OA12714A

OA12714A - Solid oral dosage form comprising a combination ofmetformin and glibenclamide.

Info

Publication number: OA12714A
Application number: OA1200400120A
Authority: OA
Inventors: Yves Bonhomme; Geoffrey Nicholson; Gillian Cave; Sarah J Nicholson
Original assignee: Lipha
Priority date: 2004-04-22
Filing date: 2004-04-22
Publication date: 2006-06-27

Description

012714

The présent invention relates to solid oral dosage forms for thetreatment of non-insulin dépendent diabètes.

Non-insulîn dépendent diabètes is a meiabolic disordercharacterized by hypergiycaemia, which occurs due to insuiin deficiency,insuiin résistance and reduced glucose toierance.

There are two main groups of oral antidiabetic drugs avaiiable:these are the sulphonylureas and the biguanidines. Sulphonylureas act bystimulating insuiin reiease and are thus oniy effective with some residua!pancreatic beta-cell activity, examples of sulphonylureas avaiiable areglibenciamide, gliciazide, toibutamide, glipizide, toiazamide, gliquidoneand chiorpropamide. The biguanidines, such as metformin, act bydecreasing gluconeogenesis and by increasing peripheral utilisation of.glucose, and as they require endogenous insuiin they are only effectivewith some residual pancreatic islet cell activity.

The initial treatment of nôn-insulin dépendent diabètes involves dietcentral and exercise. Only after this has been shown to be inadéquate areoral antidiabetic drugs used, and then only to complément the effect ofdiet and not replace it. Monotherapy with an oral antidiabetic can be aneffective treatment for many years. Kowever the efficiency can decreasewith time. Due to sulphonylureas and biguanidines naving complementarymodes of action, combined therapy is now an estabiished form oftreatment for non-insuiin dépendent diabètes.

To improve patient compliance a combined tablet wouid be anadvantage. The présent invention relates to solid oral dosage formscomprising a combination of metformin and glibenciamide (also namedglyburide). A combination of metformin with glibenciamide has been disciosedin WO 97/17975 for the treatment of type il diabètes with a defined ratio ofthe two active ingrédients/ which is a requirement in order to obtain anoptimum therapeutic effect. This prior art dermes an optimum therapeuticratio of metformin hydrochloride to glibenciamide of 100:1, for exempleSÛOmg of metformin hydrochloride with 5mg glibenciamide in a single 012714 dosage unit. This ratio ailows a range of daily doses, based on increasingthe number of tablets taken per day, that avoid poor disease controithrough underdosing of either ingrédient when there is a requirement forco-administration, and avoids hypogiycaemia by overdosing of either 5 component when so co-administered. Assurance of performance in ciinicaluse, which will dérivé from havîng a product exhibiting appropriatebioavaiiabiiity of the glibenciamide component, is a key requirement forphysicians wishing to treat patients with a combination formulation.Appropriate bioavaiiabiiity implies that 5mg of glibenciamide formulatedίο into a combination tablet with metformin is absorbed to an acceptably simiiar extent, and at a comparable rate, to glibenciamide dosed as a / single entity formulation of the same strength when dosed concurrentiywith a single entity formulation of metformin.

This prior art does not teach how to formuiate a combination 15 product of metformin with glibenciamide so as to assure appropriatebioavaiiabiiity of the glibenciamide component. There is no issue in thisrespect in the case of metformin hydrochloride on account of its highwater solubility and therefore the bioavaiiabiiity of metformin fromcombination formulations will not be discussed further. It is however a very 20 important aspect to consider for glibenciamide as this is a poorly solubledrug substance (solubility is 0.-1mg/ml in water at 25°C -"practicallyinsoluble as defined by the USP).

As such, its rate of solution after'administration of a dosage formwill influence the rate and extent of entry of the drug into the bioodstream 25 (bioavaiiabiiity). The controi of the rate and extent of entry into thebioodstream is important for appropriate therapeutic effect.

