A GLIBENCLAMIDE-METFORMIN COMBINATION FOR THE TREATMENT OF DIABETES MELLITUS OF TYPE II

Abstract: A combination of glibenclamide and metformin such that, when administered in the form of pharmaceutical composition in the treatment of diabetes mellitus of type II, the ratio between the two active principles allows to obtain an optimum therapeutical effect at any time of the progression of the disease, avoiding to make use of the insulin therapy in the most severe cases.

Description: A GLIBENCLAMIDE-METFORMIN COMBINATION FOR THE TREATMENT OF DIABETES MELLITUS OF TYPE II The present invention relates to the use of a combination consisting of glibenclamide and metformin in one specific ratio aε medicament for the treatment of diabetes mellitus of type II. Non-insulin dependent diabetes of type II (NID) is known to be a frequent metabolic disease and the main cause of hyperglycemia. In recent years, diabetes mellitus of type II has been proved to be a heterogeneous disease, with complex, unclarified metabolic aspects, which disease is characterized by three main metabolic abnormalities contributing to hyperglycemia: the partial or complete decrease in insulin secretion, the resistance of the peripheral tissues to insulin and the increased hepatic production of glucose in fasting conditions. Diet and physical exertion are unanimously recognized to be the foundation of the therapy of diabetes of type II: both of them lead to a reduction in insulin-resistance and, in the long run, to an improvement in the pancreas secretive deficit. However, these provisions are insufficient and a pharmacological aid with oral hypoglycemic agents iε necessary. At present, the two main families of oral hypoglycemic agents available are sulfonylureas and biguanides. The use of sulfonylureas and biguanides in monotherapy, in most cases, allows to obtain an effective glyco etabolic control for some years, if an appropriate diet and behavioural regimen are kept. Nevertheless, the efficacy of the therapy with oral hypoglycemic agents can decrease with time. After a positive starting response which can last 4-5 years, monotherapy becomes ineffective in a considerable percentage of patients. These are the so- called "secondary failures" of the therapy with oral hypoglycemic agents. Such a failure is estimated to occur each year in 5-10% of the patients under therapy with sulfonylureas, therefore after 10 years, only 50% of the patients still show a satisfactory response. The secondary failure in patients under treatment with metformin appears to have an incidence superimposable to the above mentioned one. Recent studies show that besides a qualitative/quantitative deficiency of insulin secretion, the combined occurrence of insulin-resistance conditions is at the bottom of NID diabetes. Since sulfonylureas are capable of stimulating insulin release, but are not capable of acting on insulin resistance, and biguanides are able to act on insulin resistance, whereas they are not able to stimulate insulin secretion, the therapeutical rationale of said studies suggested the use of combined formulations of medicaments capable of finding a remedy for both the deficiency in insulin secretion and the insulin-resistance condition. Vigneri et al. (Diabete & Metabolisme, 1991, (17), 232-234), faced the problem of secondary failure to sulfonylurea therapy in NID diabetes. The authors proposed a combination of glibenclamide-metformin in a daily dosage of 15 mg and 1500 mg, respectively, in alternative to insulin therapy in addition to glibenclamide. The combined therapy (sulfonylurea + biguanide) plays therefore a specifically important therapeutical role, since it allows to obtain an effective metabolic control in those patients with diabetes of rype II, in which the therapy with only sulfonylureas or only biguanides becomes ineffective with time. Two biguanides are used in the oral therapy of diabetes of type II: phenformin and metformin. Although the former is still widely used, a number of data in literature clearly show that metformin exerts an effective normoglycemic action with no risk