Oral Anti-Diabetic Pharmaceutical Compositions and the Preparation Thereof

This invention relates to novel pharmaceutical compositions, and, more particularly, to oral anti-diabetic pharmaceutical compositions and the preparation thereof.

Generally, in connection with the oral administration of substances which are difficultly soluble in the digestive fluids, such as the anti-diabetic substances mentioned below, the following problems arise: in many cases the active substance can only be partly absorbed, and greatly fluctuating blood levels of the active substance may occur inter- and intra-individually. However, in oral anti-diabetic agents, the start of the activity and the duration of the activity are also of particular importance since the activity should be matched to the blood glucose levels caused by the intake of food. This is not the case with the previously available preparations of anti-diabetic agents in which the effect of the substance and physiological insulin requirements in accordance with the intake of food cannot be reliably matched to one another in terms of time. The activity of the substance often occurs too late: frequently the maximum effect is only achieved at a time at which the blood glucose values are already dropping, even without medication, after the intake of food. Then, the activity of the substance continues even when the blood glucose has returned to its initial level (see Berger, in Pelzer and Froesch, Diabetische Enteropathie, Hypoglykamien, Verlag Hans Huber, Bern-Stuttgart-Wien 1974).

Attempts have been made to synchronize the hypoglycemic activity of a sulfonyl urea with the increase in blood glucose caused by food intake by taking the sulfonyl urea at a suitable time before the meal. However, it was then found that administration of the active substance thirty minutes before the meal did not result in a satisfactory improvement in activity [see Sartor et al., Eur. J. Clin. Pharmacolog. 21, 403 to 408 (1982)], partly because of the longer duration of activity mentioned above. Furthermore, a specific time difference between the taking of the medicine and the taking of food can only be reliably monitored in a clinic.

Attempts have also been made to solve these problems in the case of substances which are difficultly soluble in the digestive fluids by attempting to optimize the dissolution rate of the active substance, difficultly soluble per se, in the development of the galenic preparations. This was done, for example, by increasing the surface area of the active substance. Thus, German Patent No. 2,348,334 discloses a preparation form in which the active substance (also a hypoglycemic substance) is present with a particle surface area of from 3 to 10 m.sup.2 /gm in the presence of a wetting agent. However, this objective was also supposed to be achieved by applying the active substance in dissolved form to a substrate or carrier with the largest possible surface area and then removing the solvent [cf. H. Rupprecht, Acta Pharm. Technol. 26/1, pages 13 ff. (1980)].

Furthermore, attempts have been made to improve the dissolution rate by adding salt-forming agents (see German Offenlegungsschrift No. 31 24 090). However, to improve the solubility and the dissolution rate, solid dispersions were also produced. They consisted of the active substance and one or more water-soluble carriers, possibly combined with surface-active substances. To prepare these dispersions, a homogeneous melt is prepared from the active substance or possibly a salt thereof and a carrier (see German Offenlegungsschrift No. 2,355,743). In another process, the active substance and carrier are dissolved in a common solvent, and then the solvent is eliminated. The water soluble carriers used are, inter alia, polyvinylpyrrolidone or polyethylene glycols [see H. R. Merkle, Acta Pharm. Technol. 27/4, pages 193 ff. (1981); and W. L. Chiou, S. Riegelmann, J. Pharm. Sci. 60/9, 1281 ff. (1971)].

If the methods in the literature described below are used to produce preparations containing anti-diabetic substances, a better dissolution rate for the active substance, such as gliquidone, is scarecely obtained: the salt formation itself does not result in an increase in the dissolution rate [see Table 7, Example (c) below], and the application of active substance, such as gliquidone, to a carrier alone (see Example on page 10 below) does not produce the desired result either. In corresponding tests, which will be described in more detail hereinafter, the dissolution rate was determined, and in the case of gliquidone it was found to be no greater than the dissolution rates shown by known gliquidone-containing preparations.

It is an object of the invention to provide novel pharmaceutical compositions.

It is also an object of the invention to provide oral anti-diabetic pharmaceutical compositions.

It is a further object of the invention to provide a process for preparing said oral anti-diabetic compositions.

These and other objects of the invention will become more apparent in the discussion below.

We have discovered that compositions with a very rapid and total release of the oral anti-diabetic substance, can be produced by converting

(a) acidic active substances by means of basic excipients,

(b) amphoteric active substances by means of basic or acidic excipients, or

(c) basic active substances by means of acidic excipients into a solution in the presence of one or more solubilizing substances, and applying the solution to a water-insoluble carrier and drying it, and then further processing this product, possibly with the addition of adjuvants, to form a pharmaceutical composition. The invention also relates to the compositions thus obtained. In any case, however, the molar ratio of active substance to basic or acidic excipient must be selected so that there is an excess of basic or acidic excipient.

It is important that sufficient basic or acidic excipient is added to the active substance to ensure rapid and complete dissolution in vivo. This is only possible with a molar ratio of active substance to basic or acidic excipient of less than 1:1.

