HK1139077A - Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative - Google Patents

Abstract

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

Description

Novel pharmaceutical formulations containing biguanides and thiazolidinedione derivatives

The application is a divisional application of Chinese patent application with the application number of 200480027110.1, the application date of 2004 is 2.12.3, and the invention name of the invention is 'novel pharmaceutical formulation containing biguanide and thiazolidinedione derivative'.

Application No. 200480027110.1 is a continuation-in-part application of U.S. patent application No. 10/664,803 filed on 9/19/2003 and provisional patent applications nos. 60/412,180 and 60/412,181 filed on 9/20/2002.

Technical Field

The present invention relates to pharmaceutical formulations comprising an antihyperglycemic agent in combination with a thiazolidinedione derivative. More particularly, the present invention relates to an oral medicament comprising a biguanide, which may be, for example, metformin or buformin or a pharmaceutically acceptable salt thereof, such as metformin hydrochloride or the metformin salts described in U.S. Pat. nos. 3,957,853 and 4,080,472, which are incorporated herein by reference, and a thiazolidinedione derivative, which may be as disclosed in U.S. Pat. No. 4,687,777, which is incorporated herein by reference.

Background

A number of techniques are used to provide controlled and extended release pharmaceutical formulations in order to maintain effective serum levels of pharmaceutical agents and to minimize the side effects of the drugs caused by lack of patient compliance.

For example, sustained release tablets having an osmotically active drug core surrounded by a semipermeable membrane have been disclosed. The mechanism of action of these tablets is by allowing a fluid aqueous component (e.g. gastric or intestinal fluid) to permeate the coating film and dissolve the active ingredient thus causing the drug solution to be released through the passage in the coating film. Alternatively, if the active ingredient is insoluble in the osmotic liquid, it may be pushed through the pathway by a swelling agent, such as a hydrogel. Some representative examples of such osmotic tablet systems are described in U.S. patent nos. 3,845,770; 3,916,899; 4,034,758, respectively; 4,077,407 and 4,783,337. US 3,952,741 describes an osmotic device in which the active agent is released from a core surrounded by a semi-permeable membrane only after sufficient pressure has been applied to rupture a weakened portion of the membrane within the membrane.

The basic osmotic devices disclosed in the above-referenced patents have long been improved in providing greater control of the release of the active ingredient. For example, U.S.4,777,049 and 4,851,229 disclose an osmotic formulation having a semipermeable wall-surrounding core. The core comprises an active ingredient and a modulator, wherein the modulator causes the active ingredient to be released in a pulsatile manner through the passageway of the semi-permeable membrane. Other improvements include modifications to the semipermeable membrane surrounding the active core, such as varying the ratio of the ingredients forming the membrane, for example, U.S.5,178,867; 4,587,117 and 4,522,625, or increasing the number of coatings surrounding the active core, such as U.S.5,650,170 and 4,892,739.

Certain controlled or sustained release formulations employ an antihyperglycemic drug (e.g., metformin hydrochloride) to define an expansion or use of a gel to control the release of the drug in the pharmaceutical formulation. This limited study is described in WO 96/08243 and is addressed by GLUCOPHAGE^TMThe XR product employed, which is a controlled release metformin HCl product available from Bristol-Myers Squibb Co.

Thiazolidinedione derivatives have also been disclosed in U.S. Pat. No. 4,687,777. The efficacy of combination therapy of these compounds is described by U.S.5,859,037; 5,952,356, respectively; 5,965,584, respectively; 6,150,384 and 6,172,090 are further disclosed. However, none of these patents disclose a pharmaceutical formulation having the advantages of the present invention.

Pharmaceutical formulations containing a combination of an antihyperglycemic drug and a thiazolidinedione derivative have been proposed in the art. For example, EPO 0749751 (incorporated herein by reference) describes a pharmaceutical composition containing an insulin sensitivity enhancer, which may be a thiazolidinedione compound in combination with other antidiabetic agents. More specifically, EPO 0749751 states that the preferred insulin sensitivity enhancer is pioglitazone, which may be combined with other antidiabetic agents such as metformin, phenformin or buformin, and further that these agents may be combined (mixed and/or coated) with conventional excipients to provide taste masking or sustained release behavior. Another example of a combination of an antihyperglycemic drug and a thiazolidinedione derivative is U.S.6,011,049 (incorporated herein by reference). This patent describes a single pharmaceutical composition comprising pioglitazone or troglitazone and metformin in a slow release form such as osmotic pump or subcutaneous penetration. Other combinations of antihyperglycemic agents and thiazolidinedione derivatives may be found in U.S.6,524,621; 6,475,521, respectively; 6,451,342 and 6,153,632 and PCT patent applications WO 01/35940 and WO 01/35941, which are incorporated herein by reference.

WO 99/47125 and US patent 6,099,862 disclose a metformin osmotic tablet employing an immediate release coating containing an antihyperglycemic or a hypoglycemic drug.

Although pharmaceutical formulations comprising an antihyperglycemic compound and a thiazolidinedione derivative are described in the prior art, the present invention provides a number of advantages not available from the prior art, as will be described below.

Disclosure of Invention

It is an object of the present invention to provide a pharmaceutical formulation comprising a first active agent formulated to provide a controlled or sustained release drug delivery system. Preferably, the first active agent is an antihyperglycemic compound. The invention further provides a second active agent, which is preferably a thiazolidinedione derivative. The novel drug formulations described herein provide a delivery system for both the first and second active agents such that the bioavailability of both active agents is not reduced by the presence of food.

It is another object of the present invention to provide a pharmaceutical formulation as described above, comprising a drug delivery system of a first active agent as a controlled or sustained release formulation against hyperglycemic compounds, wherein the controlled or sustained release mechanism is not controlled by a swelling polymer, in combination with a drug delivery system of a second active agent comprising an immediate release of a thiazolidinedione derivative.

It is a further object of the present invention to provide a pharmaceutical formulation as defined above comprising a delivery system for a first active agent as a controlled or sustained release formulation for an antihyperglycemic compound in combination with a delivery system for a second active agent comprising an immediate release of a thiazolidinedione derivative, which provides continuous and non-pulsatile effective levels of said antihyperglycemic agent to a human or animal in need of such treatment for 8 hours up to 24 hours.

