effective amount of a pharmaceuti high molecular weight hydrophilic polymers, and cally active ingredient; and (iii) an auxiliary release modifying agent Selected from (b) a controlled release modifying complex wherein said the starch derivatives complex comprises: wherein Said primary, Secondary and auxiliary release (i) a primary release modifying agent; modifying agents are present in amounts that Syner gistically extend the release of the pharmaceutically (ii) a secondary release modifying agent; and active ingredient. (iii) an auxiliary release modifying agent wherein said 5. The pharmaceutical composition of claim 1 wherein the primary, Secondary and auxiliary release modifying dosage form is a tablet, caplet or capsule. agents are present in amounts that Synergistically 6. The pharmaceutical composition of claim 1, wherein extend the release of the pharmaceutically active the active pharmaceutical ingredient is a macrollide or azide ingredient. antibiotic or a derivative thereof. US 2004/0185097 A1 Sep. 23, 2004

7. The pharmaceutical composition of claim 6, wherein Chloroquine phosphate, Chloroquine Sulphate, Chlorprom the macrollide is an erythromycin derivative or its pharma azine hydrochloride, Ciprofloxacin hydrochloride, Cloxacil ceutically acceptable hydrates, Salts or esters. lin Sodium, Cycloserine, Diltiazem hydrochloride, Diethyl 8. The pharmaceutical composition of claim 6, wherein carbamazine citrate, Doxycycline hydrochloride, EthosuX the azide is azithromycin, or its pharmaceutically acceptable imide, Ferrous gluconate, Isoniazid, Levamisole hydrochlo hydrates, Salts or esters. ride, Levetiracetam, Lincomycin hydrochloride, Mebever 9. The pharmaceutical composition of claim 7, wherein ine hydrochloride, Mepyramine maleate, Metformin the erythromycin derivative is Selected from the group hydrochloride, Metoprolol tartrate, Metoprolol succinate, consisting of clarithromycin, joSamycin, midecamycin, kita Niacin, Nicotinamide, Nicotinic acid, Oxprenolol hydro mycin, roXithromycin, rokitamycin, oleandomycin, mioca chloride, Oxytetracycline hydrochloride, Penicillamine, mycin, flurithromycin, and rosaramicin, and their pharma Pentobarbitone sodium, Phenoxy Methyl Penicillin K, Phe ceutically acceptable hydrates, Salts and esters. nyloin Sodium, piperazine adipate, Potassium chloride, 10. The pharmaceutical composition of claim 1, wherein Procainamide hydrochloride, Propranolol hydrochloride, the active pharmaceutical ingredient is a penicillin antibiotic Pseudoephedrine hydrochloride, Quinalbarbitone sodium, or a derivative thereof. Quinine bisulphate, Ranitidine hydrochloride, Sodium 11. The pharmaceutical composition of claim 10, wherein amino Salicylate, Sodium fusidate, Sodium Valproate, Strep the penicillin derivative is Selected from the group consist tomycin Sulphate, Tetracycline hydrochloride, Topiramate, ing of Amoxicillin, Ampicillin, Ampicillin Sodium, Apal Troxidone, Verapamil hydrochloride and the like and their cillin, ASpoxicillin, AZlocillin, Aztreonam, Bacampicillin, pharmaceutically acceptable Salts, ester and hydrates. Cabenicillin, Carfecillin, Carindacillin, Ciclacillin, Clox 18. The pharmaceutical composition of claim 17, wherein acillin, Dicloxacillin, and their pharmaceutically acceptable the active ingredient is Nicotinic acid. hydrates, Salts and esters. 19. The pharmaceutical composition of claim 1, wherein 12. The pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient is a high Soluble low the active pharmaceutical ingredient is a cephalosporin dose API or a derivative thereof. antibiotic or a derivative thereof. 20. The pharmaceutical composition of claim 19, wherein 13. The pharmaceutical composition of claim 12, wherein the high soluble low dose API or a derivative is selected the cephalosporin derivative is Selected from the group from the group consisting of Amitriptyline hydrochloride, consisting of Cefacetrile, Cefadroxil, Cefaloridine, Cefal captopril, Clonidine hydrochloride, Colchicin, Cyclophos othin Sodium, Cefapirin, Cefazaflur, Cefazedone, Cefazolin, phamide, Diphenhydramine hydrochloride, Dothiepen Cefradine, Ceftezole, CefSulodin Sodium, Cefamandole, hydrochloride, Doxepin hydrochloride Ephedrine hydro Cefonicid, CefoperaZone, Cefuroxime, CefuZonam, Cefbu chloride, Ergometrine maleate, Ergometrine tartrate, Fenflu peraZone, CefoXitin, Cefninox, Cefinetazole, Cefotetan, ramine hydrochloride, Folic acid, Glyceryl trinitrate, Hyos Loracarbef, Cefinenoxime, Cefodizime Sodium, Cefo cine hydrobromide, Hyoscine buytlbromide, Imipramine taxime, Cefpimizole, Ce?piramide, Ceftazidime, Ceftiolene, hydrochloride, Isoprenaline Sulphate, ISOSorbide dinitrate, CeftizOXime, Ceftriaxone, Cefepime, Cefetecol, Cefpirome, ISOSorbide-5-mononitrate, Levocetrizine hydrochloride, Cefduinome, Cefalosporin C, CefoZopran Hydrochloride, Methadone hydrochloride, Methdilazine hydrochloride, Cefaclor, Cefadroxil, Cefalexin, Cefaloglycine, Cefatrizine, Metoclopramide hydrochloride, Neostigmine bromide, Cefdinir, Cefetamet Pivoxil, Cefixime, Ceforamide, Cefo Oxybutynin hydrochloride, Perindopril erbumine, Pethidine tiam, Cefpodoxime, Cefpodoxime Proxetil, Cefprozil, hydrochloride, Phenformin hydrochloride, Pheniramine Cefradine, Cefroxadine, Cefteram Pivoxil, Ceftibuten, maleate, Phenobarbitone Sodium, Primacquine phosphate, Cefuroxime Axetil, and their pharmaceutically acceptable Promethazine hydrochloride, Propantheline bromide, Pro hydrates, Salts and esters. pranolol hydrochloride, Pyridoxine hydrochloride, Salbuta 14. The pharmaceutical composition of claim 1, wherein mol Sulphate, Terbutaline Sulphate, Thiamine hydrochloride, the active pharmaceutical ingredient is a quinolone antibi Timolol