Hence, the reference discioses a suitabie ratio of the two activeingrédients in a single dosage form, in order to mode! how the twoindividual ingrédients might be desirably co-administered (based on how 30 they wouid be dosed according to usual practice associated with currentîyavaiiable singie entity formulations), it does not teach how to assure thatsuch a combination formulation will perform in terms of bioavaiiabiiity of 0 Λ 012714 3 glibenclamide. This bioavailabiiity should be as similar as possible to whenthe relevant doses of the two single entity formulations are co-administered. în addition, when a combination tablet using standard galenic 5 procedures is proceeded with standard generic giibenciamide in thecombination tablet, a reduced bioavailabiiity in comparison to the co-prescribed situation was apparent. it has now been found using in-vitro and ίη-vivo testing that thereduced bioavailabiiity is related to the particle size and the particle sizeîo distribution of the giibenciamide. It has been found that particles which aretoo small resuit in high glibenclamide blood ievels with conséquent risk ofhypogiycaemia and particles which are too large cannot dissolvesufficiently rapidiy to give comparable bioavaiiabiüty with the co-prescribedsituation, it is therefore necessary to hâve a closely defined particle size Ï5 distribution of the glibenclamide in the combination form.

The sélection of a spécifie size fraction of glibenclamide enabiesthe production of a solid oral dosage form comprising a combination ofmetformin and glibenclamide, and in particular a tablet, exhibitingglibenclamide bioavaiiabiüty comparable to the bioavailabiiity obtained 20 with the separated administration of metformin and giibenciamide, whenjudged by the area under the curve of the in-vivo analysis.

The présent invention provides in particular a tablet comprising acombination of metformin and glibenclamide, exhibiting a comparablegiibenciamide bioavaiiabiüty to the co-administered tablets. 25 In a first embodiment, the solid oral form such as a tablet, according to the invention, contains a combination of giibenciamide and metformin inwhich the size of the giibenciamide is such that at most 10% of theparticles are iess than 2 pm and at most 10% of the particles are greaterthan 60 pm. Preferably, the size of the giibenciamide is such that at most 30 10% of the particles are iess than 3 pm and at most 10% of the particles 012714 are greater than 40 pm.This spécifie particle size range of glibenclamide,may be obtained by sieving or air jet miliing,

In a second embodiment, the solid oral dosage form comprises acombination of metformin and glibenclamide in which the size of5 glibenclamide is such that at most 25 % of the particles are less than 11 pm and at most 25 % of the particles are greater than 46 pm.

Preferably, 50 % of particles are less than 23 μΐη.

Metformin may be used as a sait of metformin, such ashydrochloride, fumarate, hydrobromide, p-chlorophenoxy acetate orîo embonate. The weight ratio of metformin sait to giibenclamide should preferably be between 50/1 to 250/1.

The preferred compositions for the oral dosage form is provided inthe table below, with ranges on components being provided:

Amount of ingrédient, mg per tablet Product identity 500/5 500/2,5 250/1.25 Ingrédient Metformin hydrochloride 500.0 500.0 250.0 Glibenclamide 5.00 2.50 1.25 Croscarmellose sodium 6.0-30.0 6.0-30.0 3.0-15.0 Microcrystalline cellulose 30.0- 120.0 30.0- 120.0 15.0-60.0 Polyvinyl pyrrolidone 6.0-36.0 6.0-36.0 3.0-18.0 Magnésium stéarate 0.6-15.0 0.6-15.0 0.3-7.5 Film coat* 9.0-24.0 9.0-24.0 4.5-12.0 ' a commercially-available film coat composition is used, such as Opadry (Coiorcon, UK).

The especially preferred compositions are as follows: 012714

Amount of ingrédient, mg per tablet Product identity 500/5 500/2,5 250/1.25 Ingrédient Metformin hydrochloride 500.0 500.0 250.0 Glibenclamide 5,00 2.50 1.25 Croscarmellose sodium 14.0 14.0 7.0 Microcrystalline cellulose 54.0 56.5 28.25 Polyvinyl pyrrolidone 20.0 20.0 10.0 Magnésium stéarate 1.2 -12.0 1.2-12.0 0.6-6.0 Film coat* 9.0 - 24.0 9.0-24.0 4.5 - 12.0 ' a commercialiy-avaiiable film coat composition is used, such as Opadry (Coiorcon, UK).

The table! according to the présent invention may be obtained by a 5 process comprising: a) forming granules by wet granulation of a mixture of metforminand glibenclamide; b) blending the granules with a tabletting aid and diluent, and c) tabletting the biend thus obtained into tablets. îo Advantagepusly the mixture used for forming the granules comprises a granuiating binder, This granulating binder is in particular apolyvinyipyroiidone such as for example, a polyvinyipyrolidone having amolecular weight of 45 000. The polyvinyipyrolidone may be used in aproportion of 2 to 4% by weight with respect to the final tablet. 15 After the granulating step the granules may be sieved and dried.

