Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative

»اً AUGUST 2008

New pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative

This is a partial continuation application of U.S. Patent Application Serial No. 10 / 777,542, filed February 12, 2004, which is a partial continuation application of U.S. Patent Application Serial No. 10 / 664,804, filed on September 19, 2003, and claiming the benefit of provisional US patent applications Nos. series 60 / 412,180 and 60 / 412,181 filed September 20, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to a pharmaceutical form containing an antihyperglycemic drug in combination with a thiazolidinedione derivative. More specifically, the present invention relates to an oral dosage form containing a biguanide, for example metformin or buformin or a eutically acceptable salt thereof, for example metformin hydrochloride or the salts of metformin disclosed in the patents. American Nos. 3,957,853 and 4,080,472, which are incorporated herein by reference, in combination with a thiazolidinedione derivative, as described in U.S. Patent No. 4,687,777, also incorporated herein by reference.

Several techniques have been used to provide sustained and controlled release dosage forms to maintain therapeutic serum drug levels and to minimize the effects of missed drug doses caused by patient nonadherence.

For example, prolonged release tablets described have an osmotically active drug core surrounded by a semipermeable membrane. These tablets work by allowing an aqueous component of a fluid, such as gastric or intestinal fluid, to permeate through the coating membrane and dissolve the active ingredient so that the resulting drug solution can be released by passage through the coating membrane. Alternatively, if the active ingredient is insoluble in the permeating fluid, it can be pushed through the passage by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet systems can be found in US Patents Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and 4,783,337. U.S. Patent No. 3,952,741 discloses an osmotic device where the active agent is released from a nucleus surrounded by a semi-permeable membrane only after the development of sufficient pressure therein.

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WO 2006/107528 PCT / US2OO6 / O09082 the membrane to cause burst OR rupture of the membrane at a weak point thereof.

The basic osmotic devices described in the patents cited above have been refined over time in an effort to provide better control of the release of the active ingredient. For example, US Patents Nos. 4,777,049 and 4,851,229 describe osmotic pharmaceutical forms consisting of a semi-permeable wall surrounding a core. The core contains an active ingredient and a modulating agent, where the modulating agent causes the release of the active ingredient by passage through the semipermeable membrane in a pulsed manner. Further refinements have included modifications of the semi-permeable membrane surrounding the active core such as varying the proportions of the components that form the membrane, see, for example, U.S. Patents Nos. 5,178,867, 4,587,117 and 4,522,625, or increasing the number of coatings surrounding the active core, see for example U.S. Patents Nos. 5,650,170 and 4,892,739.

Some controlled or sustained release formulations which employ antihyperglycemic drugs, such as metformin hydrochloride, have been limited to the use of an expanding or gelling agent to control the release of the drug from the dosage form. This limited research is exemplified by the teachings of wo 96/08243 and by the insert of GLUCOPHAGE ™ XR which is a controlled release metformin HCl product marketed by Bristol-Myers Squibb Co.

Thiazolidinedione derivatives have been described in US Patent No. 4,687,777. The therapeutic value of these compounds in HAART has been further described in US Patents Nos. 5,859,037; 5,952,356; 5,965,584; 6,150,384 and 6,172,090. However, these patents do not describe a pharmaceutical form having the advantages of the present invention.

Pharmaceutical forms containing combinations of antihyperglycemic drugs and thiazolidinedione derivatives have been proposed in the art. For example, EPO 0 749 751 (which is incorporated herein by reference) discloses pharmaceutical compositions containing an insulin-sensitive improving agent, which could be a thiazolidinedione compound, in combination with other antidiabetics. More specifically, EPO 0 749 751 discloses that the preferred agent improving insulin sensitivity is pioglitazone, which can be combined with other antidiabetics such as metformin, phenformin or buformin, and also that these drugs can be combined (mixtures and / or coated) with conventional excipients to mask the taste or provide a

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WO 2006/107528 PCT / US2OO6 / OO9O82 sustained release behavior. Another example of a combination of antihyperglycemic drugs and thiazolidinedione derivatives is found in US Patent No. 6,011,049 (which is incorporated herein by reference). This patent discloses a unitary pharmaceutical composition which contains pioglitazone or troglitazone and metformin in slow release forms such as osmotic pumps or skin patches. Other combinations of antihyperglycemic drugs and thiazolidinedione derivatives can be found in US Patents Nos. 6,524,621; 6,475,521; 6,451,342 and 6,153,632 and in PCT patent applications wo 01/3594 and wo 01/3594, which are incorporated herein by reference.

Also known in the art are WO 99/47125 and US Patent No. 6,099,862 which disclose an osmotic metformin tablet coated with an immediate release coating containing a hypoglycemic or antihyperglycemic drug.

Although the prior art discloses pharmaceutical formulations which contain both an antihyperglycemic compound and thiazolidinedione derivatives, the present invention offers many advantages over the prior art teachings as will be described below.

An object of the present invention is to provide a pharmaceutical form containing a first active drug, which is formulated to provide controlled or sustained release delivery. Preferably, the first active drug is an antihyperglycemic compound. The present invention also discloses a second active drug which is preferably a thiazolidinedione derivative. The new pharmaceutical form described here ensures delivery of the first and second active drug so that the bioavailability of each of the drugs is not reduced by the presence of food.

Another object of the present invention is to provide a pharmaceutical form, as described above, ensuring delivery of a first active drug in the form of a controlled or sustained release formulation of an antihyperglycemic compound, wherein said mechanism controlled or sustained release is not controlled by an expanding polymer, in combination with the delivery of a second active drug by immediate release comprising a thiazolidinedione derivative.

Another object of the present invention is to provide a pharmaceutical form, as described above, ensuring the delivery of a first active drug in the form of a controlled or sustained release formulation of an antihyperglycemic compound in combination with the drug.

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WO 2006/107528 PCT / US2OO6 / O09082 delivery of a second active drug by immediate release comprising a thiazolidinedione derivative which can provide continuous and non-pulsed therapeutic levels of said antihyperglycemic drug to an animal or human in need of 'such treatment for a period of eight hours to twenty four hours.

An additional object of the present invention is to provide a pharmaceutical form ensuring the delivery of a first active drug in the form of a controlled or sustained release formulation of an antihyperglycemic compound in combination with the delivery of a second active drug. by immediate release comprising a thiazolidinedione derivative, which achieves peaks in plasma levels of the antihyperglycemic compound approximately 6-12 hours after administration after a meal and peaks in plasma levels of the thiazolidinedione derivative approximately 1 - 4 hours after administration of the dose.

It is also an object of the present invention to provide a pharmaceutical form comprising a first active drug in the form of a controlled or sustained release pharmaceutical core tablet having only a homogeneous osmotic core where the osmotic core component can be manufactured by means of ordinary tablet compression techniques.

An additional object of the present invention is to provide a pharmaceutical form ensuring the delivery of a first active drug in the form of a controlled or sustained release formulation of an antihyperglycemic compound in combination with the delivery of a second active drug. by immediate release comprising a thiazolidinedione derivative, which achieves peaks in plasma levels of the antihyperglycemic compound approximately 6 - 12 hours after administration and peaks in plasma levels of thiazolidinedione derivative approximately 1 - 4 hours after administration of the dose when the product is administered after a meal.

Another object of the present invention is to provide a pharmaceutical form containing an antihyperglycemic drug in the form of a controlled or sustained release component and a thiazolidinedione derivative in the form of an immediate release component, where not less than 80 % of the total amount of thiazolidinedione derivative is released from the dosage form within 30 minutes or less.

Another object of the present invention is to provide a long-lasting pharmaceutical form containing an antihyperglycemic drug in the form of a controlled release component or

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WO 2006/107528 PCT / US2OO6 / OO9O82 prolonged and a thiazolidinedione derivative in the form of an immediate release component, where the total amount of thiazolidinedione-related compounds or impurities does not exceed 0.6% after two years of storage and no individual relative compound or impurity exceeds 0.2%.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical form containing a first active drug, preferably an antihyperglycemic drug, in combination with a second active drug, preferably a thiazolidinedione derivative. More specifically, the present invention relates to an oral pharmaceutical form containing a first active drug consisting of a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof, for example metformin hydrochloride or salts of metformin. , in combination with a second active drug consisting of a thiazolidinedione derivative.

The foregoing objects are achieved by a pharmaceutical form containing a first and a second active drug, wherein the first active drug is formulated as a controlled release core, preferably an osmotic tablet, with or without a gelling or expanding polymer. The second active ingredient may be part of the controlled release core or it may preferably be combined with the controlled release core in a manner which provides immediate release of the second active ingredient. For example, the second active ingredient can be incorporated into a membrane which is applied to the core or the second active ingredient can be applied to a coated or uncoated controlled release core.

In one embodiment, the second active drug, which may be a thiazolidinedione derivative, is provided as an immediate release formulation in the dosage form while the antihyperglycemic component is provided as a controlled release formulation in the dosage form. This immediate release portion of the formulation should provide peaks in plasma levels (Tmax) of 1-12 hours, preferably 1-4 hours, of the thiazolidinedione derivative, while the controlled release portion of the formulation may provide peaks. in 6-12 hour plasma levels (Tmax) of the antihyperglycemic component when administered after a meal.

Preferably, the pharmaceutical form according to the present invention can be administered once a day, preferably with or after a meal, and most preferably with or after dinner. The dosage form can provide therapeutic levels of the drug throughout the adjournment.

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WO 2006/107528 PCT / US2OO6 / OO9O82 with peak plasma levels (Tmax) of the antihyperglycemic drug obtained between 6-12 hours after administration with a meal.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical formulation or dosage form containing a first active drug consisting of an antihyperglycemic drug in combination with a second active drug consisting of a thiazolidinedione derivative. Preferably, the antihyperglycemic drug is a biguanide, for example metformin or buformin or a pharmaceutically acceptable salt thereof. The antihyperglycemic drug is delivered in a controlled release manner from the core of a tablet, preferably an osmotic tablet core with or without a gelling or swelling polymer. The core of the tablet should contain the antihyperglycemic drug and at least one pharmaceutically acceptable excipient. In one embodiment of the present invention, the core of the tablet contains the antihyperglycemic drug, a binding agent and an absorption enhancing agent, and the core of the tablet is preferably coated with a polymeric coating to form a polymeric coating. membrane around the tablet and pierced to create a passage on either side of the membrane. The second active drug consists of a thiazolidinedione derivative, and is preferably applied to the membrane of the core of the tablet and ensures immediate or controlled release of said thiazolidinedione derivative.

The term "antihyperglycemic drug," as used in this specification, refers to drugs which are useful in the control or management of non-insulin dependent diabetes (NIDDM). Antihyperglycemic drugs include biguanides such as metformin, phenformin or buformin or the like, and pharmaceutically acceptable salts, isomers or derivatives thereof.

The term "thiazolidinedione derivative" as used in this specification refers to drugs which are useful in the control or management of DNID. These include, but are not limited to, troglitazone, rosiglitazone, pioglitazone, ciglitazone or the like, and pharmaceutically acceptable salts, isomers or derivatives thereof.

The term “binding agent” refers to any conventionally known pharmaceutically acceptable binder, such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polymethacrylate, polyvinyl alcohol and the like. Mixtures of the aforementioned binding agents can also be used. Preferred binding agents are water soluble materials

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WO 2006/107528 PCT / US2OO6 / OO9O82 such as polyvinylpyrrolidone having a weight average molecular weight of 25,000 to 3,000,000. The binding agent can constitute approximately from about 0 to about 40% of the total core weight and preferably from about 3% to about 15% of the total core weight. In one embodiment, the use of a binding agent in the core is optional.

In a preferred embodiment, the core may optionally include an absorption enhancing agent. The absorption enhancing agent can be any type of absorption enhancing agent commonly known in the art such as a fatty acid, a surfactant (anionic, cationic, amphoteric), a chelating agent, a bile salt or mixtures thereof. Examples of preferred absorption enhancing agents are lecithin, fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80 , chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-bis (P-aminoethyl ether) Ν, Ν, Ν, Ν-tetraacetic acid (EGTA). The core may contain from about 0 to about 20% absorption enhancing agent based on the total weight of the core and most preferably about 2% to about 10% of the total weight of the core.