The oral anti-diabetic compositions contain as active substances anti-diabetic sulfonyl ureas, such as gliquidone, or anti-diabetic benzoic acids. Other anti-diabetic sulfonyl ureas include glibenclamide, glibornuride, glisoxepide, glipizide and gliclazide. Gliquidone is 1-cyclohexyl-3-[[p-[2,(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2-(1H) -isoquinolyl)ethyl]phenyl]sulfonyl]urea, which has an hypoglycemic effect. Anti-diabetic benzoic acids include, but are not limited to, 4-[2-(aroylamino)-ethyl]-benzoic acids of the formula ##STR1## wherein R.sub.1 is halogen, preferably chlorine, and

R.sub.2 is alkoxy of 1 to 3 carbon atoms, preferably methoxy, piperidin-1-yl or octamethyleneimino, and substituted 4-(aralkylaminocarbonylmethyl)-benzoic acids of the formula ##STR2## wherein R is hydrogen or ethoxy,

R.sub.3 is alkyl of 1 to 4 carbon atoms, preferably n-propyl, or phenyl,

R.sub.4 is piperidino, pyrrolidino, or hexamethyleneimino, and

R.sub.5 is hydrogen, halogen, preferably chlorine or fluorine, methyl or methoxy. Mixtures of these active substances may also be used.

Micronized gliquidone is contained in a commercially available preparation consisting additionally of corn starch, lactose, and magnesium stearate. This preparation containing gliquidone has already proven satisfactory as a reliable antidiabetic agent, with the great advantage that it is not contraindicated when there is restricted kidney function.

To dissolve 2.5 parts by weight of gliquidone, for example, in 50 parts by weight of water, 0.7 parts by weight of ethylene diamine x 1H.sub.2 O, 3.0 parts by weight N-methyl-glucamine, or 3.5 parts by weight of diethanolamine are required in the presence of one or more solubilizing substances. If the molar ratios which are absolutely necessary for rapid and complete dissolution of the active substance are compared, the following picture is obtained:

Gliquidone (molecular weight: 527.6): ethylenediamine x H.sub.2 O (molecular weight: 78.1) as 1:1.89;

Gliquidone: N-methylglucamine (molecular weight: 195.21) as 1:3.24;

Gliquidone: diethanolamine (molecular weight: 105.14) as 1:7.03; and

Gliquidone: L-lysine (molecular weight: 146.2) as 1:4.33.

This finding cannot be explained by mere salt formation of the gliquidone with the basic excipients in question; it appears that the excess base has an additional stabilizing effect. The same phenomena also apply to the other active substances. This effect was not foreseeable even by someone skilled in the art.

Suitable basic excipients include a number of inorganic or organic bases which are physiologically harmless, that is, pharmaceutically acceptable, at least in the dosage ranges used, such as sodium hydroxide, potassium hydroxide, ammonia, ammonium carbonate, tert.sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine or L-lysine. The molar ratio of active substance to basic excipient or mixtures of excipients is preferably from above 1:1.8 to 1:10, but a greater excess of base may also be advantageous in some cases.

Suitable acidic excipients include inorganic acids such as sulfuric and phosphoric acid, and organic acids such as tartaric acid. The acid must be present in molar excess.

To prepare and to stabilize highly concentrated solutions such as those which are clearly obtained when using a preparation according to the invention, it is necessary to add solubilizing and/or emulsifying substances. Examples of such substances include polyvinylpyrrolidone, polyethylene glycol 4000 or 6000, polyethoxylated sorbitan monooleates, sobitol, polyoxyethylene polyoxypropylene polymers, glycerol polyethylene glycoloxy stearates, and polyoxyethylene fatty alcohol ethers. Both the nature of the solubilizing substance and also the proportions used are important in determining the dissolution rate of the active substance. The ratio of active substance to the total quantity of solubilizing substances is from about 1:1 to 1:10 by weight.

The solution of the active substance, basic or acidic excipients, and solubilizing and/or emulsifying substances is prepared primarily using water or other polar solvents such as lower alcohols, e.g., ethanol, isopropanol, ketones such as acetone, or mixtures of these substances with water.

The solutions thus propered are applied to water-insoluble carriers. Substances suitable for this purpose are preferably those which enlarge the surface area, such as highly dispersed silicon dioxide, AVICEL.RTM. (microcrystalline cellulose), basic aluminum oxide, magnesium-aluminum-trisilicates, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, tricalcium phosphate, calcium biphosphate, and mixtures thereof. Generally, a ratio of active substance to carrier of from about 1:1 to 1:12 parts by weight is sufficient. Particularly suitable carriers are those which do not dissolve in water or some other appropriate solvent; these carriers permit easier handling both in the incorporation of the active substance and also in the further processing of the intermediate product.

By using the method of solution according to the invention instead of the melting process described in German Offenlegungsschrift No. 2,355,743, even non-fusible solubilizing substances, such as the particularly advantageous polyvinylpyrrolidone, can be distributed on the carrier in molecular dispersion together with gliquidone or the anti-diabetic benzoic acid. However, in addition, water-insoluble carriers have very great advantages for galenic processes.

The solution to the problem described above is surprising for the following reasons:

The methods for incorporation of substances which are difficultly soluble in the digestive fluids, described in the literature and listed hereinafter, do not result in a significant increase in the dissolution rate of the active substance when applied to the production of compositions containing the above-mentioned active substances, nor can they improve the dissolution rate found for the commercially available preparations which contain oral anti-diabetics.

Unless otherwise stated, the dissolution rates were determined after five and 30 minutes by the USP XX Paddle Method in 900 ml of McIlvaine Buffer, at pH 7.0, at 37.degree. C., and at 100 rpm. For each measurement, a quantity of preparation corresponding to 40.0 mg of active substance was used, and each measurement was repeated twice. The average was calculated from the results obtained.