maleate, Tizanidine hydrochloride, Trifluoperazine otic or a derivative thereof. hydrochloride, Triflu promazine hydrochloride, Triprolidine 15. The pharmaceutical composition of claim 14, wherein hydrochloride, Warfarin sodium and the like and their phar the quinolone derivative is Selected from the group consist maceutically acceptable Salts, ester and hydrates. ing of Nalidixic Acid, Cinoxacin, Oxolinic Acid, Flume 21. The pharmaceutical composition of claim 20, wherein quine, Pipemidic Acid, ROSoxacin, Norfloxacin, Lomefloxa the active ingredient is Oxybutynin hydrochloride. cin, Ofloxacin, Enrofloxacin, Ciprofloxacin, Enoxacin, 22. The pharmaceutical composition of claim 1, wherein Amifloxacin, Fleroxacin, Gatifloxacin, Gemifloxacin, the active pharmaceutical ingredient is a low Soluble high Pefloxacin, Rufloxacin, Sparfloxacin, Temafloxacin, Tosu dose API or a derivative thereof. floxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, Tro 23. The pharmaceutical composition of claim 22, wherein vafloxacin, and their pharmaceutically acceptable hydrates, the low soluble high dose API or a derivative is selected Salts and esters. from the group consisting of Acetazolamide, Allopurinol, 16. The pharmaceutical composition of claim 1, wherein Atenolol, Carbamazepine, Cefadroxil, Cephalexin, the active pharmaceutical ingredient is a high Soluble high Chloramphenicol, Cefuroxime Axetil, Chlorthalidone, dose API or a derivative thereof. CilastoZol, Cimetidine, Clarithromycin, ClofaZemine, Dap 17. The pharmaceutical composition of claim 16, wherein Sone, Diclofenac Sodium, Diiodohydroxy quinolone, the high soluble high dose API or a derivative is selected Diloxamide furoate, Disulfiram, Erythromycin, Erythromy from the group consisting of Acebutolol hydrochloride, cineStolate, Erythromycin Stearate, Ethacrynic cid, Ethiona Amantadine hydrochloride, Aminocaproic acid, Aminophyl mide, Ethopropazine hydrochloride, Ferrous fumarate, Flu line, Amodiaquine hydrochloride, AScorbic acid, Bupropion conazole, Flurbiprofen, Furazolidone, Griseofulvin, hydrochloride, CarbenoXolone Sodium, Cefuroxime Sodium, Hydrochlorthiazide, Ibuprofen, Itraconazole, Ketoconazole, US 2004/0185097 A1 Sep. 23, 2004

Ketoprofen, Labetalol hydrochloride, Levodopa, LineZolid, 33. The pharmaceutical composition of claim 1, wherein Lithium carbonate, Magaldrate, Mebendazole, Mefenamic the high molecular weight polyethylene oxide has a molecu acid, Megestrol acetate, Mercaptopurine, MeSalamimne, lar weight of at least about 1,000,000. Nalidixic acid, Nateglinide, Niclosamide, Nitrofurantoin, 34. The pharmaceutical composition of claim 1, wherein Norfloxacin, Oxcarbazepine, OxyphenbutaZone, Paraceta mol, Phenindione, Phenobarbitone, Phenylbutazone, Phe the high molecular weight polyethylene oxide has a molecu nylsulphathiazole, piperazine phosphate, Proguanil hydro lar weight ranging from 1,000,000 to 9,000,000. chloride, Promethazine theoclate, Propylthiouracil, 35. The pharmaceutical composition of claim 1, wherein Quinidine Sulphate, Quinine Sulphate, Quinidochlor, the auxiliary release modifying agent is a Starch derivative Rifampicin, Simvastatin, Spironolactone, Succinylsul Selected from pregelatinized Starch, partially pregelatinized phathiazole, Sulphadiazine, Sulphadimethoxine, Sulphadi Starch, retrograded Starch, or a combination thereof. midine, Sulphafurazole, Sulphaphenazole, Thiabendazole, 36. The pharmaceutical composition of claim 1, wherein Timidazole, Tolbutamide, Triamterene, Sulphamethoxazole the auxiliary release modifying agent is a retrograded Starch. and the like and their pharmaceutically acceptable Salts, 37. The pharmaceutical composition of claim 1, wherein ester and hydrates. Said composition further comprises at least one pharmaceu 24. The pharmaceutical composition of claim 23, wherein the active ingredient is Clarithromycin. tically acceptable additive Selected from diluents, fillers, 25. The pharmaceutical composition of claim 1, wherein binders, glidants, and lubricants. the active pharmaceutical ingredient is a low Soluble low 38. The pharmaceutical composition of claim 1, wherein dose API or a derivative thereof. Said composition further comprises an optional coating 26. The pharmaceutical composition of claim 25, wherein which is designed for the modification of drug release. the low soluble low dose API or a derivative is selected from 39. The pharmaceutical composition of claim 38, wherein the group consisting of Alprazolam, Amiloride hydrochlo the coating composition is Selected from the group consist ride, Astemizole, Atorvastatin, BenZheXol hydrochloride, ing of cellulose etherS Such as ethyl cellulose, hydroxypro Betamethasone, Bromhexine hydrochloride, Bromocryptine pyl methyl cellulose, hydroxypropyl cellulose, and others meSylate, Buprenorphine hydrochloride, carbimazole, Chlo Such as polyvinyl alcohol, polyvinyl pyrrolidone, meth rdiazepoxide, Citalopram, Cortisone acetate, cyprohepta acrylic acid derivatives, resins, clays, long chain hydrocar dine hydrochloride, diazepam, Desloratadine, Dexametha bons, long chain carboxylic acids, long chain carboxylic sone hydrochloride, Dextromethorphan hydrochloride, acid esters, long chain alcohols and the like and mixtures dicyclomine hydrochloride, Dienoestrol, Digitoxin, thereof. Digoxin, Domperidone, Dydrogesterone, enalapril maleate, 40. The pharmaceutical composition of claim 1, wherein Esomeprazole, Ethinyloestradiol, Ethyloestrenol, Fludrocor Said composition further comprises an optional coating tisone acetate, Frusemide, glibenclamide, Glimepiride, halo which is not designed for the modification of drug release. peridol, Indomethacin, ISOXSuprine hydrochloride, Lanato 41. The