AU2001273290B2 - Core formulation comprising troglitazone and a biguanide - Google Patents

Description

WO 03/005993 PCT/US01/21616 Core Formulation Comprising Troglitazone and a Biguanide This application claims priority from U.S. provisional application Serial No. 60/201,233, filed May 1, 2000, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to a core formulation, and, more particularly, to a core formulation comprising a first layer comprising troglitazone, which covers at least a portion of a core comprising a biguanide, such as for example metformin glucophage), with a modulating release polymer comprising a silicate.

Description of the Related Art Metformin and troglitazone, and their salts such as the hydrochlorides, maleates, tartrates, etc., are two active ingredients of anti-diabetic drugs that are used to treat diabetic patients, e.g. human beings. These two active agents are administered orally to patients in need thereof in protocols calling for the single administration of either ingredient. Heretofore, there has not been revealed or hinted at combining both ingredients and certainly not a physically combined core formulation comprising both ingredients. The advantage of such a core formulation is advantageous to patients and prescribers because both medicaments are syunrgistic to each other in the body when used in the management of blood glucose control, diabetes. Furthermore, the use of a modulating agent, like silica gel, in the preparation, controls the rate of drug release over a clinically meaningful period to enable better control of the effect of the medicinal agents in such preparation.

SUMMARY OF THE INVENTION This invention relates to a core formulation, and, more particularly, to a core formulation comprising a first layer comprising troglitazone or a derivative thereof, e.g. troglitazone hydrochloride, which covers at least a portion of a core comprising a biguanide, one or both of which are intimately dispersed in a silicate based modulating agent.

DETAILED DESCRIPTION OF THE INVENTION A typical biguanide is metformin. It typically is used clinically as a pharmaceutically acceptable salt, preferably the hydrochloride salt. A commercial WO 03/005993 PCT/US01/21616 2 form ofmetformin hydrochloride is available as glucophage. Its chemical name is N,N-dimethylimidodicarbonimidic diamide hydrochloride. Metformin hydrochloride is a hydrochloride salt of metformin base, and as used herein, "metformin" means the base compound as well as its pharmaceutically acceptable salts. Metformin is used clinically to manage non-insulin dependent diabetes mellitus ("NIDDM"), particularly in patients who are not effectively treated with a sulfonylurea. While it is not chemically related to the sulfonylureas, it is routinely utilized in combination with a sulfonylurea, and has been shown to be synergistic in some cases. Other biguanides such as phenformin, buformin etc. can also be used.

Additionally, in the treatment of a diabetic patient the metformin and the troglitazone, e.g. its hydrochloride, are present in effective amounts to provide such treatment.

Metformin is an active ingredient for a commercially available drug employed to treat diabetes mellitus in a host or mammal, e.g. a human being, another animal. The typical daily effective dose for the oral treatment of a mammal, a human, ranges from about 500 mg to about 2550 mg. Typically, the dose is a single dose of about 500 mg to about 850 mg.

Troglitazone hydrochloride, (Rezulin®), is an active ingredient for a commercially available drug employed to treat diabetes mellitus in a host, e.g. a human being. The typical daily effective dose for the oral administration to a mammal, e.g. a human being, ranges from about 200 mg to about 400 mg, given as a single dose.

Silicates are pharmaceutical excipients generally regarded as safe and used therefore to prepare a variety of pharmaceutical systems well documented in the patent literature.

In this regard, reference is made to Remington's Pharmaceutical Sciences, 18 th Edition, Inorganic Pharmaceutical Chemistry, Silicon, pp 340-341, 1990.

Heretofore, the silicates have not been shown to modulate the release of the hypoglycemic drugs metformin and pioglitazone hydrochloride when administered together to try to improve the control and effectiveness of either drug, although co-administration of the two has been proposed [Whitcomb; et al., United States Patent No. 6,011,049]. However, a combined form of the drugs, i.e. a single WO 03/005993 PCT/US01/21616 3 integral unit thereof has not heretofore been reported. The present invention provides such a single integral unit in the form of a core formulation.