It is another object of the present invention to provide a pharmaceutical preparation comprising a first active drug delivery system as a controlled or sustained release form against hyperglycemic compounds in combination with a second active drug delivery system comprising an immediate release of a thiazolidinedione derivative, which achieves a peak plasma level of the antihyperglycemic drug at about 8-12 hours after use and a peak plasma level of the thiazolidinedione derivative at about 1-4 hours after administration.

It is also an object of the present invention to provide a pharmaceutical formulation comprising a first active agent as a controlled or sustained release drug core tablet against hyperglycemic compounds having only one osmotic core of the same nature, wherein the ingredients are made using conventional tablet compression techniques.

It is another object of the present invention to provide a pharmaceutical formulation comprising a delivery system for a first active agent in controlled or sustained release form against a hyperglycemic compound in combination with a delivery system for a second active agent comprising an immediate release of a thiazolidinedione derivative, which achieves a plasma peak for the antihyperglycemic agent at about 8-12 hours after administration and a thiazolidinedione derivative plasma peak at about 1-4 hours after administration.

It is still another object of the present invention to provide a pharmaceutical preparation comprising an antihyperglycemic drug as a controlled or sustained release component and a thiazolidinedione derivative as immediate release components, wherein not less than 85% of the total amount of the thiazolidinedione derivative is released from the preparation in 45 minutes or less.

It is another object of the present invention to provide a structurally stable pharmaceutical formulation comprising an antihyperglycemic drug as a controlled or sustained release component and a thiazolidinedione derivative as an immediate release component, the total amount or impurities of the thiazolidinedione related compounds being no more than 0.6% and the related compounds or impurities alone being no more than 0.2% after two years of storage.

Summary of The Invention

The present invention relates to a pharmaceutical formulation comprising a first active agent, preferably an antihyperglycemic agent, in combination with a second active agent, preferably a thiazolidinedione derivative. More particularly, the present invention relates to an oral medicament comprising a first active agent comprising a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or metformin salt in combination with a second active agent comprising a thiazolidinedione derivative.

The foregoing objects are achieved by a pharmaceutical formulation comprising a first and a second active agent, wherein the first active agent acts as a controlled release core, preferably an osmotic tablet, with or without a gel or swelling polymer. The second active ingredient is part of or may preferably be associated with a controlled release core in a manner that provides immediate release of the second active ingredient. For example, the second active ingredient may be incorporated into a film applied to the core or the second active ingredient may be applied to a controlled release core, which may or may not be coated.

In one embodiment of the second active agent, it may be a thiazolidinedione derivative in a pharmaceutical formulation as an immediate release formulation, and the antihyperglycemic ingredient in a pharmaceutical formulation as a controlled release formulation. Such an immediate release formulation of the pharmaceutical formulation should provide a peak plasma level (Tmax) of the thiazolidinedione derivative of 1 to 12 hours, preferably 1 to 4 hours, whereas the controlled release portion of the pharmaceutical formulation may provide a peak plasma level (Tmax) of the antihyperglycemic component of 8 to 12 hours.

Preferably, the pharmaceutical preparation according to the invention may be taken once a day, preferably within or after a meal, most preferably at or after dinner. The pharmaceutical formulation is capable of providing effective levels of the drug within a day, and the peak plasma value (Tmax) of the antihyperglycemic drug is achieved between 8 and 12 hours after administration of the drug.

Detailed Description

The present invention relates to a pharmaceutical formulation or preparation comprising a first active agent comprising an antihyperglycemic agent in combination with a second active agent comprising 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 released from the tablet core in a controlled release manner, preferably an osmotic tablet core with or without a gel or swelling polymer. The tablet core should include the antihyperglycemic drug and at least one pharmaceutically acceptable excipient. In one embodiment of the tablet core of the present invention comprising an antihyperglycemic drug, a binder and an absorption enhancer, the tablet core is preferably coated with a polymeric coating to form a film that coats the tablet and drilled (drill) to create one passageway on each face of the film. The second active agent comprises a thiazolidinedione derivative and is preferably applied to the membrane of the tablet core and provides a discrete or controlled release of the thiazolidinedione derivative.

The term antihyperglycemic drug as used herein refers to a drug used in the control or treatment of non-insulin-dependent diabetes mellitus (NIDDM). Antihyperglycemic agents include biguanides such as metformin, phenformin or buformin or analogues thereof, and pharmaceutically acceptable salts, isomers or derivatives thereof.

The term thiazolidinedione derivative as used herein refers to drugs that are used to control or treat NIDDM. These include, but are not limited to, troglitazone, rosiglitazone, pioglitazone, saxaglitazone or analogues thereof, and pharmaceutically acceptable salts, isomers or derivatives thereof.

The term binder refers to any conventionally known pharmaceutically acceptable binder, such as polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polymethacrylates, polyvinyl alcohol, waxes and the like. Mixtures of the foregoing binders may also be employed. A preferred binder is polyvinylpyrrolidone of a water-soluble material (e.g., having a weight average molecular weight of 25,000 to 3,000,000). The binder may constitute from about 0 to about 40% of the total weight of the core and preferably constitutes from about 3% to about 15% of the total weight of the core. In one embodiment, the use of a binder in the core is optional.

In a preferred embodiment, the core may optionally comprise an absorption enhancer. The absorption enhancer may be any type of absorption enhancer conventionally known in the art, such as fatty acids, surfactants (anionic, cationic, amphoteric), chelating agents, bile salts, or mixtures thereof. Examples of some preferred absorption enhancers are lecithin, fatty acids such as capric acid, oleic acid and monoglycerides thereof, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediaminetetraacetic acid (EDTA) and ethylene glycol-bis (β -aminoethyl ether) -N, N-tetraacetic acid (EGTA). The core may include from about 0 to about 20% of the absorption enhancer based on the total weight of the core and most preferably from about 2% to about 10% of the total weight of the core.