pharmaceutical composition of claim 40, wherein Side C, Lercanidipine hydrochloride, LevonorgeSrtel, the coating composition is Selected from the group consist Lomustine, Loratadine, ISOXuprine hydrochloride, methotr ing of cellulose etherS Such as ethyl cellulose, hydroxypro exate, Mecizine hydrochloride, Melphalan, Methotrexate, pyl methyl cellulose, hydroxypropyl cellulose, and others Methylergometrine maleate, Methylprednisolone, Such as polyvinyl alcohol, polyvinyl pyrrolidone, meth Mianserin hydrochloride, Mosapride, Nicoumalone, Nife acrylic acid derivatives, resins, clays, long chain hydrocar dipine, Nitrazepam, Norethisterone, nortriptyline hydro bons, long chain carboxylic acids, long chain carboxylic chloride, Omeprazole, Ormeloxifene hydrochloride, Penta acid esters, long chain alcohols and the like and mixtures Zocine hydrochloride, Phenindamine tartrate, piroXicam, thereof. prazosin hydrochloride, Prednisolone, Prednisone, Prochlo 42. The pharmaceutical composition of claim 1, wherein rperazine maleate, Repaglinide, Riboflavinee, Rosuvastatin, Said composition comprises from about 0.1 percent weight Stilbostrol, Tamoxifen citrate, Thyroxine sodium, triamci to about 90 percent weight of the active pharmaceutical nilone, Trimethoprim, Valdecoxib, Zolpidem tartrate and the ingredient. like and their pharmaceutically acceptable Salts, ester and hydrates. 43. The pharmaceutical composition of claim 42, wherein 27. The pharmaceutical composition of claim 26, wherein Said composition comprises from about 0.1 percent weight the active ingredient is Alprazolam. to about 80 percent weight of the active pharmaceutical 28. The pharmaceutical composition of claim 26, wherein ingredient. the active ingredient is Lercanidipine hydrochloride. 44. The pharmaceutical composition of claim 1, wherein 29. The pharmaceutical composition of claim 1, wherein the composition comprises from about 1 percent weight to the primary release modifying agent is a low molecular about 90 percent weight of the release modifying complex. weight polyethylene oxide. 45. The pharmaceutical composition of claim 44, wherein 30. The pharmaceutical composition of claim 1, wherein the composition comprises from about 5 percent weight to the low molecular weight polyethylene oxide has a molecu about 85 percent weight of the release modifying complex. lar weight of at least about 100,000. 46. The pharmaceutical composition of claim 45, wherein 31. The pharmaceutical composition of claim 1 wherein the composition comprises from about 10 percent weight to the low molecular weight polyethylene oxide has a molecu about 80 percent weight of the release modifying complex. lar weight ranging from 100,000 to 900,000. 47. The pharmaceutical composition of claim 1, wherein 32. The pharmaceutical composition of claim 1, wherein the primary release modifying agent comprises from about the Secondary release modifying agent is a high molecular 1 percent weight to about 90 percent weight of the release weight polyethylene oxide. modifying complex. US 2004/0185097 A1 Sep. 23, 2004

48. The pharmaceutical composition of claim 47, wherein 62. The pharmaceutical composition of claim 55, wherein the primary release modifying agent comprises from about the active pharmaceutical ingredient is a cephalosporin 5 percent weight to about 80 percent weight of the release antibiotic or a derivative thereof. modifying complex. 63. The pharmaceutical composition of claim 62, wherein 49. The pharmaceutical composition of claim 48, wherein the cephalosporin derivative is Selected from the group the primary release modifying agent comprises from about consisting of Cefacetrile, Cefadroxil, Cefaloridine, Cefal 5 percent weight to about 70 percent weight of the release othin Sodium, Cefapirin, CefaZaflur, CefaZedone, Cefazolin, modifying complex. Cefradine, Ceftezole, Cefsulodin Sodium, Cefamandole, 50. The pharmaceutical composition of claim 1, wherein Cefonicid, CefoperaZone, Cefuroxime, CefuZonam, Cefbu the Secondary release modifying agent comprises from about peraZone, CefoXitin, Cefninox, Cefinetazole, Cefotetan, 1 percent weight to about 95 percent weight of the release Loracarbef, Cefinenoxime, Cefodizime Sodium, Cefo modifying complex. taxime, Cefpimizole, Ce?piramide, Ceftazidime, Ceftiolene, 51. The pharmaceutical composition of claim 50, wherein CeftizOXime, Ceftriaxone, Cefepime, Cefetecol, Cefpirome, the Secondary release modifying agent comprises from about Cefduinome, Cefalosporin C, CefoZopran Hydrochloride, 5 percent weight to about 90 percent weight of the release Cefaclor, Cefadroxil, Cefalexin, Cefaloglycine, Cefatrizine, modifying complex. Cefdinir, Cefetamet Pivoxil, Cefixime, Ceforamide, Cefo 52. The pharmaceutical composition of claim 1, wherein tiam, Cefpodoxime, Cefpodoxime Proxetil, Cefprozil, the auxiliary release modifying agent comprises from about Cefradine, Cefroxadine, Cefteram Pivoxil, Ceftibuten, 1 percent weight to about 95 percent weight of the release Cefuroxime Axetil, and their pharmaceutically acceptable modifying complex. hydrates, Salts and esters. 53. The pharmaceutical composition of claim 52, wherein 64. The pharmaceutical composition of claim 55, wherein the auxiliary release modifying agent comprises from about the active pharmaceutical ingredient is a quinolone antibi 5 percent weight to about 95 percent weight of the release otic or a derivative thereof. modifying complex. 