A typical silicate for this purpose is Purified Siliceous Earth (National Formulary XVI), also known in some forms as silica gel or fumed silica.

It is typically used in oral pharmaceutical preparations as a bulking agent. As used herein, "silicate" means silicic acid, disilicic acid, trisilicic acid, metasilicic acid, and orthosilicic acid in their free or salt forms; silicon dioxide in either of its amporphous, crystalline, or precipitated forms; diatomacous earth; Fuller's earth, Kieselhurh, Celite; talc; attapulgite; micas; clays such as montmorilonite (MontmoriloniteTM), kaolin, aluminum oxide (Hydrargilite), bentone (BentoniteT), bentonite (Bentonite Magma T M and pumice; silanes and siloxanes. These are used typically as adsorbents, carriers, dispersants, fillers, thickeners.

As indicated above, the relative concentrations of each drug is such that a first layer comprising troglitazone is prepared. The first layer covers at least a portion of a core comprising metformin, with a portion or all of the amount of the silicate. Depending upon the rate of administration of the core preparation, the metabolism of the patient destined to be treated, and the desired concentrations of each ingredient for each drug, the first layer may cover only a portion of the core or encompass the entire core. For example, one quarter of the core to about three fourths of the tablet core. The first layer should comprise troglitazone hydrochloride, with or without any silicate, because its dose requirement is lower compared to metformin. Additionally, troglitazone hydrochloride is slightly nonpolar, its solubility rate is slower, and its absorption rate thus is dependent on its dissolution rate in the contents of the gastrointestinal tract compared with metformin.

It is to be understood, depending upon the desired rate of administration to the patient, either the first layer or the core may additionally contain a mixture of the two active ingredients or both the first layer and the core may contain the two active ingredients with different and varying concentrations of one or both active ingredients.

The first layer of the core comprises troglitazone, e.g. its hydrochloride, in an amount of about 0.01 to about 20% of the total weight of the WO 03/005993 WO 03/05993PCT/US01/21616 4 core formnulation, whereas, the metforrnin in the core is present in an amount of about 10% to about 97.5% of the total weight of the core formulation, Where combinations of the two active ingredients are present in the first layer and/or the core, the amounts of troglitazone, e.g. its hydrochloride, ranges from about 1 mg to about 45 mg whereas the metformin ranges from about 100 mg to about 2550 mg.

Finally, it is to be understood that a third pharmacologically active material, e.g. a drug, such as for example a sulfonylurea, an ca-glucosidase inhibitor, a meglitinide, and an ACE inhibitor can admixed with the active ingredients in the first layer and/or the core.

