MXPA06002692A - Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative - Google Patents

Abstract

A pharmaceutical dosage form comprising a controlled release component comprising an antihyperglycemic drug in combination with a second component comprising a thiazolidinedione derivative is herein disclosed and described.

Description

FO? MUT-ACTÓ? ? AKM? C ± UTICA CONTAINING NOVEL DERIVATIVE biguanide and thiazolidinedione This is a continuation-in-part of Patent Application US Serial No. 10 / 664.803, filed on September 19, 2003, and sQJXLciiiicies of patent. p2-QV-Lsi-QD-a.-L? s Seti_e Nos »412,1QQ 6Q and 60 / 412.181, filed EI 20 September 2002. BACKGROUND OF THE INVENTION The present invention relates to a pharmaceutical dosage it comprises an antihyperglycemic drug, in combination with a thiazolidinedione derivative. More specifically,. The present invention relates to an oral dosage form comprising a biguanide, e.g., metformin or buformin or a. salt fa.i-aia-Ge i-caiu.e. e ajc.epta.fc.ls of jaL sOaSLS.,. v-cjc, tnetfoxmine hydrochloride or the methfoxine salts described in the patents of E.U.A. Nos. 3,957,853 and - f Uau f t í ¿y c SCL J-Ci.c-.cI -, j- in combination with a thiazide derivative: olidinedione as described in the patent of E.U.A. No. 4,687,777, also incorporated, in the reference by reference to "Many techniques have been used to provide pharmaceutical dosage forms of liberation. cou. ol u.a- and rolongada, a. fLG e maitetiisrr the therapeutic serum levels of the drugs and minimize the effects of missed doses of drugs caused by a lack of patient compliance. For example, prolonged-release tablets have been described as having an osmotically active drug core surrounded by a semi-permeable membrane. These tablets work-. Let the aqueous components of a fluid such as gastric or intestinal fluid penetrate the surface of the fluid and dissolve the active solution.

The resulting drug can be released through a passage in the coating membrane. Alternatively, if the active ingredient is ipsoluble in the wetting fluid, it can be pushed through the passage by a blowing agent such as a hydrogel. Some examples of these systems of osmotic tabulation can be found in the Patents of the U.S.A. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and 4,783,337. The U.I.X. Patent No. 3,952,741 teaches an osmotic device wherein the active agent is released from a core surrounded by a semi-permeable membrane only after sufficient pressure has been de-annealed, within the membrane. burst or rupture the membrane in a weak portion of the emura a. The basic osmotic device described in the above-mentioned patents has been refined over time in an effort to provide greater control of the release of the active ingredient. For example, Patents of K.U & amp; 4, -777,049, and 4,851 * 229 describe osmotic dosage forms comprising a semipermeable wall surrounding a core. The core contains an active ingredient and a modulating agent wherein the modulating agent causes the active ingredient to be released through a passage in the semipermeable membrane in a boosted manner. E_fefi.n e. QS a ~ < ? .c onal ed included modifications to the semipermeable membrane surrounding the active core such as varying the proportions and the coiiii- ENL Q &? S q and the ILIs __o__t an _- _ _ * c-na?. r? ct_e t-en from E.U.A. Nos. 5,178,867, 4,587,117 and 4,522,625 or aurtientando nui? IEIO of tßvßstiipißntos that xodean the active core, v.gr.j __U-.?_- Patent 5,650,170 and 4,892,739 .. us. Certain formulations of controlled or sustained release, employing anti-b_perg_Lcé_icas rogas such CQ_Q ciorhidrato of -metformina have limited the use of a blowing agent or geiifícación to control the release and the. drug & the dosage form. Limited research is exemplified by the teachings of WO 96/08243 and by inserting GLUCOPHAGE1® XR product which is a product of H.C1 ina controlled meffor of it liberacló commercially available from Bristol-Myers Squibb Co. derivatives are tíazoíidíiiadiona as described in the Patent of E-.U = Z_ No. 4, 687,777 = The therapeutic value of these compounds in combination therapy was further described in the Patents of? .U.A. Nos. 5,859,037, 5,952,356, 5,965,584, 6,150,384 and 6,172,090. However, none of these patents discloses a dosage form having the advantages of the present invention. Pharmaceutical dosage forms containing combinations of antihyperglycemic drugs and thiazolidinedione derivatives have been proposed in the literature. For example, EPO 0 749 751 (which is incorporated herein by reference) teaches pharmaceutical compositions which include a first order of sensitivity of xnsulin, which could be a thiazolidinadione compound, in combination with other antidiabetics. More specifically, EPO 0 749 I i- ß-Lattua ue & _ SjO-, auu-. O-W ßttk -? _- UJ _--. J - jus3.U- a. -The. The preferred drug is piogluazine, which can be combined with other antidiabetics such as metformin, fenoformin or hnformin, and in addition these drugs can be associated (mixed and / or coated) with conventional excipients to provide taste masking or sustained release behavior. Another example of a combination of antihyperglyceral drugs and thiazidine dione derivatives is US Pat. No. 6,011,049, (which is incorporated herein by reference). This patent teaches only one. CQmpQsition far_aceu.t-L.ca containing pioglifa-zone or ixolltazone and metformin in slow release forms such as osmotic pumps or patches £ _.J_d, _L_L __S _ _ _f -_i_ CL¿_ C. -U- t? _J ___? _ __t_. l ± Z _? .I ^ - l I I C ií? < n Antihyperglycemic agents and thiazolidinedione derivatives can be found in the Patents of E.U.A. Nos. 6,524,621; 6,475,521, 6,451,342 and 6,153,632 and the PCT patent applications WO 01/3594 and WO 01/3594, which are incorporated herein by reference. They are also known in the field WO 99/47125 and U.S. Patent No. 6,099,862, which discloses an osmotic tablet of rf.etforiuine coated with an immediate release coating containing an antihyperglycemic drug or a hypoglycemic drug. Although the above branch teaches pharmaceutical dosage formulations containing both an antihypoglycemic compound and thiazolidinedione derivatives, the present invention provides numerical benefits over the teachings of the prior art: how it will be described below. It is an object of the present invention to provide a dosage form comprising a first active drug, which is formulated to provide a delivery of controlled or sustained release. Preferably, the first active drug is an anti-pergliae-JiiCQ compound. The present invention further provides a second active drug that is preferably a thiazoiidine amino acid derivative. The novel dosage form described herein provides the. delivery of the first and second active drugs so that the bioavailability of any drug is not decreased by the presence of food =, An additional object of the present invention is to provide a dosage form, as described above, comprising delivery of a first active drug as a controlled or sustained release formulation for an antihyperglycemic compound, wherein the controlled or sustained release mechanism is not regulated by an expansion polymer, in combination with delivery of a second active drug by immediate release comprising a derivative of It is also an additional object of the present invention to provide a dosage form as described above, comprising delivery of. a first active drug as a controlled or sustained release formulation for an anti-hyperglycemic compound in combination with delivery of a second active drug by immediate release comprising a derivative of iia ^ oildinadione which can