65. The pharmaceutical composition of claim 64, wherein 54. The pharmaceutical composition of claim 53, wherein the quinolone derivative is Selected from the group consist the auxiliary release modifying agent comprises from about ing of Nalidixic Acid, Cinoxacin, Oxolinic Acid, Flume 10 percent weight to about 95 percent weight of the release quine, Pipemidic Acid, ROSoxacin, Norfloxacin, Lomefloxa modifying complex. cin, Ofloxacin, Enrofloxacin, Ciprofloxacin, Enoxacin, 55. A controlled release pharmaceutical composition com Amifloxacin, Fleroxacin, Gatifloxacin, Gemifloxacin, prising a pharmaceutically active ingredient and a release Pefloxacin, Rufloxacin, Sparfloxacin, Temafloxacin, Tosu modifying complex, wherein Said release modifying com floxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, Tro plex comprises a Synergistic combination of (a) a primary vafloxacin, and their pharmaceutically acceptable hydrates, release modifying agent Selected from a low molecular Salts and esters. weight polyethylene oxide and (b) an auxiliary release modifying agent Selected from a Starch derivative, and Said 66. The pharmaceutical composition of claim 55, wherein primary release modifying agent and auxiliary release modi the active pharmaceutical ingredient is a high Soluble high fying agent are present in Synergistic effective amounts to dose API or a derivative thereof. extend the release of the active pharmaceutical ingredient. 67. The pharmaceutical composition of claim 66, wherein the high soluble high dose API or a derivative is selected 56. The pharmaceutical composition of claim 55, wherein from the group consisting of Acebutolol hydrochloride, the active pharmaceutical ingredient is a macrollide or azide Amantadine hydrochloride, Aminocaproic acid, Aminophyl antibiotic or a derivative thereof. line, Amodiaquine hydrochloride, AScorbic acid, Bupropion 57. The pharmaceutical composition of claim 56, wherein hydrochloride, CarbenoXolone Sodium, Cefuroxime Sodium, the macrollide is an erythromycin derivative or its pharma Chloroquine phosphate, Chloroquine Sulphate, Chlorprom ceutically acceptable hydrates, Salts or esters. azine hydrochloride, Ciprofloxacin hydrochloride, Cloxacil 58. The pharmaceutical composition of claim 56, wherein lin Sodium, Cycloserine, Diltiazem hydrochloride, Diethyl the azide is azithromycin, or its pharmaceutically acceptable carbamazine citrate, Doxycycline hydrochloride, EthosuX hydrates, Salts or esters. imide, Ferrous gluconate, Isoniazid, Levamisole hydrochlo 59. The pharmaceutical composition of claim 57, wherein ride, Levetiracetam, Lincomycin hydrochloride, Mebever the erythromycin derivative is Selected from the group ine hydrochloride, Mepyramine maleate, Metformin consisting of clarithromycin, joSamycin, midecamycin, kita hydrochloride, Metoprolol tartrate, Metoprolol succinate, mycin, roXithromycin, rokitamycin, oleandomycin, mioca Niacin, Nicotinamide, Nicotinic acid, Oxprenolol hydro mycin, flurithromycin, and rosaramicin, and their pharma chloride, Oxytetracycline hydrochloride, Penicillamine, ceutically acceptable hydrates, Salts and esters. Pentobarbitone sodium, Phenoxy Methyl Penicillin K, Phe 60. The pharmaceutical composition of claim 55, wherein nyloin Sodium, piperazine adipate, Potassium chloride, the active pharmaceutical ingredient is a penicillin antibiotic Procainamide hydrochloride, Propranolol hydrochloride, or a derivative thereof. Pseudoephedrine hydrochloride, Quinalbarbitone sodium, 61. The pharmaceutical composition of claim 60, wherein Quinine bisulphate, Ranitidine hydrochloride, Sodium the penicillin derivative is Selected from the group consist amino Salicylate, Sodium fusidate, Sodium Valproate, Strep ing of Amoxicillin, Ampicillin, Ampicillin Sodium, Apal tomycin Sulphate, Tetracycline hydrochloride, Topiramate, cillin, ASpoxicillin, AZlocillin, Aztreonam, Bacampicillin, Troxidone, Verapamil hydrochloride and the like and their Cabenicillin, Carfecillin, Carindacillin, Ciclacillin, Clox pharmaceutically acceptable Salts, ester and hydrates. acillin, Dicloxacillin, and their pharmaceutically acceptable 68. The pharmaceutical composition of claim 67, wherein hydrates, Salts and esters. the active ingredient is Nicotinic acid. US 2004/0185097 A1 Sep. 23, 2004

69. The pharmaceutical composition of claim 55, wherein 76. The pharmaceutical composition of claim 75, wherein the active pharmaceutical ingredient is a high Soluble low the low soluble low dose API or a derivative is selected from dose API or a derivative thereof. the group consisting of Alprazolam, Amiloride hydrochlo 70. The pharmaceutical composition of claim 69, wherein ride, Astemizole, Atorvastatin, BenzheXol hydrochloride, the high soluble low dose API or a derivative is selected Betamethasone, Bromhexine hydrochloride, Bromocryptine from the group consisting of Amitriptyline hydrochloride, meSylate, Buprenorphine hydrochloride, carbimazole, Chlo captopril, Clonidine hydrochloride, Colchicin, CyclophoS rdiazepoxide, Citalopram, Cortisone acetate, cyprohepta phamide, Diphenhydramine hydrochloride, Dothiepen dine hydrochloride, diazepam, DeSloratadine, Dexametha hydrochloride, Doxepin hydrochloride Ephedrine hydro sone hydrochloride, Dextromethorphan hydrochloride, chloride, Ergometrine maleate, Ergometrine tartrate, Fenflu dicyclomine hydrochloride, Dienoestrol, Digitoxin, ramine hydrochloride, Folic acid, Glyceryl trinitrate, Hyos Digoxin, Domperidone, Dydrogesterone, enalapril maleate, cine hydrobromide, Hyoscine buytlbromide, Imipramine Esomeprazole, Ethinyloestradiol, Ethyloestrenol, Fludrocor hydrochloride, Isoprenaline Sulphate, ISOSorbide dinitrate, tisone acetate, Frusemide, Glibenclamide, Glimepiride, ISOSorbide-5-mononitrate, Levocetrizine hydrochloride, Haloperidol, Indomethacin, ISOXSuprine hydrochloride, Methadone hydrochloride, Methdilazine hydrochloride, Lanatoside C, Lercanidipine hydrochloride, LevonorgeSrtel, Metoclopramide hydrochloride, Neostigmine