CS208196B2 - Method of making the perorally applicable preparation with the retarded liberation of the cefalexine as the active component - Google Patents

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PATENT (22) Registered 13 05 77 (21) (PV 3167-77) (32) (31) (33) Priority from 13 05 76 (54925/1976) Japan (40) Published 31 12 80 (45) Released 15 04 84

INVENTORY OFFICE DISCOVERY 208196 (11) (B2) (51) Int. C1.3A 61 K 9 / 32A 61 K 31/545 (72)

Author vynalezu MAEKAWA HIDEYDKI, QSAKA, TAKAGISHI YASUSHI, NISHINOMIYA aKATO HIROSHI, ΚΟΒΕ (Japan) (73)

SHIONOGI & CO., LTD., OSAKA (Japan) (54) Method for the manufacture of an orally administrable preparation with retarded release of cefalexin as active ingredient 1

The present invention relates to a process for the preparation of an orally administrable cephalexin retarded release active ingredient.

Cealexin, the chemical name of 7- (D-2-amino-2-phenylacetamido) -3-: methyl-3-cephem-4-carboxylic acid monohydrate, is widely used since it is one of the few -orally available cephalosporins. This antibiotic is effective against a variety of infections, and is rapidly and well absorbed throughout the digestive system. Most antibiotics are excreted in the urine without changing in the body.

Since the antibiotic level falls from 1 to 2 hours after administration, it is usually necessary to take the drug more than four times a day. Microcapsules containing cefalexin coated with sodium salt of carboxymethylcellulose are known from DOS 2,164,019. [0005] In the German Patent No. 2,164,019, microcapsules are known which contain ampicillin trihydrate and are coated with a copolymer of dimethyl amine methacrylate and methyl methacrylate. From French Patent Specification No. 2 059 978 it is known to coat drug-sensitive gastric juice, especially enzymes in powder form or in granular form, with polyvinyl acetophthalate or cellulose acetate phthalate. U.S. Pat. No. 4,222,176 discloses tablets containing penicillin or cephalosporins and magnesium carbonate, which are produced by immediate compression of the individual components of the mixture. Among the auxiliary agents, among others, are polyvinylpyrrolidone, which is used in particular in the case of microcapsules containing sodium salt of Cloxacillin. The microcapsules are mixed with the same amount of magnesium carbonate and other excipients and then compressed in tablets. No. 644,759 generally discloses the use of water-insoluble film-forming polymers and containing acidic functional groups to coat the drugs to be protected against the effects of gastric acid. Examples are copolymers of vinylbutylether and maleic anhydride, acrylonitrile and methacrylate, styrene and butyl acrylate and styryl and maleic anhydride. British Patent Specification No. 1,272,139 discloses the use of aqueous film dispersions of acrylic or methacrylic acid polymers which are physiologically acceptable for drug coating. Methacrylic acid copolymers and methacrylic acid esters are mentioned. The overlay should in this case reduce the sensitivity of said medicaments to moisture. A method for protecting drugs against the action of gastric acid is described in DOS 1 767 320, in which the medicament is powder-coated with a coating material, preferably cellulose acetate phthalate, granulated, compressed into tablets and tablets coated. the same material. DE 2 135 073 discloses a coating material for medicaments consisting of radical polymerization of vinyl monomers with carboxylic acid-containing, monoamino or dialkylaminoalkyl groups. Tytoplastics are insoluble at pH 1.5 to 8 and partially swell. If they contain a carboxyl group, they are insoluble at a pH of less than 7. In Austria Codex 1975/1976, Osterr, Apo-thekerverlag, Vienna 1975, pp. 130 and 365, oral cephalexin prepara- tions are to be taken every 6 weeks. hours.