of lactic acidosis in the patients, aε it can occur in some cases when using phenformin. Therefore, it is generally accepted that metformin is the preferred biguanide in the therapy of diabetes of type II. The Applicant found, during clinical experiments, that the sulfonylurea maximum daily dose considered optimum for the most severe, barely controllable cases is 15 mg. However, such a dose has to be combined with a biguanide maximum daily doεe of 1500 mg in order to obtain the maximum therapeutical effect together with the reduction of untoward effects. At present 4 combinations are marketed which uεe a combination of metformin with glibenclamide (Table 1). In the first combination, glibenclamide dose iε 2.5 mg and metformin (expresεed aε the hydrochloride) dose iε 500 mg for each tablet, namely a weight ratio of 1:200. In the other combinationε, doses are respectively: 2.5 mg of glibenclamide and 400 mg of metformin, namely a weight ratio of 1:160. TABLE I Ready-to-use preparations of sulfonylurea (S) Metformin (M) available at present: Name Manufacturer S (dose/cp) M (dose/cp) Glucomide Lipha Glibenclamide Metformin (2.5 mg) (500 mg) Glibomet Guidotti Glibenclamide Metformin (2.5 mg) (400 mg) Suguan M Hoechst Glibenclamide Metformin (2.5 mg) (400 mg) Bi-Euglucon M Boehringer M Glibenclamide Metformin (2.5 mg) (400 mg) It should be noted, however, that none of these formulations attain the optimum therapeutical effect due to the quantitative unbalance of the medicaments in combination. In fact, using the above mentioned formulations, in order to obtain the sulfonylurea maximum dose of 15 mg, which we consider optimum for the moεt severe, barely controllable caseε, 6 tablets of the medicament should be taken, thuε receiving 2400-3000 mg of metformin, which is a dose markedly higher than the maximum one we recommend (1500 mg). Therefore, the still unsolved problem is to find a combination capable of obtaining the maximum increase in the therapeutical effect with balanced doseε of the εingle medicamentε, thereby decreaεing in parallel their untoward effects. Such a research is of paramount importance, taking into account that in diabetes of type II it is often neceεεary to progressively increase with time the hypoglycemic medicament doses. The present invention solves the problem to provide medicament effective for the treatment of diabetes mellitus of type II in cases of secondary failure to a combination of glibenclamide-metformin currently used in therapy. Abstract of the invention Now it has been found that a combination of glibenclamide and metformin (expreεεed aε the hydrochloride) in a 1:100 weight ratio, so as to allow a daily administration of 15 mg of glibenclamide and 1500 mg of metformin, is suitable to the preparation of a medicament useful for the treatment of diabetes mellitus of type II at any time of the progresεion of the disease, from its onset to the most severe cases. Therefore, it is an object of the present invention the use of the above mentioned combination in admixture with conventional carriers and excipients for the preparation of a medicament for the treatment of diabetes mellitus of type II, particularly in the cases of "secondary failure" to a combination of glibenclamide-metformin currently used in therapy. Detailed disclosure of the invention According to a first preferred embodiment of the present invention, the combination of the two active ingredients iε used in a medicament in the form of tablets with a dosage of 5 mg of glibenclamide and 500 mg of metformin. This medicament is useful for the treatment of diabetes mellituε of type II. The balance of said doses makes the therapeutical effect optimum at any time of the progression of the disease, starting from minor cases to the most severe ones, and particularly, when it is necessary to increase progressively with time the doseε of the two substances. On the contrary, when combination ratios different from those of the present invention are used, the following cases are likely to occur: when the ratios are lower than the recommended ones, the number of metabolically