provide continuous therapeutic and non-ulsation levels of the antiliiperglycemic drug to an animal, or human in need of such treatment for a period of eight to twenty-four hours. A further object of the present invention is to provide a dosage form comprising delivery of a first active drug as a controlled or sustained release formulation for a. antihyperglycemic compound in combination with delivery of a second active drug by immediate release comprising a thiazolidinedione derivative which obtains peak plate levels of the antihyperglycemic compound approximately 8-12 hours after administration and peak plasma levels of approximately 1-4 derivative. hours after dosing. It is also an object of the present invention to provide a dosage form comprising, a first active drug such as a controlled or sustained release pharmaceutical core tablet having only a homogeneous osmotic core wherein the osmotic core component can be made using ordinary tablet compression techniques. An additional object of the present invention is to provide a dosage form comprising delivery of a first active drug as a controlled or sustained release formulation for an antrhiperg-carboxy compound in combmacron with delivery of a second active drug by release. immediate which comprises a diatolidinedione derivative which obtains pr 's? ßs UJS _3-s u & rco UÉJ. compound anfi_ur.perg.urcemi.co approximately 8-12 hours after administration and peak plasma levels of thiazolidinedione derivative to rodmad &.toenf 1-4 hours after dosing. A further object of the present invention is to provide a dosage form comprising a non-therapeutic drug or a controlled or sustained release component and a thiazolidinedione derivative as an immediate-release compound, wherein there is no need for a controlled release of the drug. t -. Q _! -? CLte. -OR- . .rt n l l l l i-i i LU Ldü. Qfc_ _L_ U-t- J L 'UT CLt-thiazolidinadione is released from the dosage form within 45 minutes or less. A further object of the present invention is to provide a shelf-stable dosage form comprising an antihyperglyceramic drug as a controlled or sustained iiberachron component and a iazolidinedione derivative as an immediate release component, wherein the total amount of Q Tp \ A fi- 3 LOS. Tk €? _? _ £ _ CI.?p. t, .. i O ¡_ CQi-X-. r -O A ... 1 ..-. * .X Xlc ?, .x? "? * '? QT? T ll T ^ _ * Z, _t s? Are more than 0.6% after two years of storage and no individual related compound or impurity it is more than 0.2% COMPENDI BE LA INVENTION The present invention relates to a pharmaceutical dosage form 5 comprising a first active drug, preferably an ani? errcet_xca drug, in combination with a second active drug, preferably a thiazolidinedione derivative More specifically, the present invention is reconstituted with an oral dosage form comprising a first active drug comprising a biguanide such as metformin or buforna or a fantaceutical-acceptable salt thereof; , e.g., inetformin hydrochloride or the salts of metforipine, in combination with a second active drug comprising an i_J (I b- *, i! V rt 1 '. JU! _- i Irt / l J 1 , 1 l 1, 1 ll r Iu t rt the previous objectives are filled by a dosage form ation comprising a first and second actrva drug, in which the first step is controlled by a controlled release core, preferably an osmotic tablet, with or without a geliffication polymer or e_iip ns Qn «EJ. The active part of the controlled release core may preferably be combined with the controlled release number in a manner that provides for immediate lipoblation of the second active ingredient. For example, the second active ingredient can be incorporated into a membrane that is applied to the core or the second active ingredient can be applied to Ui_L i i n i l i t i t.Li.i.i.i.i.i.i.i.l C-W LkU.LU-LrtU_i. J-G V C-S LY U -J 1X-J coated. In one embodiment, the second active drug, which co-or an immediate release formulation in the dosage form, while the antihyperglycemic component is provided as an irberacron formulation. controlled in the dosage form. This immediate release portion of the formulation should provide peak plasma levels. :) of 1-12 hours, preferably 1-4 hours of the iiazolidinedione derivative, while the controlled-release portion of the formulation can = -. ij ti. > i. jy t-í -it *. ^, L- _ "- H.5.1111 i __f - -í- aj: ¡^ ^ - Lt¿ Q - .. antihyperglycemic component Preferably, the dosage form in accordance with The present invention can be administered once a day, preferably with or after a meal, 20 and more preferably with or after the evening meal, the form of present invention can provide therapeutic levels of the drug through of the day with peak plasma levels {Tmax.}. of the antihyperglycemic drug Administration DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical formulation or dosage form comprising a first active drug comprising an anti-hyperglycemic drug in combination with a second drug rj i. 1- _L.V _ i LLTES n pμ i _ b-i 1 ... _? ^ lili. _Lfe_i_ _.V ¡d? JJ. _L_Í l ... J_. 3, f, .L._ A. In this case, the antihyperglycemic drug is a biguanide, e.g., metformin or buformin or a pharmaceutically acceptable salt thereof. The drug antlixrparglicemi, ca is delivered from a controlled release manner of a tablet core, preferably an osmotic tablet core with or without a gelification or swelling polymer. The tablet core should include the antihyperglycemic drug and at least one pharmaceutically acceptable excipient. muQX-J-ii .._ u- -tt. - e-. j_fc.Ss-. -u ju.y euCj 3i.Lf t =; _ LLU-C- Í-Í GAS tablet includes the antihyperglycemic drug, a binder and an absorption enhancer, and the tablet core is preferably coated with a polymeric coating to form a membrane around the tablet and perforated to create a passageway on each side of the membrane.The second active drug comprises a derivative of thiazolidinedione, and preferably applied to the membrane of the tablet core and provides release either The term, anti-iperglycemic drugs as used in this specification refers to drugs that are useful in controlling or managing diabetes mellitus 0"" U. - & - "UiS U. j_U-a? U-j-.U.rt- - ^ J-UL__; _. J-LCL-Í. QU-.Gy.c3__. Antihyperglycemics include biguanides such as etformin, fenoformin or buformin or the like, and pharmaceutically acceptable salts, isomers or derivatives thereof The term "thiazolidinedione derivative" as used in the specification is used for drugs which are useful for controlling and managing NIDDM. limited to, troglitazone, rosiglitazone, piogliazopa, ciglitazone or the like, and pharmaceutically acceptable salts, isomers or derivatives thereof The term "binding agent" refers to a, -! c_y.i-UUJ-.Urt_U.ue J_cÍ --- JJ-rt-C "U-UJ-- c_-Ui-lLLUfel Ce U-DJ-SS, conventionally known, such as polyvinylpyrrolidone, hydroxypropylceluylose, ethylcellulose, polymethacrylate, polyvinyl alcohol, waxes 0 and the like. Mixtures of binding agents 3Jj_.L-. __ 3 ____ £ _ LX- QÍ_13Í- QS t3X _? _ S_L S pI &CUS? u.- .L. * __QS? CjP-T? Preferred binders are water-soluble materials such as polyvinylpyrrolidone having a molecular weight j-_iiii? & L_Lu _: __ ¿_-. * ___ A C_fe_ ___? U LÍLÍ «__L j; UU, .. L_ L¿LÍ =. r. The binder may comprise from about 0 to about 40% of the total weight of the core and preferably from about 3% to about 15% of the total weight of the rxcleQ-. In a fashion, the use of a binding agent in the core is optional. In a preferred embodiment, the core can G? -u rn _-_ r o? C_-ot_a-mind. UJ absorption enhancer can be any type of absorption improver commonly known in the art such as a fatty acid, a tensile, ionic, cationic, amphoteric agent), a chelating agent, a bile salt or mixtures thereof. same. Examples of some of the preferred absorption enhancers are lec ipa, fatty acids such as capric acid, oleic acid and their monoglycerides. surfactants such as ic_.u- -.