HU184196B - Process for producing preparation containing 7-/d-2-amino-2-phenylacetamino/-3-methyl-3-cephem-4-carboxylic acid monohydrate - Google Patents

Abstract

LONG ACTING PREPARATION OF CEFALEXIN FOR EFFECTIVE TREATMENTS OF BACTERIAL INFECTION SENSITIVE TO CEFALEXIN A cefalexin preparation coated with a coating layer the solubility of which layer is pH-dependent and dissolves at upper intestine is preferably administered concurrently with a normal (plain, quick-releasing) cefalexin preparation. The coated preparation is preferably coated, in the particle form and when administered orally, exists in the particle form at stomach. Preferably, the coating layer is made from coating base material having dissolution pH of from 5.5 to 6.5, and the ratio in potency of the coated cefalexin to the normal cefalexin is between 15 : 85 and 60 : 40. The coated cefalexin and the normal cefalexin can be composed to a pharmaceutical preparation preferably in a unit-dosage form, e.g. capsules, tablets or particles or in strip-packages.

Description

FIELD OF THE INVENTION The present invention relates to a novel pharmaceutical composition comprising 7- (D-2-amino-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate. 7- (D-2-amino-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate (cephalexin) is widely used as one of several commercially available cephalosporin derivatives. It is effective against many infections and has an absorption rate above 90% (H, Otten, Antibiotic-Fibel, 4th Ed., 1975, p. 296).

However, 1 to 2 hours after administration, cefalexin blood levels decline rapidly and, in order to achieve a satisfactory therapeutic effect, patients should usually take more than 4 times a day.

German Patent Publication No. 2,325,410 discloses microcapsules containing cefalexin coated with sodium carboxymethylcellulose.

German Patent Publication No. 2,164,019 also discloses microcapsules containing ampicillin trihydrate coated with copolymers of dimethylaminomethacrylate and methyl methacrylate.

French Patent Application 2,059,987 discloses the coating of gastric juice sensitive drugs, in particular enzymes, with polyvinyl or cellulose acetophthalate.

British Patent No. 1,422,176 discloses tablets containing heavy magnesium carbonate and a penicillin or cephalosporin which are prepared by direct compression of a mixture of ingredients. Polyvinylpyrrolidone is mentioned as an excipient for microcapsules containing cloxacillin sodium. The microcapsules are mixed with substantially the same amount of heavy magnesium carbonate in the presence of insignificant amounts of excipient and compressed into tablets.

German Patent No. 644,759 discloses film-forming, water-insoluble, polymeric polymerizers containing acidic groups which provide protection against gastric acid and digestive fluids. Examples include vinyl butyl ether and maleic anhydride copolymers, acrylonitrile and methacrylate copolymers, butyl acrylate and styrene copolymers, and maleic anhydride and styrene copolymers.

British Patent No. 1,272,139 recommends aqueous dispersions of film-forming, physiologically tolerable acrylic and methacrylic acid polymerizable films. Examples include copolymers of methacrylic acid and methacrylic acid ester. These coatings, among other things, reduce the moisture sensitivity of sugar coatings.

German Patent No. 1,767,320 discloses a method for protecting drugs against gastric acid; the process comprises mixing an enteric coating, preferably cellulose acetate phthalate, on the powdered active ingredient, and then granulating, compressing into tablets, re-coating and optionally drageing.

German Patent Publication No. 2,135,073 discloses a drug coating prepared by radical polymerization of vinyl monomers with compounds containing a carboxyl group and / or a mono- or dialkylaminoalkyl group.

On the one hand, the polymers thus obtained are insoluble in water at a pH of from 1.5 to 8 and swell or dissolve in part of this range in water. If the polymers contain a carboxyl group, the insolubility range is below 7 pH.

The Austrian Codex 1975/1976, est. Apothekerverlag, Wien, 1975, pages 130 and 365 describes oral cefalexin formulations which must be taken every 6 hours.

French patent application 2,287,216 discloses capsules containing the active ingredient 15 in two forms, microporous powder and microcapsules, for the administration of drugs, especially aspirin. Microcapsules provide a sustained action of the active ingredient; their coating consists of ethylcellulose and agar.

Belgian Patent No. 751,815 discloses a sustained release preparation of indomethacin; in which the active ingredient is contained in microcapsules made of ethyl cellulose polyethylene or gelatin-arabic gum. Cyclohexane is used as solvent.

U.S. Patent No. 3,078,216 discloses sustained release pharmaceutical compositions in which the active ingredient is embedded in hydrophobic materials such as fats or waxes in various particle sizes.

U.S. Pat. No. 3,906,086 discloses sustained-release aspirin formulations coated with cellulose acetate phthalate.

British Patent No. 908,282 describes extended release pharmaceuticals containing particles coated with Celtulose esters.