To determine the dissolution rate with an increase in the surface area of gliquidone, 20 parts by weight of the active substance were dissolved in 150 parts by weight of methylene chloride, and the solution was applied to 210 parts by weight of a tablet carrier. After drying, the treated tablet carrier was compressed to form tablets, and the dissolution rate of the gliquidone from these tablets was determined. 5% of the active substance dissolved after 5 minutes and 7% dissolved after 30 minutes. In the case of micronized gliquidone with no excipients, 0% dissolved after 5 and 30 minutes. When the micronized gliquidone was compressed to form tablets as in Example 1(b) below, 5.8% of active substance dissolved after 5 minutes and 7.2% after 30 minutes.

No better dissolution rate was obtained by forming gliquidone salts. Gliquidone was dissolved in an aqueous solution of ethylenediamine, while heating and stirring, and the solution was further processed as described in Example 1(c) below. This product also yielded a quantity of only 4% of dissolved active substance after 5 minutes and 30 minutes.

Not even the use of a gliquidone-containing dispersion produced any better dissolution rates. Analogous to the method described in German Offenlegungsschrift No. 2,355,743, 1.47 parts by weight of gliquidone were dissolved in a melt consisting of 79.1 parts by weight of polyethyleneglycol 4000 and 5.0 parts by weight of polyoxyethylene-40-stearate, and then 14.43 parts by weight of potassium bicarbonate were dispersed therein. The solidified melt was rubbed through a screen with a mesh size of 1.0 mm. The measurement of the dissolution rate gave a result of 10% of active substance after 5 minutes and 7% after 30 minutes.

A further series of tests was carried out to check whether the use of gliquidone salts in the process described in German Offenlegungsschrift No. 2,355,743 leads to better dissolution rates. Again, a melt consisting of 79.1 parts by weight of polyethyleneglycol 4000 and 5.0 parts by weight of polyoxyethylene-40-stearate was used, in which a saturated solution of the gliquidone salt in question was prepared. Then, 14.43 parts by weight of potassium bicarbonate was dispersed in this solution. The solidified melt was passed through a screen with a mesh size of 1.0 mm.

It is easy to see from these results that the quantity of melt required for 30 mg of gliquidone cannot be contained in a disintegrating tablet which can be swallowed. Thus, the process according to German Offenlegungsschrift No. 2,355,743 is unsuitable for gliquidone salts and also for the salts of the benzoic acids mentioned hereinbefore.

As can be seen from the test described above, it is not possible to achieve rapid and total dissolution of the active substances, demonstrated by way of gliquidone, using the known methods which are described as suitable for such purposes.

If the hypoglycemic substances mentioned above are formulated by the processes described above, pharmaceutical compositions are obtained wherein the action of the active substance is matched to the physiological requirement of the patient for this medicament. These special pharmaceutical products ensure rapid and complete absorption of the active substance. Rapid absorption shortens the time which must elapse between taking of the medicament and taking of a meal to synchronize the hypoglycemic activity of the sulfonyl urea or benzoic acid with the increase in blood sugar caused by food intake. Rapid and total absorption reduces intra- and inter-individual fluctuations in the blood glucose level, minimizes the dependence of absorption on the state of the gastrointestinal tract or on the nature or quantity of food taken, and thus ensures the correct metabolic pattern and consequently a correct insulin release. The disadvantages described above relating to the compositions known at present are avoided by using the process according to the invention.

The essence of the invention will be investigated more closely hereinafter in a discussion of the results obtained from the tests described in the examples. The tests were predominantly carried out with the sulfonyl urea gliquidone, but are equally valid for the benzoic acids mentioned above.

Example 1a which follows describes a composition consisting of gliquidone, a basic excipient, and a carrier which increases the surface area, and it shows that the dissolution rate of the gliquidone formulation according to the invention in increased significantly in comparison with the dissolution rate of known gliquidone formulations.

The improvements which are achieved with the addition of solubilizing substances, compared with Example 1(a), are illustrated by the findings of Examples 2 to 9, given in tabular form, which are assembled in Table 2.

Table 3 shows examples with identical amounts of different carriers with the associated dissolution rates. Since the weight ratios of gliquidone to ethylenediamine as the base to KOLLIDON.RTM. 25 as solubilizing agent were kept constant, the influence of the carrier substance on the dissolution rate can be seen.

The influence of the particular quantity of solubilizing excipient on the dissolution rate was demonstrated using the example of KOLLIDON 25 in Table 4. Table 4 also shows that the increase in the solubilizing substance in contrast to the increase in the carrier (highly dispersed silicon dioxide, see also Table 2) does not lead to a deterioration but to an increase in the dissolution rate.

Finally, Table 5 summarizes the influence of the particular quantity of water-insoluble carriers on the dissolution rate by means of further examples. As this table shows, it is advantageous to avoid an excess of carriers.

Table 6 shows that it is also possible to use other alkaline, toxicologically harmless excipients instead of ethylenediamine.