French Patent Specification No. 2 287 216 discloses capsules for the administration of medicaments, in particular aspirin, which contain the active substance in two forms, both in microculverized form having a particle size of 40 to 200 nm and in the form of microcapsules. the active ingredient and the coating thereof is ethylcellulose and agar. In U.S. Patent No. 751,815, a sustained-release indomethacin formulation is disclosed wherein the substance is in the form of micro-capsules coated with a mixture of ethylcellulose and polyethylene or gelatin and acacia. The solvent is cyclohexane. U.S. Pat. No. 3,078,216 discloses slow-release drugs, wherein the medicaments are in the form of grains of varying size with a coating of hydrophobic substances such as fats or waxes. U.S. Pat. No. 3,906,086 describes aspirin-containing sustained release formulations coated with cellulose acetate phthalate. British Patent Specification No. 908,282 discloses sustained-release drugs consisting of ether-coated or cellulose-ester-coated particles. DE 2,030,501 discloses slow-release drugs coated with a drug containing a silicic acid matrix and coated with cellulose acetate and vinyl acetate (Eudragit retard Sj.) Is a methyl acrylate / ethyl methacrylate ocopolymer. U.S. Pat. No. 3,143,472 discloses a gastric-insoluble drug wherein the active ingredient is provided with a copolymer of maleic anhydride containing copolymers. so that the coating is insoluble in water at a pH of greater than 3.5, and ethylcellulose coated aspirin particles are known from U.S. Pat. No. 3,488,418, and cephalosporin containing antibiotic is known from U.S. Pat. 5 to 15 ο / θ excipients.

The known cephalexin preparations have the disadvantage that the blood cephalexin level can be maintained at a sufficiently high level for only a short time, so that the administration of the preparation is repeated.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for the preparation of a cephalexin preparation with proper oral administration with a partially prolonged duration of action. The composition of the invention may be effective, safe and easy to use so that it is only administered twice a day at 12 hours intervals, so that the patient's sleep is disturbed. Accordingly, the present invention provides a process for the preparation of an orally administrable composition comprising the release of cefalexin as an active ingredient, characterized in that the cefalexin particles are coated with a methacrylic acid / methyl methacrylate copolymer, soluble at pH 5.5 to 6.5, optionally as follows. the coated particles are pressed together with the animal and cefalexin in the stomach rapidly soluble in tablets.

The mixture is preferably pressed together with a binder tablet. The composition according to the invention consists of 15 to 60, preferably 20 to 50, in particular 25 to 40, and in particular 30% of cefalexin, in the stomach-juice-soluble cefalexin, based on the total amount of cefalexin used, 40 to 85, preferably 50 to 80, especially 60 to 75, and especially 70% of the coated cefalexin, based on the total amount of cefalexin, and in addition from conventional carriers, auxiliaries and / or other additives.

Each of the cephalexin components may have a granule or powder form, preferably the coated composition preferably has a particulate form and passes through the stomach in the form of an oral formulation. The compositions of the invention preferably have a cephalicin-containing capsule or tablet form as described above.

The enteric coated granules can be compressed into tablets with the addition of a suitable binder. In this case, about 25-40% of the tablet contents are washed away from the granulous coating and in the disintegration of the tablets in the gastric fluid, but the remaining granulse is intact into the intestine. The composition of the invention can be used to treat bacterial infections in humans by maintaining the ratio of conventional and coated cefalexin as described above.

Whereas the copolymer of methyl acrylate, ethyl methacrylate and trimethylmethacrylethyl ammonium chloride (Eudragit retard Sj, described in DOS 2 030 501, as a coating for medicaments has a certain permeability, the coating used in the process according to the invention for cefalexin coating, which is to be released slowly, has no permeability up to pH 5.5.

"Common cefalexin" refers to any rapidly absorbing cefalexin as is commonly used. These may be crystals, crystalline powder or granules, optionally in admixture with a pharmaceutically acceptable carrier or with other additives. These forms may be provided with a gastric juice soluble coating.

Figures 1 and 2 depict graphically the bactericidal efficacy of cefalexin in vitro depending on time. Figure 2 shows the depicted fields of exposure time of cefalexin and the dose used.

Figure 3 is a graph of blood levels of cephalexin in humans following oral administration of a normal formulation.

Fig. 4A shows the percentage of granules by an enteric coating which is dissolved per hour at different pH.

Figure 4B shows a transient increase in urinary cefalexin levels. when dissolving the same granules.

Fig. 5 is a graph similar to graph 3 but using an enteric coating composition.

Fig. 6 is a graph summarizing the results of graphs 3 and 5 with respect to cefalexin blood level using 1 mg cefalexin; the other two curves were generated from model equations mathematical simulation.