controlled diabetic patients will definitely be lower; when the recommended doseε are exceeded, there will be an actual riεk of untoward effectε. Therefore, the target area of the patientε reεponding to the therapy will increaεe and at the εame time the onset of therapeutical risks will be highly decreased only when the two medicaments are administered in combination at the doses present in the tablet, or at multiple and submultiple doseε of the same. Moreover, it has been proved that a dose increaεe beyond the maximum limits herein recommended of 15 mg of glibenclamide and 1500 mg of metformin daily causes no further favourable therapeutical effects. Finally, it should be streεsed that the above mentioned doses can theoretically be attained also using the two medicamentε εeparately. However, this involves the need of taking twice as many tablets a day, with clear compliance problems, especially in the elderly patients which require concomitant therapieε for other pathologies which are frequently connected with diabetes, such aε hypertenεion and vaεcular diseases. Said combination of dosageε can be used starting from the onset of the disease in NID diabetics since the ratio of 5 mg of glibenclamide + 500 mg of metformin will always be balanced, in both the multiple and sub ultiple dosages. In fact, when the tablets are subdivided, thus obtaining minor and/or fractional daily dosageε, the fixed ratio, which iε the balanced one, iε alwayε maintained. Therefore, according to a εecond embodiment of the preεent invention, the medicament iε in the form of a divisible tablet containing the combination described above. Alternatively, tablets containing fractions of the preferred dosage can be prepared, always keeping the 1:100 ratio between the two active principles. Analogously, in the most εevere caεeε of diabetes with metabolic decompenεation, which cannot be controlled with the commercially available combination medicamentε, (so that the patients should turn to insulin therapy), the combination of the invention allows to treat them, εtill and for a long time, with the oral therapy, with obviouε benefitε for the patientε themεelveε. In confirmation of what stated above, the study profile and the resultε of the experimentation carried out are reported in the following. Study profile Sample size About 100 diabeticε of type II (non insulin- dependent) have been studied. The sample was calculated so that a clinically εignificant average reduction of the values of glycated hemoglobin Ale equal to or higher than 0.6% and an average reduction of glycemia equal to or higher than 18 mg/dl in the 16 weeks of treatment could be detected. The standard deviations envisaged for HbAlc and for fasting glycemia are 1.46% and 44 mg/dl. The analysiε makes use of a significance level of 0.05 and a test power of 0.80 (two-tail teεt). Description of the studied panel 98 Patientε with diabeteε mellituε of type II (non insulin-dependent) were studied. The average age of the subjects was 57.3 + 6.6 years. The panel consisted of 45 males (46%) and 53 females (54%) of superi poεable age. Starting metabolic profile The faεting glycemia meaεured at examination 1 was 219 ± 37 mg/dl (95% confidence limits: 211-226 mg/dl; 10-90 * percentile: 184-272 mg/dl), 24 hour glycosuria 25 ± 36 g (95% confidence limits: 18-33 g; 10-90 percentile 7-64 g), no acetonuria in all of the patientε, glycated hemoglobin Ale 9.1 ± 0.9% (95% confidence limits 8.9- 9.2%; 10-90' percentile:8-10.1%) . TABLE A Metabolic profile of the subjects studied in each centre. Centre 4 AWOVA Oneway p= N 9 31 38 20 Fasting glycemia 219±41 211+33 221+42 226±29 ns (mg/dl) 24 hour glycosuria 11±14* 25+15 37+54 * * 0.026 (g/24 hours) Acetonuria 0 Glycated hemoglobin 8.8+1,1 9.1+0.7 8.8±1,0 9.6±0.4 * 0.002 Ale (%) p < 0.05 Centre 1 vs Centre 3 ** At the Centre 4, glycosuria was doseε with a εemiquantitative procedure p < 0.05 Centre 4 vε Centres 1, 2. 3 Evaluation of the efficacy of the treatment The parameters the evaluation of the efficacy of the treatment is based on are: 1. fasting glycemia; 2, post-prandial glycemia; 3. 