In one embodiment of the present invention, which does not employ a gelling or swelling polymer, the core 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 an absorption enhancing agent in a tablet. The core can also be formed by dry granulating the core ingredients by passing them through a roller compactor and compressing the granules with the addition of a lubricant to the tablets. Direct compression can also be used in the manufacture of tablets. Other commonly used granulation procedures are known in the art. In addition, other excipients such as lubricants, pigments or colorants can also be employed in the formulation of the present invention.

The term gelling or swelling polymer refers to polymers which gel, swell or expand in the presence of water or similar fluids. Representative examples of gelling or swelling polymers are high molecular weight hydroxypropylmethylcellulose (such as METHOCEL® Κ100Μ, which is commercially available from Dow Chemical) and high molecular weight polyethylene oxides (such as POLYOX WSR 301, WSR 303 or WSR COAGULANT). Other gelling or swelling polymers are described in US Patent No. 4,522,625 (which is incorporated herein by reference).

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The core, formed as described herein, may be coated with a membrane or a sustained release coating. Materials which are useful for forming the membrane or sustained release coating are ethyl cellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate. , cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate and cellulose acetate butyrate. Other suitable polymers are described in US Patents Nos. 3,845,770; 3,916,899; 4,008,719; 4,036,228 and 4,612,008 (which are incorporated herein by reference). The best sustained release membrane or coating material is cellulose acetate comprising an acetyl content of 39.3 to 40.3%, and is commercially available from Eastman Fine Chemicals.

In an alternative embodiment, the sustained release membrane or coating may comprise one of the polymers described above and a flow enhancing agent. The flow enhancer can increase the volume of fluid imbibed in the core to allow the dosage form to deliver substantially all of the amount of antihyperglycemic drug through the passageway and / or the porous membrane. The flow enhancing agent can be a water soluble material or an enteric material. Examples of preferred materials which are useful as flow improvers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethyleneglycols (PEG), propylene glycol, hydroxypropylcellulose, hydroxypropylmethycellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such as LUTROL F68, LUTROL F127, LUTROL F1O8 which are commercially available from BASF) and mixtures thereof. A preferred flow enhancer is PEG 400.

The flow enhancer may also be a drug which is soluble in water such as metformin or its pharmaceutically acceptable salts, or the flow enhancer may be a drug which is soluble under intestinal conditions. If the flow enhancer is a drug, the present dosage form has the additional advantage of providing immediate release of the drug which has been selected as the flow enhancer.

The flow improver constitutes approximately 0 to about 40% of the total coating weight, most preferably about 2% to about

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20٥ / ο of the total weight of the coating. The flow enhancer dissolves or leaches from the membrane or sustained release coating, allowing fluid to enter the core and dissolve the active ingredient.

The sustained release membrane or coating can also be formed using a commonly known excipient such as a plasticizer. Some commonly known plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, tri-n acetylcitrate -butyl, citric acid esters, and those described in Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, polyethyleneglycols (PEG) (i.e. PEG 400, PEG 8000), acetylated monoglyceride, grape seed oil, olive oil, olive oil, sesame, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacitrate, glycerol-troltebacitrate, glycerol-troltebacitrate and the like. Depending on the particular plasticizer, amounts of from about 0 to about 25% and preferably from about 2% to about 15% plasticizer can be used based on the total weight of the membrane or sustained release coating. .

In general, the sustained release membrane or coating around the core will constitute from about 1 / o to about 10%, and preferably about 2% to about 5%, of the total weight of the core and coating.

In a preferred embodiment, the membrane or sustained release coating surrounding the core also includes a passage that will allow controlled release of the drug from the core. As used herein, the term passage includes an opening, orifice, piercing, hole, weakened area, or an erodible element such as a gelatinous pad which erodes to form an osmotic passage for the release of the antihyperglycemic drug from the blood. pharmaceutical form. Passages used in accordance with the present invention are well known and are described in US Patents Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607.

Apart from the antihyperglycemic agent there is a second active drug, preferably a thiazolidinedione derivative. This second active drug can be formulated to provide immediate release of the thiazolidinedione derivative. In one embodiment of the present invention, the thiazolidinedione derivative is applied as a controlled or sustained release single core layer containing the antihyperglycemic drug. The thiazolidinedione derivative layer employs a binder and other conventional pharmaceutical excipients such as

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WO 2006/107528 PCT / US2OO6 / OO9O82 absorption enhancers, surfactants, plasticizers, anti-foaming agents and combinations thereof. An absorption enhancing agent may be present in the thiazolidinedione derivative layer in an amount of about 30% w / w compared to the weight of the thiazolidinedione derivative. A binding agent may be present in an amount of up to 15O٥ / ow / w of the thiazolidinedione derivative.

In one embodiment, the binder in the thiazolidinedione derivative layer is a water soluble binder, preferably a water soluble film forming binder, which has a low viscosity, typically less than 50 mPa.S, preferably less than 25 mPa.S, and most preferably less than 10 mPa.S, when tested in a 2% aqueous solution at 20 ° C. An example of a water soluble binder is hydroxypropylcellulose available from Nippon Soda Co., Ltd. in Japan under the tradenames HPC-SSL and HPC-SL which have a reported viscosity of 2-3 mPa.S and 3-6 mPa. .S respectively.

If a surfactant is employed in the thiazolidinedione derivative layer, it is preferable that the surfactant is a nonionic surfactant such as a poloxamer.

An immediate release formulation of the second active drug may be incorporated into a unit dosage form by coating on the membrane or on the sustained release coating of the dosage form by conventional methods. Alternatively, it can be incorporated by any pharmaceutically acceptable method in unit pharmaceutical form with the first active drug. Incorporation of the second active drug can be accomplished by, but not limited to, the processes selected from the group including drug layering, lamination, dry compression, deposition and etching.

When the thiazolidinedione derivative is coated onto a membrane or sustained release coating of an osmotic tablet core, the thiazolidinedione coating should be applied from a coating solution or suspension which employs 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 are employed, the ratio of water to organic solvent should range from 98: 2 to 2:98, preferably 50:50 to 2:98, most preferably 30:70 at 8:80 pm and ideally around 25:75 to 20:80. If a mixed solvent system is employed, the amount of binder required to coat the thiazolidinedione derivative on the membrane or sustained release coating can be reduced. For example, successful coatings have been obtained from a solvent mixing system where the ratio of binder to derivative of

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WO 2006/107528 PCT / US2OO6 / OO9O82 thiazolidinedione is 1: 9 to 1:11. Although acceptable coatings can be obtained when the thiazolidinedione coating is applied directly to the membrane or sustained release coating, a preferred approach is to first coat the membrane or sustained release coating with a waterproof coating prior to the release. application of the thiazolidinedione coating. As used herein, a waterproof coating is a coating which does not contain an active pharmaceutical ingredient and which disperses or dissolves rapidly in water. It may be necessary to apply an excess of about 5-20%, preferably an excess of about 10-15% of thiazolidinedione coating solution to compensate for losses during the coating process.

The thiazolidinedione coating solution or suspension may also contain a surfactant and a porogen. A porogen is preferably a water-soluble material such as sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethyleneglycols (PEG) and propylene glycol. In an alternative embodiment, the dosage form of the present invention may also contain an effective immediate release amount of the antihyperglycemic drug. The immediate-release effective amount of the antihyperglycemic drug may be coated on the membrane or the sustained release coating of the dosage form or it may be incorporated into the membrane or the sustained release coating.

In addition, various diluents, excipients, lubricants, colorants, pigments, dispersants, etc., which are disclosed in Remington's Pharmaceutical Sciences (1995), can be used to optimize the aforementioned formulations of the present invention.

Biguanides, like metformin, are usually given in dosage forms containing 500 mg, 750 mg, 850 mg and 1000 mg. Thiazolidinedione derivatives, for example pioglitazone, are usually administered in dosage forms containing 15 mg, 30 mg and 45 mg. The present invention aims to encompass the aforementioned therapeutic combinations, without providing a specific example of each possible combination of the compounds and their respective dosage amounts.

In a preferred embodiment, the pharmaceutical form will have the following composition:

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WO 2006/107528

FIRST ACTIVE DRUG

Core :

binding drug

Quantity (% of kernel)

50-98٥ / ο

0.1-40% enhancer 0-20٥ / ο lubricant absorption 0-5% (75-95٥ / ο preferred) (3-15% preferred) (2-10% preferred) (0.5-1٥ / ο preferred)

Coating: Quantity (% of coating)

<td>polymer</td><td> 50-99%</td><td>(75-95% preferred)</td>

<td>improvement agent</td><td> 0-40%</td><td>(2-20٥ / ο preferred)</td>

<td>the flow</td><td></td><td></td>

<td>plasticizer</td><td> 0-25%</td><td>(2-15% preferred)</td>

Quantity (% of total pharmaceutical form)

SECOND DRUG

ACTIVE plasticizer porogenic surfactant binding drug

0.1-20% (1-10% preferred)

0.1-30٥ / ο (1-20% preferred)

0-20٥ / ο (0.1-15٥ / ο preferred)

0-25% (0.1-15% preferred)

0-20% (0.1-15% preferred)

Dosage forms prepared in accordance with the present invention display the following dissolution profile when tested in a USP Type 2 apparatus at 75 rpm in 900 ml of intestinal fluid Simulate 5 (phosphate buffer pH 7.5) and at 37٥c:

Release of the first active drug

Duration (hours)% release

<td> 2</td><td> 0-25%</td><td>(0-20% preferred)</td>

<td> 4</td><td> 10-45%</td><td>(20-40% preferred)</td>

<td> 8</td><td> 30-90%</td><td>(45-90% preferred)</td>

<td> 12</td><td>PMQ 50%</td><td>(PMQ 60% preferred)</td>

<td> 16</td><td>PMQ 60%</td><td>(PMQ 70% preferred)</td>

<td> 20</td><td>PMQ 70%</td><td>(PMQ 80% preferred)</td>

PMQ = NOT LESS THAN

Release of the second active drug

<td>Duration (hours)</td><td>% release</td><td></td>

<td> 0.5</td><td>PMQ 60%</td><td>(PMQ 75% preferred)</td>

It has been found that the selection of excipients to be used in the thiazolidinedione component of the dosage form can drastically affect the release characteristics, efficacy and reliability.

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Stability of thiazolidinedione. Therefore, in an alternative embodiment of the present invention, the composition of the thiazolidinedione component of the present invention should be selected such that not less than 85٥ / ο, preferably not less than 90٥ / ο, and most preferably not less than 95% of the thiazolidinedione is released from the pharmaceutical form within 45 minutes, preferably within 40 minutes and best within 30 minutes when tested according to the American Pharmacopoeia (USP) 26, with the device 1 at 100 rpm, 37٥c and 900 ml of 0.3 M KC1- buffer. HCl, pH 2.0.

Other excipients for use in the thiazolidinedione component of the dosage form should be selected such that the total of the thiazolidinedione-related compounds or impurities in the final dosage form does not exceed 0.6%, preferably does not exceed not 0.5% and best not exceeding 0.25% and that each individual compound relating to thiazolidinedione or impurity in the final pharmaceutical form does not exceed 0.25%, preferably not more than 0.2% and best not more than 0.1 ٥ / o. The compounds relating to thiazolidinedione or the impurities in the final pharmaceutical form are determined by high performance liquid chromatography (HPLC) using a YMC-ODS-AQ column, 5pm, 120Â, 4.6 X 250 mm or a equivalent column, a mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: glacial acetic acid (25: 25: 1), an injection volume of approximately 40pL, a flow rate of 0.7 ml / min, a column temperature of 25٥c and a wavelength of 269 nm for the uv detector .

EXAMPLES

The following examples are presented for illustrative purposes only and are not intended to be restrictive.

EXAMPLE 1

One controlled-release tablet containing 850 mg of metformin hydrochloride and 15 mg of pioglitazone is prepared as follows:

First active drug

I. Core

Povidone K-30 'Metformin HCl, USP

Sodium phosphate tribasic

Magnesium stearate (٥/٠ of core composition)

90.54%

4.38%

4.58%

0.5%) approximate molecular weight = 50,000; dynamic viscosity (10% w / v solution at

2O٥C) = 5.5-8.5 mPa-s.

/

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WO 2006/107528 (a) Granulation

Metformin hydrochloride is broken down by passing it through a 40 mesh screen and collecting it in a clean double polyethylene container. Povidone, Κ-30, and tribasic sodium phosphate are dissolved in purified water. The disaggregated metformin HCl is then added in a top-spray fluidized bed granulator and granulated by atomizing the povidone and sodium phosphate tribasic binder solution under the following conditions: air temperature d 'inlet 5O-7O٥C, atomization air pressure 1-3 bars and atomization rate 10-100 10 ml / min.

