United States Patent (19) [11] Patent Number: 4,696,815 Schepky et al. 45 Date of Patent: Sep. 29, 1987 54 ANTI-DIABETIC PHARMACEUTICAL (56) References Cited FORMS AND THE PREPARATION THEREOF U.S. PATENT DOCUMENTS 3,668,215 6/1972 Plumpe et al....................... 548/209 3,669,966 6/1972 Amhrogi et al. .. 544/406 76 Inventors: Gottfried Schepky, 3,708,481 1/1973 Kufter et al. ... 514/866 Ulrich-von-Hutten-Weg 2, Biberach 3,883,648 5/1975 Ross et al. ...... ... 424/44 1, Fed. Rep. of Germany, D-7950; 4,430,399 2/1984 Eistetter et al. .................... 514/475 Rolf Brickl, Erienweg 37, Warthausen, Fed. Rep. of Germany, Primary Examiner-Johnnie R. Brown D-7951; Eckhard Rupprecht, Assistant Examiner-John W. Rollins Riedbachstrasse 15, Attorney, Agent, or Firm-Weissenberger, Hammond & Aulendorf-Tannhausen, Fed. Rep. of Littell Germany, D-7960; Andreas (57) ABSTRACT Greischel, Dunantstrasse 5, Biberach The invention is directed to novel galenic preparation 1, Fed. Rep. of Germany, D-7950 forms for providing an oral anti-diabetic agent having an improved release of active substance and processes (21) Appl. No.: 615,892 for producing these preparation forms. The novel phar maceutical compositions are characterized in that the onset of the activity and the duration of activity are 22 Filed: May 31, 1984 adapted to the particular needs of diabetics with regard to proper control of the metabolism and the associated 30 Foreign Application Priority Data proper release of insulin. A basic or acidic excipient in a solvent is added to the anti-diabetic active substance in Jun. 8, 1983 DE Fed. Rep. of Germany ....... 3320582 a quantity such that the active substance is made solu ble, and then a solubilizing agent is added. Polyvinyl 51) Int. Cl. ................... A61-K 31/79; A61K 31/495; pyrrolidone is dissolved as carrier in this solution, but A61K 31/47; A61K 31/415 the carrier may simultaneously serve as the solubilizing 52 U.S. C. ...................................... 424/80; 514/255; adjuvant. This solution is further processed with other 514/309; 514/378; 514/866 excipients to form corresponding preparation forms. 58) Field of Search .................. 424/80; 514/255,309, 514/378,866; 546/141, 142; 544/406 14 Claims, 1 Drawing Figure 4,696,815 1. 2 carriers, possibly combined with surface-active sub ANT-DABETIC PHARMACEUTICAL FORMS stances. To prepare these dispersions, a homogeneous AND THE PREPARATION THEREOF melt is prepared from the active substance or possibly a salt thereof and a carrier (cf., German Offenlegungss FIELD OF THE INVENTION chrift No. 2355 743). In another process, the active This invention relates to novel pharmaceutical forms. substance and carrier are dissolved in a common sol More particularly, this invention relates to oral anti-dia vent, and then the solvent is eliminated. The water betic pharmaceutical forms and the preparation thereof. soluble carriers used are, inter alia, polyvinyl pyrrol idone or polyethylene glycols (cf., H. R. Merkle, Acta BACKGROUND OF THE INVENTION 10 Pharm. Technol. 27/4, pages 193 ff. (1981), and W. L. Generally, in the oral administration of substances Chiou, S. Riegelmann, J. Pharm. Sci. 60/9, 1281 ff. which are difficultly soluble in the digestive fluids, such (1971)). as the anti-diabetic substances mentioned below, the If the methods in the literature described below are following problems arise: in many cases the active sub used to produce preparations containing anti-diabetic stance can only be partly resorbed, and greatly fluctuat 15 substances, a better dissolution rate for the active sub ing blood levels of the active substance may occur inter stance, e.g., gliquidone, is scarcely obtained: the salt and intra-individually. However, in oral anti-diabetic formation itself does not result in an increase in the agents, the start of the activity and the duration of the activity are also of particular importance since the ac dissolution rate (cf., Table 4, Example 6), and the appli tivity should be matched to the blood sugar levels 20 cation of active substance, e.g., gliquidone, to a carrier caused by the intake of food. This is not the case with alone (cf., page 9, line 24 of page 10, line 10 does not the previously available preparations of anti-diabetic produce the desired result either. In corresponding agents in which the effect of the substance and physio tests, which will be described in more detail hereinafter, logical insulin requirements in accordance with the the dissolution rate was determined and, in the case of intake of food cannot be reliably matched to one an 25 gliquidone, it was found to be no greater than the disso other in terms of time. The activity of the substance lution rates shown by gliquidone-containing prepara often occurs too late: frequently the maximum effect is tions known perse. only achieved at a time at which the blood glucose OBJECTS OF THE INVENTION values are already dropping