The granules are then blended with a diluent and tabletting aid. The düuent may be any materia! usually used for making tablets, such asmicrocrystalline ceilulose. The tabletting aid may be any materia! usuallyfor making tablets, such as magnésium stéarate. 012714

The tabiets thus obtained may then be coated with a hydrophiliccellulose polymer and talc. The hydrophilic cellulose polymer may be 2-hydroxypropyl methylcelluiose.

The following examples and tests illustrate the présent invention.

Example 1 A tabiet of metformin/glibenclamide has been prepared as follows: 66.6 g of polyvinyipyrolidone are mixed with 246 g of purified waterwith a stirrer. 1500 g metformin hydrochioride, 7.5 g of giibenciamide (witha 10 to 90% size range between 2 to 60 μιτι), 42 g croscarmellose sodiumand 234.4 g of microcrystalline cellulose are mixed in a granuîator. Thepolyvinyipyronolidone solution is added to the granuîator and the wetmass is granulated. The granules are extruded through a 1 mm mesh.The granules are emptied into a preheated fluidised bed dryer and thegranules are dried. 97.5 g of microcrystalline cellulose is mixed into thegranules using a tumbling mixer. 12 g of magnésium stéarate is added tothe tumbiing mixer and mix. The granule mix is tabletted using a suitabietabiet press. The tabiets are coated with a 2% hydroxypropylmethylcelluiose coat in a coating machine.

Examole 2 A tabiet of metformin/glibenclamide has been prepared as follows:5.83 g of giibenciamide (with a 10 to 90% size range between 2 to 60 μιυ), are prebiended with 32.67 g of croscarmellose sodium. 46.67 g ofpolyvinyipyrolidone are mixed with 93.33 g of purified water with a stirrer.The glibenciamide-croscarmellose sodium blend is mixed with 1166.6 g ofmetformin hydrochioride in a granuîator. The polyvinyipyrolidone solutionis added to the granuîator and the wet mass is granulated. The granulesare emptied into a preheated fluidised bed dryer and the granules are 012714 7 * dried. The particle size of the granules is reduced by passing through a 1mm mesh. 131.83 g of microcrystalline celuiose are mixed inio thegranules in the granulator. 16.3 g of magnésium stéarate are added to thegranulator and mixed. The granule mix is tabletted using a suitable tablet 5 press. The tablets are coated with a 2% hydroxypropyl methyicellulosecoat in a coating machine.

Testl ίο ln-vivo bioavailabiiity tests were performed with tabiets prepared as disclosed in example 2, using two batches of glibenciamide. The twobatches hâve the foilowing 10 to 90% particle size range: batch A: 3.47-38.08 pmbatch B: 15.63-91.6 pm. is The distribution of the particie size of batches A and B are iliustrated in figure 1.

The two batches of tablets were administered to heaithy patients incomparison to co-administered glibenciamide (marketed under the tradename Daonil) and metformin hydrochioride (16 patients for each group). 20 The comparative concentrations of glibenciamide in a tablet comprising a combination of metformin and respectively the batch A-andthe batch B of glibenciamide and with the co-administration are shownrespectively in figures 2 and 3.

The area under the curve (AUC) are the foilowing: AUC (ng/ml/h) 790.5353.0 869.3 combination with batch Acombination with batch Bco-administration 30 8 012714

It appears that with the combination according to the invention withbatch A the AUC is substancially the same as in the case of co-administration, whereas with the combination with batch B the AUC ismore cieariy different. 5

Test 2

Careful examination of blood leveis of giibenclamide in humansfollowing administration of a sériés of tablet formulations of metforminίο hydrochloride combined with giibenclamide (identified as formulationsCombo 1,2, 3 and 4), where the formulation are identical save for theparticie size characteristics of the giibenclamide used, compared withcommercialiy available reference formulations of metformin hydrochloride(Glucophage™, Bristol-Myers Squibb) and giibenclamide (Micronase™, 15 Upjohn) dosed together, ailowed définition of particie characteristics forgiibenclamide that wouid assure appropriate bioavaiiabiiity of thegiibenclamide component from the combination formulation. This meansthat disease controi wnen patients are first treated with such acombination formulation wiil be predicîabie, based on prior physician 20 knowledge of treatments employing either single drug.

Alternativeiy, if patients hâve undergone prior stabilisation of their disease by adding treatment with a commercial product like Micronase™to existing treatment with Glucophage™ (or vice versa), then the switchover to a more convenient treatment employing the combination in a 25 single tablet (and where the appropriate bioavaiiabiiity of the glyburidecomponent is assured) will resuit in the desired ievei of disease controibeing maintained.