When the binder solution is used up, the granules are dried in the granulator until the loss on drying is less than 2%. The dried granules are passed through a comil equipped with the equivalent of an 18 mesh screen.

(b) Manufacture of tablets

The magnesium stearate is passed through a 40 mesh stainless steel screen and mixed with the metformin HCl granules for approximately five (5) minutes. After mixing, the granules are compressed on a rotary tablet press fitted with standard 15/32 round concave punches (plain bottom punch, top punch with approximately 1mm indent pin).

As stated above, the orifice can be formed by any means usually employed in the pharmaceutical industry.

(c) Waterproof coating (optional)

The core tablet is optionally coated with a waterproof coating with an Opadry material or other suitable water soluble material, first dissolving the Opadry material, preferably Opadry Clear, in purified water. The Opadry solution is then atomized on the core tablet by means of a turbine coating device under the following conditions: exhaust air temperature 38-42٠C, atomization pressure 28-40 psi and rate of. atomization 10-15 ml / min. The core tablet is coated with the sealant solution until a theoretical coating level of approximately 2-4% is achieved.

II. Membrane (% of membrane composition)

<td>Cellulose acetate (398-10) 2</td><td> 85%</td>

<td>Triacetin</td><td> 5%</td>

<td>PEG 400</td><td> 10%</td>

<td colspan="2">³acetyl content 39.3-40.3%</td>

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WO 2006/107528 (a) Method of coating a membrane

Cellulose acetate is dissolved in acetone while stirring with a homogenizer. Polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The clear membrane coating solution is then atomized onto the sealed coated tablets in a fluidized bed coating device under the following conditions: product temperature 16-22٥c, atomization pressure approximately 3 bar and rate d. atomization 120 150 ml / min. The sealed coated core tablet is coated to a theoretical coating level of approximately 3%.

III. Second active drug layer (% of the composition of the second component)

Pioglitazone HCl 43.5%

Tween 80 2.0%

Hydroxypropylmethylcellulose 54.5%

Tween 80 and hydroxypropylmethylcellulose are dissolved in purified water. The pioglitazone HCl is then dispersed in this solution. The resulting suspension is then sprayed onto the aforementioned membrane coated tablets.

EXAMPLE 2

A controlled release tablet containing 850 mg of metformin hydrochloride and 15 mg of pioglitazone is prepared as follows:

First active drug

I. Core

Metformin HCl

Povidone K-90³, USP (٠ / o of the core composition)

88.555%

6.368%

Sodium Lauryl Sulphate

4.577%

Magnesium stearate

0.5% ³approximate molecular weight = 1,000,000, dynamic viscosity (10% w / v solution)

300-700 mPa-s at 20٥C.

(a) Granulation

Metformin hydrochloride and sodium lauryl sulfate are disaggregated by passing them through a 40 mesh screen and collecting them in a clean polyethylene lined container. Povidone, Κ-90, is dissolved in purified water. The disaggregated metformin HCl and sodium lauryl sulfate are then added in a top-spray fluidized bed granulator and granulated by atomizing the povidone binder solution under the following conditions: air temperature

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When the binder solution is used up, the granules are dried in the granulator until the loss on drying is less than 2٥%. The dried granules are passed through a comil fitted with the equivalent of an 18 mesh screen.

(b) Manufacture of tablets

The magnesium stearate is passed through a 40 mesh stainless steel screen and mixed with the metformin hydrochloride granules for approximately five (5) minutes. After mixing, the granules are compressed on a rotary tablet press fitted with standard 15/32 round concave punches (plain bottom punch, top punch with approximately 1mm indentation pin).

As stated above, the orifice can be formed by any means usually employed in the pharmaceutical industry.

(c) Waterproof coating (optional)

The core tablet is sealed coated with an Opadry material or other suitable water soluble material, first dissolving the Opadry material, preferably Opadry Clear, in purified water. The Opadry solution is then atomized on the core tablet by means of a turbine coating device under the following conditions: temperature of the exhaust air 38-42 ° C, atomization pressure 28-40 psi and rate d atomization 10-15 ml / min. The core tablet is coated with the sealed solution until a theoretical coating level of approximately 2% is obtained.

<td>II</td><td>Membrane</td><td>(٥/٥ of the composition of the membrane)</td>

<td></td><td>Cellulose acetate (398-10) 4</td><td> 85٥/٥</td>

<td></td><td>Triacetin</td><td> 5٥/٥</td>

<td></td><td>PEG 400</td><td> 10٥/٥</td>

acetyl content 39.3-40.3٥ / ο (a) Process for coating a membrane

Cellulose acetate is dissolved in acetone while stirring with a homogenizer. Polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred. The coating solution is then atomized on the tablets coated with a sealed coating in a coating device in a fluidized bed under the following conditions: product temperature 16-22٥c, atomization pressure approximately 3 bars and atomization rate 120 -150 ml / min. The coated core tablet

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III. Second active drug layer (% of the composition of the second component)

Pioglitazone HCl 43.5%

Tween 80 2.0٥ / ο

Hydroxypropylmethylcellulose 54.5%

Tween 80 and hydroxypropylmethylcellulose are dissolved in purified water. The pioglitazone HCl is then 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 metformin hydrochloride and 15 mg of pioglitazone is prepared as follows:

I. First active drug

A 500 mg membrane coated metformin tablet is prepared as described in Example 2 above except that cup tooling is used during the manufacture of the tablets. The 500 mg membrane-coated metformin tablet has the following composition:

CORE

Metformin HCl

Povidone Κ-90, USP Sodium Lauryl Sulfate, NF Magnesium Stearate, NF

WATERPROOF COATING Opadry Clear (YS-l-7006)

MEMBRANE COATING Cellulose acetate, 398-10, NF Triacetine, USP Polyethylene glycol 400, NF

Total weight

500 mg / tablet

35.96 mg / tablet

25.84 mg / tablet

2.82 mg / tablet

23.53 mg / tablet

23.56 mg / tablet

1.39 mg / tablet

2.77 mg / tablet

615.87 mg / tablet

II. Layer of the second active component

An immediate release amount of pioglitazone HCl is applied to the 500 mg membrane coated metformin HCl tablet prepared in step I. The final compound has the following composition:

<td>Membrane-coated metformin HCl tablet</td><td>615.87 mg / tablet</td>

<td>Pioglitazone coating Pioglitazone HCl</td><td>16.53 mg / tablet</td>

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<td>Tween 80 Polyplasdone XL Opadry Clear (YS-l-7006) Color coating</td><td>2.0 mg / tablet 15.0 mg / tablet 8.47 mg / tablet</td>

<td>Opadry white Polishing coating</td><td>10.0 mg / tablet</td>

<td>Candelilla wax powder</td><td>2.0 mg / tablet</td>

The pioglitazone coating is directly applied to the 500 mg metformin HCl tablets coated with a membrane. The pioglitazone coating is prepared by dissolving 0.252 kg of Opadry Clear, 0.269 kg of Polyplasdone XL and 0.036 kg of Tween 80 in 9.908 kg of purified water using a homogenizer. When these ingredients are dissolved, 0.296 kg of pioglitazone HCl is dispersed in the solution and homogenized. The homogenized dispersion is then directly applied to the 500 mg metformin HCl tablets coated with a membrane by means of a 24 O'Hara Labcoat III turbine coating device under the following conditions:

<td>Atomization rate</td><td>15-27 mL / min</td>

<td>Exhaust air temperature Atomizing air pressure Turbine speed Air flow admitted</td><td>42-47٥C 25 psi 5-9 rpm 300-400 CFM</td>

When the pioglitazone coating is applied to the membrane coated 500 mg Metformin HCl tablets, an aesthetic or Opadry white colored coating is applied to the pioglitazone coated tablets. The color coating is prepared by dispersing 0.179 kg of Opadry White in 1.791 kg of purified water. Opadry White suspension is applied to tablets coated with pioglitazone by means of a 24 O'Hara Labcoat III turbine coating device under the following conditions:

Atomization rate 20-35 mL / min

Exhaust air temperature 35-45٥C

Atomizing air pressure 25 psi

Turbine speed 9 rpm

Intake air flow 390-500 CFM

When the color coating is applied, the tablets are polished using 0.036 kg of powdered Candelilla wax.

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EXAMPLE 4

A controlled release tablet containing 500 mg of metformin hydrochloride and 15 mg of pioglitazone is prepared as follows:

I. First active drug

A tablet coated with a 500 mg membrane is prepared as described in Example 2 except that cup tooling is used during the manufacture of the tablets. The compound coated with a 500 mg membrane has the following composition:

<td>CORE Metformin HCl Povidone Κ-90, USP Sodium Lauryl Sulfate, NF Magnesium stearate, NF</td><td>500 mg / tablet 35.96 mg / tablet 25.84 mg / tablet 2.82 mg / tablet</td>

<td>WATERPROOF COATING Opadry Clear (YS-l-7006)</td><td>23.53 mg / tablet</td>

<td>MEMBRANE COATING Cellulose acetate, 398-10, NF Triacetine, USP Polyethylene glycol 400, NF Total weight</td><td>23.56 mg / tablet 1.39 mg / tablet 2.77 mg / tablet 615.87 mg / tablet</td>

II. Second active compound layer

An immediate release amount of pioglitazone HCl is applied to the 500 mg membrane-coated metformin HCl tablet prepared in step I. The final tablet has the following composition:

Membrane-coated metformin HCl tablet

Waterproof coating

Opadry Clear (YS-l-7006)

Pioglitazone coating

Pioglitazone HCl

Tween 80

Sodium chloride

Opadry Clear (YS-l-7006)

Color coating

Opadry white

Polishing coating

Candelilla wax

615.87 mg / tablet

13.8 mg / tablet

16.53 mg / tablet

2.0 mg / tablet

4.27 mg / tablet

2.0 mg / tablet

8.10 mg / tablet

0.20 mg / tablet

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The leak-proof coating solution is prepared by dissolving 0.258 kg of Opadry Clear in 2.576 kg of purified water and atomizing the solution on approximately 12.088 kg of 500 mg metformin HCl tablet cores coated with a membrane using a 24 O'Hara Labcoat III turbine coating device. The waterproof coating is

<td>applies under the following conditions: Atomization rate Exhaust air temperature Atomizing air pressure Turbine speed Inlet air flow</td><td>20-35 mL / min 35-45٥C 25 psi 9 rpm 390-500 CFM</td>

The pioglitazone coating is directly applied to tablets coated with a 500 mg HCl metformin membrane. The pioglitazone coating is prepared by dissolving 0.040 kg of Opadry Clear, 0.085 kg of sodium chloride and 0.040 kg of Tween 80 in 4.915 kg of purified water by means of a homogenizer. When these ingredients are dissolved, 0.328 kg of pioglitazone HCl is dispersed in the solution and homogenized. The homogenized dispersion is then applied to the 500 mg metformin HCl tablets coated with a membrane by means of a 24 O'Hara Labcoat III turbine coating device under the following conditions:

Atomization rate 10-30 mL / gun / min

Exhaust air temperature 35-45٥C

Atomizing air pressure 20-40 psi

Model air pressure 20-40 psi

Turbine speed 8-12 rpm

Intake air flow rate 250-450 CFM.

When the pioglitazone coating is applied to the membrane coated, waterproof coated 500 mg metformin HCl tablets, an aesthetic or colored coating of Opadry White is applied to the pioglitazone coated tablet. The color coating is prepared by dispersing 0.159 kg of Opadry White in 1.585 kg of purified water. The Opadry White suspension is applied to the pioglitazone coated tablet under conditions similar to those described above for the application of the waterproof coating. When the color coating is applied, the tablets are polished using 0.004 kg of powdered Candelilla wax.

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EXAMPLE 5

A controlled release tablet containing 1000 mg of metformin hydrochloride and 30 mg of pioglitazone is prepared as follows:

1. First active drug

A. Core

Metformin HCl

Povidone Κ-90١ USP

Sodium Lauryl Sulphate

Magnesium stearate (% of core composition) 88.07٥ / ο

6.87%

4.55%

0.5%) approximate molecular weight = 1,000,000, dynamic viscosity (10% w / v solution) 300-700 mPa-s at 20٥C.