__- __Su.i_-rt.uu Q-ss au Lü f uc_.u_uuu.Q -i-i.uQ? -_ s S? ulu and [juj -auJ-D -LU 80, chelating agents such as citric acid, phytic acid, ethylene diamine tetraacetic acid (EDTA) and ethylene glycolic acid (/ 3-aminoethyl ethene) -NfNrNrN-tetraacetic acid (EGTA). The core may comprise about 0 to about 20% of the absorption enhancer based on v p_ssa ~ .u--. 4 u-Q __- 4u-c-t .- "iI -_? - 1 - 1? .-. - X -. -.__? _t __. ^.?.-.- I-? ._- _ ^ _ ~ -.? -. ___.__- J? .J?.-._ -J? S_ U_AJ- UU J _-_ IQ and? __ c_-5- ¿.'j_-si-tij _._ snu-su_ CJ-Y-J-SUJ-SU-UU IIS __-- &about 10% of the total weight of the core In one embodiment of the present invention, which does not employ a polymer of -if c c- The nucleus of the present invention is preferably formed by granulating an antihyperglycemic drug with a binding agent and compressing the granules with the addition of a lubricant and absorption enhancer in a tablet. It can also be formed by dry granulating the core ingredients and passing them through a roller corapactador and compressing the granules with the addition of a lubricant to tablets. Direct compression can also be used to form tablets. Other known methods of co-operation are known in the art. Additionally, other excipients such as lubricants, pigments and dyes can also be used in the formation of the present invention. The term "gelling polymer" or "swelling" refers to polymers that gel, swell or expand in the presence of water Q biological fluids .- Representative examples of gelling or swelling polymers are hydroxypropylmethylcellulose of high molecular weight (such as L___HQCE_LCR! KiQC, which is commercially available from Dow Chemical) and high molecular weight polyethylene oxides (such as POLYOX WSR 301, WSR 303 or WSR CQA_GUI_AMT.) Other gelling or tilting polymers are described in U.S. Patent No. 4,522,6215 (which is incorporated herein by reference). The core formed core is described herein, it can be coated with a membrane or sustained release coating. The materials that are useful in forming the sustained release membrane or coating are. cellulose esters, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ether-ether, cellulose acrylate, cellulose diaclylae, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, propionate cellulose acetate and cellulose acetate butyrate. Other suitable polymers are described in the patents of E.Ü.A. Nos. 3,845,770; 3,916,899, 4,008,719; 4,036,228 and 4,612,008 (which are incorporated herein by reference) The most preferred membrane or sustained release coating material is cellulose acetate comprising an acetyl content of 39.3 to 40X3%, and is commercially available from Eastman Fine Chemicals . In an alternative embodiment, sustained release membrane or coating can bind one of the polymers described above and an agent that improves flow. The flow enhancing agent can increase the volume of fluid imbibed in the core to allow the dosage form to substantially deliver all of the drug to thihiperglycemic through the passageway and / or the porous H-ep. - E.1 agent Flow improver can be a water soluble material or an enteric material. Examples of preferred materials that are useful as flow improvers are sodium chloride, potassium chloride, sucrose, sorbital, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydrogen peroxide, 1-cellophane. bear cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such as LÜTROL F68, LUTRO F127, LUTROL F108 which are co-consumable diapaniblea of BASE) and mixtures thereof. preferred flow is PEG 400. The flow improver may also be a drug that is soluble in water such as metformin or its pharmaceutically acceptable salts, or the flow improver may be a drug that is soluble under intestinal conditions. If the flow meter is a drug, the prescribing dosage form has the added advantage of providing an immediate release of the drug, which has been selected as the best-of-breed. The flow improver comprises from about 0 to about 40% of the total weight of the coating, more preferably from about 2% to about 20% of the total weight of the coating. The flow enhancing agent dissolves or leaches from the sustained 1i and oi 6p membrane or coating to form channels in the membrane or sustained release coating that allows fluid to enter the core and dissolve the active ingredient. The sustained release membrane or coating may also be formed using a commonly known excipient such as a plasticizer. Some of the commonly known plasticizers include adipate, azelaid, enzoafa, citrate, is earate, iscebucate, sebacate, triethyl citrate, citrate tri-n-butyl, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyciopedia of Poiy_er Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. Preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributyl citrate, ethyl acetate, glycerin sorbitol, diethyl oxalate, diethylmaloute, adiimethyl fumarate, dibutyl succinate, diethylmalonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate, tributylsitrate, glyceroltributirate and the like .. Depending on the particular astificue, amounts of from about 0 to about 25%, and preferably from about 2% to about 15% of the plasticizer can be used based on the total weight of the membrane or sustained release coating. Generally, the diaphragm membrane or coating held around the core co ____ prer? _ie_cá. from about 1% to about 10% and preferably about 2% to about 5% based on the total weight of core and coating. In a preferred embodiment, the membrane or sustained release coating that surrounds the core further comprises a passage that will allow controlled release of the drug from the core. As used herein, the term "passage" includes an opening, orifice, perforation, hole, weakened area or a tau co erodible element or a gelatin plug that erodes to form an osmotic passage for the release of the antihyperglycemic drug from the Dosage form. The adhesives used in accordance with the present invention are well known and are described in US Pat. . Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607, Independent of the antihyperglycemic there is a second active drug, preferably a derivative of tla-olidinedione, the second active drug can be formulated to provide an immediate release of the thiazolidinedione derivative. In one embodiment of the present invention, the derivative of kallidix? Adione is applied in the form of a layer to a controlled or sustained release core comprising the drug? binder and other conventional pharmaceutical excipients such as absorption enhancers, surfactants, plasticizers, antifoaming agents, and combinations of the foregoing, - An absorption enhancer may be present in the thiazolidinedione derivative layer in an amount of up to about 30%. / p compared to the weight of the derivative of i T ii nadi ona. A binder can be present in an amount up to 150% w / w of the thiaolidine derivative. A second active drug of immediate-U-beration formulation can be incorporated in a single dosage form by coating on the membrane or sustained release coating of the dosage form by conventional methods. " Alternatively, it can be incorporated by any pharmaceutically acceptable method into a single dosage form with the first active drug. The incorporation of the second active drug can be performed by, but not limited to, the processes selected from the group consisting of coat, drug, dry compression lamination, deposition and printing. When the thiazolidinedione derivative