When pharmaceutical preparations are developed, optimization is carried out using in vitro methods. The release and dissolution of the active substance are determined using dissolution tests. To create conditions comparable to those which are obtained in vivo, these tests are normally carried out in an acid medium at a pH of 1.2. If this pH is used with the compositions according to the invention containing gliquidone, no measurable release rates are obtained. In vitro dissolution tests must, in this case, therefore be carried out at a pH of 7 (or higher), which is due to the fact that the solubility of the active substance is no longer sufficient at pH levels below 7. It would therefore be expected that there would be only a slight release of active substance in vivo in the acid range of the intestinal tract. The rapid and total absorption of the active substance even in the upper region of the intestinal tract is therefore surprising to one skilled in the art. It is also rather surprising that in spite of the difference between the in vivo situation and the measurement of the dissolution rate in vitro, there is considerable agreement between in vitro and in vivo results. This is shown by Examples 1(c), 17, and 22 if the results, which are assembled in Table 7, are compared with the corresponding human blood glucose reduction curves which are shown in FIGS. 6 and 7 of the attached drawings. For other active substances suitable pH-values derived from in vivo results are to be chosen for these purposes.

The following examples are intended to illustrate the invention and should not be construed as limiting the invention thereto. Moreover, in the examples, the following substances are employed:

AVICEL.RTM., a microcrystalline cellulose available from FMC Export Corporation, Philadelphia, PA;

KOLLIDON.RTM. 25, a poly-N-vinylpyrrolidone(-2), available from BASF, D-6700 Ludwigshafen, West Germany;

TWEEN.RTM. 80, a polyoxyethylene (20) sorbitan mono-oleate, available from Atlas Chemie, D-4300 Essen 1, West Germany;

PLURONIC.RTM. F 68, a polyoxyethylene polyoxypropylene polymer, available from Wyandotte Chemicals Corporation, Wyandotte, MI;

CREMOPHOR.RTM. RH 40, a glycerol polyethylene glycoloxy stearate, available from BASF, D-6700 Ludwigshafen, West Germany;

AEROSIL.RTM., an X-ray amorphous silicon dioxide, available from Deutsche Gold- und Silberscheideanstalt, D-6000 Frankfurt, West Germany;

MASIGEL.RTM., a di-magnesium-aluminium-trisilicate, available from Dr. Karl Thomae, D-7950 Biberach an der Riss, West Germany;

EXPLOTAB.RTM., a sodium carboxymethyl starch, available from Eastman Kodak Company, Rochester, NY;

KOLLIDON CL, a cross-linked insoluble polyvinyl pyrrolidone, available from BASF, D-6700 Ludwigshafen, West Germany; and

AMBERLITE.RTM. IRP 80, a potassium salt of polymers of methacrylic acid and divinylbenzene (methacrylic acid polymer with vinylbenzene, potassium salt), available from Rohm and Haas Deutschland GmbH, Philadelphia, PA.

Composition of a gliquidone-containing powder:

The basic excipient (2) is dissolved in 100 parts by weight of water at 70.degree. C. while stirring. The active substance (1) is added, and the mixture is stirred until the active substance is completely dissolved. The carrier (3) is suspended in this solution. The suspension is concentrated to dryness in vacuo while stirring, and the product is rubbed through a 1 mm mesh screen.

31% gliquidone dissolved after 5 minutes;

53% gliquidone dissolved after 30 minutes.

(b) Comparison with a known gliquidone-containing preparation of the following composition:

5.8% gliquidone after 5 minutes;

7.2% gliquidone after 30 minutes.

(c) Comparison with a gliquidone-containing powder without carrier:

The basic excipient (2) is dissolved in 100 parts by weight of water at 70.degree. C. while stirring. The active substance (1) is added, and the mixture is stirred until fully dissolved. This solution is dried in vacuo in a rotary evaporator, and the solid product is screened through a 1.00 mm mesh screen.

4% gliquidone after 5 minutes;

4% gliquidone after 30 minutes.

Examples 2 to 9, which are reflected in Table 2 below, show the possibilities of influencing the dissolution rate (in percent of dissolved gliquidone) when different solubilizing substances and different quantities of one and the same carrier are used. The various compositions were prepared as follows:

The basic excipient was dissolved in water at 70.degree. C. while stirring, and the gliquidone was added. The mixture was stirred at 70.degree. to 80.degree. C. until the active substance had dissolved. Then, the remaining constituents were stirred in, and the suspension was concentrated by evaporation in vacuo. The product thus formed was passed through a 1 mm mesh screen.

Table 3 below shows Examples 10 to 14 and also Example 2. These are examples of compositions containing identical amounts, that is, 60 mg. of different carriers and identical amounts of the same basic excipient, gliquidone, and the same solubilizing excipient, that is, 5 mg of gliquidone, 1.9 mg of ethylenediamine x H.sub.2 O, and 30 mg of KOLLIDON 25. Table 3 shows the effect of the particular carrier excipient on the dissolution rate. The individual compositions were prepared as described for Table 2.

Table 4 below contains Examples 15 and 16 together with Example 2 as a comparison. These are examples with identical quantities of gliquidone, ethylenediamine, and AEROSIL, that is, 5 mg of gliquidone, 1.9 mg of ethylenediamine x H.sub.2 O, and 60 mg of AEROSIL, but different quantities of KOLLIDON 25. The effect of the particular quantity of solubilizing excipient on dissolution rate of the active substance is shown. The individual compositions were prepared as described with reference to Table 2.