In one embodiment of the invention, which does not use a gel or swellable polymer, the core of the invention is preferably compressed to form a tablet by granulating the antihyperglycemic drug with a binder and adding a lubricant and an absorption enhancer. The core may also be formed into tablets by drying the granulated core ingredients by a roller compactor and adding a lubricant to compress the granules. Direct compression to form tablets may also be employed. Other conventional granulation processes are known in the art. In addition, other excipients such as lubricants, pigments or dyes may also be used in the formulations of the present invention.

The term gel or swelling polymer refers to a polymer that is capable of gelling, swelling in the presence of water or biological fluids. A representative example of a gel or swellable polymer is high molecular weight hydroxypropyl methylcellulose (e.g., HPMC)K100M, available from Dow Chemical) and high molecular weight polyethylene oxide (e.g. POLYOX WSR 301, WSR 303 or wsrcoguar). Other gel or swelling polymers are disclosed in US patent US 4,522,625 (incorporated herein by reference).

The cores formed as described herein may be coated with a film or sustained release coating. Materials that can be used to form the film or sustained release coating are ethyl cellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetates, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. Other suitable polymers are described in U.S.3,845,770; 3,916,899; 4,008,719, respectively; 4,036,228 and 4,612,008, which are incorporated herein by reference. The most preferred film or sustained release coating material is cellulose acetate, which includes an acid concentration of 39.3 to 40.3% and is commercially available from Eastman Fine Chemicals.

In an alternative embodiment, the film or sustained release coating may comprise one of the polymers described above and a co-solvent. The co-solvent can increase the volume of liquid absorbed into the core to allow the agent to disperse substantially all of the antihyperglycemic agent through the passageway and/or porous membrane. The cosolvent may be a water soluble or enteric material. Preferred examples of materials for use as a hydrotrope are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid copolymers, poloxamers (e.g. LUTROL F68, LUTROL F127, LUTROL F108, available from BASF) and mixtures thereof. A preferred hydrotrope-enhancer is PEG 400.

The dissolution enhancer may also be a water soluble drug such as metformin or a pharmaceutically acceptable salt thereof, or the dissolution enhancer may be a drug that dissolves under conditions in the intestine. If the dissolution enhancer is a drug, the pharmaceutical formulation of the present invention advantageously provides an immediate release drug which is selected to act as a dissolution enhancer.

The co-solvent comprises from about 0% to about 40% by weight of the total coating, most preferably from about 2% to about 20% by weight of the total coating. The co-solvent is dissolved or filtered from the membrane or sustained release coating to form channels in the membrane or sustained release coating to allow liquid to enter the core and dissolve the active ingredient.

Known excipients, such as plasticizers, may also be used to form films or sustained release coatings. Some known plasticizers include azelaic acid adipate, azoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate acetate, citrate esters, and those disclosed in Encyclopedia of Polymer science and Technology, Vol.10(1969) (published by John Wiley & Sons). Preferred plasticizers are triacetin, acetylated monoglycerides, grapeseed oil, olive oil, sesame oil, tributyl acetate citrate, triethyl acetate citrate, sorbitol glycerate, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, tributyrin and the like. Depending on the particular plasticizer, from about 0 to about 25%, preferably from about 2% to about 15%, of the plasticizer may be used (based on the total weight of the film or sustained release coating).

Typically, the film or sustained release coating surrounding the core comprises from about 1% to about 10%, preferably from about 2% to about 5%, by weight of the total weight of the core and coating.

In a preferred embodiment, the membrane or sustained release coating surrounding the core further comprises a pathway for release of the controlled release drug from the core. The term access as used herein includes slits, ports, perforations, holes, areas of weakness or corrodible elements such as animal bone plugs that corrode to form a permeation pathway for the release of the antihyperglycemic drug from the drug formulation. The pathways employed according to the present invention are known and described in U.S.3,845,770; 3,916,899; 4,034,758, respectively; 4,077,407, respectively; 4,783,337 and 5,071,607.

Independently of the antihyperglycemic is a second active agent, preferably a thiazolidinedione derivative. The second active agent may be formulated to provide immediate release of the thiazolidinedione derivative. In one embodiment of the invention, the thiazolidinedione derivative is added as a monolayer to a controlled or sustained release core comprising the antihyperglycemic drug, using a binder and other pharmaceutical excipients such as absorption enhancers, surfactants, plasticizers, anti-foaming agents and combinations thereof. The absorption enhancer may be present in the thiazolidinedione derivative layer at about 30% w/w based on the weight of the thiazolidinedione derivative. The binder is present at about 150% w/w of the weight of the thiazolidinedione derivative. The second active agent immediate release formulation may be incorporated into a single pharmaceutical formulation by coating onto a film or sustained release coating according to conventional means. Alternatively, it may be added to the single pharmaceutical formulation with the first active agent in any pharmaceutically acceptable form. The addition of the second active agent may be achieved by, but is not limited to, a process selected from the group consisting of: layering, laminating, dry pressing, depositing or printing the medicament.

When the thiazolidinedione derivative is coated onto the membrane or sustained release coating of the osmotic tablet core, the thiazolidinedione coating should be applied as a coating solution or suspension using an aqueous solvent, an organic solvent, or a mixture of both. Typical organic solvents include acetone, isopropanol, methanol and ethanol. If a mixture of aqueous and organic solvents is used, the ratio of water to organic solvent should be from 98: 2 to 2: 98, preferably from 50: 50 to 2: 98, most preferably from 30: 70 to 20: 80, and ideally from about 25: 75 to 20: 80. If a mixed solvent system is used, the amount of binder required for coating the thiazolidinedione derivative onto the membrane or sustained release coating can be reduced. For example, coatings have been successfully obtained from mixed solvent systems in which the ratio of binder to thiazolidinedione derivative is 1: 9 to 1: 11. Although acceptable coatings may also be obtained when the thiazolidinedione coating is applied directly to the membrane or sustained release coating, a preferred method is to first apply a seal coat as the first coating of the membrane or sustained release coating before applying the thiazolidinedione coating. The seal coat used herein is a coating which does not contain an active pharmaceutical ingredient and rapidly disperses or dissolves in water.