Data from the studies with metformin hydrochloride/gübenclamide tablets formufated with glibenciamide of different particie size 30 characteristics ailowed the development of a corrélation between drug particie size and the in vivo performance. The properties of the lots of 9 012714 glyburide used in the sériés of combination tablets empioyed are shown inthe table below: giibenclamide particle size (microns) Tablet batch 25 % undersize 50 % undersize 75 % undersize Combo 1 15 33 62 Combo 2 28 58 88 Combo 3 10 25 52 Çombo 4 6 11 19 5 When four compositionally-identical individuai batches of tablets of metformin hydrochloride-glyburtde 50û/2.5mg were prepared using eachof these lots of giibenclamide and dosed to humans, the foîlowingpharmacokinetic parameters were found on analysis of the giibenclamide " plasma concentration-time curves:

Pharmacokinetic parameters giibenclamide Tablet batch Cmax (ng/ml, geo. mean) AUC (ng/ml/hr, geo. . mean) Cmax (ng/ml, arith. mean) AUC (ng/ml/hr, arith. mean) Combo 1 71 478 76 493. Combo 2 52 .. 345 54 339 " Combo 3 64 513 67 531 Combo 4 88 642 93 | 716 A reasonable corrélation can be obtained between particle size andthe maximum attained géométrie mean giibenclamide plasmaconcentration, Cmax, and also with the géométrie mean area under the 15 giibenclamide plasma concentration-time curve, AUC.

From these corrélations, projected limits on particle size for glyburide that would give predicted Cmax and AUC values ± 25 % of a 10 012714 mean value for batches of the .référencé giibenclamide formulation,Micronase™ utiiised in the in vivo studies become:

Cmax

AUC 25% undersize iimits <0-18 microns<0-11 microns 50% undersize iimits <0-37 microns<0-25 microns 75% undersize Iimits <0-63 microns<0-46 microns

Accommodating both Cmax and AUC requirements, the projected Iimitsthen become:. 25% undersize iimits 50% undersize Iimits 75% undersize iimits<11 microns < 23 microns < 46 microns

Giibenclamide having these particle size characteristics hâvepowder surface area values in the range 1.7 to 2.2 m2g'1 as determined bynitrogen absorption. Therefore rnaterial of these properties whenformuiated as described in this work is distinct from the rnaterial disclosedin US 3 979 520 which required giibenclamide of powder surface area inexcess of 3m2g'1 (preferably 5 to 10 mV1) to yieid appropriategiibenclamide bioavaiiabiiity. The giibenclamide of particle size propertiesdetailed in this work, when. formuiated as described here-producesappropriate glibenciamide bioavaiiabiiity in humans as described in thenext test.

Test 3 A batch of metformin hydrochloride-glibenclamide tablets 500/5mgwas prepared as follows. Glibenciamide (1.0kg) with the above definedsize was tumble mixed with 2.8kg of croscarmellose sodium and thismixture was then blended in a high shear mixer with metforminhydrochloride (100kg) to which 0.5% by weight of magnésium stéaratehad been added. 012714 li -¼

This dry mix was wet granulated in a high shear mixer with 12.1kgof an aqueous solution of povidone (containing 4kg of povidone). The wetgranules were dried in a fluid bed drier at 60°C to a defined moisturecontent. The dried (loss on drying 2-3% w/w) granules were size reduced5 in a osciilator (1.0mm screen aperture) then tumble mixed with 10.8kg ofmicrocrystailine cellulose, foilowed by mixing with 0.9kg of the tabletlubricanî magnésium stéarate. The lubricated granules were compressedusing 16mm x 8mm capsule shaped tooling and the tablet cores were film coated (weight gain approximateiy 2% w/w) with the proprietary film coatίο material Opadry 32920 to yield the final yeiiow, capsule-shaped tabiets. Ina human pharmacokinetic study volunteer either were dosed with one ofthese tabiets or with a treatment being one 500mg Glucophage™ tabletpius one 5mg Micronase™ tablet co-administered. Glibenciamide plasma- levets following dosing were analysed and the foliowing pharmacokinetic 15 were found for this component:

Trsatmsnt Parameter Mean Adjusted géométrie mean Ratio of means (Point estimate) Combination Cmax 122 116 1.14 Tablet 500/5 AUC (O-T) 859 831 1.07 Glucophage + Cmax • .113 101 Micronase AUC (O-T) 842 780 -