Approximately 206.34 kg of purified water is added to a stainless steel tank, followed by approximately 10.86 kg of povidone Κ-90. The solution is mixed at about 330-360 rpm for about 45 minutes or until the povidone is completely dissolved. Approximately 139.14 kg of metformin HCl is passed through a Comil fitted with a # 813 sieve and no spacer at 840-850 rpm.

The sieved metformin HCl is loaded into a GPCG-60 brand fluidized bed embedding device (Glatt) with a Wurster insert (size 32 and 35 mm high) with 3 nozzles of 1.5 mm. The metformin HCl is fluidized and the temperature of the product is adjusted to about 38-43٥C. The povidone solution is atomized onto the fluidized metformin HCl with an atomization pressure of about 2.5-3.0 bar and a pump speed:

0- 15 minutes 491 -515 g / min (target 500g / min)

16-30 minutes 680-710 g / min (target 700 g / min)

31-45 minutes 860-910 g / min (target 900 g / min)

46-60 minutes 1090-1170 g / min (target 1100 g / min) minutes at the end 1170-1220 g / min (target 1200 g / min).

When the povidone solution is exhausted, the granules are dried in the fluidized bed at approximately 2100 CFM and an inlet air temperature of 6O٥C until the loss on drying (LOD) does not exceed 2٥ / ο . The resulting granules are passed through a Comil fitted with a # 1143 stainless steel screen and a # 075 spacer at a speed of 1086-1088 rpm to produce approximately 150 kg of metformin HCl granules. The granulation process is repeated a second time to produce approximately 300 kg of metformin HCl granules.

300 Approximately kg of metformin granules are added to a 50 cubic foot Slant-Cone mixer with approximately 14.38 kg of sodium lauryl sulfate and mixed for approximately 20 minutes. About

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1.58 kg of magnesium stearate is passed through a # 40 stainless steel mesh screen, then added to the mixture in a Slant-Cone mixer. The resulting mixture is mixed for about 5 minutes, then compressed into tablets using a conventional tablet press equipped with a round compound die 2 ا ؛, with a precompression force of 6 and a main compression force of 38. The resulting tablets display a weight range of 1044 g to approximately 1226 g with a target weight of 1135g, a hardness of 20-36 kp (target 28 kp) and a friability of 0.8% or less.

B. Waterproof coating

About 57.61 kg of the core tablets prepared above are coated with a waterproof coating of Opadry material or other suitable water soluble material by first dissolving the Opadry material, preferably about 3.98 kg of Opadry Clear YS-1-7006, in approximately 21.49 kg of purified water. The Opadry solution is then atomized on the core tablets by means of a coating device in an O'Hara Lab Coat III turbine with a turbine of 36, 3 atomizing guns under the following conditions: temperature of the exhaust air 40- 47٥C, atomization pressure 50 ± 10 psi and atomization rate 180 ± 60 g / min / 3 guns, turbine speed 4-8 rpm and air volume 1000Τ200 CFM. The core tablet is coated with the sealant solution until a theoretical coating level of 2.8-4.4% is obtained.

C. Membrane coating

A membrane coating of cellulose acetate is applied to the cores of the metformin HCl tablets to produce membrane coated metformin HCl tablets having the following composition:

Metformin HCl tablet 1000 mg 98.456%

Cellulose acetate (398-10) 4 1.33 / 0

Triacetine 0.077%

PEG 400 1.54%

4 acetyl content 39.3-40.3%

Approximately 29.95 kg of acetone is added to a stainless steel tank, followed by approximately 0.788 kg of cellulose acetate and mixed for approximately 20 minutes until the solution becomes clear. When the solution becomes clear, approximately 0.092 kg of polyethylene glycol 400 is added to the solution and mixed for approximately 5 minutes, then approximately 0.046 kg of triacetin is added. The solution is mixed for an additional 5 minutes.

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Approximately 59.07 kg of the sealed-coated metformin HCl tablets are loaded into a GPCG-60 brand fluid bed embedding device (Glatt) with a Wurster insert (size 18 for 45mm height) with a 1.5 nozzle. mm. The sealed-coated metformin HCl tablets are fluidized and the product temperature is adjusted to about 21 ± 3 ±c. The cellulose acetate solution is atomized onto the fluidized tight-coated metformin HCl tablets with atomization pressure of about 2.0-3.0 bar, air volume of 1600 ٠ 300 CFM and atomization rate of 400,000 g / min until a weight gain of l-2٥ / o is obtained (target 1.38٥ / ο). When the desired amount of membrane coating is applied, the membrane coated tablets are dried in the coating pan at 21 ± 3٥c and 1350 00 CFM for about 10 minutes followed by 4O٥C and 1350 ± 100 CFM for about 5 minutes.

The resulting membrane coated tablets are laser drilled to create an orifice in the approximate center of each side of the membrane coated tablet (i.e. 2 holes) with an average diameter of 0.5 mm per. orifice. The upper micrometer is 6.5 ± 2mm, the lower micrometer is 6.75 ± 2mm, the laser pulse width is 170 ± 70, and the pulse delay is 340 ± 150 and 350 ± 150 respectively.

II. Second active drug

An immediate release amount of pioglitazone HCl is applied to the 1000 mg membrane coated metformin HCl tablets prepared in step I. The final tablet has the following composition:

<td>Metformin HCl tablet coated with a membrane Leakproof coating</td><td>1201.0 mg / tablet</td>

<td>Opadry Clear (YS-l-7006)</td><td>16.0 mg / tablet</td>

<td>Pioglitazone coating Pioglitazone HCl Sodium chloride Opadry Clear (YS-l-7006) Color coating</td><td>33.06 mg / tablet 4.27 mg / tablet 3.0 mg / tablet</td>

<td>Opadry II White (Υ-22-7719)</td><td>20.27 mg / tablet</td>

<td>Polishing coating Candelilla wax powder</td><td>0.40 mg / tablet</td>

The waterproof coating is prepared by dispersing 0.174 kg of Opadry Clear 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 metformin HCL tablets coated with a membrane using a 24 O'Hara Labcoat III turbine coating device. The

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Atomization rate 10-30ml / gun / min

Exhaust air temperature 25-45٥C

Atomizing air pressure 20-40 psi

Turbine speed 6-12 rpm

Model air pressure 20-40 psi

Intake air flow 250-450 CFM

The pioglitazone coating is then applied to the membrane coated, waterproof coated 1000 mg metformin HCl tablets. The pioglitazone coating is prepared by dissolving 0.036 kg of Opadry Clear and 0.046 kg of sodium chloride in 5.344 kg of ethanol using a homogenizer. When the ingredients are dispersed, 0.359 kg of pioglitazone HCl is dispersed in the solution and homogenized. The homogenized dispersion is then applied to the 1000 mg metformin HCl tablets coated with a membrane, waterproof coating, by means of a 24 O'Hara Labcoat III turbine coating device under the following conditions:

Atomization rate Exhaust air temperature Atomization air pressure Turbine speed

Model air pressure

Air flow admitted

10-30 mL / gun / min

25-45٥C

20-40 psi

6-12 rpm

20-40 psi

250-450 CFM

When the pioglitazone coating is applied, an aesthetic or colored coating of Opadry II White is applied to the tablets coated with pioglitazone. The color coating is prepared by dispersing 0.220 kg of Opadry II White in 4.407 kg of ethanol. The Opadry II White suspension is then applied to the pioglitazone HCl coated tablets by means of a 24 O'Hara Labcoat III turbine coating device under conditions similar to those described above for the waterproof coating. When the color coating is applied, the tablets are polished using 0.004 kg of powdered Candelilla wax.

EXAMPLE 6

A controlled release tablet containing 1000 mg of metformin HCl and 30 mg of pioglitazone is prepared as follows:

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I. First active drug

A 1000 mg membrane coated tablet is prepared as described in Example 5 above. 1000 mg has the following composition CORE

Metformin HCl

Povidone Κ-90, USP Sodium Lauryl Sulfate, NF Magnesium Stearate, NF

WATERPROOF COATING Opadry Clear (YS-l-7006)

MEMBRANE COATING Cellulose acetate, 398-10, NF Triacetine, USP Polyethylene glycol 400, NF

Total weight

The tablet coated with a

1000 mg / tablet

78.0 mg / tablet

51.69 m / tablet

5.65 mg / tablet

47.05 mg / tablet

15.77 mg / tablet

0.92 mg / tablet

1.85 mg / tablet

1201.0 mg / tablet

II. Second active drug

An immediate release amount of pioglitazone HCl is applied to the 1000 mg membrane coated metformin HCl tablets prepared in step I. The final tablet has the following composition:

<td>Membrane-coated metformin HCl tablet Waterproof coating</td><td>1201.0 mg / tablet</td>

<td>Opadry Clear (YS-l-7006)</td><td>21.0 mg / tablet</td>

<td>Pioglitazone coating Pioglitazone HCl Sodium Chloride Opadry Clear (YS-l-7006) Color coating</td><td>33.06 mg / tablet 5.0 mg / tablet 3.7 mg / tablet</td>

<td>Opadry II White (Υ-22-7719)</td><td>21.54 mg / tablet</td>

<td>Polishing coating Candelilla wax powder</td><td>0.40 mg / tablet</td>

The second coating is applied to the 1000 mg metformin HCl tablets coated with a membrane. The waterproof coating is prepared by dispersing 0.229 kg of Opadry Clear in 4.573 kg of USP alcohol and mixing the dispersion for 15 minutes. The dispersion is then atomized onto approximately 13.08 kg of 1000 mg metformin HCl tablet cores by means of a turbine coating device.

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O'Hara Labcoat III with the nozzle tip set 4 ± 2 above the bed

WO 2006/107528 static under the following conditions:

Atomization rate

Exhaust air temperature

Atomizing air pressure

Turbine speed

Supply air flow

Model air pressure ± 10 mL / gun / min

25٠c ± 5٥c

10-40 psi

4-9 rpm

200 ± 100 CFM

10-40 psi

The dispersion of the waterproof coating is stirred continuously until it is exhausted during the coating process.

The pioglitazone coating is then applied to the membrane coated, waterproof coated 1000 mg metformin HCL tablets. The pioglitazone coating is prepared by mixing 4.434 kg of USP alcohol and 1.250 kg of purified water (approximately 78:22 alcohol to purified water ratio) and slowly dispersing 0.040 kg of Opadry Clear into the mixture. solvents. When Opadry Clear is dispersed, it is homogenized for approximately 10 minutes. When the Opadry Clear dispersion is homogenized, 0.054 kg of sodium chloride is added to the dispersion and homogenized for approx. 2 minutes. After homogenization of the sodium chloride, 0.360 kg of pioglitazone HCl is slowly dispersed in the mixture of solvents and then homogenized for about 10 minutes. When the pioglitazone HCl is homogenized, the homogenizer is removed from the mixing vessel and replaced with an air mixer which mixes for an additional 15 minutes. The pioglitazone suspension is stirred until exhaustion of the coating suspension during the coating process. The pioglitazone HCl suspension is applied to the cores of the 1000 mg, membrane-coated, leak-proof coated metformin HCl tablets using an O'Hara Labcoat III 24 hrrbin coating device with the tip. of the nozzle adjusted to 4 ± 2 above the static bed under the following conditions:

Atomization rate Exhaust air temperature

Atomizing air pressure

Turbine speed

Model air pressure

Supply air flow

25 ± 10 mL / gun / min

25 ± 5٥c

10-40 psi

4-9 rpm

10-40 psi

200 00 CFM

When the pioglitazone coating is applied to tablets of

1000 mg metformin HCl coated with a membrane, coated

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WO 2006/107528 waterproof, an aesthetic coating of Opadry II White is applied to the pioglitazone coated tablet. The aesthetic coating is prepared by dispersing 0.235 kg of Opadry II White (Υ-22-7719) in 4.691 kg of USP alcohol and mixing the dispersion for about 1 hour. The Opadry II White dispersion is then sprayed onto the pioglitazone HCl coated tablets using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set at 4 ± 2 above the static bed. and under the following conditions:

Atomization rate Exhaust air temperature Atomization air pressure

Turbine speed

Supply air flow Model air pressure

2510 لج mL / gun / min

25٥Ci5٥C

10-40 psi

4-9 rpm

200 ± 100 CFM

10-40 psi

The color coating dispersion is stirred continuously until the dispersion is exhausted during the coating process.