The thiazolidinedione coating solution or suspension may also comprise a surfactant and a pore former. The pore former is preferably a water soluble material such as sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid copolymers, poloxamers (e.g., LUTROL F68, LUTROL F127, LUTROL F108, available from BASF) and mixtures thereof. In an alternative embodiment, the pharmaceutical formulation of the present invention may further comprise an immediate release (immediate release) amount of an antihyperglycemic drug the immediate release amount of the antihyperglycemic drug may be coated onto or incorporated into a membrane or sustained release coating of the formulation.

In addition, various diluents, excipients, lubricants, dyes, pigments, dispersants, and the like, which are disclosed in Remington's Pharmaceutical Sciences (1995), may be used to optimize the above-described formulation of the present invention.

Conventional dosages of biguanides, e.g., metformin, in medicaments are 500mg, 750mg, 850mg, and 1000 mg. Thiazolidinedione derivatives, such as pioglitazone, are routinely dosed in the medicament at 15mg, 30mg and 45 mg. The present invention is intended to encompass the above effective combinations and does not provide specific examples of each possible combination and dosage amounts thereof.

A preferred embodiment of a pharmaceutical formulation will have the following composition:

amount of first active drug (% of core)

The core is as follows:

50-98% (preferably 75-95%) of the medicine

0.1-40% (preferably 3-15%) of adhesive

Absorption enhancement of 0-20% (2 preferably-10%)

Agent for treating cancer

0-5% (preferably 0.5-1%) of lubricant

Coating:

50-99% (7 is preferably 5-95%)

Cosolvent 0-40% (preferably 2-20%)

Plasticizer 0-25% (preferably 2-15%)

The amount of the second active agent (% of the total pharmaceutical formulation)

Medicine 0.1-20% (preferably 1-10%)

0.1-30% (preferably 1-15%) of adhesive

0-20% (preferably 0.1-15%) of surfactant

Pore former 0-25% (preferably 0.1-15%)

Polymer (optional) 0-30% (preferably 0.1-20%)

The pharmaceutical preparation prepared according to the invention showed the following dissolution profile in 900ml simulated intestinal fluid (ph7.5 phosphate buffer) at 75rpm using USP model 2 apparatus at 37 ℃:

release of first active agent

NLT ≥ not less than

Delivery of a second active agent

Time in hours% release

0.5 NLT 60% (preferably NLT 75%)

It has been found that the excipients selected in the thiazolidinedione component of the pharmaceutical formulation can greatly affect the release profile, potency and stability of the thiazolidinedione. Thus, in an alternative embodiment of the invention, the composition of the thiazolidinedione component of the invention should be selected such that no less than 85%, preferably no less than 90% and most preferably no less than 95% of the thiazolidinedione is released from the pharmaceutical formulation within 45 minutes, preferably within 40 minutes and most preferably within 30 minutes as measured according to the United States Pharmacopeia (USP)26 using apparatus 1 at 100rpm, 37 ℃ and 900ml of 0.3MKCl-HCl buffer, pH 2.0.

The excipients used in the thiazolidinedione component of the pharmaceutical formulation should be selected so that the total amount of thiazolidinedione related compounds or impurities in the final pharmaceutical formulation is no more than 0.6%, preferably no more than 0.5% and most preferably no more than 0.25% and each individual thiazolidinedione related compound or impurity in the final pharmaceutical formulation is no more than 0.25%, preferably no more than 0.2% and most preferably no more than 0.1%. The thiazolidinedione related compounds or impurities in the final pharmaceutical preparation are purified by High Performance Liquid Chromatography (HPLC) using YMC-ODS-AQ, 5 μm,4.6X 250mm or equal volume column, 0.1M ammonium acetate buffer, methyl cyanide, glacial acetic acid (25: 1) mobile phase, approximately 40ul injection volume, 0.7mL/min flow rate, 25 ℃ column temperature and 269nm UV detector wavelength.

Detailed Description

The following examples are provided for illustration only and are not meant to be limiting.

Example 1

Controlled release tablets containing 850mg metformin HCl and 15mg pioglitazone were prepared as follows:

a first active agent

I. Core (% core composition)

Metformin HCl 90.54%

Polyvinylpyrrolidone K-301, USP 4.38%

Sodium tribasic phosphate 4.58%

Magnesium stearate 0.5%

¹About 50,000 molecular weight;

kinetic viscosity (in 10% w/v solution at 20 ℃) 5.5-8.5 mPa-s.

(a) Granulating

Metformin HCI was passed through a 40 mesh screen to remove lumps, which were then collected in a clean, polyethylene-series container. Polyvinylpyrrolidone, K-30 and sodium tribasic phosphate were dissolved in pure water. Adding the de-agglomerated metformin HCl to a top-jet fluidized bed granulator and forming granules by spraying a combination solution of povidone and sodium tri-basic phosphate at an inlet air temperature of 50-70 ℃; the spraying air pressure is 1-3bars and the spraying rate is 10-100 ml/min.

Once the binding solution is exhausted, the granules are dried in a granulator until the loss on drying is less than 2%. The dried granules were passed through a pulverizer equipped with an 18 mesh screen.

(b) Into tablets

Magnesium stearate was passed through a 40 mesh stainless steel sieve and mixed with the metformin HCl granulate for approximately five (5) minutes. After mixing, the pellets were pressed on a roller compactor equipped with 15/32 "ring standard concave punches (flat bottom punch with approximately 1mm print pins, top punch).

As mentioned above, the holes may be made by any conventional means used in the pharmaceutical arts.

(c) Sealing coating (optional)

The coated core tablet may be encapsulated with opadry material or other suitable water-soluble material by first dissolving the opadry material (preferably opadry clear) in purified water. The opadry solution obtained was then sprayed onto the core tablets using a pan coater under the following conditions: the temperature of the discharged air is 38-42 ℃; spraying pressure of 28-40psi and spraying rate of 10-15 ml/min. The core tablets are coated with the sealing solution until a theoretical coating level of about 2-4% is obtained.

II film (% film composition)

Cellulose acetate (398-10) 285%

5 percent of triacetyl

PEG 400 10％

²The concentration of acetic acid is 39.3-40.3%

(a) Film coating process

Cellulose acetate was dissolved in acetone while stirring with a homogenizer. Polyethylene glycol 400 and triacetate were added to the cellulose acetate solution and stirred until a clear solution was obtained. Subsequently, the clear film coating solution was sprayed onto the seal coated tablets using a fluidized bed coater under the following conditions: the production temperature is 16-22 ℃; the spraying pressure is about 3bar and the spraying rate is 120-150 ml/min. The sealed core tablets are coated with the sealing solution until a theoretical coating level of about 3% is obtained.