Glibenciamide bioavailabiiity from the combination tablet iscomparable to that from the reference glibenciamide formulation,20 Micronase™. This would thus ailow patients to conveniently take onetablet of the combination product instead of two tabiets of existingthérapies together, without concern that !ow glibenciamide blood levelswould result, which might occur with prior art formulations and lead to ioss of controi.of disease. 012714 12

Example 3 lnstead of compressing into tablet granulation as prepared for test 35 was filîed into size 00 capsules to either provide for metforminhydrochloride/giibenclamide 500mg/5mg product or the 500mg/2.5mgproduct. Granulation was filled into size 1 capsules to provide the 25ûmg/2.5mg product.

These · capsule exhibited acceptable physical properties andîo provide an alternative to the tabiets. Formulations as described in WO97/17975 could not be filled in capsules of a size acceptable to mostpatients because of the larger amount of excipients employed the formulations they described.

Claims

- 13 - 012714 Claims 5 1. A pharmaceutical composition comprising a single solid oral dosage form containing an effective dose of metformin and an effective dose ofglibenclamide wherein, after oral administration thereof to a human, thebioavailibility of glibenclamide is comparable to the bioavailability of glibenclamideachieved by oral administration of separate solid oral dosage forms to a human, îo one containing glibenclamide and the other metformin, in the same respectiveeffective doses as in said single oral dosage form.
2. A pharmaceutical composition comprising a single solid oral dosageform containing an effective dose of metformin and an effective dose of is glibenclamide wherein, after oral administration thereof to a human, the Cmax andAUC of glibenclamide are comparable to the Cmax and AUC of glibenclamideachieved by oral administration of separate solid oral dosage forms to a human,one containing glibenclamide and the other metformin, in the same respectiveeffective doses as in said single oral dosage form. 20
3. A pharmaceutical composition comprising a single solid oral dosageform containing an effective dose of metformin and an effective dose ofglibenclamide wherein, after oral administration thereof to a human, the Cmax andAUC of glibenclamide are ± 25% of the Cmax and AUC, respectively, of the 25 glibenclamide achieved by oral administration to a human of separate solid oraldosage forms, one containing glibenclamide and the other metformin, in the samerespective effective doses as in said single oral dosage form.
4. A pharmaceutical composition comprising a single solid oral dosage 30 form containing an effective dose of metformin and an effective dose of glibenclamide wherein, after oral administration thereof to a human, the mean Cmax and mean AUC values of glibenclamide are, respectively, ± 25% of 113 ng/ml and - 14 - 012714 ± 25% of 842 ng/ml/hr, for a 5 mg unit dose of glibenclamide, or proportionallyhigher or lower values for higher or lower unit doses of glibenclamide, respectively.
5. A pharmaceutical composition comprising a single solid oral dosages form containing an effective dose of metformin and an effective dose of glibenclamide wherein, after oral administration thereof to a human, the adjustedgéométrie mean Cmax and adjusted géométrie mean AUC values of glibenclamideare, respectively, ± 25% of 101 ng/ml and ± 25% of 780 ng/ml/hr, for a 5 mg unitdose of glibenclamide, or proportionally higher or lower values for higher or lower îo unit doses of glibenclamide, respectively.
6. A pharmaceutical composition comprising a single solid oral dosageform containing an effective dose of metformin and an effective dose ofglibenclamide wherein, after oral administration thereof to a human, the CmaX and 15 AUC of glibenclamide are comparable to the Cmax and AUC of glibenclamideachieved by oral administration of separate solid oral dosage forms to a human,one containing glibenclamide and the other metformin, in the same respectiveeffective doses as in said single oral dosage form, the particle size of theglibenclamide in said single dosage form not being such that it alone achieves said 20 comparable bioavailability.
7. A composition of one of daims 1 -6 wherein the weight ratio ofmetformin to glibenclamide is 50/1 to 250/1. 25 8. A composition of one of daims 1-6 wherein the weight ratio of metformin to glibenclamide is about 100/1.
9. A composition of one of daims 1-6 wherein the weight ratio ofmetformin to glibenclamide is about 200.
10. A composition of one of daims 1-6 wherein the unit dose ofmetformin is about 500 mg or about 250 mg. 30 - 15 - 012714
11. A composition of claim 10 wherein the unit dose of glibenclamide is5, 2.5 or 1.25 mg.
12. A composition of one of daims 1 -6 in the form of a tablet or capsule.