Figures 7A, 7B, 7C illustrate the dependence of Figure 6, with emphasis on levels sufficient to inhibit infectious microorganisms.

FIG. 8 shows the A and B curves of the effective blood level and the time required to reach an effective blood level using a combination formulation with different contents of the individual components of cefalexin.

Fig. 9 is a graph showing a transient increase in blood level following administration of the combination formulation in a preferred ratio compared to conventional cefalexin.

On the abscissa axis, time is applied in hours, and the cefa-lexin level in blood serum in mg / ml is deposited on the ordinate axis. Da C curves depict 500 mg and 250 mg of conventional cephalexin excretion curves. Curves A and B show excretion of 1000 and 500 mg cefalexin, respectively, with a ratio of normal cephalexin to terephthalate of 30: 70.

Fig. 91 shows the result of similar experiments as in Fig. 9, with the only difference that the experiment, the results of which are shown in Fig. 91, was performed on twelve volunteers. Otherwise, all data is identical to that in Fig. 9.

Figure 10 is a graph showing the incidence of viable bacterial cells in the urine of patients suffering from the presence of bacteria without additional symptoms after administration of three types of cephalexin preparations. Dependence of bactericidal effect in time on time

Usually, it is believed that the bactericidal effect of an antibiotic depends on its concentration and time. However, it has been unexpectedly found that this view does not correspond to the reality as shown in Figures 1 and 2 based on the following facts. a] More than 3 hours of cefalexin binding is required to reduce the viable Stahplococcus aureus 209P (ATCC 6538PJ. The minimum inhibitory concentration (MIC) of cefalexin for this strain is 3.13 µg / ml according to standard methods recommended by B) Exposure of bacteria to cefalexin concentrations above up to 3 hours is less effective than exposure to 4 and more hours. The critical time ranges from 4 to 6 hours [FIG. 1J. Similar observations were made at a cefalexin concentration of 12.5 micrograms / ml, ie four times the MIC. d] Simultaneous experiments showed similar results for 9 other S. aureus strains, including S. aureus # 120160 (clinical isolate), and for 6 strains of Escherichia coli. These results were initially considered to be defective and postponed. e) At exposures up to 6 hours, the decrease in viable cells was not sufficient due to the relatively high concentration of ce- falexin. f) When the bacteria were exposed twice to a concentration of 12.5 µg / ml cefalexin for 2 hours, ranging from 0 to 2 hours and 6 to 8 hours, there was no significant decrease in viable cells, whereas in continuous exposure 6 hours at a concentration of 3.13 µg / ml cefalexin for 6 hours, a decrease in viable cells of 1% or less was observed (Fig. 2). g] From these results it can be concluded that the bactericidal effect of cefalexin depends more on the duration of exposure than on blood level antibiotics when the MIC is maintained.

Experiment 1 (Fig. 1) 1. Staphylococcus aureus 209P (ATCC6538PJ in logarithmic growth phase is added to ABM3 broth (DifcoJ in a quantity of 10 5 cells / ml. 2. Cefalexin is added to said culture medium at a concentration of 3.13) The µg / ml and medium are allowed to stand for a specified period of time (0 hours for the control group shown in line 0, 2 hours, represented by line D, 3 hours, represented by line C, 4 hours, represented by line B, or 6 hours, depicted 3. The medium is centrifuged, the separated bacteria are washed to remove cephalexin and reintroduced into the same medium for a period of time 4. The medium containing viable 208196 7 8 cells is diluted and The agar plate suspension of the senanese thus obtained is counted after 24 hours and counted in the original medium according to the number of results. 2. The minimum number of viable cells depends on the duration of action of cephalexin; no cells left after 2 hours, less than 1% after 6 hours. 3. There is a clear difference between exposure to 4 and 6 hours.

Experiment 2 (Fig. 2)

The same microorganism was used and essentially the same procedure as in Experiment 1, except that cefalexin was added to the nutrient medium at a concentration of i) 0 µg / ml, shown by the line O in Fig. 2, ii) 3, 13 [mu] g / ml for 6 hours continuously, represented by line A, iii) 12.5 [mu] g / ml twice 2 hours with a certain interval, for example 0 to 2 hours and 6 to 8 hours, represented by line B.