24 hour glycoεuria; 4, preεence of acetone in the urines; 5. glycated hemoglobin (HbAlc). Other important parameters evaluated during the study are: 1. body weight 2. total cholesterol plasma levels; 3. HDL cholesterol plasma levels; 4. LDL cholesterol plaεma levels; 5. arterial presεure valueε. Fasting glycemia The average valueε of the fasting glycemia evidenced during the study are reported in Table B. TABLE B Examinations 1 2 2b 3 4 5 6 Variance analysis for repeated Weeks -3 0 2 4 8 12 16 measurements p < 1 factor analysis Whole 219 226 194* 192* 192* 186* 184* 0.0001 Panel: M±(ds) (37) (58) (52) (50) (55) (51) (53) (F = 24) Single Centres: 1 factor analysis Centre 1 224 248 225 236 232 221 232 0.426 Centre 2 214 197 171§ 173§ 1711 161§ 174§ 0.0001 Centre 3 222 247 207$ 206$ 216$ 213$ 203#$ 0.0001 Centre 4 226 220 184* 174* 162* 156* 145* 0.0001 Anova ns 0.002 0.003 0.003 0 . 001 0 . 001 0 . 001 Oneway (P <) 2 factor analysis among centres 0.0001 among examinations 0.0001 * p < 0.001 vs Examination 1 and Examination 2 § p < 0.001 vs Examination 1. p < 0.01 vs Examination 2 # p < 0.05 vs Examination 1 $ p < 0.01 vε Examination 2 In the whole panel, the faεting glycemia underwent a εignificant reduction already after two weekε of treatment (p < 0.001); εaid reduction waε maintained subsequently during all the study (16 weeks). Similar resultε were obtained from the analyεiε carried out at the εingle Centreε (Centres 2-4). Only in Centre 1, no reduction in glycemia waε detected, partly probably due to the small number (n. 9) of the studied subjectε(Table B). Table C reportε the results of the glycemia course in subjects stratified as a function of the Body Mass Index (BMI; normal weight: BMI < 25 kg/m 2 - n = 21; overweight BMI 25-30 kg/m 2 - n = 52; obeses BMI 2 30 kg/m 2 - n = 259). TABLE C Fasting glycemia: changes during the study. The subjects were stratified depending on BMI (Body Mass Index) Examinations 1 2 2b 3 4 5 6 Variance Weeks -3 0 2 4 8 12 16 for analysis repeated measurements p < BMI 1 Factor analysis < 25 kg/m 2 214 212 180* 167* 173* 175* 168* 0.0001 ω 25-30 kg/m 2 220 223 192* 196* 194* 186* 182* 0.0001 2 30 kg/m 2 227 247 208§ 208§ 207§ 196§ 205§ 0.035 Anova ns ns ns 0.02 ns ns Oneway (p <) 2 Factor analysis among groups 0 . 0001 among examinations 0 . 0001 * p < 0.001 vs Examination 1 and Examination 2 § p < 0.05 vs Examination 2 The effectε of the treatment are clear (variance analysis for repeated measurements, p < 0.0001) in the subjectε with normal body weight and in the overweight εubjectε (BMI 25-30 kg/m 2 ), which are leεε εenεitive, but εtill εtatiεtically εignificant (p < 0.035 in the obeεe subgroup (BMI > 30 kg/m 2 )). Post-prandial αlvcemia The mean values of the fasting glycemia evidenced during the εtudy are reported in Table D. The post¬ prandial glycemia, measured at the beginning and at the end of the study, underwent a significant reduction both in the whole panel (318 to 267/mg/dl) and in each of the subgroups defined depending on the Body Masε Index. TABLE D Post-prandial glycemia: changes during the study. In the second part of the table the subjectε were stratified depending on the BMI (Body Masε Index). Examinations Student's t test for coupled data weekε (p <) 16 Whole 318 267 0.0001 Panel: (64) (79) BMI: Variance analysiε for meaεurementε (1 factor) <25 kg/m 2 317 252 0.0001 25-30 kg/m 2 320 263 0.0001 >.30 kg/m 2 313 287 0.001 Anova ns ns Oneway (p <) 2 Factor analysiε among groupε ns among examinationε 0.0001 Adverse events The untoward effectε were infrequent and slight; in practice, only gastro-inteεtinal untoward effects such as nausea, abdomen pains and diarrhoea, more or lesε combined together, occurred. Conclusions about the therapeutical efficacy In the clinical εtudy carried out, the proposed combination (glibenclamide 5 mg - metformin 500 mg) was administered for 16 weeks to patients with diabetes of type II, in which the combined treatment with glibenclamide-metformin at the presently available doεageε gave no longer an acceptable metabolic control. The main reεult from the evaluation