When the aesthetic coating suspension is used up, the tablets are dried in the coating pan for about 5 minutes with a turbine speed of about 2-8 rpm and an exhaust air temperature of 25 ± 5 ° C. . When the tablets are dried, the exhaust air is stopped and the speed of the turbine is adjusted to about 3-4 rpm and 0.004 kg of powdered Candelilla wax which has been passed through a 60 mesh sieve is dispersed over them. tablets. After rolling the tablets in wax for about 5 minutes, the exhaust air is turned on and the tablets are rolled for an additional 10 minutes.

The finished polished tablet displays the following pioglitazone HCl dissolution profile when tested in a USP Type 1 apparatus at 100 rpm in HC1-0.3M KCl pH 2.0 buffer solution:

<td>Duration</td><td>٥/٠ of pioglitazone released</td>

<td>10 minutes</td><td> 42%</td>

<td>20 min</td><td> 79%</td>

<td>30 min</td><td> 95%</td>

<td>45 mins</td><td> 102%</td>

The finished polished tablet also contains the following pioglitazone-related compounds when tested by HPLC using a YMC-ODSAQ column, 5pm, 120Â, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: acid glacial acetic (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٥c and wavelength 269 nm for the uv detector.

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<td>Last name</td><td>Relative retention time</td><td>amount (%)</td>

<td>RS-1</td><td> 0.7</td><td>ND *.</td>

<td>Pioglitazone</td><td> 1.0</td><td></td>

<td>RS-2</td><td> 1.5</td><td> 0.03</td>

<td>RS-3</td><td> 3.4</td><td> 0.04</td>

<td>RS-4</td><td> 1.2</td><td> 0.03</td>

<td>RS-5</td><td> 2.8</td><td> 0.04</td>

<td>* ND = not detected</td><td></td><td></td>

RS-1 is (-i - / -) - 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] benzylidenej-2,4thiazolidinedione.

RS-3 is (-t / -) - 5- [p- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] -3- [2- (5-ethyl2-pyridyl) ethylj-2,4 -thiazolidinedione.

RS-4 is (-t - / -) - ethyl-2-carbamoyltio-3- [4- [2- (5-ethyl-2-pyridyl) ethoxy] phenylj-propionate.

RS-5 is ethyl-3-p- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl-propionate.

The final polished tablet is packaged in a 100 cc HDPE bottle containing one (1) container of 2g SORB-ΙΤ® desiccant and subjected to accelerated stability conditions of 4O٥C and 75% relative humidity for 3 months. After storage, the final polished tablet is tested and displays the following pioglitazone HCl dissolution profile when tested in a USP type 1 apparatus at 100 rpm in HC1-0.3M KCl pH 2.0 buffer solution:

Duration% pioglitazone released min 38٥ / ο min 73% min 92% min 101%

The final polished tablet stored also contains the following compounds related to pioglitazone when tested by HPLC using a YMC-ODS-AQ column, 5pm, 120Â, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: glacial acetic acid (25: 25: 1), injection volume 40 pL, flow rate 0.7 ml / min, column temperature 25٥c and wavelength 269 nm for the uv detector.

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<td>Last name</td><td>Relative retention time</td><td>Ouantite (%}</td>

<td>RS-1</td><td> 0.7</td><td>ND *</td>

<td>Pioglitazone</td><td> 1.0</td><td></td>

<td>RS-2</td><td> 1.5</td><td> 0.03</td>

<td>RS-3</td><td> 3.4</td><td> 0.03</td>

<td>RS-4</td><td> 1.2</td><td> 0.02</td>

<td>RS-5</td><td> 2.8</td><td> 0.04</td>

* ND = not detected

EXAMPLE?

A controlled release tablet containing 1000 mg of metformin HCl and 30 mg of pioglitazone is prepared as follows:

A. Novau with first active drug

A cellulose acetate-coated metformin HCl tablet is prepared as described in Example 5.

B. Second active drug

An immediate release amount of pioglitazone HCL is applied to the 1000 mg membrane coated Metformin HCl tablets, prepared above in step A. The final tablet has the following composition:

Metformin HCl tablet coated with a membrane 1201.0 mg / tablet

Waterproof coating opadry Clear (YS-1 -7006) 9.00 mg / tablet

Pioglitazone coating

Pioglitazone HCl 33.06 mg / tablet

Hydroxypropylcellulose, NF (HPC-SSL) 9.0 mg / tablet

Lactose monohydrate, NF 30.0 mg / tablet (modified, spray dried)

Polyethylene glycol 8000, NF 0.450 mg / tablet

Titanium dioxide, USP 0.90 mg / tablet

Polishing coating

Candelilla wax powder 0.40 mg / tablet

The waterproof coating is applied to approximately 12.09 kg of 1000 mg membrane coated metformin HCL tablets prepared in step A described above. The waterproof coating is prepared by dispersing about 0.91 kg of Opadry Clear (YS-l-7006) in about 1.133 kg of purified water for 30 minutes. The dispersion is atomized onto approximately 12.09 kg of 1000 mg metformin HCL tablet cores coated with a membrane by means of a coating device.

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PCT / US2OO6 / OO9O82 24 0'14ara Labcoat III turbine with the nozzle tip set to 4 ± 2 above the static bed, 3 atomizing guns and under the following conditions:

± 10 mL / gun / min

4O٥C ± 5٥C

10-40 psi

4-9 rpm

300 00 CFM

10-40 psi

Atomization rate

Exhaust air temperature Atomizing air pressure Turbine speed

Supply air flow Model air pressure

The pioglitazone coating is applied to tablets coated with a 1000 mg metformin HCl membrane, waterproof coating. The pioglitazone coating is prepared by slowly dispersing approximately 0.104 kg of hydroxypropylcellulose, NF (HPC-SLL), in approximately 8.499 kg of purified water. HPC-SSL and water are mixed for about 20 minutes, then 0.347 kg of lactose monohydrate, NF (modified, spray-dried) is added to the HPC-SSL / water mixture and mixed for about 2 minutes. After mixing the lactose, approximately 0.005 kg of polyethylene glycol 8000 NF and 0.010 kg of titanium dioxide USP are added to the mixture of water, HPC-SSL and lactose and mixed for approximately 5 minutes. After about 5 minutes of mixing, about 0.383 kg of pioglitazone hydrochloride is dispersed in the coating solution. This coating solution contains approximately 15% excess material to compensate for material loss during the coating process. The pioglitazone suspension is stirred until the suspension is exhausted during the coating process. The pioglitazone HCl suspension is applied to the cores of the 1000 mg membrane-coated, leak-proof coated Metformin HCl tablets using a 24 O'Hara Labcoat III turbine coating device with a nozzle. the nozzle set at 4 ± 2 above the static bed, 3 atomizing guns under the following conditions:

Atomization rate 20 ± 10 mL / gun / min

Exhaust air temperature 4O ± 5٥C

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Model air pressure 10-40 psi

Supply air flow 300 ^ 100 CFM

When the pioglitazone tablets are dried, the exhaust air is stopped and the speed of the turbine is adjusted to about 3-4 rpm; 0.004 kg of powdered Candelilla wax which has passed through a 60 mesh sieve is dispersed on the tablets. After rolling the tablets in the wax

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The finished polished tablet releases more than 95٥ / ο of the pioglitazone when tested in a USP type 1 apparatus at 100 rpm in HCl0.3Μ KCl pH 2.0 buffer solution. The final tablets also exhibit a hardness greater than 35 kp and a friability of 0.00%. The final tablet is tested for compounds relating to pioglitazone by HPLC using a YMC-ODS-AQ column, 5pm, 120A, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: acetic acid glacial (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٥c and wavelength 269 nm for the uv detector. The results of the test are reported in Table 1 below.

The final polished tablet is packaged in a 100 cc HDPE bottle containing one (1) container of 3g SORB-ΙΤ® desiccant and subjected to accelerated stability conditions of 4O٥C and 75% relative humidity for fifteen days, 1 month, 2 months, 3 months and 6 months. After storage, the final polished tablet is tested and found to contain the following pioglitazone compounds when tested by HPLC using a YMC-ODSAQ column, 5pm, 120A, 4.6 x 250 mm, mobile phase: buffer 0.1 Ammonium acetate: acetonitrile: glacial acetic acid (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperahire 25٠c and wavelength 269 nm for the uv detector.

TABLE 1

<td></td><td>Initial</td><td>0.5 M</td><td>IM</td><td>2Μ</td><td>3Μ</td><td>6Μ</td>

<td>Last name</td><td> (٥/٥)</td><td> (٥/٥)</td><td> (٥/٥)</td><td> (٥/٠)</td><td> (%)</td><td> (٥/٥)</td>

<td>RS-1</td><td> 0.01</td><td> 0.01</td><td> 0.01</td><td>ND</td><td>ND</td><td>ND</td>

<td>RS-2</td><td> 0.02</td><td> 0.03</td><td> 0.03</td><td> 0.02</td><td> 0.03</td><td> 0.02</td>

<td>RS-3</td><td> 0.03</td><td> 0.04</td><td> 0.03</td><td> 0.03</td><td> 0.04</td><td> 0.04</td>

<td>RS-4</td><td> 0.03</td><td> 0.02</td><td> 0.03</td><td> 0.03</td><td> 0.02</td><td> 0.02</td>

<td>RS-5</td><td> 0.04</td><td> 0.04</td><td> 0.04</td><td> 0.04</td><td> 0.03</td><td> 0.04</td>

<td>M ”</td><td>= month</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2">EXAMPLE 8</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>A tablet at</td><td>release</td><td>controlled</td><td>container</td><td>1000 mg of</td><td>HCl '</td>

metformin and 30 mg of pioglitazone is prepared as follows:

A. Core with first active drug

A cellulose acetate coated metformin HCl tablet is prepared according to the procedure described in Example 5.

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B. Second active drug

An immediate release amount of pioglitazone HCl is applied to the 1000 mg membrane coated metformin HCl tablets prepared above in step A. The final tablet has the following composition:

Metformin HCl tablet

<td>membrane coated</td><td>1201.0 mg / tablet</td>

<td>Waterproof coating</td><td></td>

<td>Opadry Clear (YS-l-7006)</td><td>9.00 mg / tablet</td>

<td>Pioglitazone coating</td><td></td>

<td>Pioglitazone HCl</td><td>33.06 mg / tablet</td>

<td>Hydroxypropylcellulose, NF (HPC-SSL)</td><td>9.0 mg / tablet</td>

<td>Lactose monohydrate, NF</td><td>30.0 mg / tablet</td>

<td>(modified, spray dried)</td><td></td>

<td>Polyethylene glycol 8000, NF</td><td>0.450 mg / tablet</td>

<td>Titanium dioxide, USP</td><td>0.90 mg / tablet</td>

<td>Color coating</td><td></td>

<td>Hydroxypropylcellulose, NF (HPC-SSL)</td><td>5.5 mg / tablet</td>

<td>Polyethylene glycol 8000, NF</td><td>1.38 mg / tablet</td>

<td>Titanium dioxide, USP</td><td>0.60 mg / tablet</td>

<td>Polishing coating</td><td></td>

<td>Candelilla wax powder</td><td>0.40 mg / tablet</td>

The waterproof coating is applied to approximately 13.02 kg of the 1000 mg membrane-coated metfomiine HCl tablets prepared in Step A described above. The waterproof coating is prepared by dispersing about 0.098 kg of Opadry Clear (YS-1-7006) in about 1.220 kg of purified water for 30 minutes. The dispersion is then sprayed onto approximately 13.02 kg of 1000 mg metformin HCl tablet cores using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set to 4 ± 2 in above the static bed, 3 atomizing guns and under the following conditions:

Atomization rate 20 ± 10 mL / gun / min

Exhaust air temperature 4O٥C ± 5٥c

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Supply air flow 300 00 CFM

Model air pressure 10-40 psi

The pioglitazone coating is then applied to the 1000 mg metformin HCl tablets coated with a membrane, coated

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WO 2006/107528 PCT / US2OO6 / OO9O82 waterproof. The pioglitazone coating is prepared by slowly dispersing about 0.108 kg of hydroxypropylcellulose (HPC-SLL) in about 8,753 kg of purified water. The HPC-SSL and water are mixed for about 20 minutes, after which 0.358 kg of lactose monohydrate, NF (modified, spray-dried), is added to the HPC-SSL / water mixture and mixed for about 2 minutes. After mixing the lactose, approximately 0.006 kg of polyethylene glycol 8000 NF and 0.011 kg of titanium dioxide USP are added to the mixture of water, HPC-SSL and lactose and mixed for approximately 5 minutes. After about 5 minutes of mixing, about 0.394 kg of pioglitazone hydrochloride is dispersed in the coating solution. This coating solution contains approximately 10% excess material to compensate for the loss of material during the coating process. The pioglitazone suspension is stirred until the suspension is exhausted during the coating process. The pioglitazone HCl suspension is applied to the cores of the 1000 mg membrane-coated, leak-proof coated metformin HCL tablets using a 24 O'Hara Labcoat III turbine coating device with the tip of the nozzle adjusted to 4 ± 2 above the static bed, 3 spray guns, under the following conditions:

Atomization rate 20 ± 1 OmL / gun / min

Exhaust air temperature 4O ± 5٥C

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Model air pressure 10-40 psi

Supply air flow 300 = 00 CFM

When the pioglitazone coating is applied to the membrane coated, waterproof coated 1000 mg metformin HCL tablets, a color or aesthetic coating is applied to the pioglitazone coated tablets. The color coating is prepared by dispersing approximately 0.060 kg of HPC-SSL NF, 0.015 kg of polyethylene glycol 8000 NF and 0.007 kg of titanium dioxide USP in 0.810 kg of purified water and mixing the dispersion for approximately 30 minutes. The color coating is then atomized onto the pioglitazone HCl coated tablets using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set 4 ± 2 ”above the static bed. , 3 spray guns and under the following conditions:

Atomization rate

Exhaust air temperature

Atomizing air pressure

Turbine speed

Supply air flow

0 mL / gun / min

4O٥C5٥C

10-40 psi

4-9 rpm

300Ü00 CFM

Model air pressure 10-40 psi

<img file="MA29675B1_D0001.tif" />

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The color coating dispersion is stirred continuously until the dispersion is exhausted during the coating process.