These exposures are shown obliquely in the boxes shown in Figure 2. Results: 1. Even at high concentration, 12.5 µg / ml, it was not possible to observe a 4-hour intermittent, i.e. at time 0, at intermittent exposure for 2 hours. up to 2 hours and 6-8 hours, a significant decrease in viable cell count. 2. Continuous exposure for 6 hours at a concentration of 3.13 g / ml effectively reduces viable cells to a minimum of 8 hours. 3. The bactericidal effect of cefalexin depends more on the duration of action than on the concentration of the experimental conditions used.

Human Cephalexin Blood Levels: Exceptionally high blood levels of cephalexin, which can only be observed when extraordinarily high doses are given, can cause undesirable side effects, which are negligible at low concentrations.

In an effort to avoid adverse side effects, it is advantageous to keep the blood level at a necessary minimum for a desired period of time, whereby a minimum to the desired time can be achieved, thereby providing an effective and safe treatment for cefalexin infections. Regarding the relationship between the cephalexin blood level and the duration of action in conventional formulations, reference may be made to the following citations: K. Seiga, Chemotherapy (Japan), 18 (6), 899, 1970, H Nishimura, Saishin Igaku, 24 (9), 1983, 1969, RS Griffith et al., Clin. Copper. 75, 14, 1968, P. Brawn, Applied Microbiology, 16 (11), 1984, 1968 and T. S. Thornhill, Applied Microbiology, 17 (3), 457, 1969.

Experiment 3 (Figure 3) 1. Granules of conventional cefalexin containing 200 mg (line C in Figure 3), 300 mg (line B) or 400 mg (line A) are administered orally to 6 healthy volunteers just after meal. 2. Blood levels of cefalexin by measuring the antibacterial activity of a blood sample in a conventional manner. 3. Mean blood levels, calculated by groups of 6 people, are averaged over an hour between 0 and 6 hours · each hour. Results: 1. Blood levels rise rapidly to max 1 to 2 hours after administration. 2. After 3 to 4 hours, the level drops to 50%, after 5 to 6 hours to 10 to 0, the highest value. 3. The maximum level is 4 µg / ml at 200 mg, 6 µg / at 300 mg and 7 µg / ml at 400 mg. From these results it can be seen that even an exceptionally high dose of 1000 mg or more could not achieve an inhibitory concentration of 3, 13 (Ugulin for more than 6 hours with a conventional type of cephalexin preparation).

The reported MIC of 3.13 µg / ml is the value valid for almost all clinically isolated strains of Staphylococcus aureus, Streptococcus haemolyticus and Streptococcus pneumoniae.

Thus, it is evident that it is not possible to achieve a longer duration of blood levels other than slow release of cephalexin.

Attempts to prolong the effect of cephalexin:

Obviously, it is necessary to obtain a preparation of phalexin from which the active ingredient would be released over an extended period of time. Only in this way can a safe and effective treatment of a variety of infectious diseases be achieved.

Possible chemical or physiological modifications of cephalexin, for example, structural alterations or controlled excretion with concomitant use for bencid, have been considered, but these experiments have been unsuccessful in clinical practice.

Thus, it is clear that the pharmacokinetic method of slow absorption is the only way to achieve the desired result. A. Coating of Cephalexin Formulations 208196 9

In order to obtain a slow release formulation, 4-cell cephalexin granules of ethylcellulose were coated to give a 50% dissolution time of these granules of 0.5, 1.5, 2.5 and 3.5 hours by addition of the apparatus described in Pharmacopeia XIX. at pH 2.2 and 7.0 and 100 rpm.

The coated granules were administered to healthy volunteers and were measured by excretion. The following results were obtained: a) Solubility dependence was determined. time for each group of granules in different solutions. It has been found that there are only small differences at different pHs. bj The rate of dissolution of the coating decreases when the diffusion of solution into the drug deteriorates. Only a small difference was found between the time at which the highest excretion occurs, but statistically significant differences were found in excretion because the diffusion of the solution into the granule core was different. The total amount excreted in the urine was reduced by the deteriorating permeability of the air and the core, i.e. the total amount of active substance excreted in the urine was also reduced by slow dissolution.