of the efficacy conεiεtε in the εignificant decrease in the fasting glycemia (-35 mg/dl), in the glycemia 2 hours after mealε (-51 mg/dl) and in the HbAlc (-0.9%). Theεe reεultε are of particular value when considering that: 1. Whereas the patients with a more severe diabetic condition (so aε to be necesεary the use of high dosages of glibenclamide and metformin), actually were no longer responsive to the sulfonylurea- metformin combinations commercially available and as a consequence it was necessary to start the subsequent therapeutical option, i.e. the addition of insulin to the oral therapy or the complete substitution of the latter with insulin itself. These caseε were treated εuccessfully and the obtained reεultε prove that the combination glibenclamide 5 mg + metformin 500 mg iε an important therapeutical tool, which allowε to obtain an effective control of glycid metaboliεm εtill making uεe of the only hypoglycemizing oral therapy, thuε obtaining a further favourable effect on life-quality of the patients themselveε. 2. On the contrary, for the leεε εevere cases, the ratio 5 mg of glibenclamide + 500 mg of metformin, can be εubdivided aε deεired, thereby having lower and/or fractional daily doεages thus allowing to treat the diseaεe from itε onεet, aε the glibenclamide to metformin ratio, even when fractioned, will turn out to be very well balanced. As far as the industrial applicability aspectε are concerned, the medicamentε according to the invention are provided in the form of pharmaceutical compoεition, which can be prepared according to conventional techniqueε known to thoεe εkilled in the art, for example aε described in Remington'ε Pharmaceutical Scienceε Handbook, Mack. Pub., N.Y., U.S.A. Among the pharmaceutical compoεitions intended for the treatment of diabetes mellitus of type II, those which are administered orally are preferred, such as coated or non-coated tablets, capsules, sugar-coated pills, granulates, oral suεpenεionε, microgranuleε, controlled-releaεe tabletε. Metformin iε uεed preferably in the form of metformin hydrochloride εalt. Of courεe, it is alεo poεεible to uεe equivalent amountε of other phoεphate, εolfite, dithionate, acetate, benzoate, citrate εaltε and the like, optionally together with suitable bufferε. On the contrary, glibenclamide iε an inεoluble substance. Since said compound haε to be ad iniεtered in comparatively high dosages (5 mg of Glibenclamide + 500 mg of Metformin HCl) and for long times in order to obtain a complete action, the oral route was considered the εi plieεt administration method. In the galenic study carried out to accomplish the most suitable pharmaceutical form, the following objectives were taken into account: ready contact of the active ingredient in the dispersed state with gastroenteral mucosae easiness of swallowing posology flexibility - optimization of the technological characteristics of the granulate for the working up with fast devices choice of the material suitable for the preservation of the product - manufacturing process easy to carry out and economical. Considering the high unitary dosage required, the pharmaceutical formulation in lozenge-shaped tablets, with a central breaking division, has been chosen since it is considered the most suitable one. Such a tablet can have the composition as shown in Example 1. In fact this allows, with comparatively limited sizes, to carry suitably the active ingredient, so aε to combine a favourable working-up with optimum bio- pharmaceutical and technical characteriεtics besides an improved swallowability. The tablets were subjected to wet-granulation; the excipients reported hereinbelow were selected, after a number of laboratory teεtε in order to find the amount of each excipient to attain the best workability together with biopharmaceutical and technological characteristicε of the tabletε: maize εtarch: diluent and diεintegrant; precipitated εilica: it promoteε the coheεion of the granulates improving their flowability; microcriεtalline celluloεe (Avicel PH 101): a diluent, which favourε the formation of compact granules and