is coated to a sustained release membrane or coating of an osmotic tablet core, the thiazolidinedione coating should be applied to a suspension coating solution using an aqueous solvent, an organic solvent or a mixture of an aqueous solvent and an organic solvent. Typical organic solvents include acetone, isopropyl alcohol, methanol and ethanol. If a mixture of aqueous and organic solvents is used, the ratio of water to organic solvent should vary from 98: 2 to 2:98, preferably 5Q50 to 2:98, more preferably 30T.7Q to 2Q.8Q. ideally about 25i75 to 20 i80. If a mixed solvent system is employed, the amount of binder required to coat the diolitine derivative di nadiate towards the membrane, or sustained release coating can be reduced. For example, satisfactory coatings have been obtained from a mixed solvent system wherein the ratio of binder to thiazolidinedione derivative is 1: 9 to 1:11. Although acceptable coatings can be obtained when the tia-JJ-lJ-dinadione layer is applied directly to the sustained release membrane or coating, a preferred approach is to first coat the membrane or release liner with a seal layer before application. Inapplication of the thiazolidinedione coating. As used herein a seal layer is a coating that does not contain an active pharmaceutical ingredient and that disperses or dissolves rapidly in water. A thiazolidinedione coating solution or suspension may also contain a surfactant and a pore forming agent. A pore formation is preferably a water-soluble material such as sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycols (PE.G), propylene glycol, hydrosylpropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate. , polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such as LUTROL F68, LÜTROL F127, LUTROL F108 which are commercially available from BASF) and m-aclas of the same. In an alternative embodiment, the dosage form of the present invention may also comprise an effective immediate release amount of the antihyperglycemic drug. The effective immediate release amount of the antihyperglycemic drug can be coated on the coated coating in the dosage form or can be incorporated into the membrane or sustained release coating. FurtherVarious diluents, excipients, lubricants, colorants, pigments, dispersants, etc., which are described in the Re- gion 's Pharmaceutical Sciences (1995), can be used to optimize the abovementioned forms of the present invention. Biguanides, such as metformin are commonly administered in dosage forms containing 500 mg, 750 mg, 850 mg, and 1000 mg.The thiazolidinedione derivatives, for example pioglitin, are commonly administered in dosage forms containing 15 mg, mg and 45 mg The present invention is intended to encompass the aforementioned therapeutic combinations, without providing a specific example of each possible GS-binacl? -n of composition and a number of respective dosage dosages. the next camnoalcl? or FIRST ACTIVE DRUG Nucleus C Caannttiiddaad (% core) * _.- ro' -.- r-3r-a_.50.-98% (75-95% preferred) agglutinate! e 0.1-40% (3-15% preferred) absorption enhancer Q-2Q% (2-10% preferred) Lubricant 0-5% (0.5-1% preferred) Coating CCacity (% coating) polymer 5500-90% (75-95% preferred) flow improver 0-40% (2-20% preferred) plasticizer 0-25% (2-15% preferred) SELGUNDA DRUG ACTIVE Can i ad (% of total dosage) Drug 0.1-20% (1-10% preferred) binder 0.1 = 30% (1 = 5% preferred) surfactant 0-20% (0.1-15% preferred) pore former 0-25% (0.1-15% preferred) plasticizer 0-30% (0.1-20% preferred) Dosage forms prepared in accordance with the present invention exhibit the following dissolution profile when tested on a USP Tipa 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pE 7.5 phosphate buffer) and at 37 ° C. : First Active Drug Release Time (hour)% Release 2 0 = 25% (0 = 15% preferred) 4 10-45% (20-40% preferred) 8 30-90% (45-90% preferred) 12 NMD 50% (NMD 60% preferred) 16 NMD 60% (NMD 70% preferred) 20 NMD 70% (NMD 80% preferred) NMD = NO LESS Second Active Drug Release Time (hours)% Release 0.5 • NMD 60% (NMD 75% preferred) It has been found that the selection of excipients for use in the ttaz-olidlnadlone component of the form of The composition of the thiazolidinedione component of the present invention should be selected so that not less than 85% of the composition of the thiazolidinedione component of the present invention is selected. preferably at 90% hands and preferably at 95% of the thiazolidinedione is released from the dosage within 45 minutes, preferably within 40 minutes and preferably less than 30 minutes when tested in accordance with the United States Pharmacopoeia. United (USP) 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 ml of 0.3 M buffer of KC1-HCL, pE 2.0. A. In addition, excipients for use in the thiazolidinedione component of the dosage form should be selected so that the total of thiazolidinedione-related compounds or impurities in the final dosage form are no more than 0.6%, preferably no more. from. 0.5% and more preferably no more than 0 = 25% and each taxa related to individual thiazolidinedione or impurity in the final dosage form is not more than 0.25%, preferably T ± O. more than 0.2% and more preferably not more than 0.1%. Thiazolidinedione compounds or impurities in the final dosage form are determined by high performance chromatography (HPLC) using a YMC-ODA-AQ column, 5 um, 120A , 45. X 250 mm or equivalent, 0.1 M buffer. of mobile phase, approximately 40 uL of injection volume, flow rate of 0.7 mL / min, column temperature 25 ° C and wavelength of 269 nm for the detector of mobile ammonia acetonitrile acetic acid acetate 825: 25: 1) of UV, EXAMPLES The following are provided by way of example only and in no way are intended to be limiting. EXAMPLE 1 A controlled release tablet containing 850 mg of metformin HCl and 15 mg of pioglitazone is prepared as follows: First Active Drug I. Nucleus (% core composition) Metformin HCl 90.54% Bovidana K-3Q1, USE 4.38% Tribasic Sodium Phosphate 4.58% Magnesium Stearate 0.5% 1 apra-tiiated peao-aiecular - 50,000; dynamic vlacaaldad (solution of 10% p / v at 20 ° C) = 5.5-8.5 mPa-s. (a) Granulation The irtetforrtrin HCl is comminuted by passing it through a 40 mesh screen and collecting it in a clean, polyethylene coated container. The pavldana, -3Q, and phosphate, tribasic gives aodia aa dlauaLyan in purified water. The crumbled metformin HCl is then added to a fluidized bed granulator by overhead spraying and granulated by spraying the povidone-tribasic sodium phosphate binding solution under the following conditions: inlet air temperature of 50-70 ° C; air pressure of atomization of 1-3 bars and spraying rate of 10-100 ml / min. Once the binding solution is exhausted, the granules are dried in the granulator until the loss during drying at less than 2%, The granules aecae ae paaan through a mill equipped with the equivalent of a 18 mesh screen. (b) Formation of Tables Magnesium Stearate It is passed through a 40 mesh stainless steel screen and mixed with the granule of the EC1 data source apnas-imadamanta five (5) minutes. After mixing, the granules are compressed on a rotary press equipped with 11.9 mm (15/32") ravine concave punches (flat lower punch, upper punch with an indentation pin of approximately 1 mm). ? Low, the orifice may be formed by any means commonly employed in the pharmaceutical industry. (c) da Seal (optional) The core tablet may be sealed with an Opadry material or other water-soluble material by first dissolving the Opadry material. , preferably opaque and transparent, in purified water.The Opadry solution is then sprayed to the core tablet using a tray coater under the following conditions: air temperature and discharge at 38-42 ° C; atomization pressure of 1,968-2,812 kg / cm2 (28-40 psi) and spraying rate of 10-15 mil / min. The core tablet is coated with the sealing solution until a theoretical coating level of about 2-4% is obtained. II. Membrane (% membrane composition) Cellulose Acetate (39T-1Q 85% Triacetin 5% PEG 400 10% 2 Acetyl Content 39.3-40.3% (a) Membrane Coating Process Cellulose acetate dissolves in Acetone Mi as it is stirred With a homogenizer, polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The solution gives a clear perennial solution and is then sprayed onto the coated tablets. with seal using a fluidized bed coater that uses the alguyanfa candiciona .. prada-Cta temperature of 16-22 ° C, atomization pressure of approximately 3 bars and spraying rate of 120-150 ral / min. The coating is coated until a theoretical coating level of approximately 3% is obtained.