even without medication after the intake of food. Then the activity of the sub 30 It is an object of the invention to provide novel phar stance continues even when the blood glucose has re maceutical forms. turned to its initial level (cf., Berger, in Pelzer and Fro It is also an object of the invention to provide oral esch, Diabetische Enteropathie, Hypoglykämien, Ver anti-diabetic pharmaceutical forms. lag Hans Hiber, Bern-Stuttgart-Wien 1974). It is a further object of the invention to provide a Attempts have been made to synchronize the hypo 35 process for preparing said oral anti-diabetic prepara glycemic activity of a sulfonyl urea with the increase in tions. blood sugar caused by food intake by taking the sulfo These and other objects of the invention will become nyl urea at a suitable time before the meal. However, it more apparent in the discussion below. was then found that administration of the active sub DETAILED DESCRIPTION OF THE stance thirty minutes before the meal did not result in a 40 satisfactory improvement in activity (cf., Sartor et al., INVENTION Eur. J. Clin. Pharmacolog. 21, 403 to 408 (1982)), partly It has now been surprisingly found that preparation because of the longer duration of activity mentioned forms containing compounds, particularly gliquidone, above. Furthermore, a specific time difference between with a very rapid and total release of the active sub the taking of the medicine and the taking of food can 45 stance, can be produced by dissolving only be reliably monitored in a clinic. (a) acidicly reacting active substances by means of There have also been attempted to solve these prob basic adjuvants, lems in the case of substances which are difficultly solu (b) amphotericly reacting active substances by means ble in the digestive fluids by attempting to optimize the of basic or acidic adjuvants, or dissolution rate of the active substance difficultly solu 50 (c) basicly reacting active substances by means of ble per se in the development of the galenic prepara acidic adjuvants tions. This was done, for example, by increasing the in a solvent in the presence of one or more solubilizing surface area of the active substance. Thus, a preparation substances comprising polyvinyl pyrrolidone and, op form is described (German Pat. No. 2,348,334) in which tionally, other solubilizing substances. The solution is the active substance (also a hypoglycemic substance) is 55 evaporated to dryness and optionally processed further present with a particle surface area of from 3 to 10 to form the desired pharmaceutical preparation. The m/gm in the presence of a wetting agent. However, invention also relates to the preparation forms thus this objective was also supposed to be achieved by obtained. In any case, however, the molar ratio of ac applying the active substance in dissolved form to a tive substance to basic or acidic excipient must be se substrate or carrier with the largest possible surface area lected so that there is an excess of basic or acidic excipi and then eliminating the solvent (cf., H. Rupprecht, ent. Acta Pharm. Technol. 26/1, pages 13 ff (1980). It is important that sufficient basic or acidic excipient Furthermore, attempts have been made to improve is added to the active substance to ensure rapid and the dissolution rate by adding salt forming agents (cf., complete dissolution in vivo. This is only possible with German Offenlegungsschrift No. 31 24 090.9). How 65 a molar ratio of substance to basic or acidic excipient of ever, to improve the solubility and the dissolution rate, less than 1:1. solid dispersions were also produced. They consisted of The oral anti-diabetic agents contain as active sub the active substance and one or more water-soluble stances sulfonyl ureas such as gliquidone or substituted 4,696,815 3. 4 phenylcarboxylic acids. Other preferred sulfonyl ureas The solutions are prepared with polyvinyl pyrrol include glibenclamide, glibornuride, glisoxepide, glipi idone as solubilizing agent. After evaporation, this sub zide, and gliclazide. Gliquidone is 1-cyclohexyl-3-(p- stance also acts as carrier at the same time. It is not 2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2- possible to incorporate the active substance and basic (1H)-isoquinolyl)-ethyl-phenyl)-sulfonyl)-urea, which excipient directly in a melt of polyvinyl pyrrolidone has a hypoglycemic effect. However, other anti-dia since this carrier decomposes even before reaching the betic substances which may be used are 4-2- melting point. (aroylamino)-ethyl-benzoic acids of the formula Suitable basic excipients include a number of inof ganic or organic bases which are physiologically harm 10 less, that is, pharmaceutically acceptable, at least in the R (I) dosage ranges used, such as sodium hydroxide solution, potassium hydroxide solution, ammonia, tertsodium phosphate, diethanolamine, ethylenediamine, N CO-NH-CH-CH COOH methylglucamine, or L-lysine.