bromide, Lomustine, Loratadine, ISOXuprine hydrochloride, methotr Oxybutynin hydrochloride, Perindopril erbumine, Pethidine exate, Mecizine hydrochloride, Melphalan, Methotrexate, hydrochloride, Phenformin hydrochloride, Pheniramine Methylergometrine maleate, Methylprednisolone, maleate, Phenobarbitone Sodium, Primacquine phosphate, Mianserin hydrochloride, Mosapride, Nicoumalone, Nife Promethazine hydrochloride, Propantheline bromide, Pro dipine, Nitrazepam, Norethisterone, nortriptyline hydro pranolol hydrochloride, Pyridoxine hydrochloride, Salbuta chloride, Omeprazole, Ormeloxifene hydrochloride, Penta mol Sulphate, Terbutaline Sulphate, Thiamine hydrochloride, Zocine hydrochloride, Phenindamine tartrate, piroXicam, Timolol maleate, Tizanidine hydrochloride, Trifluoperazine prazosin hydrochloride, Prednisolone, Prednisone, Prochlo hydrochloride, Triflu promazine hydrochloride, Triprolidine rperazine maleate, Repaglinide, Riboflavinee, Rosuvastatin, hydrochloride, Warfarin sodium and the like and their phar Stilbostrol, Tamoxifen citrate, Thyroxine sodium, triamci maceutically acceptable Salts, ester and hydrates. nilone, Trimethoprim, Valdecoxib, Zolpidem tartrate and the 71. The pharmaceutical composition of claim 70, wherein like and their pharmaceutically acceptable Salts, ester and the active ingredient is Oxybutynin hydrochloride. hydrates. 72. The pharmaceutical composition of claim 55, wherein 77. The pharmaceutical composition of claim 76, wherein the active pharmaceutical ingredient is a low Soluble high the active ingredient is Alprazolam. dose API or a derivative thereof. 78. The pharmaceutical composition of claim 76, wherein 73. The pharmaceutical composition of claim 72, wherein the active ingredient is Lercanidipine hydrochloride. the low soluble high dose API or a derivative is selected 79. The pharmaceutical composition of claim 55, wherein from the group consisting of Acetazolamide, Allopurinol, the primary release modifying agent is a low molecular Atenolol, Carbamazepine, Cefadroxil, Cephalexin, weight polyethylene oxide. Chloramphenicol, Cefuroxime Axetil, Chlorthalidone, 80. The pharmaceutical composition of claim 55, wherein CilastoZol, Cimetidine, Clarithromycin, ClofaZemine, Dap the low molecular weight polyethylene oxide has a molecu Sone, Diclofenac Sodium, Diiodohydroxy quinolone, lar weight of at least about 100,000. Diloxamide furoate, Disulfiram, Erythromycin, Erythromy 81. The pharmaceutical composition of claim 55, wherein cineStolate, Erythromycin Stearate, Ethacrynic cid, Ethiona the low molecular weight polyethylene oxide has a molecu mide, Ethopropazine hydrochloride, Ferrous fumarate, Flu lar weight ranging from 100,000 to 900,000. conazole, Flurbiprofen, Furazolidone, Griseofulvin, Hydrochlorthiazide, Ibuprofen, Itraconazole, Ketoconazole, 82. The pharmaceutical composition of claim 55, wherein Ketoprofen, Labetalol hydrochloride, Levodopa, LineZolid, the auxiliary release modifying agent is a Starch derivative Lithium carbonate, Magaldrate, Mebendazole, Mefenamic Selected from pregelatinized Starch, partially pregelatinized acid, Megestrol acetate, Mercaptopurine, MeSalamimne, Starch, retrograded Starch, or a combination thereof. Nalidixic acid, Nateglinide, Niclosamide, Nitrofurantoin, 83. The pharmaceutical composition of claim 55, wherein Norfloxacin, Oxcarbazepine, OxyphenbutaZone, Paraceta the auxiliary release modifying agent is a retrograded Starch. mol, Phenindione, Phenobarbitone, Phenylbutazone, Phe 84. The pharmaceutical composition of claim 55, wherein nylsulphathiazole, piperazine phosphate, Proguanil hydro Said composition further comprises at least one pharmaceu chloride, Promethazine theoclate, Propylthiouracil, tically acceptable additive Selected from diluents, fillers, Quinidine Sulphate, Quinine Sulphate, Quinidochlor, binders, glidants, or lubricants. Rifampicin, Simvastatin, Spironolactone, Succinylsul 85. The pharmaceutical composition of claim 55, wherein phathiazole, Sulphadiazine, Sulphadimethoxine, Sulphadi Said composition further comprises an optional coating midine, Sulphafurazole, Sulphaphenazole, Thiabendazole, which is designed for the modification of drug release. Timidazole, Tolbutamide, Triamterene, Sulphamethoxazole 86. The pharmaceutical composition of claim 85, wherein and the like and their pharmaceutically acceptable Salts, the coating composition is Selected from the group consist ester and hydrates. ing of cellulose etherS Such as ethyl cellulose, hydroxypro 74. The pharmaceutical composition of claim 73, wherein pyl methyl cellulose, hydroxypropyl cellulose, otherS Such the active ingredient is Clarithromycin. as polyvinyl alcohol, polyvinyl pyrrollidone, methacrylic 75. The pharmaceutical composition of claim 55, wherein acid derivatives, resins, clays, long chain hydrocarbons, long the active pharmaceutical ingredient is a low Soluble low chain carboxylic acids, long chain carboxylic acid esters, dose API or a derivative thereof. long chain alcohols and the like or mixtures thereof. US 2004/0185097 A1 Sep. 23, 2004