- III Layering of (% of Second Second Active Drug composition) Piogiitiione EC1 43_5% Tween 80 2.0% Hydroxypropyl methylcellulose 54.5% Tween 80 e hi drnxi prppi 1meti 1 r.eT ul osa dissolve in purified water. Pioglitizone HCi is then dispersed towards this solution. The resulting suspension is then sprayed onto the above membrane coated tablets. EXAMPLE 2 A controlled release tablet containing 850 mg of metformin HCl and 15 mg of piolitazone is prepared as follows: First. Active Drug I. Nucleus (% core composition) Metformin HCl 88.555% Pavidone K-9Q3, üSP 6.368% Sodium Lauryl Sulfate 4.577% Magnesium Stearate 0.5% 3 molar weight approx. 1,000,000, dynamic viscosity (10%) v / p of solution) 300-700 rnPa-s at 20 ° C. (a) Granulation Metformin HCl and sodium lauryl sulfate are deafed by passing them through a 40 mesh screen and collecting them in a clean, polyethylene coated container. Povidone, K-90, is dissolved in purified water. The ___atfarmin ECl is damaged and the rilsulfata is added then added to a top-spray fluidized-bed granulator and granulated by spraying with the agri-tive solution of novi dona under the following conditions _ inlet air temperature of 50-70 ° C; atomization air pressure of 1-3 bars and a spraying rate of 10-100 rnl / min- Once the binder solution is dropped, the granules are dried in the granulator until the loss dates back to menoa da.2 % ,. The granules are passed through a mill equipped with the equivalent of a 18 mesh screen. (B) Table Aggregation Magnesium stearate is passed through a 40 mesh stainless steel screen and mixed with the granule. gives maufarinin ECl for about five (5) minutes. After mixing, the granules are compressed on a rotary press equipped with concave convention-to-alloy punches of 11.906 pmi (15/32") (flat lower punch, upper punch with an indentation pin of approximately 1 mm). was manifested above, the orifice can be formed by any drug used in the pharmaceutical industry. (c) Seal Coating (optional) The tablet is labeled with a seal with an Opadry material or other suitable water-soluble material by dissolving first Opadry material, preferably O Dry Transparent in purified water. The Opadry solution was then sprayed onto the core tablet using a tray coater under the following conditions: discharge air temperature of 38-42 ° C atomization pressure of 1,968-2,812 kg / cm2 (28-40 psi) and spraying rate of 10-15 rnl / min. The core tablet is coated with the seal solution until it is. obtains the level of xoric coating of approximately 2%. eleven . Membrane (% membrane composition) Cellulose Acetate (398-10 4 85% Triacetin 5% PEG 400 10% 4 Acetyl Content 39.3-40.3%, (a) Membrane Coating Process Cellulose acetate dissolves in acetone while stirring with a homogenelzador.Polyetylene glycol 400 and triacetin are added to the cellulose acetate solution and shaken.The coating solution is then sprayed onto the salt-coated tablets.In addition, the following conditions apply: a product temperature of 16-22 ° C, an atomization pressure of approximately 3 bars and a spraying rate of 120-150 ml / mi n. t, a sealed core tablet is coated until a theoretical coating level of about 3% is obtained. 111, Ea_-maciQLi da Capaa a (% da cai-ipaaici n n Second Second Active Drug) Pioglitizone HCl 43.5% Tween 80 2-0% Hydroxypropylcellulose 54.5% Tween 80 and hydroxypropylmethylcellulose are dissolved in purified water. Then pioglitizone HCl is dispersed in this solution. The resulting suspension is then sprayed onto the tablets described above. EXAMPLE 3 A controlled release tablet containing 500 mg of me o mi na HC-i and 15 mg of piogilta_or_a ae prepared as follows: I. First Active Drug A tablet coated with 500 mg metformin membrane is prepared as described in Example 2 above, except that compound cup tools are used during tablet formation. The tablet coated with a 500 mg mformamide membrane has the following composition: NUCLEUS Metfarmin ECl 500 mg / tablet Povídone K-90, USP 35.96 mg / tablet Sodium lauryl sulfate, NF 25. 84 mg / tablet Magnesium stearafo .. NF -8 mg / tablet Opadry Transparent SEAL COATING (yS-1-7006) 23.53 mg / tablet MEMBRANE COATING Cellulose acetate, 398-10, NF 23.56 mg / tablet Triacetin, USP 1.39 mg / tablet Polyethylene glycol 400, NF 2 -77 mg / tablet Total weight 615.87 mg / tablet II. Layer Formation of Second Active Drug An immediate release amount of pioglitiazone HCL is applied to the membrane-coated tablet of 500 g of metformin HCl prepared in step I. The tablet has the following composition. Membrane coated with Metformin HCl membrane 615.87 mg / tablet Coating of Pioglita ona- Píoglitazona HCl 16.53 mg / tablet Tween 80 2.0 mg / tablet Poliplastone XL 15.0 mg / tablet Opadry Transparent (YS-1-7006) 8 * 47 mg / tablet Opadry Color Coating White 10.0 mg / tablet Eulldo coating Candelilla wax powder 2.0 mg / tablet The coating of pioglitazone is applied directly to the tablets coated with mernhrana 500 mg of metformin HCl = The coating of Poglitazone is prepared by dissolving 0.252 kg of Opadry Transparent, 0.269 kg of Poliplasdopa XL and 0.036 kg of Tween 80 in 9-908 kg of purified water using a homogenizer. Once these ingredients are dissolved, 0.296 kg of pioglitazone HCl is dispersed into the solution and homageneized. The homogenized dispersion is then applied directly to the metformin ECL 500 mg membrane-coated tablets using a Qr tray eraser Eara Labcoat Lli of 60.96 ero. (24") under the following conditions: Spray Rate 20-35 L / min Discharge Temperature 35-45 ° c Atomization Air Pressure 1,757 kg / cm2 (25psi) Tray Speed 9 rprn Input Air Flow 390- 500 CFM Once the color coating is applied. the tablets are polished using 0.036 kg of Candelilla wax powder. EXAMPLE 4 A controlled release tablet containing 500 mg of metformin HCl and 15 mg of pioglitazone is prepared as follows. I: First Active Drug A tablet coated with a 500 g membrane is repaired as described in Example 2 above - except that composite cup tools are used during tablet formation. The tablet coated with 500 mg membrane has the following composition NUCLEUS Metformin HCl 500 mg / tablet Povidone K-90, USP 35.96 mg / tablet Sodium lauryl sulfate, NF 25.84 mg / tablet Magnesium stearate, NF 2.82 mg / tablet Opadry Transparent SEAL COATING (YS-1-7006) 23.53 mg / tablet MEMBRANE COATING Cellulose acetate, 398-10, RF 23 »56 mg / tablet Triacetine, USP 1.39 mg / tablet Polyethylene glycol 400, NF 2.77 mg / tablet Total weight 615.87 mg / tablet II - Formation of Layers of Second Active Drug An immediate release amount of HLP is applied to the 500 mg labeled tablet prepared with Step I, prepared in Step