When the color coating slurry is used up, the tablets are dried in the coating pan for about 5 minutes with a turbine speed of about 2-8 rpm and an exhaust air temperature of 40 ± 5٥c. When the tablets are dried, the exhaust air is stopped and the speed of the turbine is adjusted to about 3-4 rpm; 0.004 kg of powdered Candellia wax which has been passed through a mesh sieve is dispersed over the tablets. After rolling the tablets in the wax for about 5 minutes, the exhaust air is turned on and the tablets are rolled for an additional 10 minutes.

The finished polished tablet releases more than 90٥ / ο of the pioglitazone when tested in a USP type 1 apparatus at 100 rpm in HCl 0.30 KCl pH 2.0 buffer solution. The average of the 12 containers tested is 96٥ / ο of release. The final tablets also exhibit a hardness greater than 35 kp and a friability of 0.1٥ / ο. The final tablet is tested for compounds relating to pioglitazone by HPLC using a YMC-ODS-AQ column, 5μη, 120Â, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: acid glacial acetic (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٠c and wavelength 269 nm for the uv detector. The results of this test are reported in Table 2 below.

The final polished tablet is packaged in a 100 cc HDPE bottle containing one (1) container of 3g SORB-ΙΤ® desiccant and subjected to accelerated stability conditions of 4O٥C and 75٥ / ο relative humidity for fifteen days, 1 month, 2 months, 3 months and 6 months. After storage, the final polished tablet is tested and found to contain the following pioglitazone compounds when tested by HPLC using a YMC-ODSAQ column, 5pm, 120A, 4.6 X 250 mm, mobile phase: buffer 0.1 Ammonium acetate: acetonitrile: glacial acetic acid (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25 ° C and wavelength 269 nm for the UV detector.

TABLE 2

<td>Last name</td><td>Initial (٥/٥)</td><td>0.5 M (%)</td><td>IM (%)</td><td>2Μ (٥/٥)</td><td>3Μ</td><td>6Μ (٥/٥)</td>

<td>RS-1</td><td> 0.01</td><td> 0.01</td><td> 0.01</td><td>ND</td><td>ND</td><td>ND</td>

<td>RS-2</td><td> 0.02</td><td> 0.03</td><td> 0.03</td><td> 0.02</td><td> 0.03</td><td> 0.03</td>

<td>RS-3</td><td> 0.03</td><td> 0.03</td><td> 0.03</td><td> 0.03</td><td> 0.04</td><td> 0.04</td>

<td>RS-4</td><td> 0.02</td><td> 0.02</td><td> 0.03</td><td> 0.02</td><td> 0.02</td><td> 0.01</td>

<td>RS-5</td><td> 0.04</td><td> 0.04</td><td> 0.03</td><td> 0.04</td><td> 0.04</td><td> 0.04</td>

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EXAMPLE 9

A controlled release tablet containing 1000 mg of metformin HCl and 15 mg of pioglitazone is prepared as follows:

1. First active drug

A 1000 mg membrane coated tablet is prepared as described in Example 5 above. The tablet coated with a 1000 mg membrane has the following composition:

CORE

Metformin HCl

Povidone Κ.-90, USP Sodium Lauryl Sulfate, NF Magnesium Stearate, NF

WATERPROOF COATING Opadry Clear (YS-l-7006)

MEMBRANE COATING Cellulose acetate, 398-0, NF Triacetine, USP Polyethylene glycol 400, NF

Total weight

1000 mg / tablet

78.0 mg / tablet

51.69 mg / tablet

5.65 mg / tablet

47.05 mg / tablet

15.77 mg / tablet

0.92 mg / tablet

1.85 mg / tablet

1201.0 mg / tablet

II. Second active drug

An immediate release amount of pioglitazone HCL is applied to the membrane coated metformin HCl tablets prepared in step I. The final tablet has the following composition:

Metformin HCl tablet coated with a membrane 1201.0 mg / tablet

Waterproof coating

Opadry Clear (YS-l-7006)

Pioglitazone coating

21.0 mg / tablet

Pioglitazone HCl Sodium Chloride

16.53 mg / tablet

Opadry Clear (YS-l-7006)

Color coating

Opadry II White (Υ-22-7719)

Polishing coating

Candelilla wax powder

2.5 mg / tablet

1.850 mg / tablet

21.54 mg / tablet

0.40 mg / tablet

The waterproof coating is applied to the 1000 mg metformin HCl tablet coated with a membrane. The waterproof coating is

PCT / US2OO6 / OO9O82 is prepared by dispersing 0.249 kg of Opadry Clear in 4.981 kg of USP alcohol and mixing the dispersion for 15 minutes. The dispersion is then atomized onto approximately 14.24 kg of 1000 mg metformin HCl tablet cores by means of a pan coating device 24.

O'Hara Labcoat III with the nozzle tip set 4 ± 2 above the static bed, 3 spray guns and under the following conditions:

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Atomization rate Exhaust air temperature Atomization air pressure Turbine speed

Model air pressure Supply air flow rate

250 mL / gun / min

25٥c ± 5٥c

10-40 psi

4-9 rpm

10-40 psi

300 ± 150 CFM

The waterproof coating dispersion is stirred continuously until exhausted during the coating process.

The pioglitazone coating is applied to the 1000 mg metformin HCl tablets coated with a membrane, sealed coating. The pioglitazone coating is prepared by mixing 3,793 kg of USP alcohol and 1.07 kg of purified water and slowly dispersing 0.024 kg of Opadry Clear in the solvent mixture. When Opadry Clear is dispersed, it is homogenized for approximately 10 minutes. When the Opadry Clear dispersion is homogenized, 0.032 kg of sodium chloride is added to the dispersion and homogenized for about 2 minutes. After homogenization of the sodium chloride, 0.212 kg of pioglitazone HCl is slowly dispersed in the mixture of solvents and then homogenized for approximately 10 minutes. When the pioglitazone HCl is homogenized, the homogenizer is removed from the mixing tank and replaced with an air mixer which churns a mixture for an additional 15 minutes. The pioglitazone suspension is stirred until the suspension is exhausted during the coating process. This coating solution contains approximately 8% excess material to compensate for material loss during the coating process. The pioglitazone HCl suspension is applied to the cores of the 1000 mg membrane-coated, tight-coated metformin HCl tablets using a 24 O'Hara Labcoat III turbine coating device with the tip of the nozzle set at 4 ± 2 above the static bed, 3 spray guns and under the following conditions:

Atomization rate

Exhaust air temperature

Atomizing air pressure

Turbine speed

25 ± 10 mL / gun / min

25 ± 5٥c

10-40 psi

4-9 rpm

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Model air pressure 10-40 psi

Supply air flow 300Ü50 CFM

When the pioglitazone coating is applied to the membrane coated, waterproof coated 1000 mg metformin HCl tablets, a colored or aesthetic coating of Opadry II White is applied to the pioglitazone coated tablets. The aesthetic coating is prepared by dispersing 0.255 kg of Opadry II White (Υ-22-7719) in 5.109 kg of USP alcohol and mixing the dispersion for approximately 1 hour. The Opadry II White dispersion is sprayed onto the pioglitazone HCl coated tablets using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set at 4 ± 2 above the static bed, 3 atomizing guns and under the following conditions:

Atomization rate 25 = 0 mL / gun / min

Exhaust air temperature 25٥c ± 5٥c

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Supply air flow 300 ± 150 CFM

Model air pressure 10-40 psi

The color coating dispersion is stirred continuously until the dispersion is exhausted during the coating process.

When the aesthetic coating slurry is used up, the tablets are dried in the coating pan for about 5 minutes with a turbine speed of about 2-8 rpm and an exhaust air temperature of 5٥٥c. When the tablets are dried, the exhaust air is stopped and the speed of the turbine is adjusted to about 3-4 rpm; 0.004 kg of wax Candellia powder which has been passed through a 60 mesh sieve is dispersed on the tablets. After rolling the tablets in the wax for about 5 minutes, the exhaust air is turned on and the tablets are rolled for an additional 10 minutes.

The finished polished tablet releases an average of 95% of pioglitazone when tested in a type 1 USP apparatus at 100 rpm in a buffer solution HC1-0.3M KCl pH 2.0. The final tablets also exhibit a hardness greater than 35 kp and a friability of 0.00٥ / ο. The final tablet is tested for the following compounds relating to pioglitazone by HPLC using a YMC-ODS-AQ column, 5μπι, 120Â, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: acid glacial acetic (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٥c and wavelength 269 nm for the uv detector. The results of the test are reported in Table 3 below.

t

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The final polished tablet is packaged in a 100 cc HDPE bottle containing one (1) container of 2g SORB-ΙΤ® desiccant and subjected to accelerated stability conditions of 4O٠C and 75% relative humidity for one month. After storage, the final polished tablet is tested and found to contain the compounds relating to pioglitazone when tested by HPLC using a YMC-ODS-AQ column, 5pm, 120Â, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: acetic acid (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٥c and wavelength 269 nm for the UV detector.

TABLE 3

<td>Last name</td><td>Relative retention time</td><td>Initial quantity (٥/٥)</td><td>Quantity of a month (٥/٥)</td>

<td>RS-1</td><td> 0.7</td><td>ND</td><td>ND</td>

<td>Pioglitazone</td><td> 1.0</td><td></td><td></td>

<td>RS-2</td><td> 1.5</td><td> 0.02</td><td> 0.02</td>

<td>RS-3</td><td> 3.4</td><td> 0.03</td><td> 0.05</td>

<td>RS-4</td><td> 1.2</td><td> 0.03</td><td> 0.02</td>

<td>RS-5</td><td> 2.8</td><td> 0.05</td><td> 0.04</td>

EXAMPLE 10

One controlled release tablet containing 1000 mg of metformin HCl and 15 mg of pioglitazone is prepared as follows:

A. Core with first active drug

A cellulose acetate coated metformin HCl tablet is prepared as described in Example 5.