The alpha.-glucosidase inhibitors [Jean-Bernard Ducep et al., US Patent No. 5,504,078], bisgiucosylmoranoline derivatives [UK Patent No. GB 2 088 365 and glucosylmoranoline derivatives [European Patent No. 87112480.6] include the following medicaments: I .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)- 1 ,5-[6,7-dideoxy-7-D-glucoheptopyranosyl)imino] -D-glucitol; 1. 5-Dideoxy-4- O(.alpha.,D-glucopyranosyl)- -deoxy-D-fructofuranosyl)imino]-D-glucitol; 1 .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)- 1,5-[(4-deoxy-4-Dglucopyranosyl)imino]-D-glucitol; 1 .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N- [6-deoxy-lI-(6-O-D-glucopyranosyl)-.alpha.-.D-glucopyranosyl]- 1, glucitol; 1. 5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N-[16,7-dideoxy-l-(6-O-Dglucopyranosyl)-7--.alpha.-D -glucoheptopyranosyl]- 1,5-imino-D-glucitol; Dideoxy-4-O(.alpha.,D-glucopyranosyl)- 1,5-[(4-deoxy-4-Dglucopyranosyl)methyliminoj-D-glucitol; 1 .5-Dideoxy-4-O(.alpha.,Dglucopyranosyl)-N-[4-deoxy-1 -(4-O-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]- 1 ,5-imino-D-glucitol; 1 .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)- [2(1 -Darabinofuranose)ethyl]imino) -D-glucitol; 1 .5-Dideoxy-4-O(.alpha.,Dglucopyranosyl)-N-[4-deoxy-1 -(6-O-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]- 1 ,5-imino-D-glucitol; 1 .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N- {[4-deoxy- 1- (4-O-D-glucopyranosyl)-4-.alpha.-D -glucopyranosyljmethyl} -1 1 .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N- [4-deoxy-1 glucopyranosyl)-4-.alpha.-D -glucopyranosyllmethyl} -1 ,5-imino-D-glucitol; Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1 ,5-[(6-deoxy- 1 methyl-6-f3-Dglucopyranosyl)-imino-D -glucitol; 1 .5-Dideoxy- 4 -O(.alpha.,D-glucopyranosyl)- WO 03/005993 WO 03/05993PCT/US01/21616 1 ,5-[(6,7-dideoxy-1 -O-methyl-7-B-D-glucoheptopyranosyl) imino]-D-glucitol; -deoxy-2-0-methyl-3-Dfructofuranosyl)imino] -D-glucitol, 1 .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-l1,5-[(4-deoxy- 1 methyl-4-B-Dglucopyranosyl)imino]-D-glucitol; 1 .5-Dideoxy-4-0(.alpha.,D-glucopyranosyl)-N- [6-deoxy- 1 -0-metiyl-6-0-3-D-glucopyranosyl)-.alpha.-D -ghicopyranosyl]- imino-D-glucitol; 1 .5-Dideoxy-4-0(.alpha.,D-glucopyranosyl)-N-[6,7-dideoxy-l1-(1- O-methyl-6-0-13-D-glucopyranosyl)-7-.alph-a.-D-glucoieptopyraiosyl]-1 glucitol; 1 .5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)- 1,5-[(4-deoxy- 1 methyl-4i3-D-glucopyranosyl)methylimino]-D-glucitol; 1 .5-Dideoxy-4-0(.alplia.,Dglucopyranosyl)-N-[4-deoxy-l1-(1 -O-methyl-4-0-8-D-glucopyranosyl)-.alpha.-D glucopyranosyl]- 1,5-imino-D-glucitol; 1 .5-Dideoxy-4-0(.alpha.,D-glucopyranosyl)- 1-0-methyl-i -B-D-arabinofrranosyl)ethyl]imino}-D-glucitol; 1 4-0(.alpha.,D-glucopyranosyl)-N-[4-deoxy-l1-(1 -0-methyl-6-0-3-Dglucopyranosyl)-.alpha.-D-glucopyranosyl]- 1,5-iminio-D-glucitol; 1. 5-Dideoxy-4- 0(.alpha.,D-glucopyranosyl)-N- {[4-deoxy-l1-(1 glucopyranosyl)-4-.alpha.-D-glucopyranosyl]methyl}- 1,5-imino-D-glucitol; Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N- {[4-deoxy-l1-(1 -0-methyl-6-0-B-Dglueopyranosyl)-4-.alpha.