A second active agent layer (% second component composition)

Batch glitazone HCl 43.5%

Tween 80 2.0％

Propyl methyl cellulose 54.5%

Tween 80 and hydroxypropylmethylcellulose were dissolved in pure water. Pioglitazone HCl was then dispersed in this solution. The resulting suspension was sprayed onto the above film-coated tablets.

Example 2

Controlled release tablets containing 850mg metformin HCl and 15mg pioglitazone were prepared as follows:

a first active agent

I. Core (% core composition)

Metformin HCl 88.555%

Polyvinylpyrrolidone K-90³，USP 6.368％

Sodium lauryl sulfate 4.577%

Magnesium stearate 0.5%

³About 1,000,000,

dynamic viscosity (10% w/v solution) 300-.

(a) Granulating

Metformin HCI and sodium lauryl sulfate were passed through a 40 mesh screen to remove lumps, which were then collected in a clean, polyethylene-series container. Polyvinylpyrrolidone, K-30 and sodium tribasic phosphate were dissolved in pure water. The de-agglomerated metformin HCl and sodium lauryl sulfate were then added to a top-spray fluidized bed granulator and granulated by spraying a combination solution of povidone and sodium phosphate tribasic under the following conditions: the inlet air temperature is 50-70 ℃; the spraying air pressure is 1-3bars and the spraying rate is 10-100 ml/min.

Once the binding solution is exhausted, the granules are dried in a granulator until the loss on drying is less than 2%. The dried granules were passed through a pulverizer equipped with an 18 mesh screen.

(b) Into tablets

Magnesium stearate was passed through a 40 mesh stainless steel sieve and mixed with the metformin HCl granulate for approximately five (5) minutes. After mixing, the pellets were pressed on a roller compactor equipped with 15/32 "ring standard concave punches (flat bottom punch with approximately 1mm print pins, top punch).

As mentioned above, the formation of the pores may be carried out by any conventional means employed in the pharmaceutical art.

(c) Sealing coating (optional)

The core tablet may be seal coated with opadry material or other suitable water soluble material by first dissolving the opadry material (preferably opadry clear) in purified water. The opadry solution was then sprayed onto the core tablet using a pan coater under the following conditions: the temperature of the discharged air is 38-42 ℃; the spraying pressure is 28-40psi and the spraying rate is 10-15 ml/min. The core tablets were coated with the sealing solution until a theoretical coating level of about 2% was obtained.

II film (% film composition)

485% of cellulose acetate (398-10)

5 percent of triacetyl

PEG 400 10％

⁴The concentration of acetic acid is 39.3-40.3%

(a) Film coating process

Cellulose acetate was dissolved in acetone while stirring with a homogenizer. Polyethylene glycol 400 and triacetate were added to the cellulose acetate solution and stirred. The film coating solution was then sprayed onto the seal coated tablets using a fluid bed coater under the following conditions: the production temperature is 16-22 ℃; the spraying pressure was about 3bars and the spraying rate was 120-150 ml/min. The sealed core tablets were coated to obtain a theoretical coating level of about 3%.

A second active agent layer (% second component composition)

Pioglitazone HCl 43.5%

Tween80 2.0％

Hydroxypropyl methylcellulose 54.5%

Tween 80 and hydroxypropylmethylcellulose were dissolved in pure water. Pioglitazone HCl was then dispersed in this solution. The resulting suspension is then sprayed onto the film-coated tablets described above.

Example 3

Controlled release tablets containing 500mg metformin HCl and 15mg pioglitazone were prepared as follows:

I. a first active agent

500mg metformin film coated tablets were prepared as described above in example 2, except that a compound cupped tool was used in the tableting process. The 500mg metformin film-coated tablet has the following composition:

core(s)

Metformin HCl 500 mg/tablet

Polyvinylpyrrolidone K-90, USP 35.96 mg/tablet

Lauryl sulfate sodium NF 25.84 mg/tablet

Magnesium stearate, NF 2.82 mg/tablet

Sealing coating

Opadry transparent (YS-1-7006) 23.53 mg/tablet

Film coating

398-10 g/piece of cellulose acetate and 23.56 mg/piece of NF

Triacetin, USP 1.39 mg/tablet

Polyethylene glycol 400, NF 2.77 mg/tablet

Total weight 615.87 mg/tablet

Second active pharmaceutical layer

A immediate release amount of pioglitazone HCL was applied to the 500mg metformin HCL film coat prepared in step 1. The final tablet had the following composition:

metformin HCl film coating 615.87 mg/tablet

Pioglitazone coating

Pioglitazone HCl 16.53 mg/tablet

Tween 802.0 mg/tablet

Cross-linked polyvinylpyrrolidone XL 15.0 mg/tablet

Opadry transparent (YS-1-7006) 8.47 mg/tablet

Color coating

Opadry white 10.0 mg/tablet

Glazing coating

Candelilla wax powder 2.0 mg/tablet

The pioglitazone coating was applied directly to 500mg metformin HCl film coated tablets. Pioglitazone coating was prepared by dissolving 0.252kg opadry, 0.269kg crospovidone XL and 0.036kg Tween 80 in 9.908kg of purified water using a homogenizer. Once these ingredients were dissolved, 0.296kg pioglitazone HCl was dispersed into the solution and homogenized. The homogenized dispersion was then applied directly to 500mg metformin HCl film coated tablets using a 24 "0' Hara Labcoat III pan coater under the following conditions:

the spraying rate is 15-27mL/min

The escaping temperature is 42-47 DEG C

Spray air pressure 25psi

Rotating disc speed 5-9rpm

Inlet air flow 300-

Once the pioglitazone coating was applied to the 500mg metformin HCl film coated tablet, an aesthetic or color coating of opadry was applied to the pioglitazone coated tablets. A colored coating was prepared by dispersing 0.179kg of opadry in 1.791kg of purified water. The opadry suspension was applied directly to the pioglitazone coated tablets using a 24 "0' Hara Labcoat III pan coater under the following conditions:

the spraying rate is 20-35mL/min

The escape temperature is 35-45 DEG C

Spray air pressure 25psi

Turntable speed 9rpm

Inlet air flow 390-

Once the color coat is applied, the tablets are glossed with 0.036kg of Candelilla wax powder.