I, The final tablet has the following composition; Tablet coated with MetfQ__L__ HCl membrane 615.87 mg / tablet Opadry Seal Coating Transparent (Y8-1-7QQ6) 13.8 mg / tablet Coating Piogiitazone Pioglitazone HCl 16.53 mg / tablet Tween 80 2.0 mg / tablet Sodium Chloride 4.27 mg / tablet Opadry Transparent (YS-1-7006) 2.0 mg / tablet Opadry Color Coating White 8.10 mg / tablet Polishing Coating Candelilla wax 0.20 mg / tablet Seal coating solution is dissolved by dissolving 0.258 kg of Transparent Opadry in 2.576 kg of purified water and spraying the solution towards approximately 12.088 kg cié 500 tablet mg of metformin HCl coated with a membrane using a tray coater! It will make Labsoat III 60.96 cm (24") .The seal layer is applied under the following conditions: Spray Rate 20-35 mL / in Discharge Temperature 35-45 ° C Atomization Air Pressure 1,757 kg / sm2 (25 psi Tray Speed 9 rpm Inlet Air Flow 390-500 CFM The pioglitazone coating is applied to the membrane coated tablets of 500 mg metformin HCl coated with seal.The coating of pioglitazone is prepared by dissolving 0.040 kg of Opadry Transparent, 0.085 kg of sodium chloride and 0.040 kg of Tween 80 in 4,915 kg of purified water using a homogenizer Once these ingredients are dissolved, 0.328 kg of Piogliphalopa HCl is dispersed into the solution and homogenized. then applied to 500 mg metho-mine HCl tablets coated with 500 mg membraria of seal-coated _atformi_.a using a O'Hara Labcoat III 60.96 cm (24") coater with the following conditions: Spray rate 10-30 L / cannon / mir. Discharge Temperature 35-45 ° C Atomizing Air Pressure 1,406-2,812 kg / cm2 Air Pressure ié Standard 1,406-2,812 kg / cm2 Tray Speed 8-12 rpm Inlet Air Flow 250-450 CFM Once the Pioglitazone coating has been applied to the membrane-coated tablets of 500 mg metformin HCl stamped, an aesthetic or colored coating of Opadry White is applied to the tablet coated with pioglitazone. The coating and color is prepared by dispersing 0.159 kg of Opadry Blanco in 1585 kg of purified water. The Opadry Blanco suspension is applied to the pioglitazone-coated tablet using conditions similar to those described above for the application of the seal coating. • Once the colored coating is applied, the tablets are polished using 0 = 004 kg of Candelilla wax powder. EXAMPLE 5 A controlled release tablet containing 1000 mg of metformin of HCl and 30 mg of pioglitazone is prepared as follows:? . First Active Drug A tablet coated with a 1000 mg metformin membrane is prepared as described in Example 3 above. The tablet coated with a 1000 mg membrane has the following composition: NUCLEUS M_t £ o__Ln_ ECl 1000 mg / tablet Povidone -90, USP 78 = 0 mg / tablet Sodium laurilsuiphate, NF 51.69 mg / tablet Stearate d -magnesium, NF 5-66 mg / tablet Opadry Transparent SEAL COATING (YS-1-7006) 47 = 05 mg / tablet MEMBRANE COATING Cellulose Acetate, 398-10, NF 15.77 mg / tablet Triacetin, USP 0 = 92 mg / tablet Polyethylene glycol 400, NF 1.85 mg / tablet Total weight 1201.0 mg / tablet II. Second Active Drug An immediate release amount of pioglitazone HCL is applied to the membrane-coated tablets of 1000 mg of metformin HCl prepared in Table 1. The final tablet has the following composition: Metformin tablet HCl Coated with membrane 1201.0 mg / tablet Opadry Transparent Seal Coating (YS-1-7006) 16.0 mg / tablet Pioglitazone Coating Pioglitazone HCl 33.06 mg / tablet Sodium Chloride 4.27 mg / tablet Opadry Transparent (YS-1-7006) 3.0 mg / tablet Opadry II Color Coating White (Y-22-7719) 20.27 mg / tablet Polishing Coating Candelilla Wax Powder 0.40 mg / tablet The seal coating is prepared by dispersing 0.174 kg of Transparent Opadry in 3.478 kg of ethanol and mixing the dispersion for 15 minutes. The dispersion is then sprayed onto approximately 13,174 kg of 1000 mg ethoxylated membrane HCl etforiairia tablets using a tray coater O Hará Labsoat III of 60.96 c (24"), The seal coating is applied to the 10QQ mg tablets. Metformin HCl coated with membrane with the following conditions: Spray Regimen 10-30 mL / cannon / min Discharge Temperature 25-45 ° c Atomization Air Pressure 1,406-2,812 kg / cm2 Tray Speed 6-12 rpm Pattern Air Pressure 1,406-2-812 kg / cm2 Inlet Air Flow 250-450 CFM The coating of pioglitazone is then applied to tablets coated with seal, membrane coated metformin HCl 1000 g. The pioglitazone coating is prepared by dissolving 0.036 kg of Transparent Opadry and 0.046 kg of sodium chloride in 5.344 kg of ethanol using a homogenizer. Once the ingredients are dispersed, 0.359 kg of pioglitazone HCl is dispersed into the solution and homogenized. The homogenized dispersion is then applied to the membrane-coated metformin HCl 1000 mg tablets coated with seal using my O'Hara Labcoat III 60.96 cm (24") tray coater with the following conditions: Spray Regimen 10-30 mL / cannon / min Atomization Air Pressure 1,968-2,812 kg / cm2 Tray Speed 6-12 rpm Standard Air Pressure 1,968-2,812 kg / cm2 Inlet Air Flow 250-450 CFM Once the pioglitazone coating has been applied, an esthetic or colored coating of Opadry II White is applied to the pioglitazone coated tablets. The color coating is prepared by dispersing 0.220 kg of Opadry II White in 4,407 kg of ethanol. The suspension of Qpadry II hite is then applied to the pioglitazone HCl-coated tablets using a 60.96 cm (24") Labcoat III Tray Coater using conditions similar to those described above for the seal coating. the colored coating, the tablets are polished using 0.004 kg of Candelilla wax powder EXAMPLE 6 A controlled release tablet containing 1000 mg of metformi to HCl and 30 g of pioglitazone is prepared as follows: It First Active Drug A 1000 g tablet coated with membrane is prepared as described in example 3 above. The membrane-coated 1000 mg tablet has the following composition: NUCLEUS Metformin HCl 1000 mg / tablet Povidone K-90, U3P 78.0 mg / tablet Sodium lauryl sulfate NF 51.69 mg / tablet Magnesium stearate, NF 5.65 mg / tablet SEAL COATING Transparent Opadry (YS-1-7006) 47.05 mg / tablet MEMBRANE COATING Cellulose Acetate, 398-10, NP 15.77 mg / tablet Triacetin, USP 0.92 mg / tablet Polyethylene glycol 400, NF 1 = 85 mg / tablet Total weight 1201.0 mg / tablet II. Second Active Drug An immediate release amount of pioglitazone HCL is applied to the 1000 mg tablets of metformi to HCl coated with ff "mbraná prepared in the Step 1. The final tablet has the following composition: Metformin tablet HC1 Coated with melania 1201-0 mg / tablet Opadry Transparent Seal Coating (YS-1-7006) 21.0 mg / tablet Coating Pioglitazone Pioglitazone HCl 33.06 mg / tablet Sodium chloride 5.0 mg / tablet Opadry Transparent (? S-1-7006) 3.7 mg / tablet Opadry II Color Coating White (Y-22-7719) 21.54 mg / tablet Polishing Coating Candelilla Wax Powder 0.40 mg / tablet The seal coating is applied to the 1000 mg tablet of metformin HCl coated with membrane. The seal coating is prepared by dispersing 0 = 229 kg of Transparent Opadry in 4.573 kg of USP alcohol and mixing the dispersion for 15 minutes. The dispersion is then sprayed at about 13. 8 kg of the 1000 tablet nuclei of metformin HCl using a O'Hara tray coater of 60.96 cm. { 2") with the tip of the nozzle set to 10 = 16 + 5.08 (4 + 2") from the top of the static bed and the following conditions: Dispersion Rate 25 + 10 mL / cation / min Discharge Temperature 25 ° C + 5 ° C Air pressure of A.Timerization 0.703-2.812 kg / cm2 Tray Speed 4-9 rpm Supply Air Flow - 200 + 100 CFM Standard Air Pressure 0.703-2.812 kg / cm2 Coating dispersion Seal is continuously stirred until it is consumed during the coating process.