B. Second active drug

An immediate release amount of pioglitazone HCl is applied to the membrane coated 1000 mg metformin HCl compounds prepared in step A. The final tablet has the following composition:

<td>Membrane-coated metformin HCl tablet Waterproof coating</td><td>1201.0 mg / tablet</td>

<td>Opadry Clear (YS-l-7006)</td><td>9.00 mg / tablet</td>

<td>Pioglitazone coating Pioglitazone HCl Hydroxypropylcellulose, NF (HPC-SSL) Lactose monohydrate, NF (modified, spray dried)</td><td>16.53 mg / tablet 4.5 mg / tablet 15.0 mg / tablet</td>

<td>Polyethylene glycol 8000, NF Titanium dioxide, USP</td><td>0.225 mg / tablet 0.450 mg / tablet</td>

PCT / US2OO6 / OO9O82

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Color coating

Hydroxypropylcellulose, NF (HPC-SSL)

Polyethylene glycol 8000, NF

Titanium dioxide, USP

Polishing coating

Candelilla wax powder

<img file="MA29675B1_D0002.tif" />

5.5 mg / tablet

1.375 mg / tablet

0.60 mg / tablet

0.40 mg / tablet

The waterproof coating is applied to approximately 14.36 kg of 1000 mg membrane coated metformin HCl tablets prepared in step A described above. The waterproof coating is prepared by dispersing about 0.108 kg of Opadry Clear (YS-1-7006) in about 1345 kg of purified water for 30 minutes. The dispersion is then sprayed onto approximately 14.36 kg of 1000 mg metformin HCl tablet cores using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set at 4 ± 2 in above the static bed, 3 spray guns and under the following conditions:

Atomization rate 20 ± 10 mL / gun / min

Exhaust air temperature 4O٥C ± 5٥c

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Supply air flow 300 ± 100 CFM

Model air pressure 10-40 psi

The pioglitazone coating is applied to 1000 mg metformin HCl tablets coated with a membrane, sealed coating. The pioglitazone coating is prepared by slowly dispersing about 0.059 kg of hydroxypropylcellulose (HPC-SLL) in about 6.034 kg of purified water. The HPC-SSL and water are mixed for about 20 minutes, then 0.197 kg of lactose monohydrate, NF (modified, spray-dried), is added to the HPC-SSL / water mixture and mixed for about 2 minutes. After mixing the lactose, approximately 0.003 kg of polyethylene glycol 8000 NF and 0.006 kg of titanium dioxide, USP are added to the mixture of water, HPC-SSL, NF and lactose and mixed for about 5 minutes. After about 5 minutes of mixing, about 0.217 kg of pioglitazone hydrochloride is dispersed in the coating solution. This coating solution contains approximately 10% excess material to compensate for loss of material during the coating process. The pioglitazone suspension is stirred until the suspension is exhausted during the coating process. The pioglitazone HCl slurry is applied to the cores of the membrane-coated, tight-coated 1000 mg metformin HCl tablets by means of a 24 O'Hara Labcoat III impeller coater with the end of the t

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Atomization rate

Exhaust air temperature

Atomizing air pressure

Turbine speed

Model air pressure

Supply air flow

200 mL / gun / min

4O ± 5٥C

10-40 psi

4-9 rpm

10-40 psi

300 00 CFM

When the pioglitazone coating is applied to the membrane coated, waterproof coated 1000 mg metformin HCl tablets, a color or aesthetic coating is applied to the pioglitazone coated tablets. The color coating is prepared by dispersing approximately 0.066 kg of HPC-SSL, 0.016 kg of polyethylene glycol 8000 NF and 0.007 kg of titanium dioxide USP in 0.894 kg of purified water and mixing the dispersion for approximately 30 minutes. The color coating is atomized onto the pioglitazone HCl coated tablets using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set at 4 ± 2 above the static bed, 3 atomizing guns and under the following conditions:

Atomization rate Exhaust air temperature Atomization air pressure Turbine speed

Supply air flow Model air pressure

20 ± 10 mL / gun / min

4O٥C ± 5٥C

10-40 psi

4-9 rpm

300 ± 100 CFM

10-40 psi

The color coating dispersion is stirred continuously until the dispersion is exhausted during the coating process.

When the color coating slurry is used up, the tablets are dried in the coating pan with a turbine speed of about 2-8 rpm and an exhaust air temperature of 4O ± 5٥C. When the tablets are dried, the exhaust air is stopped and the speed of the turbine is adjusted to about 3-4 rpm; 0.005 kg of powdered Candellia wax which has been passed through a 60 mesh sieve is dispersed on the tablets. After rolling the tablets in wax for about 5 minutes, the exhaust air is turned on and the tablets are rolled for an additional 10 minutes.

The finished polished tablet releases more than 95% of the pioglitazone when tested in a USP type 1 apparatus at 100 rpm in a HCl0.3Μ KCl buffer solution pH 2.0. The final tablets have a hardness greater than 35

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WO 2006/107528 PCT / US2OO6 / OO9O82 kp and a friability of 0.0%. The final tablet is tested for the compounds relating to pioglitazone by HPLC using a YMC-ODS-AQ column, 5pm, 120A, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: glacial acid acetic (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٠c and wavelength 269 nm for the uv detector. The results of the test are reported in Table 4 below.

The final polished tablet is packaged in a 100 cc HDPE bottle containing one (1) container of 3g SORB-ΙΤ® desiccant and subjected to accelerated stability conditions of 4O٥C and 75% relative humidity for fifteen days, 1 month, 2 months and 3 months. After storage, the final polished tablet is tested and found to contain the following pioglitazone-related compounds when tested by HPLC using a YMC-ODS-AQ column, 5pm, 120Â, 4.6 x 250 mm, mobile phase: 0.1 M buffer ammonium acetate: acetonitrile: glacial acetic acid (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٥c and wavelength 269 nm for the UV detector.

TABLE 4

<td></td><td>Initial</td><td>0.5 M</td><td>IM</td><td>2Μ</td><td>3Μ</td>

<td>Last name</td><td> (٥/٠)</td><td> (%)</td><td> (%)</td><td> (%)</td><td> (%)</td>

<td>RS-1</td><td>ND</td><td> 0.01</td><td>ND</td><td>ND</td><td>ND</td>

<td>RS-2</td><td> 0.02</td><td> 0.03</td><td> 0.03</td><td> 0.03</td><td> 0.02</td>

<td>RS-3</td><td> 0.03</td><td> 0.04</td><td> 0.04</td><td> 0.04</td><td> 0.03</td>

<td>RS-4</td><td> 0.03</td><td> 0.02</td><td> 0.02</td><td> 0.02</td><td> 0.02</td>

<td>RS-5</td><td> 0.03</td><td> 0.04</td><td> 0.04</td><td> 0.04</td><td> 0.04</td>

<td colspan="2">EXAMPLE 11</td><td></td><td></td><td></td><td></td>

<td></td><td>One tablet</td><td>release</td><td>controlled</td><td>container</td><td>500 mg of HCl</td>

metformin and 15 mg pioglitazone is prepared as follows:

A. Core with first active drug

1. Metformin granules (٥/٥ of composition)

Metformin HCl 92.76%

Povidone Κ-90, USP 7.24%

Approximately 139.14 kg of metformin HCl is broken down by passing it through a Comil equipped with an 813 sieve and no spacer at 840-850 rpm and collecting it in a clean container lined with polyethylene. About 10.86 kg of povidone Κ-30 is dissolved in about 206.34 kg of purified water. The disaggregated metformin HCl is then added to a top spray fluidized bed granulator (Glatt Brand GPCG-60) and granulated by atomizing the povidone and water binder solution under the following conditions: product temperature of about 38-43٥C, inlet air temperature of

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60-95٥, atomizing air pressure of 2.5-3 bar and atomization rate of 500 g / min (491-515 g / min) for the first 15 minutes, 700 g / min (680-710 g / min) for 15-30 minutes, 900 g / min (860-910 g / min) for 30-45 minutes, 1100 g / min (1090-1170 g / min) for 45-60 minutes and about 1200 g / min (1170-1220 g / min) for the rest of the atomization time. After atomization of the binder solution, the granules are dried in a fluidized bed until the loss on drying (LOD) is less than 2%.

When the granules are dried, they are passed through a Comil fitted with a 1143 stainless steel screen and a # 075 spacer at a speed of 1086-1088 rpm. The above process is repeated a second time to produce a total of about 300 kg of metformin granules.

II. Metformin mixture (% of the composition)

Metformin 94.95% HCl granules

Sodium Lauryl Sulfate, NF 4.55%

Magnesium stearate, NF 0.50٥ / ο

The approximately 300 kg of metformin granules prepared above in Step I are added to a 50 cubic foot Slant-Cone mixer with approximately 14.38 kg of sodium lauryl sulfate NF and mixed for approximately 20 minutes. About 1.58 kg of magnesium stearate NF is then passed through a stainless steel 40 mesh screen, added to the SlantCone mixer and mixed for an additional five minutes.

The mixture is compressed into uncoated metformin cores by means of a rotary tablet press fitted with 15/32 cup toolings, with a precompression force of 14 kp and a main compressive force of 34 kp. The resulting tablets have a height of between 523-613 g with a target weight of 568 g, a hardness of between 14-26 kp (target 20 kp) and a friability less than or equal to 0.8٥ / ο.

III. Leak-tight metformin tablets (٥ / o of the composition)

Uncoated Metformin HCl Tablets 96.02%

OPADRY Clear (YS-l-7006) 3.98%

Approximately 57.61 kg of uncoated tablets prepared in step II above are coated with a waterproof coating by applying a solution of approximately 2,388 kg of OPADRY Clear (YS-l-7006) and 21.50 kg of purified water to the tablets. compressed by means of a turbine coating device. The Turbine Coater is a 36 inch O'Hara Labcoat III with three (3) spray guns 8-11 inches from the bed. The coating conditions are as follows:

Exhaust air temperature 40-47٥C

Atomization pressure 50 ± 10psi

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Air volume

Atomization rate

Turbine speed

IV Membrane

Leak-Coated Metformin Tablets

Cellulose acetate (398-10) 2

Triacetin

PEG 400

1000 00 CFM

180 ± 60 g / min (60 ± 20 ml / gun / min) 4-8 rpm.

(% of composition)

95.521%

3.807%

0.145%

0.289% acetyl content 39.3-40.3% (a) Method of coating a membrane

Approximately 51.06 kg of acetone is added to a stainless steel tank followed by approximately 2,281 kg of cellulose acetate and is mixed for approximately 20 minutes until the solution becomes clear. When the solution becomes clear, approximately 0.269 kg of polyethylene glycol 400 is added to the solution and mixed for approximately 5 minutes followed by the addition of approximately 0.135 kg of triacetin. The solution is mixed for an additional 5 minutes.

Approximately 59.07 kg of sealed-coated metformin HCl tablets are loaded into a GPCG-60 brand fluid bed embedding device (Glatt) with a Wurster insert (size 18 for 45mm height) with a 1.5 nozzle. mm. The tight-coated metformin HCl tablets are fluidized and the product temperature is adjusted to about 21 ± 3٥c. The cellulose acetate solution is atomized onto the fluidized sealed-coated metformin HCl tablets with an atomization pressure of about 2.0-3.0 bar, an air volume of 1400 ± 300 CFM and an atomization rate of 400 ± 100 g / min until a weight gain of 3-5% is obtained (target 3.8٥ / ο). When the desired amount of membrane coating is applied, the membrane coated tablets are dried in the fluidized bed at 21 ± 3٥c and 120000 CFM for about 10 minutes followed by 40C and 1200 ± 100 CFM for about 5 minutes.

The resulting membrane coated tablets are laser drilled to create a hole in the approximate center of each side of the membrane coated tablet (i.e. 2 holes) with an average diameter of 0.5 mm per hole. The upper micrometer is 5.4 ± 2mm, the lower micrometer is 6.75 ± 12mm, the laser pulse width is 1700, and the pulse delay is 290 ± 150.

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B. Second active drug

An immediate release amount of pioglitazone HCl is applied to the 500 mg membrane coated metformin HCl tablets prepared in step A. The final tablet has the following composition:

<td>Membrane-coated metformin HCl tablet Waterproof coating</td><td>618.9 mg / tablet</td>

<td>Opadry Clear (YS-l-7006)</td><td>11.5 mg / tablet</td>

<td>Pioglitazone coating Pioglitazone HCl Sodium Chloride Opadry Clear (YS-l-7006) Color coating</td><td>16.53 mg / tablet 2.5 mg / tablet 1.850 mg / tablet</td>

<td>Opadry II White (Υ-22-7719)</td><td>10.77 mg / tablet</td>

<td>Polishing coating Candelilla wax powder</td><td>0.20 mg / tablet</td>

The waterproof coating is applied to 500 mg metformin HCl tablets coated with a membrane. The waterproof coating is prepared by dispersing 0.243 kg of Opadry Clear in 3.473 kg of USP alcohol and mixing the dispersion for 15 minutes. The dispersion is then sprayed onto approximately 13.08 kg of 1000 mg metformin HCl tablet cores using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set to 4 ± 2 in above the static bed, 3 spray guns and under the following conditions:

<td>Atomization rate</td><td>25 ± 10 mL / gun / min</td>

<td>Exhaust air temperature Atomizing air pressure Turbine speed Supply air flow Model air pressure</td><td>25٥c ± 5٥c 10-40 psi 4-9 rpm 200 ± 00 CFM 10-40 psi</td>

The waterproof coating dispersion is stirred continuously until exhausted during the coating process.