A detailed description of the results is not given, since the inclusion of these values would prolong the descriptive part of the application.

Notwithstanding this, it is known that cefalexin is absorbed predominantly by the restricted upper part of the small intestine (J.S. Wells et al., Anti icrobial Agent and Chemothe-rapy, 489, 1968). The current results can confirm this.

From the results obtained, it can be seen that the formulation of this type has very little bioavailability in the case that the thickness of the coating is sufficient to slow down the absorption and thus the excretion. Thus, a prolonged action formulation cannot only be accomplished by delaying decomposition without the use of a pH dependent solubility coating. This means that infectious diseases can only be treated efficiently by using a cephalexin preparation whose solubilization is only at a certain pH range so as to dissolve in the upper part of the thin film, otherwise a larger portion of the active ingredient will be wasted. this upper part passes unchanged.

B. Coatings whose pH-dependent solubility H. Maekawa et al., Yakuzaigaku, 30 (2) 94-101 and 102-110 (1970) discloses that enteric coated granules exude the upper part of the thin stomach after administration just after eating. intestines for several hours and then fall off in the upper part of the small intestine. For this reason, it would be advantageous to coat the cephalexin with a similar 10-type coating so that it can be slowed down in the stomach.

Experiment 4 (Figs. 4A and 4B) The hydroxypropylmethylcellulose in the form of phthalate (HMPCP) and EudragitL and Eudragit S were used to coat the cephalexin formulations, the compositions being a methyl methacrylate / methacrylic acid copolymer. These substances are dissolved in an alkaline medium, in particular in the intestine.

Enteric coatings are distinguished by the pH at which they dissolve. In the course of the application, this term is defined as the pH at which the coating dissolves to such an extent that the entire composition falls (Fig. 4A). Three formulations of enteric granules of solubility at pH 5.0, 6.0, and 7.0 were labeled E, F, and G, and were prepared with a conventional cephalexin type coated with HMPCP Eudragit L and S .

The dissolution rate in different buffers at different pHs and the transient increase in human urine concentration in the three above formulations was measured as described above. The results obtained are shown in FIG. 4A and 4B. Results (Figure 4B): a) Granules F dissolve at pH 6 and excretion of this formulation in urine has a maximum of 5 hours after administration. b) Up to 83% of this formulation could be detected in the urine, resulting in good excretion absorption. c) Granule G dissolves at pH 7 and the formulation maximum can be detected in the urine for 9 hours, but there is a significant decrease in total urine volume. d) The pH 5 curve of granules E increases and decreases relatively quickly. e) G and E granules are not suitable as a long-term preparation containing cephaloxin. f) In this case, the thickness of the coating had less effect on the disintegration rate than the non-resistant properties of the coating. The results show that the optimum pH for the coating dissolution is 5.5 to 6.5, preferably 6. In this case, it is possible to maintain a blood level sufficient to increase the bioavailability of the formulation. C. Cephalexin blood levels obtainable by use in said preparations

A number of experiments were carried out to determine these values, the results of which are shown in FIG. 5 compared to the results of experiment 3 shown in FIG. 3. 208196 11 12

Experiment 5 (Fig. 5) 1. Enteric-coated granules containing 300 mg (Cj curve, 600 mg (curve B) or 900 mg (curve A in Fig. 5) of cefalexin at pH 6.0 were administered to 6 healthy volunteers just after 2. Measurement of blood levels and determination of mean blood levels versus time was performed in the same manner as in Experiment 3. Results: a) The maximum level was reached 6 hours after administration. bj The blood level exceeding 1/2 of the maximum level is maintained for 6 hours (curve B). cj The lag period to achieve 1/2 of the maximum value is 3 hours (curve B i. dj Approximately the same results were obtained with the use of 300 doses). mg and 900 mg D. Time lag to achieve the desired blood pressure and reduce it

Said cephalexin enteric preparation has a maximum blood level of up to 5 or 6 hours after administration, so that the time to reach the desired blood level is too long, for example 3 hours.

Because it is desirable for the blood-level ill to rise as fast as possible, this period too long.