13. A composition of claim 3 wherein said Cmax and AUC values ofglibenclamide in said single solid oral dosage form are ± 20% of said Cmax andAUC values, respectively, of glibenclamide in said separate glibenclamide solidoral dosage form.
14. A composition of claim 3 wherein said Cmax and AUC values ofglibenclamide in said single solid oral dosage form are ± 15% of said Cmax andAUC values, respectively, of glibenclamide in said separate glibenclamide solidoral dosage form.
15. A composition of claim 3 wherein said Cmax and AUC values ofglibenclamide in said single solid oral dosage form are ± 10% of said Cmax andAUC values, respectively, of glibenclamide in said separate glibenclamide solidoral dosage form.
16. A composition of claim 3 wherein said Cmax and AUC values ofglibenclamide in said single solid oral dosage form are ± 5% of said Cmax and AUCvalues, respectively, of glibenclamide in said separate glibenclamide solid oraldosage form.
17. A composition of one of daims 4 or 5 wherein said Cmax and AUCvalues are + 20% of said numerical ranges.
18. A composition of one of daims 4 or 5 wherein said Cmax and AUCvalues are ± 15% of said numerical ranges. - 16 - 012714
19. A composition of one of daims 4 or 5 wherein said Cmax and AUCvalues are ± 10% of said numerical ranges.
20. A composition of one of daims 4 or 5 wherein said Cmax and AUCvalues are ± 5% of said numerical ranges.
21. Use of a composition according to any of daims 1 -6 for thepréparation of a médicament for treating non-insulin dépendent diabètes orhyperglycaemia.
22. Use of a composition for the préparation of a médicament forachieving a bioavailability of glibenclamide in a human upon administering orally asingle solid oral dosage form containing an effective dose of metformin and aneffective dose of glibenclamide, said bioavailability being comparable to thebioavailability of glibenclamide achieved by oral administration of separate solidoral dosage forms to a human, one containing glibenclamide and the othermetformin, in the same respective effective doses as in said single oral dosageform, said formulation comprising formulating glibenclamide with metformin in saidsingle solid oral dosage form so as to assure said comparable bioavailability.
23. Use of a composition for the préparation of a médicament forachieving a bioavailability of glibenclamide in a human upon administering orally asingle solid oral dosage form containing an effective dose of metformin and aneffective dose of glibenclamide, said bioavailability being comparable to the _bioavailability of glibenclamide achieved by oral administration of separate solidoral dosage forms to a human, one containing glibenclamide and the othermetformin, in the same respective effective doses as in said single oral dosageform, sais composition comprising formulating glibenclamide with metformin insaid single solid oral dosage form so as to assure said comparable bioavailability,said formulating not being achieved solely by sélection of particle size ofglibenclamide. - 17 - 012714
24. Use of a composition for the préparation of a médicament forincreasing bioavailability of glibenclamide in a human upon administering orally asingle solid oral dosage form containing an effective dose of metformin and aneffective dose of glibenclamide, such that said increased bioavailability iscomparable to the bioavailability of glibenclamide achieved by oral administrationof separate solid oral dosage forms to a human, one containing glibenclamide andthe other metformin, in the same respective effective doses as in said single oraldosage form, said composition comprising formulating glibenclamide withmetformin in said single solid oral dosage form so as to assure said comparablebioavailability.
25. Use of a composition for the préparation of a médicament forincreasing bioavailability of glibenclamide in a human upon administering orally asingle solid oral dosage form containing an effective dose of metformin and aneffective dose of glibenclamide, such that said increased bioavailability iscomparable to the bioavailability of glibenclamide achieved by oral administrationof separate solid oral dosage forms to a human, one containing glibenclamide andthe other metformin, in the same respective effective doses as in said single oraldosage form, said composition comprising formulating glibenclamide withmetformin in said single solid oral dosage form so as to assure said comparablebioavailability, said formulating not being achieved solely by sélection of particlesize of glibenclamide.
26. The use of one of daims 23 or 25 wherein said formulating is notachieved by sélection of particle size of glibenclamide.
27. A composition of one of daims 1 -6 wherein metformin is présent as ametformin sait.
28. A use of one of daims 22-25 wherein metformin is présent as ametformin sait. - 18 - 012714
29. A use of claim 21 wherein metformin is présent as a metformin sait.
30. A use of claim 26 wherein metformin is présent as a metformin sait. 5