-D-glucopyranosyl]methyl}-1 ,5-imino-D-glucitol; Dideoxy-6-0(.alpha.,D-glucopyranosyl)-1I,5-[6,7-dideoxy-7-Dglucoheptopyranosyl)imino] -D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,Dglucopyranosyl)-1I,5-[(1-deoxy-D-fructofiaranosyl)imino]-D-glucitol; 1 1,5- [(4-deoxy-4-D-glucopyranosyl)imino]-Dglucitol; 1 .5-Dideoxy-6-0(.alpha.,D-glucopyranosyl)-N-[6-deoxy-l1-(6-O-Dglucopyranosyl)-.alpha.-D-glucopyranosyl] -1 ,5-imino-D-glucitol; 1 .5-Dideoxy-6- O(.alpha.,D-glucopyranosyl)-N- [6,7-dideoxy- 1 -(6-0-D-glucopyranosyl)-7-. alpha. -D -glucoheptopyranosyl]- 1,5-imino-D-glucitol; 1.5-Dideoxy-6-0(.alpha.,Dglucopyranosyl)- 1,5-[(4-deoxy-4-D-glucopyranosyl)methylimino]-D-glucitol; Dideoxy-6-0(.alpha.,D-glucopyranosyl)-N-[4-deoxy-l1-(4-O-D-glucopyranosyl)- .alpha.-D-glucopyranosyl]-1 ,5-imino-D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,Dglucopyranosyl)-1 -D-arabinofuranose)ethyllimino}-D-glucitol; Dideoxy-6-0(.alpha.,D-glucopyranosyl)-N-[4-deoxy-l1-( 6 -0-D-glucopyranosyl)- .alpha.-D-glucopyranosyl]-1 ,5-imino-D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,D- WO 03/005993 WO 03/05993PCT/US01/21616 6 glucopyranosyl)-N-{ [4-deoxy-l1-(4-0-D-glucopyranosyl)-4-.alpha.-D glucopyranosyllmethyl} -1 ,5-imino-D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,Dglucopyranosyl)-N- {[4-deoxy-l1-(6-0-D-glucopyranosyl)-4-.alpha.-D glucopyranosyl]methyl} -1 ,5-imino-D-glucitol; 1 .5-Dideoxy-6-0(.alpha. ,Dglucopyranosyl)- 1,5-[(6-deoxy-1 -0-methyl-6-B-D-glucopyranosyl) -imino-Dglucitol; 1. 5-Dideoxy-6-O(.alpha. ,D-glucopyranosyl)- 1,5-L(6,7-dideoxy- 7-1-D-glucoheptopyranosyl) imino]-D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,Dglucopyranosyl)- 1,5-f(1 -deoxy-2-0-methyl-13-D-fructofuranosyl)imino]-D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,D-glucopyranosyl)- 1,5-[(4-deoxy- 1-0-mthyl-4-13-Dglucopyranosyl)imino]-D-glucitol; 1 .5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N- [6-deoxy-l1-(1 -0-methyl-6-O-B-D-glucopyranosyl)-.alpha.-D -glucopyranosyl]- imino-D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,D-glucopyranosyl)-N-[6,7-dideoxy-l1-(1- 0-methyl-6-O-B-D-glucopyranosyl) -7-.alphia.-D-glucoheptopyranosyl]- D-glucitol; 1 .5-Dideoxy-6-0(.alpha.,D-glucopyranosyl)-1 [(4-deoxy- 4-B-D-glucopyranosyl)rnethylimino]-D-glucitol; 1 .5-Dideoxy-6-0(.alpha. ,Dglucopyranosyl)-N-[4-deoxy-l1-(1 -0-rnethyl-4-0-B-D-glucopyranosyl)-.alpha.-D glucopyranosyl]- 1,5-irnino-D-glucitol; 1. 5-Dideoxy-6-0(.alpha.,D-glucopyranosyl)- -0-methyl-i -B-D-arabinofhranosyl)eth-yl]imino }-D-glucitol; Dideoxy-6-0(.alpha.,D-glucopyranosyl)-'N-[4-deoxy-l1-(1 -0-methyl-6-0-B-Dglucopyranosyl)-.alpha.-D -glucopyranosyl] -1 ,5-imino-D-glucitol; I .5-Dideoxy-6- 0(.alpha.,D-glucopyranosyl)-N-([4-deoxy-1 -0-methyl-4-0-3-D-glucopyranosyl)- 4-.alpha.-D-glucopyranosyl]methyl} -1 ,5-imino-D-glucitol; 1 .5-Dideoxy-6- 0(.alpha.,D-glucopyranosyl)-N-([4-deoxy- 1-(1 -0-methyl-6-0-3-D-glucopyranosyl)- 4-.alpha.-D-glucopyranosyl]methyl} -1 The list of medicaments includes acid addition salt forms with such inorganic acids, such as, for example, hydrochloric, hydrobirmic, sulfuric, phosphoric and like acids; with organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, maloriic, succinic, fumaric, maleic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymalcic, bcnzoic, 2acetoxybenzoic, mandelic and like acids; and with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.