The pioglitazone coating is then applied to the membrane coated tablets of 1000 mg of metformin HCl coated with seal. The pioglitazone coating is prepared by mixing 4 434 kg of USP alcohol and 1,250 kg of purified water (approximately 78:22 ratio of alcohol to purified water) and slowly dispersing 0.040 kg of Clear Opadry to the solvent mixture. Once the Transparent Opadry is dispersed, it is homogenized during ap oxim for 10 minutes. Once the Opadry Transparent dispersion is homogenized, 0.054 kg of chloride is added to the dispersion and homogenized for about 2 minutes. After the sodium chloride is homogenized, 0.360 kg of pioglitazone HCl is slowly dispersed into the solvent mixture and then homogenized for about 10 minutes. Once the pioglitazone HCl is homogenized, the homogenizer is separated from the mixing vessel and replaced with an air mixer and mixed for an additional 15 minutes. The pioglitazone suspension is stirred until the suspension is consumed during the coating process. The pioglitazone HCl suspension is applied to membrane coated boards of 1000 mg metformin HCl membrane coated using O'Hara Labcoat III 60.96 cm (24") tray coater with the nozzle tip set at 10.16 + 5 = 08 cm (4 ± 2") from the top of the static bed and the following conditions: Spray Regime 25+ 10 aüj / cañóñ / r? In Discharge Temperature 25 + 5 ° C Atomization Air Pressure 0.703-2.812 kg / cm2 crate speed Tray 4-9 rpm Air Pressure of Pattern 0.703-2 = 812 kg / cm2 Supply Airflow 200 + 100 CFM Once the pioglitazone coating has been applied to the membrane coated tablets coated with membrane metformin HCl 1000 mg, an Opadry II White cosmetic coating is applied to the tablet coated with pioglitazone. . The cosmetic coating is prepared by dispersing 0.235 kg of Opadry 11 White (Y- 2-7719) in 4,691 kg of USP alcohol and mixing the dispersion for about 1 hour. The White Opadry dispersion is then sprayed onto pioglitazone HCl-coated tablets using an O-Labcoat III tray coater of 60.96 cm (24") from the top of the static bed and the following conditions. 25 + 10 ML / cannon / min Discharge Temperature 25 ° C + 5 ° C Atomization Air Pressure 0.703-2.182 kg / cm2 Tray Speed 4-9 rpm Supply Air Flow 200 + 100 CFM Standard Air Pressure 0.703-2.812 kg / cm2 Dispersion The color coating is continuously stirred until the dispersion is consumed during the re-stretching process. Once the cosmetic coating suspension is consumed, the tablets are dried in the coating tray for about 5 minutes and a tray speed of about 2-8 μm. and a discharge temperature of 25 _ 5 ° C. Once the tablets are dried, the discharge air is disconnected and the tray speed is adjusted to around 3-4 rpm, and 0.004 kg of Candelilla wax powder that had passed through a 60 mesh screen is sprayed towards the tablets. After the tablets have been stirred in the wax for about 5 minutes and the discharge air is disconnected, the tablets are moved for an additional 10 minutes. The finished polished tablet exhibited the following solution profile of PEGLItazone HCl when tested on a USP type 1 apparatus at 100 rpr? in a buffer solution of pH 2.0 HC1-0.3M KCl: Pioglitazone Time% Released 10 min 42% 20 min 79% 30 min 95% 45 ruin 102% The finished polished tablet also contained the following pioglitazone-related compounds when tested using HPLC using a YMC-ODS-AQ column, 5 um, 120 A, 4.6 x 250 mm, a mobile phase of 0.1 M ammonium acetate buffer: glacial acetic acid (25: 25: 1), an injection volume of 40 uL, flow regime of 0.7 i? iL / ffliñ, 25 ° C temperature of column de 269 ??? of wavelength for the UV detector. Name Relative Retention Time Quantity RS-1 0.7 N.D. * Pioglitazone 1.0 RS-2 1.5 0.03 RS-3 3.4 0.04 RS-4 1.2 0.03 RS-5 2.8 0.04 * N.D. = none detected RS-1 is (+/-) -5- [p- [2- (5-ethyl-2-pyridyl) ethoxy] -benzyl] -5-hydroxy-2,4-thiazolidinedione. RS-2 is (z) -5- [p- [2- (5-ethyl-2-pyridyl) ethoxy] -benzylidene] -2,4-thiazolidinedione. RS-3 is (+/-) - 5 - [? - [2- (5-ethyl-2-? Yl) ethoxy] -Benzyl] -3- [2- (5-ethyl-2-pyridyl) ethyl] -2, 4-iazolidinedione. RS-4 is (+/-) - ethyl-2-carbamoyl-3- [4- [2- (5-ethyl-2-iridyl) ethoxy] phenyl] -propionate. RS-5 is ethyl-3 -? - [2- (5-etiI-2-? Íridyl) ethoxy] -phenyl-? Ro-ionato. The final polished tablet was packed in a 100 cc HDPE bottle containing one (1) 2 g desiccant canister of SQRB-ITíiy and subjected to accelerated stability conditions of 40 ° C and 75% relative humidity for three (3 months . After storage, the final polished tablet was tested and exhibited the following solution profile of pioglitazone HCl when tested in a type 1 apparatus USP at 100 rpm in a buffer solution of pH 2.0 of HC1-Q.3M KCl. Time% of Pioglitazone Released 10 min. 38% 20 min. 73% 30 min. 92% 45 rain. 101% The final polished tablet stored tarabien contained the following pioglitazone-related compounds when tested by HPLC using a YMC-ODS-AQ, 5 um, 120a, 4.6 x column. 250 mm? a mobile phase of 0.1 M of ammonium acetate buffer: acetonitrile: glacial acetic acid (25: 25: 1), an injection volume of 40 uL, 0.7 ir- / rai? of flow rate, column temperature of 25 ° C and wave length of 269 nm for the UV detector. Name Relative Retention Time Amount (%) RS-1 0.7 N.D. * Pioglitazone 1.0 RS-2 1.5 0.03 RS-3 3.4 0.05 RS-4 1.2 0.02 RS-5 2.8 0.04 * N.D. = nothing detected While certain preferred and alternative embodiments of the invention have been set forth for purposes of describing the invention, modifications to the described embodiments may occur to those who are experienced in the field. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof that do not abandon the spirit and scope of the invention.

Claims (3)

1. CLAIMS 1. A pharmaceutical dosage form having a first and second active drug, the dosage form comprising: (a) a controlled release core comprising an antihyperglycemic drug and at least one pharmaceutically acceptable excipient; Y . { fo) an immediate-release thiazolinadinedione derivative containing no less than 85% component of the thiazolidinedione is released from the denitr dosage form of 45 min when tested in accordance with the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 ml of 0-3 M of KC1-HC1 buffer, pH 2.0.