Example 17, together with Examples 2, 8, 9 and 10, shows the effect of the particular quantity of carrier on the dissolution rate. The values can be seen in Table 5 below. These compositions, which each comprised 5 mg of gliquidone and 1.9 mg of ethylenediamine x H.sub.2 O, were also prepared in analogy to those in Table 2. Table 5 shows that increasing quantities of carrier reduces the dissolution rate.

The effect of different basic substances on the dissolution rate is shown by Examples 18 to 20 in Table 6. The compositions, which each comprised 5 mg of gliquidone and 27.5 mg of KOLLIDON 25, were prepared according to Table 2.

The composition in Example 21 was prepared as described in Table 2. The composition in Example 22 was prepared by dissolving the active substance and the solubilizing substance together in ethanol. The solution was evaporated to dryness, and the product was passed through a screen with a mesh size of 1 mm.

As can be seen from Table 7 above, the presence of a basic excipient alone does not lead to a useful dissolution rate [see Example 1(c)] nor does the sole presence of a solubilizing substance (without a basic excipient and a carrier) lead to a product with a useful dissolution rate (see Example 22). If a carrier is added, however [see Example 1(a)], more than half the active substance has gone into solution after 30 minutes. If a solubilizing agent is then also added (see Example 17), excellent values are obtained within a very short time. This shows that the combination of gliquidone with a basic excipient and solubilizing agent in the presence of a water-insoluble carrier yields the best results in terms of rapid and fullest possible dissolution of the active substance.

The fact that the good dissolution rate of the compositions according to the invention cannot be explained solely by salt formation is also demonstrated by the following examples of tablets which were tested in vitro and partly also in vivo (see FIGS. 8 and 9 of the attached drawings).

(a) Each tablet had the following composition:

Round biconvex tablets weighing 300 mg each and measuring 10 mm in diameter were compressed from the mixture of components (1) to (4) and coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate: 0% gliquidone after 5 minutes; 11% gliquodine after 30 minutes.

(b) A granulate of active substance/tablet had the following composition:

Processing was carried out analogous to Examples 2 to 9. The following were added for each tablet:

The EXPLOTAB, cellulose, and magnesium stearate were added. Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter were compressed from this mixture and coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate: 46.3% gliquidone after 5 minutes; 51.2% gliquidone after 30 minutes.

(c) A granulate of active substance/tablet had the following composition:

Processing was carried out analogous to Examples 2 to 9.

The following were added to each tablet:

Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter were compressed from the mixture and coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate: 100% gliquidone after 5 minutes.

If the salt-forming agent lysine is omitted from the above composition, and gliquidone is dissolved in a solution of KOLLIDON 25 and PLURONIC F 68 in water and subsequently the resulting granulate of active substance is processed in the same way to form film-coated tablets, these tablets show the following dissolution rates:

7.4% gliquidone after 5 minutes;

8.3% gliquidone after 30 minutes.

(a) A granulate of active substance/tablet has the following composition:

The granulate was prepared using a procedure analogous to that of Examples 2 to 9.

The following were added to the granulated active substance for each tablet:

and the finished mixture was compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter. These were coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of gliquidone: 97.6% after 5 minutes.

(b) A granulate of active substance/tablet had the following composition:

The granulate was prepared using a procedure analogous to that of Examples 2 to 9.

The following were added to the granulate of active substance of each tablet:

and the finished mixture was compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter. These were coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of gliquidone: 91.1% after 5 minutes; 87.9% after 30 minutes.

A granulate of active substance/tablet had the following composition:

The granulate of active substance was prepared analogous to Examples 2 to 9.

The following were added to the granulate of active substance for each tablet:

and the finished mixture was compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter. These were coated with a hydroxypropyl methylcellulose coating to mask the flavor. Dissolution rate of gliquidone: 92.6% after 5 minutes.

Each tablet had the following composition:

The tablet constituents were mixed together, compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter, and then coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of active substance: 25.6% after 5 minutes; 36.3% after 30 minutes.

A granulate of active substance/tablet had the following composition:

Processing was carried out analogous to Examples 2 to 9.

The following were added to the granulate thus produced for each tablet:

Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter were compressed from this mixture and coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of active substance: 46.8% after 5 minutes; 94.5% after 30 minutes.

Each tablet had the following composition:

The tablet ingredients were mixed together, compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter, and coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of active substance: 15.8% after 5 minutes; 20.9% after 30 minutes.

A granulate of active substance/tablet had the following composition:

Processing was carried out analogous to Examples 2 to 9.

The following were added to the granulate thus prepared for each tablet:

Round bixonvex tablets weighing 300 mg and measuring 10 mm in diameter were compressed from this mixture and coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of active substance: 53.6% after 5 minutes; 98.2% after 30 minutes.

Each tablet had the following composition:

The tablet ingredients were mixed together, compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter, and then coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of active substance: 18.4% after 5 minutes; 27.2% after 30 minutes.

A granulate of active substance/tablet had the following composition:

Processing was carried out analogous to Examples 2 to 9.

The following were added to the granulate thus prepared for each tablet:

Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter were compressed from this mixture and coated with hydroxypropyl methylcellulose to mask the flavor. Dissolution rate of active substance: 98.2% after 5 minutes; 98.7% after 30 minutes.