The sulfonylureas are a class of compounds that have been widely employed to treat diabetes. Such compounds are well known, for example, as WO 03/005993 PCT/US01/21616 7 described in U.S. Pat. Nos. 3,454,635; 3,669,966; 2,968,158; 3,501,495; 3,708,486; 3,668,215: 3,654,357; and 3,097,242. Especially preferred sulfonylureas to be employed in the combinations or core formulations of this invention are glyburide, gliquidone, glipizide, tolbutamide, tolazamide, glisoxepid, chlorpropamide, glibornuride, gliclazide, glimepiride, phenbutamide, and tolcyclamide. Other medicaments, such as, for example, an antibiotic, a vitamin, a drug that works on the heart or in the liver, may be admixed with the active ingredients in the first layer and/or the core.

As indicated above, the modulating silicate polymer, silica gel, may be associated with the metformin core alone or with the first layer alone or with both the metformin and troglitazone hydrochloride. The type of association as well as the concentration of the modulating agent is dependent upon the concentrations of the core active ingredient, and the layer active ingredient, the degree of coverage of the core by the first layer and the desired rate of administration of each active ingredient.

The resultant core having the first layer thereon is prepared by any conventional means known in the pharmaceutical art, e.g. compression, tabletting technology, spraying technology, or encapsulation in a pharmaceutically acceptable presentation, such as a gelatin capsule. In particular, typically the core formulation of the present invention is preferably fabricated by compression into a tablet.

The resultant core formulation of the present invention is useful to treat diabetes mellitus. Surprisingly the resultant core formulation of the invention is as user friendly and clinically effective as compared to the administration of metformin alone or troglitazone hydrochloride alone as demonstrated by coadministration of the two agents [Whitcomb; et al., United States Patent No.

6, 011, 049], where in general, the incidence of adverse events was not influenced by age or menopausal status; and further, patients treated with the combination therapy attained better glycemic control than with either monotherapy.

It is to be understood, however, that for any particular subject being treated, a mammal, specific dosage regimens should be adjusted according to the individual need. It is further to be understood that the dosages set forth herein are examples only and that they do not, to any extent limit the scope of the practice of the present invention.

WO 03/005993 PCT/US01/21616 8 The core formulation of the present invention may be administered orally, for example, with inert diluent or with an edible carrier. For the purpose of oral therapeutic administration, the core formulation may have other excipients incorporated therein. The subject core formulation may also contain the following adjuvants: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, corn starch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.

The subject core formulation of the invention may contain other various materials which modify the physical form of the dosage unit (the subject core formulation), for example, as coatings. Thus, the subject core formulation of the present invention may be coated with sugar, shellac or other enteric coating agents. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

In an alternative embodiment of the present invention the resultant core formulation (having a first layer completely or partially covering the core), is treated whereby an outer shell is formed, at least a portion of which comprises the biodegradable modulating silicate material present in an amount having a predetermined rate of degradation or metabolism in the host being treated,.

The silicate material is a high molecular weight compound, which is physiologically acceptable and excreted from the body of the human being or other animal almost intact.