In order to overcome this disadvantageous composition, it was proposed to use cefalexin in a rapidly absorbable form at the same time. However, the prescribing physician is sometimes very difficult to consider prescribing two different formulations for single use, and may sometimes misrepresent the ratio of the two products to the desired blood level. Therefore, the combination of the enteric preparation with the conventional formulation is most preferred. E. Determination of the Most Favorable Ratio The results of experiments 3 and 5 shown in FIG. 3 and 5, show the relationship between blood pressure and time between administration of the drug and measurement of blood level. The information obtained was analyzed to determine the average values of cefalexin corresponding to 1 mg of active ingredient in both types of granules. The results are shown in Fig. 6. The curves A and B in Fig. 6 are shown as if they were real blood levels, corresponding use however, the results were obtained by mathematical calculation. The results in Figure 6 also calculated the transient increase in blood levels of cefalexin in humans given three types of cefalexin 500 mg at different ratios of conventional and entero-cefalexin at the following ratios: A. 70:30, B. 50:50, C. 30: 70. The results are shown in Figures 7A, 7B and 7C.

The duration of the inhibitory conditions in the formulation of this type was calculated and shown in curve A in Fig. 8 of the curves in Fig. 6 to confirm that this inhibition period is prolonged if the formulation contains at least 40% of the enteric component, preferably at least 50% of the component.

On the other hand, the lag period to achieve an effective blood level in the range of 0 to 100% with increments of 10 o / 0 is shown in curve B in Fig. 8, these results being also obtained by mathematical calculation. It can be seen from curve B (FIG. 8) that the blood level decrease in a formulation containing at least 15% cefalexin conventional type is substantially different from that obtained with a 100% entefined cefalexin formulation and can be further shortened. when using formulations containing at least 20% of conventional cephalexin. The proportion of cefalexin may be increased to 60%. Taking into account the appropriate compromise with both of these aspects, it has been found that a suitable amount of the fast-release component in the mixed formulation is 15 to 60%, preferably 20 to 50%, and especially 25 to 40%, whereas the enteric coating content should be 40 to 40%. 85%, preferably 50 to 80%, and especially 60 to 75%. F. Verification of blood levels in vivo

As can be seen from the curve of FIG. 7C, the MIC duration is over 6 hours, obtained using a 30:70 conventional and enterosol cefalexin mixture formulation, particularly preferred by volunteer assays. as shown in Fig. 9.

A formulation containing 500 mg or 1000 mg of the above mixture was used. The preparation was administered orally to healthy volunteers just after the meal. The determined blood level, i.e. 3.13 µg / ml on curve B or 6.25 µg / ml on curve A at an average number of 8 men, was maintained for 6 hours continuously between 1.5 and 7, 5 hours after administration.

In contrast, it was found that the administration of a conventional formulation of 250 or 500 mg of cefalexin of the conventional type after 6 hours could achieve the desired blood level in the range of 2 to 4 and 8 to 10 hours after the first administration as shown by the C or D curves. in Figure 9. Although the drug was administered again after 6 hours, continuous blood pressure could not be achieved. It can be seen from the results in FIG. 9 that the cephalexin composition of the invention is much more effective than a conventional type formulation at the same total dose. G. The number of viable cells in the urine

A further clinical trial was performed by monitoring the bacterial efficacy of the mixed formulation prepared according to F. The results are shown in Figure 10.

The mixed preparation at 500 mg (curve A) and the two common preparations (250 mg, curve B and 500 mg, curve C) were administered immediately after meals 9, 8 and 5 patients, all of whom had the presence of bacteria in the urine of other symptoms. These bacteria belonged to the strains Escherichia, Pseudomonas, Streptomyces, Klebsiella, Retigeralla and Enrobobacter. The number of viable cells was determined at certain intervals after oral administration. The assay was run-to-run to obtain the curve of Figure 10 as an average value.

It is evident that almost complete bacterial suppression was achieved using a mixed preparation after 22 hours, whereas the use of a common type of cephalexin to suppress bacteria did not occur at all.

The same results are described by various authors of the conventional type used in animals. In the mixed preparation according to the invention, far better results were achieved in use in dogs and rabbits, but there was no slow absorption and most of the drug was excreted in the faeces prior to absorption. The cause of this phenomenon is apparently the variation of the digestive system in the animals and humans used, especially in terms of the length of the tube.