The following are additional examples of the production of pharmaceutical compositions:

A quantity of granulate from Example 9 corresponding to 15 mg of gliquidone is mixed with a corresponding quantity of corn starch and magnesium stearate, and the mixture is filled into size 2 hard gelatin capsules.

A quantity of granulate from Example 13 corresponding to 15 mg of gliquidone is mixed with a corresponding quantity of corn starch and magnesium stearate, and the mixture is filled into size 1 hard gelatin capsules.

A quantity of granulate from Example 13 corresponding to 30 mg of gliquidone is mixed with AVICEL and magnesium stearate and compressed to form oval cores measuring 16.times.8 mm in diameter and weighing 700 mg in a tablet-press. The cores are then coated in a coating pan with a flavormasking coating of hydroxypropyl methylcellulose corresponding to 14 mg of dry substance.

A quantity of granulate from Example 17 corresponding to 30 mg of gliquidone is combined with an auxiliary granulate of lactose, corn starch and AEROSIL, and after the addition of magnesium stearate the mixture is compressed to form round biconvex cores measuring 11 mm in diameter and weighing 400 mg in a tablet-press. These cores are then coated in a coating pan with a flavor-masking coating of hydroxypropyl methylcellulose corresponding to 8 mg of dry substance.

Quantities of 3.5 mg of glibenclamide, 4.2 mg of N-methylglucamine, 19.25 mg of KOLLIDON 25, and 14.0 mg of AVICEL are processed as described for Table 2. A quantity of this preparation corresponding to 42 mg of glibenclamide is used, according to the particular requirements. Dissolution rate found:

Glibenclamide - 97.9% after 5 minutes;

Glibenclamide - 93.6% after 30 minutes.

By contrast, the corresponding commercially available product EUGLUCON.RTM. N showed the following results in the dissolution test (12 tablets/900 ml):

Glibenclamide - 16.8% after 5 minutes;

Glibenclamide - 13.8% after 30 minutes.

If only 21 mg of glibenclamide are used instead of 42 mg of glibenclamide, the following dissolution rates are obtained:

(a) with the above preparation:

Glibenclamide - 95.6% after 5 minutes;

Glibenclamide - 98.8% after 30 minutes.

(b) with EUGLUCON N (=6 tablets/900 ml):

Glibenclamide - 29.4% after 5 minutes;

Glibenclamide - 27.3% after 30 minutes.

The preparation of glibenclamide according to the invention is far superior to the commercially available EUGLUCON N in its dissolution rate, as is shown predominantly by the comparison carried out with 42 mg of glibenclamide/900 mg of liquid.

Each tablet had the following composition:

The active substance is dissolved in a mixture of ethanol and 1N sulfuric acid. PLURONIC F 68 and KOLLIDON 25 are then dissolved in this solution. The solution is evaporated, and the residue is passed through a screen with a mesh size of 1 mm and mixed with the following remaining tablet constituents:

Round bixonvex tablets weighing 300 mg are compressed from this mixture and then coated with hydroxypropyl methylcellulose to mask the flavor.

The results and explanations of human testing set forth below and in FIGS. 1 to 10 show that the compositions prepared according to the instant invention have the advantages mentioned hereinbefore:

FIG. 1 shows the path of the blood sugar level after the administration of a preparation according to Example 1(b) (commercial gliquidone preparations), a preparation according to the invention, and a preparation containing glibenclamide, with the brand name EUGLUCON N or SEMI-EUGLUCON.RTM. N. On the basis of the human testing described in German Patent No. 2,348,334 and the data on EUGLUCON N in the literature, it must be assumed that this preparation is produced analogously to the recipe in the patent specification. It is found that the start of the activity occurs much faster when using the preparation according to the invention and stops in a shorter time than with the other two preparations. With the known and highly effective glibenclamide, the maximum activity is not achieved until about 1.5 hours after administration, and the activity does not end until more than four hours later.

FIG. 2 shows gliquidone plasma levels after the administration of a preparation according to Example 1(b) (commercial gliquidone preparation) and a preparation produced according to the invention (Example 18). It is apparent that the faster onset of the activity is clearly caused by faster absorption.

FIG. 3 illustrates blood glucose levels after the administration of a placebo and a preparation according to the invention in a cross-over test on healthy volunteers with an intake of 50 gm of carbohydrate in the form of a mixture of glucose, disaccharides, and oligosaccharides (DEXTRO OGT.RTM.). FIG. 4 again shows blood glucose levels, but upon consumption of a standard breakfast. A standard breakfast is made up of two cups of black tea each containing 10 gm of sugar, two half rolls with 5 gm of butter each, and 7 gm of honey. FIGS. 3 and 4 show that the rise in the blood glucose level flattens out almost completely after the meal of carbohydrate. This means that the start of the activity and the course of the activity are optionally adapted to the course of the carbohydrate levels on the intake of food.

FIG. 5 shows the course of the blood glucose level upon consumption of a standard breakfast after administration of a preparation according to Example 17 (preparation according to the invention), Example 1(b) (commercial gliquidone preparation), and two preparations containing glibenclamide (EUGLUCON N and SEMI-EUGLUCON), breakfast being taken 15 minutes after the administration of the drug. It is found with one of the preparations that the higher dosage does indeed reduce the increase in the blood glucose level but then causes a sharp fall in blood glucose after some time. This means that even by increasing the dosage the desired effect cannot be achieved without risk. In contrast to the commercial forms, with the preparation according to the invention the rise in the blood glucose level after the taking of breakfast can be almost completely absorbed without leading to excessively low blood levels.