German long-term pharmaceutical compositions are known from German Patent Publication No. 2,030,501; in these, the active ingredient is embedded in 40 silica gels and coated in layers. In addition to various cellulose compounds and polyvinyl acetate, Eudragit retard S is mentioned. It is a copolymer of methyl (e) ethyl (meth) acrylate and trimethyl methacrylethylammonium chloride and has a certain permeability.

U.S. Patent 3,143,472 discloses a pharmaceutical composition insoluble in gastric juice; the active ingredient is coated with a maleic anhydride copolymerizate which is soluble in water above pH 3.5.

Aspirin coated with ethylcellulose is known from U.S. Patent 3,488,438.

From German Patent Publication No. 2,259,646, up to 55 other high-active antibiotics containing a cephalosporin derivative and 5-15% excipients are known for oral administration.

The disadvantage of known cephalexin formulations is that cefalexin blood levels remain only briefly at the 60 required for satisfactory antibacterial activity.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a cephalexin composition which is orally administrable to humans and is partially delayed and effective-21

184 196 safety and safety, it is more advantageous for the patient, since he / she should take the patient twice a day at 12 hour intervals so that he / she does not need to interrupt his / her sleep.

It is contemplated that the required cefalexin blood levels can be maintained for a sufficient period of time by the use of a cefalexin formulation containing a defined weight ratio of a gastric-soluble and a slow-release cefalexin component.

The present invention therefore relates to a process for the preparation of a partially delayed oral cefalexin active ingredient which comprises (a) a granule; cefalexin coated with stomach-soluble cephalexin and (b) copolymerized methacrylic acid polymer, preferably methyl methacrylate and methacrylic acid monomers in a pH of at least 5.5, at a ratio of from 15: 85 to 60:40 by weight relative to the active ingredient, which is 15 to 10% by weight of the total active ingredient in the first component, the total active ingredient in the second component ;; 40-85% by weight, optionally in combination with conventional carriers, excipients and / or additives.

Preferably the mixture is compressed with a binder to form tablets.

The composition of the invention (1) contains from 15% to 60%, preferably from 20% to 50%, preferably from 25% to 40%, in particular 30% of cephalexin, based on effective total cephalexin in component (a);

(2) 40-85%, preferably 50-80%, preferably 60-75%, especially 70%, based on the effective total cephalexin in component (b);

(3) and optionally any conventional carrier, excipient and / or excipient.

While German Patent Application Publication No. 2,030,501, recommended as a coating, among other materials, has a certain permeability to the methyl and ethyl (meth) acrylate and trimethyl methacrylethylammonium chloride copolymer (Eudragit retard S), the present invention is intended to coat component (b). The methacrylic acid polymer soluble at pH 5.5 used has no permeability. The known coating is only recommended for use in sustained release pharmaceuticals; the polymerizate used in the present invention is not recommended for such purpose.

The cephalexin formulations (1) and (2) can be prepared in both granules and powders. If the composition (2) is prepared primarily in coated form, it is preferable to form the coating on each particle. Thus, for oral administration, the active ingredient is coated in the stomach.

The composition of the present invention may be presented as a unit dose in the form of a capsule or tablet containing the two cephalexin formulations in the proportions given in (1) and (2).

A unit dose determination is one or a portion of a single prescribed dose.

Enteric coated granules can be compressed into tablets with a suitable binder.

In this case, the coating of the granules is partially broken and the cefalexin core is released and then, when disintegrated in the gastric juice, a portion of the cefalexin, usually 25-40% of the total tablet, diffuses, but the remaining coated portion of the granules gradually enter the intestine.

The composition of the present invention can be used to combat bacterial infections by administering an effective amount of the granulated cephalexin composition and the coated cephalexin composition, preferably in the ratios (1) and (2) above.

The term "granular cephalexin composition" is intended to mean any of the fast-release cephalexin formulations commonly used in medicine. This may generally be cryoprecipitate, powdered crystalline, granular or granular cephalexin, optionally with a pharmaceutical carrier or excipient or the like. In addition, it may be coated with a layer soluble in weed juice.

The figures illustrate the efficacy and advantages of the cephalexin composition of the present invention.

Figures 1 and 2 graphically illustrate the in vitro antibacterial activity of cefalexin versus time of exposure. In Figure 2, the shaded area represents the level and duration of administration of cefalexin.

Figure 3 is a graph showing blood levels of cefalexin in humans over time following oral administration of a conventional formulation.

4A. The graph of Fig. 3B shows the dissolution of the coated granules soluble in three different pH values within one hour.

4B. FIG. 3B illustrates the amount of urine excreted in the previous formulations.

Figure 5 is a view similar to Figure 3 showing the water level of the coated composition over time.