87. The pharmaceutical composition of claim 55, wherein 101. The pharmaceutical composition of claim 100, Said composition further comprises an optional coating wherein the active pharmaceutical ingredient is a macrollide which is not designed for the modification of drug release. or azide antibiotic or a derivative thereof. 88. The pharmaceutical composition of claim 87, wherein 102. The pharmaceutical composition of claim 101, the coating composition is Selected from the group consist wherein the macrollide is an erythromycin derivative or its ing of cellulose etherS Such as ethyl cellulose, hydroxypro pharmaceutically acceptable hydrates, Salts or esters. pyl methyl cellulose, hydroxypropyl cellulose, and others 103. The pharmaceutical composition of claim 100, Such as polyvinyl alcohol, polyvinyl pyrrolidone, meth wherein the azide is azithromycin, or its pharmaceutically acrylic acid derivatives, resins, clays, long chain hydrocar acceptable hydrates, Salts or esters. bons, long chain carboxylic acids, long chain carboxylic 104. The pharmaceutical composition of claim 102, acid esters, long chain alcohols and the like and mixtures wherein the erythromycin derivative is selected from the thereof. group consisting of clarithromycin, joSamycin, midecamy 89. The pharmaceutical composition of claim 55, wherein cin, kitamycin, roXithromycin, rokitamycin, oleandomycin, Said composition comprises from about 0.1 percent weight miocamycin, flurithromycin, and rosaramicin, and their to about 90 percent weight of the active pharmaceutical pharmaceutically acceptable hydrates, Salts and esters. ingredient. 105. The pharmaceutical composition of claim 100, 90. The pharmaceutical composition of claim 89, wherein wherein the active pharmaceutical ingredient is a penicillin Said composition comprises from about 0.1 percent weight antibiotic or a derivative thereof. to about 80 percent weight of the active pharmaceutical 106. The pharmaceutical composition of claim 105, ingredient. wherein the penicillin derivative is Selected from the group 91. The pharmaceutical composition of claim 55, wherein consisting of Amoxicillin, Ampicillin, Ampicillin Sodium, the composition comprises from about 1 percent weight to Apalcillin, ASpoxicillin, AZlocillin, Aztreonam, Bacampicil about 90 percent weight of the release modifying complex. lin, Cabenicillin, Carfecillin, Carindacillin, Ciclacillin, 92. The pharmaceutical composition of claim 91, wherein Cloxacillin, Dicloxacillin, and their pharmaceutically the composition comprises from about 5 percent weight to acceptable hydrates, Salts and esters. about 85 percent weight of the release modifying complex. 107. The pharmaceutical composition of claim 100, 93. The pharmaceutical composition of claim 92, wherein wherein the active pharmaceutical ingredient is a cepha the composition comprises from about 10 percent weight to losporin antibiotic or a derivative thereof. about 80 percent weight of the release modifying complex. 108. The pharmaceutical composition of claim 107, 94. The pharmaceutical composition of claim 55, wherein wherein the cephalosporin derivative is Selected from the the primary release modifying agent comprises from about group consisting of Cefacetrile, Cefadroxil, Cefaloridine, 1 percent weight to about 90 percent weight of the release Cefalothin Sodium, Cefapirin, Cefazaflur, Cefazedone, modifying complex. Cefazolin, Cefradine, Ceftezole, CefSulodin Sodium, Cefa 95. The pharmaceutical composition of claim 94, wherein mandole, Cefonicid, CefoperaZone, Cefuroxime, Cefu the primary release modifying agent comprises from about Zonam, CefbuperaZone, Cefoxitin, Cefninox, Cefinetazole, 5 percent weight to about 80 percent weight of the release Cefotetan, Loracarbef, Cefinenoxime, Cefodizime Sodium, modifying complex. Cefotaxime, Ce?pimizole, Ce?piramide, Ceftazidime, Cefti 96. The pharmaceutical composition of claim 95, wherein olene, CeftizOXime, Ceftriaxone, Cefepime, Cefetecol, Cef the primary release modifying agent comprises from about pirome, Cefduinome, Cefalosporin C, CefoZopran Hydro 5 percent weight to about 70 percent weight of the release chloride, Cefaclor, Cefadroxil, Cefalexin, Cefaloglycine, modifying complex. Cefatrizine, Cefdinir, Cefetamet Pivoxil, Cefixime, Cefora 97. The pharmaceutical composition of claim 55, wherein mide, Cefotiam, Cefpodoxime, Cefpodoxime Proxetil, Cef the auxiliary release modifying agent comprises from about prozil, Cefradine, Cefroxadine, Cefteram Pivoxil, Ceftib 1 percent weight to about 95 percent weight of the release uten, Cefuroxime Axetil, and their pharmaceutically modifying complex. acceptable hydrates, Salts and esters. 98. The pharmaceutical composition of claim 97, wherein 109. The pharmaceutical composition of claim 100, the auxiliary release modifying agent comprises from about wherein the active pharmaceutical ingredient is a quinolone 5 percent weight to about 95 percent weight of the release antibiotic or a derivative thereof. modifying complex. 110. The pharmaceutical composition of claim 109, 99. The pharmaceutical composition of claim 98, wherein wherein the quinolone derivative is Selected from the group the auxiliary release modifying agent comprises from about consisting of Nalidixic Acid, Cinoxacin, OXolinic Acid, 10 percent weight to about 95 percent weight of the release Flumequine, Pipemidic Acid, ROSoxacin, Norfloxacin, Lom modifying complex. efloxacin, Ofloxacin, Enrofloxacin, Ciprofloxacin, Enoxa 100. A controlled release pharmaceutical composition cin, Amifloxacin, Fleroxacin, Gatifloxacin, Gemifloxacin, comprising a pharmaceutically active ingredient and a Pefloxacin, Rufloxacin, Sparfloxacin, Temafloxacin, Tosu release modifying complex, wherein Said release modifying floxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, Tro complex comprises a Synergistic combination of (a) a Sec vafloxacin, and their pharmaceutically acceptable hydrates, ondary release modifying agent Selected from a high Salts and esters. molecular weight polyethylene oxide and (b) an auxiliary 111. The pharmaceutical composition of claim 100, release modifying agent Selected from a Starch derivative, wherein the active pharmaceutical ingredient is a high and Said primary release modifying agent and auxiliary soluble high dose API or a derivative thereof. release modifying agent