Thus, it will be appreciated that the composition of the present invention is suitable exclusively for use in humans. A detailed description of the animal species has been omitted for excessive length. Preferred Embodiments of the Process of the Invention The compositions of the invention may be in the form of a powder, granules, microcapsules, preferably capsules, tablets or granules packaged so that a single dose can be easily delivered.

The single dose usually contains 50-2000 mg cefalexin, preferably 500-1000 mg, and provides a blood level of 3.13 to 6.25 µg / ml in adults.

The ratio of conventional and enteric preparation is 15:85 to 60:40, preferably 50: 50 to 20:80, especially 40:60 to 25:75, most preferably 30:70.

The enteric coating is to be soluble in the upper small intestine, i.e., at higher pH. The range is 5.5 to 6.5, preferably 6.0. A preferred coating is a methyl methacrylate / methacrylic acid copolymer (Eudragit LJ, whose pH is dependent on solubility. In carrying out the process of the invention, either A. and the enteric form are mixed, or B. both are mixed separately and mixed). pharmacist, doctor or sick.

Type A is more convenient for the patient. However, in the case of B, the doctor or pharmacist may still adjust the ratio of the two components in specific cases, such as children. In both cases, very satisfactory results were obtained in all cephalexin-sensitive bacte infections. Type A or B formulations may be administered at 12 hour intervals, preferably just after meal. The invention will be illustrated by the following example. Example a) Conventional Cephalexin Granules

A mixture of 1117 g of cefalexin, 270 g of lactose and 97 g of corn starch is sieved with 500 g of 8% starch paste and the mixture is granulated in a roller granulator and dried for one hour at 60 ° C.

The dried granules are held in a Fitzpatrick mill and passed through a 16 to 24 mesh sieve. b) Enteric granules 1000 g of the above granules are placed in a 40 cm diameter pan and sprayed in a conventional manner by spraying the eudragit L alcohol solution (containing 52 g of Eudragit L and 52 g of talc in 1000 g of ethanol - 3500 g total) Antibacterial Activity The efficacy of the thus prepared granules of conventional cephalexin is measured in a manner known per se.

Spraying can be carried out at room temperature, at an air pressure of 0.2 MPa, the diameter of the nozzle used is 1.2 mm, the speed of 5 g / s.

Repeat spraying for 20 seconds and air drying at 70 ° C at 8 m 3 / min for 25 seconds. d) Packing of granules into plastic films

Conventional cefalexin granules of 150 mg and enteric-coated cefalexin of 350 mg are mixed and packaged after 205 and 650 mg in the usual manner into plastic films. (e) Hard gelatin capsules

The mixture of granules, of the same ratio as d), is filled into hard gelatin capsules at a total dose of 125 mg per capsule. Advantages of the Method of the Invention A. For Bacteriological Assay

Claims (3)

The strains of Stap-hylococcus aureus 209P, 9 other strains of this microorganism and 6 strains of Escherichia coli were used according to the invention. A number of other microorganisms react to cefalexin in a similar manner to that of used bacteria. Thus, it is to be expected that the composition of the invention will be clinically effective as well as a host of other bacteria. Thus, the disadvantages of the clinical use of a conventional type of cephalexin can be overcome. B. The composition of the present invention makes it possible to reduce the time of treatment and thus the total amount of cefalexin required and the risk of side effects with the same bactericidal effect. C. The composition of the invention allows for application once every 12 hours without reducing the effect, does not interfere with the sleep of the patient as a conventional type of cephalexin, which must be administered four times daily after 6 hours. D. The composition of the invention reduces the additional effects of passing conventional cephalexin through the gastrointestinal tract, such as the stomach. PREDMEl CLAIMS 1. A process for the preparation of an orally administrable composition with delayed release of cefalexin as an active ingredient, characterized in that the cefalexin particles are coated with a methacrylic acid / methyl methacrylate copolymer, soluble at pH 5.5 to 6.5. such coated particles are pressed together with the binder and, together with cephaloxin, rapidly soluble in the stomach to form tablets. 2. The method of claim 1, wherein the stomach-soluble cephalexin is 15: 85 to 60:40. 5 sheets of drawings 3 Soverography, n. P., Race 7, Most