The pioglitazone coating is then applied to the 500 mg metformin HCl tablets coated with a membrane. The pioglitazone coating is prepared by mixing 5.656 kg of USP alcohol and 1.595 kg of purified water and slowly dispersing 0.045 kg of Opadry Clear in the mixture of solvents. When Opadry Clear is dispersed, it is homogenized for approximately 10 minutes. When the Opadry Clear dispersion is homogenized, 0.061 kg of sodium chloride is added to the dispersion and homogenized for about 2 minutes. After t

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WO 2006/107528 PCT / US2OO6 / OO9O82 homogenization of sodium chloride, 0.402 kg of pioglitazone HCl is slowly dispersed in the mixture of solvents and then homogenized for about 10 minutes. When the pioglitazone HCl is homogenized, the homogenizer is removed from the mixing vessel and replaced with an air mixer which mixes for an additional 15 minutes. The pioglitazone suspension is stirred until the suspension is exhausted during the coating process. This coating solution contains approximately 15% excess material to compensate for loss of material during the coating process. The pioglitazone HCl suspension is applied to the cores of the 500 mg membrane-coated, sealed-coated metformin HCl tablets using a 24 O'Hara Labcoat III turbine coating device with the tip of the nozzle adjusted to 4 ± 2 above the static bed with 3 spray guns and under the following conditions:

Atomization rate 25 ± 10 mL / gun / min

Exhaust air temperature 25 ± 5٥c

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Supply air flow 200 ± 100 CFM

Model air pressure 10-40 psi

When the pioglitazone coating is applied to the membrane coated, waterproof coated 500 mg metformin HCl tablets, a color or aesthetic coating of Opadry II White is applied to the pioglitazone coated tablet. The aesthetic coating is prepared by dispersing 0.228 kg of Opadry II White (Υ-22-7719) in 3,253 kg of USP alcohol and mixing the dispersion for approximately 1 hour. The Opadry II White dispersion is then sprayed onto the pioglitazone HCl coated tablets using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set at 4 ± 2 above the static bed. , with 3 atomizing guns and under the following conditions:

Atomization rate 25 ± 10 mL / gun / min

Exhaust air temperature 25٥c ± 5٥c

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Model air pressure 10-40 psi

Supply air flow 200 ± 100 CFM

The color coating dispersion is stirred continuously until the dispersion is exhausted during the coating process.

When the cosmetic coating suspension is used up, the tablets are dried in the coating machine for about 5 minutes.

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WO 2006/107528 PCT / US2OO6 / OO9O82 with a turbine speed of about 2-8 rpm and an exhaust air temperature of 25 ± 5٥c. When the tablets are dried, the exhaust air is stopped and the speed of the trrbine is adjusted to about 3-4 rpm; 0.004 kg of powdered Candellia wax which has been passed through a 60 mesh sieve is dispersed over the tablets. After rolling the tablets in the wax for about 5 minutes, the exhaust air is turned on and the tablets are rolled for an additional 10 minutes.

The finished polished tablet releases more than 95٥ / ο of the pioglitazone when tested in a USP type 1 apparatus at 100 rpm in HC1-0.3M KCl pH 2.0 buffer solution. The final tablets also exhibit a hardness greater than 35 kp and a friability of 0.00٥ / ο. The final tablet is tested for the compounds relating to pioglitazone by HPLC using a YMC-ODS-AQ column, 5 pm, 120Â, 4.6 X 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: acid glacial acetic (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٠c and wavelength 269 nm for the uv detector. The results of the test are reported in Table 5 below.

The final polished tablet is packaged in a 100 cc HDPE bottle containing one (1) container of SORB-ΙΤ® lg desiccant and subjected to accelerated stability conditions of 40 ° C and 75% relative humidity for one month. After storage, the final polished tablet is tested and found to contain the following compounds related to pioglitazone when tested by HPLC using a YMC-ODS-AQ column, 5pm, 120Â, 4.6 X 250 mm, mobile phase: 0.1 M buffer ammonium acetate: acetonitrile: glacial acetic acid (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٠c and wavelength 269 nm for the uv detector.

TABLE 5

Initial IM

Name (%&gt; (%)

<td>RS-1</td><td>ND</td><td>ND</td>

<td>RS-2</td><td> 0.03</td><td> 0.03</td>

<td>RS-3</td><td> 0.04</td><td> 0.05</td>

<td>RS-4</td><td> 0.03</td><td> 0.02</td>

<td>RS-5</td><td> 0.04</td><td> 0.04</td>

<td colspan="2">EXAMPLE 12</td><td></td>

A controlled-release tablet containing 500 mg of metformin HCl and 15 mg of pioglitazone is prepared as follows:

A. Core with first active drug

The 500 mg metformin HCl core coated with cellulose acetate is prepared as described in Example 11.

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B. Second active drug

An immediate-release amount of pioglitazone HCl is applied to 500 mg metformin HCl tablets coated with a

<td colspan="2">membrane prepared above in step A. The final tablet has the following composition:</td>

<td>Metformin HCl tablet</td><td></td>

<td>membrane coated</td><td>618.9 mg / tablet</td>

<td>Waterproof coating</td><td></td>

<td>Opadry clear (YS-l-7006)</td><td>4.50 mg / tablet</td>

<td>Pioglitazone coating</td><td></td>

<td>Pioglitazone HCl</td><td>16.53 mg / tablet</td>

<td>Hydroxypropylcellulose (HPC-SSL)</td><td>6.0 mg / tablet</td>

<td>Lactose monohydrate, NF</td><td>50.0 mg / tablet</td>

<td>(modified, spray dried)</td><td></td>

<td>Polyethylene glycol 8000, NF</td><td>0.300 mg / tablet</td>

<td>Titanium dioxide, USP</td><td>0.600 mg / tablet</td>

<td>Color coating</td><td></td>

<td>Hydroxypropylcellulose (HPC-SSL)</td><td>2.75 mg / tablet</td>

<td>Polyethylene glycol 8000, NF</td><td>0.688 mg / tablet</td>

<td>Titanium dioxide, USP</td><td>0.300 mg / tablet</td>

<td>Polishing coating</td><td></td>

<td>Candelilla wax powder</td><td>0.20 mg / tablet</td>

The waterproof coating is applied to approximately 12.36 kg of 500 mg membrane coated metformin HCl tablets prepared in step A described above. The waterproof coating is prepared by dispersing about 0.090 kg of Opadry Clear (YS-1-7006) in about 1.124 kg of purified water for 30 minutes. The dispersion is then atomized onto approximately 12.36 kg of 500 mg metformin HCl tablet cores using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set to 4 ± 2 on top. static bed, 3 spray guns and under the following conditions:

Atomization rate 20 10 غ mL / gun / min

Exhaust air temperature 4O٥C 5٥ غ c

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Supply air flow 300 ± 100 CFM

Model air pressure 10-40 psi

The pioglitazone coating is then applied to the membrane coated 500 mg metformin HCl tablets. The coating of

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WO 2006/107528 PCT / US2OO6 / OO9O82 pioglitazone is prepared by slowly dispersing about 0.134 kg of hydroxypropylcellulose (HPC-SLL) in about 13.692 kg of purified water. The HPC-SSL and water are mixed for about 20 minutes, then 1.119 kg of lactose monohydrate NF (modified, spray-dried) are added to the HPC-SSL / water mixture and mixed for about 2 minutes. After mixing the lactose, approximately 0.007 kg of polyethylene glycol 8000 NF and 0.013 kg of titanium dioxide USP are added to the mixture of water, HPC-SSL and lactose and mixed for approximately 5 minutes. After about 5 minutes of mixing, about 0.370 kg of pioglitazone hydrochloride is dispersed in the coating solution. This coating solution contains approximately 12% excess material to compensate for loss of material during the coating process. The pioglitazone suspension is stirred until the suspension is exhausted during the coating process. The pioglitazone HCl suspension is applied to the cores of the 500 mg membrane-coated, leak-proof coated metformin HCl tablets using a 24 O'Hara Labcoat III turbine coating device with the tip of the nozzle adjusted to 4 ± 2 above the static bed, 3 spray guns, under the following conditions:

Atomization rate 20 ± 10 mL / gun / min

Exhaust air temperature 4O ± 5٥C

Atomizing air pressure 10-40 psi

Turbine speed 4-9 rpm

Model air pressure 10-40 psi

Supply air flow 300 00.CFM

When the pioglitazone coating is applied to the membrane coated, waterproof coated 500 mg metformin HCl tablets, a color or aesthetic coating is applied to the pioglitazone coated tablets. The color coating is prepared by dispersing approximately 0.055 kg of HPC-SSL NF, 0.014 kg of polyethylene glycol 8000 NF and 0.006 kg of titanium dioxide, USP in 0.747 kg of purified water and mixing the dispersion for approximately 30 minutes. The colored coating is then atomized onto the tablets coated with pioglitazone HCl using a 24 O'Hara Labcoat III turbine coating device with the nozzle tip set at 4 ± 2 above the static bed, 3 atomizing guns and under the following conditions:

Atomization rate Exhaust air temperature

Atomizing air pressure Turbine speed

Supply air flow

Model air pressure

20 ± 10 mL / gunmin

4O٥C ± 5٥C

10-40 psi

4-9 rpm

30 ± 100 CFM

10-40 psi

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The color coating dispersion is stirred continuously until the dispersion is exhausted during the coating process.

When the color coating suspension is used up, the tablets are dried in the coating pan for about 5 minutes with a turbine speed of about 2-8 rpm and an exhaust air temperature of 4O ± 5٥C. When the tablets are dried, the exhaust air is stopped and the speed of the turbine is adjusted to approximately 3-4 rpm and 0.004 kg of powdered Candellia wax which has been passed through a 60 mesh sieve is dispersed over them. tablets. After rolling the tablets in the wax for about 5 minutes, the exhaust air is turned on and the tablets are rolled for an additional 10 minutes.

The finished polished tablet releases more than 95% of the pioglitazone when tested in a USP type 1 apparatus at 100 rpm in a HCl0.3Μ KCl buffer solution pH 2.0. The final tablets also display a hardness greater than 35 kp and a friability of 0.01%. The final tablet is tested for the compounds relating to pioglitazone by HPLC using a YMC-ODS-AQ column, 5pm, 120A, 4.6 x 250 mm, mobile phase: buffer 0.1 M ammonium acetate: acetonitrile: acetic acid glacial (25: 25: 1), injection volume 40pL, flow rate 0.7 ml / min, column temperature 25٥c and wavelength 269 nm for the uv detector. The results of the test are reported in Table 6 below.

The final polished tablet is packaged in a 100cc HDPE bottle containing one (1) 3g SORB-ΙΤ® desiccant container and subjected to accelerated stability conditions of 4OC and 75٥% relative humidity for 1 month and 2 months. After storage, the final polished tablet is tested and found to contain the following compounds relating to pioglitazone when tested by HPLC using a YMC-ODS-AQ column, 5pm, 120A, 4.6 X 250 mm, mobile phase: 0.1 M buffer ammonium acetate: acetonitrile: glacial acetic acid (25: 25: 1), injection volume 40pL, flow rate 0.7 mL / min, column temperature 25٥c and wavelength 269 nm for the UV detector.

TABLE 6

Initial IM 2Μ

Last name (%) (%) (%)

<td>RS-1</td><td>ND</td><td>ND</td><td>ND</td>

<td>RS-2</td><td> 0.02</td><td> 0.02</td><td> 0.02</td>

<td>RS-3</td><td> 0.03</td><td> 0.03</td><td> 0.04</td>

<td>RS-4</td><td> 0.03</td><td> 0.02</td><td> 0.02</td>

<td>RS-5</td><td> 0.04</td><td> 0.03</td><td> 0.04</td>

Although certain preferred and alternative embodiments have been set forth for the purpose of disclosing the invention, modifications to the disclosed embodiments may be made by those skilled in the art.

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Art. Hence, the appended claims are intended to cover all embodiments of the invention and their modifications which do not depart from the spirit and scope of the invention.

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