are present in Synergistic effective 112. The pharmaceutical composition of claim 111, amounts to extend the release of the active pharmaceutical wherein the high soluble high dose API or a derivative is ingredient. Selected from the group consisting of Acebutolol hydrochlo US 2004/0185097 A1 Sep. 23, 2004 ride, Amantadine hydrochloride, Aminocaproic acid, Ami Diloxamide furoate, Disulfiram, Erythromycin, Erythromy nophylline, Amodiaquine hydrochloride, AScorbic acid, cineStolate, Erythromycin Stearate, Ethacrynic cid, Ethiona Bupropion hydrochloride, CarbenoXolone Sodium, mide, Ethopropazine hydrochloride, Ferrous fumarate, Flu Cefuroxime Sodium, Chloroquine phosphate, Chloroquine conazole, Flurbiprofen, Furazolidone, Griseofulvin, Sulphate, Chlorpromazine hydrochloride, Ciprofloxacin Hydrochlorthiazide, Ibuprofen, Itraconazole, Ketoconazole, hydrochloride, Cloxacillin sodium, Cycloserine, Diltiazem Ketoprofen, Labetalol hydrochloride, Levodopa, LineZolid, hydrochloride, Diethyl carbamazine citrate, Doxycycline Lithium carbonate, Magaldrate, Mebendazole, Mefenamic hydrochloride, EthosuXimide, Ferrous gluconate, Isoniazid, acid, Megestrol acetate, Mercaptopurine, MeSalamimne, Levamisole hydrochloride, Levetiracetam, Lincomycin Nalidixic acid, Nateglinide, Niclosamide, Nitrofurantoin, hydrochloride, Mebeverine hydrochloride, Mepyramine Norfloxacin, Oxcarbazepine, OxyphenbutaZone, Paraceta maleate, Metformin hydrochloride, Metoprolol tartrate, mol, Phenindione, Phenobarbitone, Phenylbutazone, Phe Metoprolol Succinate, Niacin, Nicotinamide, Nicotinic acid, nylsulphathiazole, piperazine phosphate, Proguanil hydro Oxprenolol hydrochloride, oxytetracycline hydrochloride, chloride, Promethazine theoclate, Propylthiouracil, Penicillamine, Pentobarbitone sodium, Phenoxy Methyl Quinidine Sulphate, Quinine Sulphate, Quinidochlor, Penicillin K., Phenyloin Sodium, piperazine adipate, Potas Rifampicin, Simvastatin, Spironolactone, Succinylsul sium chloride, Procainamide hydrochloride, Propranolol phathiazole, Sulphadiazine, Sulphadimethoxine, Sulphadi hydrochloride, Pseudoephedrine hydrochloride, Quinalbar midine, Sulphafurazole, Sulphaphenazole, Thiabendazole, bitone sodium, Quinine bisulphate, Ranitidine hydrochlo Timidazole, Tolbutamide, Triamterene, Sulphamethoxazole ride, Sodium amino Salicylate, Sodium fusidate, Sodium and the like and their pharmaceutically acceptable Salts, Valproate, Streptomycin Sulphate, Tetracycline hydrochlo ester and hydrates. ride, Topiramate, Troxidone, Verapamil hydrochloride and 119. The pharmaceutical composition of claim 118, the like and their pharmaceutically acceptable Salts, ester wherein the active ingredient is Clarithromycin. and hydrates. 120. The pharmaceutical composition of claim 100, 113. The pharmaceutical composition of claim 112, wherein the active pharmaceutical ingredient is a low wherein the active ingredient is Nicotinic acid. Soluble low dose API or a derivative thereof. 114. The pharmaceutical composition of claim 100, 121. The pharmaceutical composition of claim 120, wherein the active pharmaceutical ingredient is a high wherein the low soluble low dose API or a derivative is Soluble low dose API or a derivative thereof. Selected from the group consisting of Alprazolam, Amiloride 115. The pharmaceutical composition of claim 114, hydrochloride, Astemizole, Atorvastatin, Benzhexol hydro wherein the high soluble low dose API or a derivative is chloride, Betamethasone, Bromhexine hydrochloride, Bro Selected from the group consisting of Amitriptyline hydro mocryptine meSylate, Buprenorphine hydrochloride, carbi chloride, captopril, Clonidine hydrochloride, Colchicin, mazole, Chlordiazepoxide, Citalopram, Cortisone acetate, Cyclophosphamide, Diphenhydramine hydrochloride, cyproheptadine hydrochloride, diazepam, DeSloratadine, Dothiepen hydrochloride, Doxepin hydrochloride Ephedrine Dexamethasone hydrochloride, Dextromethorphan hydro hydrochloride, Ergometrine maleate, Ergometrine tartrate, chloride, dicyclomine hydrochloride, Dienoestrol, Digi Fenfluramine hydrochloride, Folic acid, Glyceryl trinitrate, toxin, Digoxin, Domperidone, Dydrogesterone, enalapril Hyoscine hydrobromide, Hyoscine buytlbromide, Imi maleate, Esomeprazole, Ethinyloestradiol, Ethyloestrenol, pramine hydrochloride, Isoprenaline Sulphate, ISOSorbide Fludrocortisone acetate, Frusemide, glibenclamide, Glime dinitrate, ISOSorbide-5-mononitrate, Levocetrizine hydro piride, haloperidol, Indomethacin, ISOXSuprine hydrochlo chloride, Methadone hydrochloride, Methdilazine hydro ride, Lanatoside C, Lercanidipine hydrochloride, chloride, Metoclopramide hydrochloride, Neostigmine bro LevonorgeSrtel, Lomustine, Loratadine, ISOXuprine hydro mide, Oxybutynin hydrochloride, Perindopril erbumine, chloride, methotrexate, Mecizine hydrochloride, Melphalan, Pethidine hydrochloride, Phenformin hydrochloride, Phe Methotrexate, Methylergometrine maleate, Methylpredniso niramine maleate, Phenobarbitone Sodium, Primaquine lone, Mianserin hydrochloride, Mosapride, Nicoumalone, phosphate, Promethazine hydrochloride, Propantheline bro Nifedipine, Nitrazepam, Norethisterone, nortriptyline mide, Propranolol hydrochloride, Pyridoxine hydrochloride, hydrochloride, Omeprazole, Ormeloxifene hydrochloride, Salbutamol Sulphate, Terbutaline Sulphate, Thiamine hydro Pentazocine hydrochloride, Phenindamine tartrate, piroxi chloride, Timolol maleate, Tizanidine hydrochloride, Trif cam, prazosin hydrochloride, Prednisolone, Prednisone, luoperazine hydrochloride, Triflupromazine hydrochloride, Prochlorperazine maleate, Repaglinide, Riboflavinee, ROSu Triprolidine hydrochloride, Warfarin sodium and the like vastatin, Stilbostrol, Tamoxifen citrate, Thyroxine sodium, and their pharmaceutically acceptable Salts, ester and triamcinilone, Trimethoprim, Valdecoxib, Zolpidem tartrate hydrates. and the like and their pharmaceutically acceptable Salts, 116. The pharmaceutical composition of claim 115, ester and hydrates. wherein the active ingredient is Oxybutynin hydrochloride. 