FIG. 6 shows blood glucose levels in a type 2 diabetic after the administration of a placebo and a preparation according to the invention, breakfast being taken 10 minutes after the administration of the drug. As can be seen from these curves, the administration of the preparation according to the invention adapts the rise in blood glucose, in terms of its level and duration, to physiological conditions which occur in people with healthy metabolism (cf., Placebo curve, FIG. 4).

FIG. 7 shows, as already described on pages 14, 26 and 27, the agreement between the in vitro results and in vivo results.

However, measurement of the peripheral insulin levels also illustrates the advantageous course of effect of the preparations according to the invention.

By measuring the peripheral insulin levels during the consumption of glucose or breakfast, the quantity of insulin released was calculated. The preparation according to the invention does not cause more insulin to be released as a whole than does glucose on its own. Calculation of the incremental areas clearly shows the early stimulation of the group treated with the preparation according to the invention. In the time from 0 to 42 minutes, twice the amount of insulin is released as compared with the placebo group (Table 8). For the phase from 42 to 300 minutes, the differences are small and do not reach a significant level in any case. The powerful effect on blood glucose can therefore be explained by an increase in early insulin secretion. There is no therapeutically undesirable excessively long high-lasting stimulation of insulin secretion.

The effect on insulin secretion in seven diabetics, of whom two were stabilized by diet alone, two used EUGLUCON or SEMI-EUGLUCON N (preparations containing glibenclamide), and three used a preparation according to the invention containing gliquidone, showed the superiority of the new preparation according to the invention compared with the standard medication (Table 9 below) tested in a cross-over test. In relation to basal insulin secretion, the new form demonstrated significantly greater stimulation of the early phase of insulin secretion (0 to 40 minutes) than the corresponding standard medication. In the subsequent period (40 to 300 minutes) there was a trend toward a reduction in insulin levels. This shows that the stimulation of only the earlier insulin secretion in accordance with the objective of the therapy is achieved not only with those of healthy metabolism but also in the target group, namely, type 2 diabetics.

The findings mentioned above show that the medical objectives:

(a) avoiding a non-physiological rise in blood glucose after the intake of food;

(b) avoiding a massive drop in blood glucose some hours after food intake; and

(c) early, brief release of insulin during the intake of food, are achieved with the gliquidone-containing preparations according to the invention.

FIG. 8 shows the course of the plasma levels of gliquidone after the administration of two preparations containing L-lysine as the basic excipient. It is clear that the composition analogous to Example 23(b) results in only relatively low plasma levels, whereas excellent results are obtained on administration of preparations according to Example 23(c). This proves that a significant excess of basic active substance is necessary for an adequate in vivo release of the active substance, i.e., the positive effect is not only due to salt formation.

FIG. 9 shows that the requirements regarding an optimal pharmaceutical preparation for diabetics mentioned hereinbefore can be achieved with various compositions [Examples 23(c), 24(b), 25]. However, the quantity of excipients must be optimized individually in each separate case.

Experiments were also carried out to find out whether faster acting forms are possible with the active substance glibenclamide, which does not have an ideal profile for the blood glucose curve in its commercial form of EUGLUCON N. For this purpose, the commercial form and a composition analogous to Example 36 were compared on eight and six healthy volunteers, respectively.

FIG. 10 shows blood glucose patterns in a test subject who took both forms on different days. It is apparent that a faster onset of activity and a shorter duration of activity can also be achieved for glibenclamide.

(a) Tablets without addition of base and solubilizing agent (for comparison with (b))

Each tablet had the following composition:

The active substance and the excipients were uniformly admixed with each other and the mixture was compressed into tablets having a diameter of 10 mg and a weight of 300 mg.

It was carried out in 900 ml buffer of pH 1.2, 2.0, 3.0, 4.0, 5.0, 6.0 and 7.0 at 37.degree. C. and 100 rpm in accordance with USP XXI/Paddle Method.

Samples were taken after 5, 10, 30 and 60 minutes. The results are shown in FIGS. 11 to 14 of the attached drawings.

(b) Tablets with addition of base

Each tablet had the following composition:

The ratio of active substance to lysine x H.sub.2 O is 1:1.38.

Ingredients (02), (03) and (04) were dissolved in aqueous ammonia, ingredient (01) was added thereto and dissolved at 85.degree. C. Ingredient (05) was suspended in the resulting solution. The suspension was processed into a spray granulate with the aid of a spray drier. The remaining tablet excipients (06), (07), (08) and (09) were admixed with the granulate, and the resulting mixture was compressed into tablets having a diameter of 10 mm and a weight of 260.0 mg.

It was carried out in accord with USP XXI/Paddle Method at 100 rpm in 900 ml buffer of pH 5.0 (the active substance exhibits the poorest solubility in this pH range).

After 5, 10 and 30 minutes.

After 5 minutes 82% of the active substance went into solution,

after 10 minutes 94% of the active substance went into solution, and

after 30 minutes 96% by weight of the active substance went into solution.

Each tablet had the following composition:

Components (01) to (04) are dissolved in a mixture of 83 ml of 1N NH.sub.4 OH and 117 ml of water. Component (05) is suspended in this mixture. The suspension is evaporated by spray-drying, the granulate thus obtained is mixed with components (06) and (07), and the mixture is processed in a tablet-press to form 500 mg-tablets with a diameter of 12 mm.