The biodegradable silicate material, comprising the outer shell, having a predetermined rate of degradation or metabolism or break down, is selected from silic acid and its derivatives, examples of which include those listed previously. Other materials well known in the art, which do not react with metformin and/or troglitazone hydrochloride such as biodegradable polymers, like polyorthoesters, polyanhydrides, polyamides based on glutamic acid, polyalkyl cyanoacrylates, polyesters of lactic and glycolic acid, polyactide polymers, cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinylchloride, natural and synthetic rubbers, polyacrylates, polystyrene, etc., may be used. Additionally, WO 03/005993 PCT/US01/21616 9 reference is made to U.S. Patents Nos. 4,166,800, and 4,389,330, which disclose additional shell forming materials and are incorporated hereinto by reference in their entirety.

The shell encapsulating the particles ofpioglitazone hydrochloride of the first layer and/or the particles ofmetformin of the core is obtained by any conventional microencapsulation process whereby microspheres ofmetformin and/or pioglitazone hydrochloride are formed, e.g. a solvent removal process, a phase separation technique, coacervation etc. In this regard reference is made to U.S. Patents Nos. 4,166,800 and 4,389,330, Conte et al, J Controlled Release, vol.

26, (1993), pages 39-47; and U.S. Patent No. 4,839,177; all of which are incorporated hereinto by reference in their entirety.

In a variation of the above alternative embodiment, the resultant core formulation is treated whereby only the top surface area of the first layer comprising pioglitazone hydrochloride has a shell coating thereon. In this regard, reference is made to U.S. Patent No. 5,916,584, incorporated hereinto by reference in its entirety, which describes the process for forming such a shell. The resulting core formulation having the first layer encapsulated by the shell comprising the shell material, is one which provides a delay time prior to release of the active ingredients, i.e.

pioglitazone hydrochloride and metformin, to the patient being treated for diabetes mellitus.

In a second alternative embodiment of the present invention, the resultant core formulation (having a first layer completely or partially covering the core), is treated with a outer shell comprising a natural polysaccaride, in its free acid a or salt form such as guar gum; gum arabic; gum karaya; gum Benjamin, plantago ovata gum; agar; carrageenan; cellulose; gelatin; pectin; or galacturonic acid is formed which encloses the particles of the first layer and/or the core..

Silicates are naturally occurring polymers consisting of silicon chains. These polymers have the propensity to absorb water thus swelling to become gel-like structures in solution. The gel dissolves slowly thus releasing its drug payloads in a dissolution controlled manner.

The silicate shell provides excellent stability to the core formulation while at the same time modulates drug release. Upon ingestion by a patient being treated, the silicate shell swells to become a gel-like structure in solution in the body WO 03/005993 PCT/US01/21616 of the patient, e.g. the stomach. The gel ultimately dissolves slowly, e.g. typically, in several minutes to a few hours, usually within a day, releasing its drug payload, e.g. metformin and/or pioglitazone hydrochloride in a dissolution controlled manner.

As previously discussed, the polymer shell encapsulating the particles of troglitazone, e.g. its hydrochloride, of the first layer and/or the particles of metformin of the core, is obtained by any conventional microencapsulation process whereby microspheres of metformin and/or troglitazone, e.g. its hydrochloride, are fonned, e.g. a solvent removal process, a phase separation technique, coacervation etc. In this regard reference is made to U.S. Patents Nos. 4,166,800 and 4,389,330, Conte et al, J. Controlled Release, vol. 26, (1993), pages 39-47; and U.S. Patent No.

4,839,177; all of which are incorporated hereinto by reference in their entirety.

In a variation of the above alternative embodiment, the resultant core formulation is treated whereby only the top surface area of the first layer comprising troglitazone has a shell coating, e.g. silical gel, thereon. In this regard, reference is made to U.S. Patent No. 5,916,584, incorporated hereinto by reference in its entirety, which describes the process for forming such a shell. The resulting core formulation having the first layer encapsulated by the shell comprising the polymer shell material, is one which provides a delay time prior to release of the active ingredients, i.e. troglitazone and metformin, to the patient being treated for diabetes mellitus.