Example 4

Controlled release tablets containing 500mg metformin HCl and 15mg pioglitazone were prepared as follows:

I.a first active agent

500mg metformin film coated tablets were prepared as described above in example 2, except that a compound cupped tool was used in the tableting process. The 500mg metformin film-coated tablet had the following composition:

core(s)

Metformin HCl 500 mg/tablet

Polyvinylpyrrolidone K-90, USP 35.96 mg/tablet

Lauryl sulfate sodium NF 25.84 mg/tablet

Magnesium stearate, NF 2.82 mg/tablet

Sealing coating

Opadry transparent (YS-1-7006) 23.53 mg/tablet

Film coating

398-10 g/piece of cellulose acetate and 23.56 mg/piece of NF

Triacetin, USP 1.39 mg/tablet

Polyethylene glycol 400, NF 2.77 mg/tablet

Total weight 615.87 mg/tablet

II.Formation of the second active agent layer

The immediate release amount of pioglitazone HCL was applied to the 500mg metformin HCL film coat prepared in step 1. The final tablet had the following composition:

metformin HCI film-coated tablets 615.87 mg/tablet

Sealing coating

Opadry transparent (YS-1-7006) 13.8 mg/tablet

Pioglitazone coating

Pioglitazone HCI 16.53 mg/tablet

Tween 802.0 mg/tablet

Sodium chloride 4.27 mg/tablet

Opadry transparent (YS-1-7006) 2.0 mg/tablet

Color coating

Opadry white 8.10 mg/tablet

Glazing coating

Candelilla wax 0.20 mg/tablet

A seal-coated solution was prepared by dissolving 0.258kg opadry in 2.576kg purified water and spraying the resulting solution onto approximately 12.088kg of 500mg film-coated metformin HCl tablet cores using a 24 "0' Hara Labcoat III pan coater. The sealed coating was applied using the following conditions:

the spraying rate is 20-35mL/min

The escape temperature is 35-45 DEG C

Spray air pressure 25psi

Turntable speed 9rpm

Inlet air flow 390-

The pioglitazone coating was applied to 500mg seal-coated metformin HCl film-coated tablets. Pioglitazone coating was prepared by dissolving 0.040kg opadry, 0.085kg sodium chloride and 0.040kg Tween 80 in 4.915kg purified water using a homogenizer. Once these ingredients were dissolved, 0.328kg pioglitazone HCl was dispersed into the solution and homogenized. The homogenized dispersion was then applied directly to 500mg metformin HCl film coated tablets using a 24 "0' Hara Labcoat III pan coater under the following conditions:

the spraying rate is 10-30mL/gun/min

The escape temperature is 35-45 DEG C

Spray air pressure is 20-40psi

Molding air pressure of 20-40psi

The speed of the rotating disc is 8-12rpm

Inlet air flow 250-.

Once the pioglitazone coating was applied to the 500mg metformin HCL film-coated tablet of the seal coating, an aesthetic or color coating of opadry was applied to the pioglitazone coated tablets. A color coating was prepared by dispersing 0.159kg opadry in 1.585kg pure water. The opadry suspension is applied to the pioglitazone coated tablets under similar conditions as previously applied to the seal coat. Once the color coat is applied, the tablets are glazed with 0.004kg of Candelilla wax powder.

Example 5

Controlled release tablets containing 1000mg metformin HCl and 30mg pioglitazone were prepared as follows:

I.a first active agent

1000mg of metformin film-coated tablets were prepared as described in example 3 above. The 1000mg metformin film-coated tablet had the following composition:

core(s)

Metformin HCl 1000 mg/tablet

Polyvinylpyrrolidone K-90, USP 78.0 mg/tablet

Lauryl sulfate sodium NF 51.69 mg/tablet

Magnesium stearate, NF 5.66 mg/tablet

Sealing coating

Opadry transparent (YS-1-7006) 47.05 mg/tablet

Film coating

Cellulose acetate 398-10, NF 15.77 mg/tablet

Triacetin, USP 0.92 mg/tablet

Polyethylene glycol 400, NF 1.85 mg/tablet

Total weight 1201.0 mg/tablet

II.A second active agent

An immediate release amount of pioglitazone HCL was applied to the 1000mg metformin HCL film coat prepared in step 1. The final tablet had the following composition:

metformin HCl film-coated tablet 1201.0 mg/tablet

Sealing coating

Opadry transparent (YS-1-7006) 16.0 mg/tablet

Pioglitazone coating

Pioglitazone HCl 33.06 mg/tablet

Sodium chloride 4.27 mg/tablet

Opadry transparent (YS-1-7006) 3.0 mg/tablet

Color coating

Opadry II white (Y-22-7719) 20.27 mg/tablet

Glazing coating

Candelilla wax powder 0.40 mg/tablet

A seal coating solution was prepared by dispersing 0.174kg opadry in 3.478kg ethanol and the dispersion was mixed for 15 minutes. The solution was then sprayed onto approximately 13.174kg of 100mg metformin HCl film coated tablets using a 24 "0' Hara Labcoat III pan coater. A seal coat was applied to 1000mg metformin HCl film coated tablets using the following conditions:

the spraying rate is 10-30ml/gun/min

The escape temperature is 25-45 DEG C

Spray air pressure is 20-40psi

Turntable speed of 6-12rpms

Molding air pressure of 20-40psi

Inlet air flow 250-

Subsequently, the pioglitazone coating was applied to 1000mg of the metformin HCl film-coated tablets of the seal coat. Pioglitazone coating was prepared by dissolving 0.036kg opadry and 0.046kg sodium chloride in 5.344kg ethanol using a homogenizer. Once these ingredients were dissolved, 0.359kg of pioglitazone HCl was dispersed into the solution and homogenized. The homogenized dispersion was then applied to seal-coated 1000mg metformin HCl film-coated tablets using a 24 "0' Hara Labcoat III pan coater under the following conditions:

the spraying rate is 10-30mL/gun/min

The escape temperature is 25-45 DEG C

Spray air pressure is 20-40psi

The speed of the rotating disc is 6-12rpm

Molding air pressure of 20-40psi

Inlet air flow 250-

Once the pioglitazone coating was applied, an aesthetic or colored coating of opadry II white was applied to the pioglitazone coated tablets. The color coat was prepared by dispersing 0.220kg opadry II white in 4.407kg ethanol. The opadry II white suspension was then applied to the pioglitazone coated tablets under similar conditions as previously applied to the seal coat. Once the color coat is applied, the tablets are glazed with 0.004kg of Candelilla wax powder.