The dissolution rate was measured in 900 ml of a buffer solution of pH 4.6 (=pH-value at which the active substance shows its least solubility) at a temperature of 37.degree. C. and 100 rmp in accordance with USP XXI/Paddle Method.

41% of the active substance is dissolved after 5 minutes.

FIG. 15 shows blood glucose levels in six healthy volunteers who received 50 mg-tablets according to Example 39 in comparison to an oral solution. The blood glucose levels show that the tablet time course of blood glucose levels is quite similar to an oral solution which is, per definition, the ideal oral immediate release form. Minimal blood glucose levels are achieved with 50 minutes and thereafter glucose levels increase again.

FIG. 16 shows time profiles of insulin levels which are similar. This demonstrates that both forms are bioequivalent and that the absorption profile is very rapid. A preliminary study with 45 mg of the same active principle administered as a microcrystalline powder to two volunteers showed a reduction of blood glucose levels of only 9% and 10%. Time of minimal glucose levels was 2.5 hours after drug administration. This proves a clear-cut difference and a big advantage of the tablets according to the invention compared to microcrystalline material.

Each tablet had the following composition:

Components (02), (03) and (04) are dissolved in water, and component (01) is dissolved in this aqueous solution at 60.degree. C. Component (05) is suspended in the resulting solution, and the suspension is evaporated by spray-drying. Components (06) to (09) are added to the granulate thus obtained, and the mixture is compressed into 350 mg-tablets with a diameter of 10 mm in a tabletpress.

The dissolution rate was measured in 900 ml of a buffer solution of pH 5.0 (=pH where the active substance has its lowest solubility) at 37.degree. C. and 100 rpm according to USP XXI/Paddle Method.

90% of the active substance is dissolved after 5 minutes.

The methods of measurement used were as follows:

The blood sugar was measured in whole venous blood. Fifty microliters of blood were freed from protein with 500 .mu.l of 0.32 M perchloric acid. After centrifuging, the glucose in the supernatant was measured by the hexokinase method using an automatic substrate.

Insulin was determined from venous plasma by radioimmunology using the active charcoal method.

Six hundred microliters of whole blood were mixed with 50 .mu.l of Trasylol-EDTA-heparin mixture (5 ampules of Trasylol/Bayer, 1.2 gm of EDTA + ethylenediaminetetraacetate, 150 mg heparin, and 75 ml of physiological saline solution), then the mixture was centrifuged, and immunoreactive insulin in the supernatant was measured. One hundred microliters of plasma were dissolved with 100 .mu.l of .sup.125 I-pig insulin (Novo), in a phosphate buffer according to Soerensen, and 250 .mu.l of anti-pig insulin-guinea pig serum M 8309 (Novo) was incubated at 4.degree. C. for 23 hours. Then, the free insulin was separated from the bound insulin using active charcoal (Norit/Serva) and DEXTRAN T 70 (Pharmacia), filtered, and measured in a gamma counter.

The plasma levels were determined by HPLC. The measurement was carried out in a semi-automatic HPLC machine with column switching (for apparatus, see Journ. of Chromatography, 222 (1981), pages 13 to 22). The measurement was made using an external standard. In the analytical column 5.mu. f reversed phase material (HYPERSIL ODS.RTM.) was used; CORASIL C 18.RTM. was used for the preliminary column, in an amount of 37 to 50.mu. . The mobile phase used was a mixture of methanol, water, and piperidone (600:500:1). The substance was measured by fluorimetry (excitation wavelengths 318 nm, emission wavelengths 412 nm).

Blood samples were taken through long-turn catheters with heparinized disposable syringes. After a preliminary period of 15 minutes in which the course of the blood sugar level and of the insulin level without any medicament was measured, the galenic preparation was administered in the form of a granulate or in tablet form in the appropriate dosage with 70 ml of water.

The anti-diabetically active substances useful according to the invention are administered orally, optionally in combination with other active ingredients, in known manner. The daily dose for adults is from about 5 to 150 mg (from about 0.07 to 2 mg/kg of body weight), preferably from about 10 to 120 mg (from about 0.18 to 1.6 mg/kg of body weight), generally administered in the form of several, preferably from 2 to 4, individual doses to achieve the desired results. Dependent upon the type and body weight of the patient to be treated, on the type and severity of the disease, on the type of preparation and on the route of administration as well as on the period or interval over which the administration takes place, it may, however, be necessary to deviate from the above dosages. Thus it may be sufficient in some cases to administer more or less than the above-mentioned amounts of active ingredient. The optimum dosage and route of administration of the active ingredients which are necessary in each case can easily be determined by one skilled in the art.

The compositions prepared according to the invention can be further processed to produce pharmaceutical compositions useful for administration according to the invention. For example, the compositions can be admixed with conventional pharmaceutical excipients to form tablets, coated tablets, capsules, solutions and the like. Such conventional excipients include for example, microcrystalline cellulose, potassium salt of polymers of methycrylic acid and divinylbenzene, magnesium stearate, lactose, corn starch, polyvinylpyrrolidone, gelatin, and the like.

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, however, that other expedients known to those skilled in the art or disclosed herein, may be employed without departing from the spirit of the invention or the scope of the appended claims.