The amount of the polymer, e.g. fumed silica gel, employed will depend upon the medicament release profile desired, the particular polymer employed, the particular medicament or medicaments encapsulated or coated and the thickness of the coat of polymer contained on the particular medicament. Such amount can be readily determined by those of ordinary skill in the art with due consideration of the factors set forth above.

In a second alternative embodiment, the polymer, e.g. silica gel, is first combined or mixed with at least one of the medicaments, e.g. the troglitazone hydrochloride first layer, whereafter the resultant core having the first layer thereon is prepared in any conventional manner, e.g. compression into a tablet.

The amount of the polymer combined or mixed with at least one of the medicaments, e.g. metformin, troglitazone, depends on the medicament release profile desired. This is readily determined by one of ordinary skill in the art.

WO 03/005993 PCT/US01/21616 11 Typically, for a release of of about 2 to 6 hours, the thickness ranges from about 0.0001 mm to about 1 mm with a concentration of the polymeric material ranging from about 10 ppm to about 100,000 ppm.

Accordingly, based upon the above discussion, the polymer, e.g.

silica gel, is "associated' with the resultant core medicament. By "associated" or "association" is meant that the natural polysaccharide polymer, either fully or partially coats or encompass the particles of at least one medicament, e.g. the first layer of troglitazone, or is combined or mixed with the particles of at least one medicament, e.g. metformin, prior to forming the resulting core medicament, in the formation of a modulate release core formulation.

It is again to be understood that for either metformin or troglitazone, any pharmaceutically acceptable form encompasses the free acids, free bases, salts and various hydrate forms, including semi-hydrate forms of these medicaments, as well as other pharmaceutical materials which are used in the formulation process as acceptable excipient materials generally known to those skilled in the art.

It is understood that any one of the biguanides, i.e. drugs having actions of stimulation of anaerobic glycolysis, is covered by this invention as these, like metformin, increase the sensitivity to insulin in peripheral tissues. These compounds also are involved in the inhibition of glucose absorption from the intestine, suppression of hepatic gluconeogenesis, and inhibition of fatty acid oxidation. Examples of other typical biguanides included in this application are phenformin, buformin etc.

Claims (14)

1. A core formulation comprising, a first layer comprising troglitazone or a pharmaceutically acceptable salt thereof as an active ingredient, a core, at least a portion of which is enclosed by said first layer, comprising a biguanide as an active ingredient; and a polymer selected from the group consisting of a silicate; diatomacous earth; Fuller's earth, Kieselhurh, Celite; talc; attapulgite; micas; montmorilonite, kaolin, aluminum oxide, bentonite, pumice; silanes and siloxanes and a mixture of any of the foregoing polymers, and a mixture thereof, associated with at least one of said active ingredients.

2. The formulation as defined in claim 1 wherein said first layer comprises troglitazone hydrochloride present in an amount ranging from about 1 mg to about 15 mg and said core comprises metformin present in an amount ranging from about 100 mg to about 500 mg.

3. The formulation as defined in claim 1, wherein said polymer is associated by forming a shell having a predetermined rate of active ingredient release covering at least a portion of said first layer to provide a predetermined delay in the time period of release of at least said troglitazone active ingredient.

4. The formulation as defined in claim 1, wherein said troglitazone and/or said biguanide are present as biodegradable microspheres with said polymer associated therewith by having a shell coating and where said shell coating has a predetermined rate of active ingredient release. A method of administering troglitazone and metformin to a mammal, which comprises treating the mammal with the formulation defined in claim 2.