122. The pharmaceutical composition of claim 121, 117. The pharmaceutical composition of claim 100, wherein the active ingredient is Alprazolam. wherein the active pharmaceutical ingredient is a low 123. The pharmaceutical composition of claim 121, soluble high dose API or a derivative thereof. wherein the active ingredient is Lercanidipine hydrochlo 118. The pharmaceutical composition of claim 117, ride. wherein the low soluble high dose API or a derivative is 124. The pharmaceutical composition of claim 100, Selected from the group consisting of Acetazolamide, wherein the Secondary release modifying agent is a high Allopurinol, Atenolol, Carbamazepine, Cefadroxil, Cephal molecular weight polyethylene oxide. exin, Chloramphenicol, Cefuroxime Axetil, Chlorthalidone, 125. The pharmaceutical composition of claim 100, CilastoZol, Cimetidine, Clarithromycin, ClofaZemine, Dap wherein the high molecular weight polyethylene oxide has a Sone, Diclofenac Sodium, Diiodohydroxy quinolone, molecular weight of at least about 1,000,000. US 2004/0185097 A1 Sep. 23, 2004

126. The pharmaceutical composition of claim 100, 136. The pharmaceutical composition of claim 100, wherein the high molecular weight polyethylene oxide has a wherein the composition comprises from about 1 percent molecular weight ranging from 1,000,000 to 9,000,000. weight to about 90 percent weight of the release modifying 127. The pharmaceutical composition of claim 100, complex. wherein the auxiliary release modifying agent is a Starch derivative Selected from pregelatinized Starch, partially 137. The pharmaceutical composition of claim 136, pregelatinized Starch, retrograded Starch, or a combination wherein the composition comprises from about 5 percent thereof. weight to about 85 percent weight of the release modifying 128. The pharmaceutical composition of claim 100, complex. wherein the auxiliary release modifying agent is a retro 138. The pharmaceutical composition of claim 137, graded Starch. wherein the composition comprises from about 10 percent 129. The pharmaceutical composition of claim 100, wherein Said composition further comprises at least one weight to about 80 percent weight of the release modifying pharmaceutically acceptable additive Selected from diluents, complex. fillers, binders, glidants, and lubricants. 139. The pharmaceutical composition of claim 100, 130. The pharmaceutical composition of claim 100, wherein the Secondary release modifying agent comprises wherein Said composition further comprises an optional from about 1 percent weight to about 95 percent weight of coating which is designed for the modification of drug the release modifying complex. release. 131. The pharmaceutical composition of claim 130, 140. The pharmaceutical composition of claim 139, wherein the coating composition is Selected from the group wherein the Secondary release modifying agent comprises consisting of cellulose etherS Such as ethyl cellulose, from about 5 percent weight to about 90 percent weight of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, the release modifying complex. otherS Such as polyvinyl alcohol, polyvinyl pyrrolidone, 141. The pharmaceutical composition of claim 100, methacrylic acid derivatives, resins, clays, long chain hydro wherein the auxiliary release modifying agent comprises carbons, long chain carboxylic acids, long chain carboxylic from about 1 percent weight to about 95 percent weight of acid esters, long chain alcohols and the like and mixtures the release modifying complex. thereof. 132. The pharmaceutical composition of claim 100, 142. The pharmaceutical composition of claim 141, wherein Said composition further comprises an optional wherein the auxiliary release modifying agent comprises coating which is not designed for the modification of drug from about 5 percent weight to about 95 percent weight of release. the release modifying complex. 133. The pharmaceutical composition of claim 132, 143. The pharmaceutical composition of claim 142, wherein the coating composition is Selected from the group wherein the auxiliary release modifying agent comprises consisting of cellulose etherS Such as ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, from about 10 percent weight to about 95 percent weight of and otherS Such as polyvinyl alcohol, polyvinyl pyrrolidone, the release modifying complex. methacrylic acid derivatives, resins, clays, long chain hydro 144. A process for the preparation of controlled release carbons, long chain carboxylic acids, long chain carboxylic pharmaceutical composition of the present invention. acid esters, long chain alcohols and the like and mixtures 145. A pharmaceutical composition which gives an thereof. improved method of extended release of the API from the 134. The pharmaceutical composition of claim 100, wherein Said composition comprises from about 0.1 percent dosage form, comprising of the API, the release retarding weight to about 90 percent weight of the active pharmaceu complex and the other required pharmaceutically acceptable tical ingredient. additives, the improvements comprising the Synergistic 135. The pharmaceutical composition of claim 134, combination of release retardant complex in Synergistic wherein Said composition comprises from about 0.1 percent effective amounts to extend the release of the API. weight to about 80 percent weight of the active pharmaceu tical ingredient.