Example 6

Controlled release tablets containing 1000mg metformin HCl and 30mg pioglitazone were prepared as follows:

I.a first active agent

1000mg of metformin film-coated tablets were prepared as described above in example 3. A 1000mg metformin film coated tablet has the following composition:

core(s)

Metformin HCl 1000 mg/tablet

Polyvinylpyrrolidone K-90, USP 78.0 mg/tablet

Lauryl sulfate sodium NF 51.69 mg/tablet

Magnesium stearate, NF 5.65 mg/tablet

Sealing coating

Opadry transparent (YS-1-7006) 47.05 mg/tablet

Film coating

Cellulose acetate 398-10, NF 15.77 mg/tablet

Triacetin, USP 0.92 mg/tablet

Polyethylene glycol 400, NF 1.85 mg/tablet

Total weight 1201.0 mg/tablet

II.A second active agent

The immediate release amount of pioglitazone HCL was applied to the 1000mg metformin HCL film coat prepared in step 1. The final tablet had the following composition:

metformin HCl film-coated tablet 1201.0 mg/tablet

Sealing coating

Opadry transparent (YS-1-7006) 21.0 mg/tablet

Pioglitazone coating

Pioglitazone HCl 33.06 mg/tablet

Sodium chloride 5.0 mg/tablet

Opadry transparent (YS-1-7006) 3.7 mg/tablet

Color coating

Opadry II white (Y-22-7719) 21.54 mg/tablet

Glazing coating

Candelilla wax powder 0.40 mg/tablet

The seal coat was applied to 1000mg metformin HCl film coated tablets. Seal coatings were prepared by dispersing 0.229kg opadry clear in 4.573kg ethanol USP and mixing the dispersion for 15 minutes. The solution was then sprayed onto approximately 13.08kg of 1000mg metformin HCl tablet cores using a 24 "0' Hara Labcoat III pan coater with a 4 + -2" series nozzle head at the top of the fixed bed and under the following conditions:

the spraying rate is 25 plus or minus 10mL/gun/min

The escape temperature is 25 ℃ plus or minus 5 DEG C

Spray air pressure 10-40psi

Turntable speed 4-9rpm

Providing an airflow of 200 + -100 CFM

Molding air pressure of 10-40psi

The seal coat dispersion was continuously stirred until used up during the coating process.

Subsequently, the pioglitazone coating was applied to 1000mg metformin HCl film coated tablets of the seal coat. The pioglitazone coating was prepared by mixing 4.434kg of ethanol USP with 1.250kg of purified water (ethanol to purified water ratio approximately 78: 22) and slowly dispersing 0.040kg of opadry clear into the solvent mixture. Once opadry clear was dispersed, it was homogenized for 10 minutes. Once the opadry clear dispersion was homogenized, 0.054kg of sodium chloride was added to the dispersion and homogenized for approximately 2 minutes. After the sodium chloride was homogenized, 0.360kg of pioglitazone HCI was slowly dispersed into the solvent mixture and then homogenized for about 10 minutes. As soon as pioglitazone HCl was homogenized, the homogenizer was removed from the mixing vessel and replaced with an air mixer and mixed for an additional 15 minutes. The pioglitazone suspension was stirred until the suspension was used up during the coating process. Pioglitazone HCl suspension was applied to a seal-coated 1000mg metformin HCl tablet core using a 24 "0' Hara Labcoat III pan coater with a 4 ± 2" series nozzle head at the top of the fixed bed and under the following conditions:

the spraying rate is 25 plus or minus 10mL/gun/min

The escape temperature is 25 +/-5 DEG C

Spray air pressure 10-40psi

Turntable speed 4-9rpms

Molding air pressure of 10-40psi

Providing an airflow of 200 + -100 CFM

Once the aesthetic coating suspension is exhausted, the tablets are dried in a coating pan at a speed of about 2 to 8rpms and a spill temperature of 25 + -5 deg.C for about 5 minutes. Once the tablets were dry, the exhaust air was turned off and the turntable speed was adjusted to approximately 3-4rpms and 0.004kg of candelilla wax powder that had passed through a 60 mesh screen was spread over the tablets. After the tablets had rolled in the wax for about 5 minutes, the exhaust air was turned on and the tablets rolled for an additional 10 minutes.

The final glazed tablets, when tested using USP apparatus type 1 in HCl-0.3MKCI buffer at 100rpm, pH 2.0, showed pioglitazone HCl dissolution properties as follows:

time% released pioglitazone

10min. 42％

20min 79％

30min 95％

45min 102％

The final polished tablets were prepared by HPLC using YMC-ODS-AQ, 5 μm,4.6X 250mm column, 0.1M ammonium acetate buffer, methyl cyanide, glacial acetic acid (25: 1) mobile phase, 40. mu.L injection volume, 0.7mL/min flow rate, 25 ℃ column temperature and for UV detector wavelength 269nm detection also contains the following pioglitazone related compounds.

Number of names relative retention time (%)

RS-1 0.7 N.D^*.

Pioglitazone 1.0

RS-2 1.5 0.03

RS-3 3.4 0.04

RS-4 1.2 0.03

RS-5 2.8 0.04

^*N.d. ═ undetected

RS-1 is (+/-) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzyl ] -5-hydroxy-2, 4-thiazolidinedione.

RS-2 is (z) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzylidene ] -2, 4-thiazolidinedione.