2. 2. The pharmaceutical dosage form according to claim 1, wherein not less than 90% of the inadital thiazolin is released from the dosage form within 45 minutes when tested in accordance with the United States Pharmacopeia (USP). ) 26, with Apparatus 1 at 100 rpm, 3 DC and 900 ml of Buffer 0.3 M C1-HC1, pH 2.0. 3. The pharmaceutical dosage form according to claim 1, wherein not less than 95% of the thiazolidmadxone is released from the dosage form within 45 minutes when tested in accordance with the United States Pharmacopeia (USP) 26, with üy iatO ia? U xpiu,? ~, and what about my Tapipon? .or n KC1-HC1, pH 2.0. 4. The pharmaceutical dosage form according to claim 1. wherein not less than 100% of the thiazolidinedione is released from the dosage form within 45 minutes when tested in accordance with the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37aC and 900 ml of Buffer 0.3 M KCl-HCl, pH 2.0 = 5.- The pharmaceutical dosage form according to claim 1, wherein not less than 85% of the thiazolidinedione is free from the dosage form within 40 minutes when tested in accordance with the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 ml of Buffer 0.3 M KC1-HC1. pH 2.0. 6. The pharmaceutical dosage form according to claim 1, wherein not less than 90% of the thiazolidinedione is released from the dosage form within 40 minutes when tested in accordance with the United States Pharmacopeia (USP). 26, with Apparatus 1 at 100 rpm, 3 QC and 900 ml of Buffer 0.3 M KC1-HC1, pH 2.0. 7 = - The pharmaceutical dosage form according to claim 1, wherein not less than 95% of the thiazolidinedione is released from the dosage form within 40 minutes when tested in accordance with the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 3 ° C and 900 ml of Tamper 0.3 M KC1-HC1, pH 2.0. 8. The pharmaceutical dosage form according to claim 1, wherein not 100% of the thiazolidinedione is released from the foa & amp; a dosage within 40 minutes when tested in accordance with the United States Pharmacopoeia ( USP) 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 ml of Buffer 0.3 M KC1-HC1, pH 2.0. 9. The pharmaceutical dosage form according to claim 1, wherein not less than 85% of the thiazolidinedione is released from the dosage form within 30 minutes when tested in accordance with the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 ml of Buffer 0.3 M C1-HC1, pH 2.0. 10. The pharmaceutical dosage form according to claim 1, wherein not less than 90% of the thiazolidinedione is released in the dosage form within 30 minutes when tested in accordance with the United States Pharmacopeia (USP). 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 ml of Buffer 0.3 M KC1-HC1, pH 2.0. 11. The pharmaceutical dosage form according to claim 1, wherein not less than 95% of the thiazolidinedione is released from the dosage form within 30 minutes when tested in accordance with the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 ml of Buffer 0.3 M KC1-HC1, pH 2.0. 12 = - The pharmaceutical dosage form according to claim 1, wherein not less than 100% of the thiazolidinedione is released from the dosage form within 30 minutes when tested in accordance with the United States Pharmacopoeia (USP) 26, with Apparatus 1 at 100 rpm, 37 ° C and 900 μl of Tá pón 0.
3. 3 M KCl-HCl, pH 2.0. 13. - A pharmaceutical dosage form having a first and second active drug, the dosage form comprising: (a) a controlled release core comprising an α-tihyperglycemic drug and at least one pharmaceutically acceptable excipient; and (b) an immediate-release thiazolinadinedione derivative containing a component wherein the total thiazolidinedione-related compounds or impurities in the final dosage are not more than 0.6 as determined by high performance liquid chromatography. pharmaceutical dosage form according to claim 13, wherein the total of compounds related to trazolidinedione are not more than 0.5%. 15.- The pharmaceutical dosage form of C? Ii -a. i _? v li_Q ._- Cc.ClGi- J- ~ > , t i uuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuu 16. The pharmaceutical dosage form according to claim 13, wherein each individual compound related to thiazolidinedione or impurity in the final dosage form is not more than 0.25%. 17. The pharmaceutical dosage form according to claim 16, wherein each individual compound or impurity related to thiazolidinedione in the final dosage form is not Q. __. 0- & 18. The pharmaceutical dosage form according to claim 17, wherein each individual coiupußst or impurity related to thiazolidinedione in the final dosage form is not more than 0.10%. 19. The dosage form according to claim 1, wherein the controlled release core is an osmotic tablet, 20. The dosage form according to claim 19, wherein the osmotic tablet comprises: (a) a core comprising: \? -) Ou J OD Q € xa. ui? ya au L uljJGiyxl? ciTi ±? Qf (ii) 0 = 1-40% of a binding agent, (iii) 0-20% of an absorption enhancer; and (iv) 0-5% of a lubricant; (b) optionally a seal coating surrounding the core, and (c) a sustained release membrane comprising: (i) 50-995 of a polymer; (ii) 0-40% of a flow improver and (iii) 0-25% of a plasticizer, the membrane having at least one passage formed therein for release of the antiniperglycemic drug. 21, - the dosage form of claim 1, wherein the anti-hyperglycemic drug is a briganide. 22 «- The dosage form according to claim 1, wherein the thiazolidinedione derivative is txogliatozone, rosiglitazone, pioglitazone, cyclitazone or pharmaceutically acceptable salts, isomers or derivatives thereof, 23.- The dosage form in accordance with Claim 1, wherein the core is substantially free of any gelation or expansion polymer. 2 ^ - The dosage form according to claim 1, wherein the controlled release of the antihyperglycemic drug provides a Tmax of 8-12 hours. 25. The dosage form according to claim 1, wherein the release of the thiazolidinedione derivative provides a Tmax of 1-12 hours ". 26, - The dosage form according to claim 25, wherein the release of the thiazolidinedione derivative provides a Tmax of 1-4 hours. 27, - The dosage form according to claim 13, wherein the controlled release core is an osmotic tablet. 28. The dosage form according to claim 27, wherein the osmotic tablet comprises. (d) a core comprising: (i) 50 to 98% of the antihyperglycemic drug; (ii) 0.1-405 of a binder; (ni) Q-205 from an absorption speaker; Y . { iv) 0-5% of a lubricant, 5 (e) optionally a seal coating surrounding the core; Y . { f) a sustained-release membrane comprising: (i) u &???? Ole Ole Ole Ole Ole Ole Ole Ole???? ii ii (((((((((((((((((((((((((((((( (vi) 0-25% of a plasticizer, the membrane having at least one passage formed therein for release of the antihyperglycemic drug 29.- The dosage form in accordance with I the ? 6? Vmui --- i? U ± j é Qu -U< ? a G_Qyc¡. c i - J- ci-yAÍUK-? LL.GC¡. It is a biguanida. 30. The dosage form according to claim 13, wherein the thiazolidinedione derivative is troglitazone, rosiglitazone, or pioglitazone, cyglitazone, or salts, isomers or derivatives aimaCeu Li u cuucji LG aCfi L íu? _o Qc _Os uii.auiuS. 31.- The dosage form according to claim 13, wherein the core is substantially free of any polymer of 5 or exoansión. 32, - The dosage form according to claim 13, wherein the controlled release of the antihyperglycemic drug provides a Tmax of 8-12 hours. 33.- the dosage form according to J cu OAA U.C i_ IJJXX C- -IUII QCJ. Qci v a.v_.v_i of thiazolidinedione provides a Tmax of 1-12 hours. 34. The dosage form according to claim 33, wherein the release of the thiazolidinedione derivative provides a Tmax of 1-4 hours.