therefore of more resistant tabletε contributing at the same time to disaggregation of the pharmaceutical form, promoting the penetration of liquid inside it by capillarity; gelatin: a binder used in solution to wet the granular mixture; glycerin: it is used in the gelatin solution to promote wetting and as a plasticizer; - talc: a lubricant; magneεium εtearate: a solid lubricant which iε effective in amounts which do not significantly affect the disaggregation time of the tablets. In order to improve handling and swallowing, a coating was moreover applied onto the tablets, which consists of a methylhydroxypropyl cellulose film as a film-forming agent, titanium dioxide as an opacifier and polyethylene glycol 400 aε a plasticizer. The compatibility among the active ingredient and the selected excipients was ascertained by preliminary accelerated stability studies. Finally, for the choice of the container, the phyεico-chemical characteristicε of the active ingredient and of the tablet were conεidered in order to guarantee a safe preservation; the medicament of the invention showed a very good stability in an opaque blister consisting of PVC/PVDC and aluminium. The manufacturing process waε carried out by wet granulation both by meanε of kneading in a faεt granulator and drying in air-circulation drier, and in fluidized bed granulator-drier. In both caεes, tablets with the desired characteristics were obtained. The following examples further illustrate the invention. EXAMPLE 1 A coated tablet contains; Glibenclamide mg 5.00 Metformin hydrochloride mg 500.00 Maize starch mg 57.50 Precipitate silica mg 20.00 Microcrystalline cellulose mg 65.00 Gelatin mg 40.00 Glycerin mg 17.50 Talc mg 17.50 Magnesium εtearate mg 7.50 Methylhydroxypropylcellulose mg 12.50 Titanium dioxide mg 6.25 Polyethylene glycol 400 mg 1.25 Unitary theor. average weight mg 750.0 EXAMPLE 2 Granulate sachets: Glibenclamide: mg 5.00 Metformin hydrochloride mg 500.00 Polyvinylpyrrolidone mg 22.00 Saccharose mg 1000.00 Mannitol mg 821.00 Sodium saccharinate mg 10.00 Orange flavour mg 37.00 Lemon flavour mg 10.00 Unitary theor. average weight mg 2405.00 EXAMPLE 3 Suspension: Glibenclamide g 10.100 Metformin hydrochloride g 0.047 Sodium carboxymethylcellulose g 0.079 Microcrystalline cellulose g 0.300 Wild black cherry essence g 0.089 Anise esεence g 0.050 Glycerol g 10.000 Methyl p-hydroxybenzoate g 0.050 Saccharose g 77.470 Depurated water q.s. to ml 100

Claims: CLAIMS 1. The use of a combination of glibenclamide-metformin hydrochloride in a 1:100 weight ratio for the preparation of a single-dose medicament useful for the treatment of diabetes mellitus of type II in cases of secondary failure to a combination of glibenclamide- metformin hydrochloride in a weight ratio higher than 1:100. 2. The use of a combination of glibenclamide-metformin hydrochloride in a 1:100 weight ratio for the preparation of a single-dose medicament useful for the treatment of diabetes mellitus of type II in cases of secondary failure to a combination of glibenclamide- metformin hydrochloride in a weight ratio of 1:160 or 1:200. 3. The use according to claim 1 or claim 2, characterized in that the medicament is εuitable to the administration of a daily dosage of up to 15 mg of glibenclamide and 1500 mg of metformin. 4. The use according to claim 1 or 2, characterized in that, in the medicament, the unitary dose contains 5 mg of glibenclamide and 500 mg of metformin. 5. The use according to claim 4, wherein the medicament is in the form of a tablet. 6. The use according to claim 5, wherein the medicament is in the form of divisible tablet. 7. The uεe according to claimε 1 or 2 and anyone of claimε 3-7, characterized in that in the medicament metformin hydrochloride iε replaced with an equivalent amount of another pharmaceutically acceptable salt.

Inventors: BARELLI GIULIO, DE REGIS MASSIMO, BARELLI, GIULIO, DE REGIS, MASSIMO
Applicants: BARELLI GIULIO, GENTILI IST SPA, REGIS MASSIMO DE, BARELLI, GIULIO, DE REGIS, MASSIMO, ISTITUTO GENTILI S.P.A.
Application year: 1996
Main classification: A61K31
IPC codes: A61K31