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

RS-4 is (+/-) -ethyl-2-methionyl-3- [4- [2- (5-ethyl-2-pyridyl) ethoxy ] phenyl- ] propionate.

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

The final glazed tablets were packaged in 100cc HDPE bottles containing one (1)2g SORB-IT desiccant canister held for three months under accelerated stabilization conditions of 40 ℃ and 75% relative humidity. After storage, the finished glossed tablets were tested and showed the following pioglitazone HCl dissolution properties when tested in HCl-0.3M KCl buffer at 100rpm, pH 2.0 using USP type 1 apparatus:

time% released pioglitazone

10min. 38％

20min 73％

30min 92％

45min 101％

The final polished tablets after storage were subjected to HPLC using YMC-ODS-AQ, 5 μm,4.6X 250mm column, 0.1M ammonium acetate buffer, methyl cyanide, glacial acetic acid (25: 1) mobile phase, 40. mu.L injection volume, 0.7mL/min flow rate, 25 ℃ column temperature and for UV detector wavelength 269nm detection also contains the following pioglitazone related compounds.

Number of names relative retention time (%)

RS-1 0.7 N.D.^*

Pioglitazone 1.0

RS-21.5 0.03

RS-33.4 0.05

RS-41.2 0.02

RS-52.8 0.04

^*N.d. ═ undetected

Although certain preferred and alternative embodiments have been described for purposes of disclosing the present invention, variations from the disclosed embodiments will occur to those skilled in the art. Therefore, the appended claims are intended to cover all such embodiments and modifications of the invention which do not depart from the scope and spirit of the invention.

Claims (7)

1. A pharmaceutical formulation, comprising:

(a) a controlled release osmotic tablet core comprising metformin hydrochloride which exhibits the following dissolution profile in simulated intestinal fluid at 75rpm, 900ml pH7.5 and 37 ℃ using a USP model 2 apparatus,

after 2 hours 0-25% of metformin hydrochloride is released;

after 4 hours, 10-45% of metformin hydrochloride is released;

after 8 hours, 30-90% of metformin hydrochloride is released;

not less than 50% of metformin hydrochloride is released after 12 hours;

not less than 60% of metformin hydrochloride is released after 16 hours; and

not less than 70% of metformin hydrochloride is released after 20 hours; and

(b) a layer of immediate release pioglitazone hydrochloride coating the core comprising no less than 90% pioglitazone hydrochloride released within 30 minutes from the pharmaceutical formulation as measured according to the united states pharmacopeia 26 using an instrument 1 at 100rpm, 37 ℃ and 900ml of 0.3M KCI-HCl buffer, pH 2.0, and the formulation comprising no more than 0.25% of the following compounds:

(i) (+/-) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzyl ] -5-hydroxy-2, 4-thiazolidinedione;

(ii) (z) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzylidene ] -2, 4-thiazolidinedione;

(iii) (+/-) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzyl ] -3[2- (5-ethyl-2-pyridyl) ethyl ] -2, 4-thiazolidinedione;

(iv) (+/-) ethyl-2-carbamoylthio-3- [4- [2- (5-ethyl-2-pyridyl) ethoxy ] phenyl- ] propionate;

and (v) ethyl-3-p- [2- (5-ethyl-2-pyridyl) ethoxy ] phenylpropionate.

2. The pharmaceutical formulation according to claim 1, wherein not less than 95% of the pioglitazone hydrochloride contained therein is released from the pharmaceutical formulation within 30 minutes as measured according to the united states pharmacopeia 26 using the apparatus 1 at 100rpm, 37 ℃ and 900ml of 0.3MKCI-HCl buffer solution, pH 2.0.

3. The pharmaceutical formulation according to claim 1, wherein not less than 100% of the pioglitazone hydrochloride contained is released from the pharmaceutical formulation within 30 minutes as measured according to the united states pharmacopeia 26 using the instrument 1 at 100rpm, 37 ℃ and 900ml of 0.3MKCI-HCl buffer, pH 2.0.

4. The pharmaceutical formulation of claim 1, wherein the osmotic tablet core is free of any gel or swelling polymer.

5. The pharmaceutical formulation of claim 1, wherein the osmotic tablet core exhibits the following dissolution profile in simulated intestinal fluid at 900ml pH7.5 at 75rpm and 37 ℃ using a USP model 2 apparatus,

after 2 hours 0-15% of metformin hydrochloride is released;

after 4 hours, 20-40% of metformin hydrochloride is released;

after 8 hours 45-90% of metformin hydrochloride is released;

not less than 60% of metformin hydrochloride is released after 12 hours;

not less than 70% of metformin hydrochloride is released after 16 hours; and

not less than 80% of the metformin hydrochloride is released after 20 hours.

6. The pharmaceutical formulation of claim 1, comprising no more than 0.2% of the following compounds:

(i) (+/-) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzyl ] -5-hydroxy-2, 4-thiazolidinedione;

(ii) (z) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzylidene ] -2, 4-thiazolidinedione;

(iii) (+/-) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzyl ] -3[2- (5-ethyl-2-pyridyl) ethyl ] -2, 4-thiazolidinedione;

(iv) (+/-) ethyl-2-carbamoylthio-3- [4- [2- (5-ethyl-2-pyridyl) ethoxy ] phenyl- ] propionate;

and (v) ethyl-3-p- [2- (5-ethyl-2-pyridyl) ethoxy ] phenylpropionate.

7. The pharmaceutical formulation of claim 1, comprising no more than 0.1% of the following compounds:

(i) (+/-) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzyl ] -5-hydroxy-2, 4-thiazolidinedione;

(ii) (z) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzylidene ] -2, 4-thiazolidinedione;

(iii) (+/-) -5- [ p- [2- (5-ethyl-2-pyridyl) ethoxy ] benzyl ] -3[2- (5-ethyl-2-pyridyl) ethyl ] -2, 4-thiazolidinedione;

(iv) (+/-) ethyl-2-carbamoylthio-3- [4- [2- (5-ethyl-2-pyridyl) ethoxy ] phenyl- ] propionate;

and (v) ethyl-3-p- [2- (5-ethyl-2-pyridyl) ethoxy ] phenylpropionate.