6. A method for producing a controlled release formulation, which comprises: producing a hollow outer shell comprising a gel-like material of a polymer selected from the group consisting of silica gel, fumed silica gel, silicic acid, disilicic acid, trisilic acid, metasilicic acid, and orthosilicic acid in their free or salt forms; silicon dioxide in either of its amporphous, crystalline, or precipitated forms; diatomacous earth; Fuller's earth, Kieselhurh, Celite; talc; attapulgite; micas; WO 03/005993 PCT/US01/21616 13 montmorilonite, kaolin, aluminum oxide (Hydrargilite), bentonite, Bentonite Magma T M pumice; a silane, a siloxane and a mixture of any of the foregoing polymers having a predetermined rate of medicament release to provide a predetermined delay in the time period of release of the contents destined to be enclosed by said shell; inserting a core comprising metformin and having an outer layer comprising troglitazone partially enclosing said core, into said hollow outer shell; and sealing said core within said hollow outer shell.

7. A method of producing a modulated release formulation of troglitazone hydrochloride medicament and metformin medicament, which comprises: forming a core of the metformin medicament; and depositing a layer of the troglitazone hydrochloride medicament on at least a portion of a surface of said core; and associating a polymer selected from the group consisting of silica gel, fumed silica gel, silicic acid, disilicic acid, trisilic acid, metasilicic acid, and orthosilicic acid in their free or salt forms; silicon dioxide in either of its amporphous, crystalline, or precipitated forms; diatomacous earth; Fuller's earth, Kieselhurh, Celite; talc; attapulgite; micas; montmorilonite, kaolin, aluminum oxide, bentonite, pumice; silanes and siloxanes and a mixture of any of the foregoing with at least one of the medicaments to form the modulated release formulation.

8. A method of treating diabetes mellitus in a patient in need thereof, which comprises administering to the patient the formulation of claim 1 wherein said active ingredients are each present in an effective amount.

9. A drug controlled-release pharmaceutical composition comprising an effective amount of troglitazone hydrochloride combined with an effective amount of metformin associated with an effective controlled-release amount of a polymer selected from the group consisting of silica gel, fumed silica gel, silicic acid, disilicic acid, trisilic acid, metasilicic acid, and orthosilicic acid in their free or salt forms; silicon dioxide in either of its amporphous, crystalline, or precipitated forms; diatomacous earth; Fuller's earth, Kieselhurh, Celite; talc; WO 03/005993 PCT/US01/21616 14 attapulgite; micas; montmorilonite, kaolin, aluminum oxide, bentonite, pumice; silanes and siloxanes and a mixture of any of the foregoing polymers. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 9.

11. A drug controlled-release pharmaceutical composition comprising an effective amount of troglitazone hydrochloride combined with an effective amount ofphenformin associated with an effective controlled-release amount of a polymer selected from the group consisting of silica gel, fumed silica gel, silicic acid, disilicic acid, trisilic acid, metasilicic acid, and orthosilicic acid in their free or salt forms; silicon dioxide in either of its amporphous, crystalline, or precipitated forms; diatomacous earth; Fuller's earth, Kieselhurh, Celite; talc; attapulgite; micas; montmorilonite, kaolin, aluminum oxide, bentonite, pumice; silane; a siloxane and a mixture of any of the foregoing polymers.

12. A controlled-release pharmaceutical composition comprising an effective amount of troglitazone hydrochloride combined with an effective amount of buformin associated with an effective controlled-release amount of a polymer selected from the group consisting of silica gel, fumed silica gel, silicic acid, disilicic acid, trisilic acid, metasilicic acid, and orthosilicic acid in their free or salt forms; silicon dioxide in either of its amporphous, crystalline, or precipitated forms; diatomacous earth; Fuller's earth, Kieselhurh, Celite; talc; attapulgite; micas; montmorilonite, kaolin, aluminum oxide, bentonite, pumice; a silane; a siloxane and a mixture of any of the foregoing polymersor.

13. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 11.

14. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 12. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 1 wherein the biguanide is phenformin.

16. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 1 wherein the biguanide is buformin. WO 03/005993 PCT/US01/21616

17. A method of treating diabetes mellitus in a patient in need thereof, which comprises, administering to the patient the composition of claim 1 wherein the biguanide is metformin.