The graph in Fig. 6 summarizes the intersections of Figures 3 and 5 and shows the blood levels corresponding to the efficacy of 1 mg of cefalexin as determined by a mathematical model.

7A, 7B. and 7C. Figure 6 is a graph derived from Figure 6 and shows the time of constant inhibition effect at various mixing ratios.

Figure 8 shows curves A and B, the former showing the duration of effective blood levels, the latter showing the time needed to achieve effective blood levels when administered in various proportions of a combination of conventional and sustained release formulations.

9 and 9A. FIG. 6A shows the change in blood levels of the preferred composition after administration compared to the conventional composition upon repeated administration.

Figure 10 shows the change in the number of viable bacterial cells in the urine of asymptomatic bacterial emptying patients after administration of three different cephalexin formulations.

In contrast to the prevailing notion, which is that the concentration of an antibiotic has a proportional to the antimicrobial activity, or at least the concentration is related to the absorption time, specific findings have been made in the bacterial inhibition studies of cefalexin, typically summarized in Figures 1 and 2, the following.

a) The absorption of cefalexin should be greater than three hours to reduce the viable cell count of Staphylococcus aureus 209P (ATCC 6538P). The minimum inhibitory concentration (MIC) of cefalexin against this strain was 3.13 pg / ml by the method of the Japanese Pharmaceutical Society. determined.

Exposure of the bacteria to cefalexin at 3.13 pg / ml for up to 3 hours was significantly less potent.

184,196 kitchens for 4 hours or more. The critical exposure time is between 4 and 6 hours (Figure 1).

c) A similar observation was made in experiments with cefalexin at 12.5 pg / ml (four times the MIC).

d) Simultaneous experiments yielded similar results with 9 additional S. aureus strains, including Staphylococcus aureus 120160 (clinically isolated) and 6 strains of Escherichia coli. These experiments are for control purposes only and are not described in the description due to their scope.

e) During a short exposure period (up to 6 hours), the reduction in viable cell count was not clearly matched with cefalexin concentration.

f) Bacteria were exposed to 12.5 pg / ml of cefalexin twice (intermittently) for 2 hours, i.e. 0 to 0, followed by 6-8. hours, no significant decrease in viable cells was observed, while continuous exposure to cefalexin at 3.13 pg / ml for 6 hours reduced viable cells to less than 1% (Figure 2).

g) The bactericidal activity of cefalexin is determined to be dependent on the exposure time and not on the blood level of the drug, provided that the desired minimum inhibitory concentration is maintained throughout the exposure period.

Experiment 1 (Figure 1)

Method

1. Staphylococcus aureus 209P (ATCC 6538P) was inoculated at 10 ⁵ cells / ml in ABM3 (Difco) medium at log growth time.

2) Cefalexin was added to the medium at a concentration of 3.13 pg / ml and left to act for a predetermined time. [0 hours, i.e., control (0 curve), 2 hours (curve D), hours (curve C), 4 hours (curve B) and 6 hours (curve A)].

3. To harvest the bacteria, the culture was centrifuged and then washed to remove cefalexin, inoculated in the same medium, and cultured for a fixed period of time.

4. The culture containing viable cells was diluted and part of the bacterial suspension was plated on agar plates. After 24 hours of storage, the number of colonies was determined and compared to the number of viable cells in the original culture.

Results

1. Cefalexin killed a certain number of bacteria, but after removal of the drug the needle bacteria continued to proliferate,

2. The minimum number of viable cells and the growth rate of viable cells (digestion) were dependent on the exposure time (the 2-hour exposure shows no minimum whereas the 6-hour exposure is less than 1%).

3. There was a significant difference between the exposure time of 4 and 6 hours.

Experiment 2 (Figure 2)

The same microorganisms were used and essentially the same as in Experiment 1 with the following differences.

1. Cefalexin was added to the medium at the following concentrations:

(i) 0 pg / ml (0 curve, control), (ii) 3.13 pg / ml (curve A) for 6 hours continuously, (iii) 12.5 pg / ml (curve B), interrupted for 2X2 hours, i.e. 0 -2. 6-8. hours (The exposure time is represented by the lined area in the figure.) Results

1. Even at high exposure concentrations of 12.5 pg / ml, where the exposure lasted 2 hours with a 4 hour interval, i.e. 0-2. and 6-8 hours, the number of viable cells did not substantially decrease.

2. Continuous exposure for six hours at a concentration of 3.13 pg / ml significantly reduces the number of viable cells for a minimum of 8 hours.

3. The antimicrobial efficacy of cefalexin is not dependent on the concentration used during the experiment.

Cefalexin blood levels in humans

Extremely high blood levels require very high doses, which can cause adverse side effects, but can be avoided at low concentrations.

In order to eliminate the adverse side effects, it is advisable to keep blood levels to a minimum for a certain amount of time, and thus to treat the infection effectively and safely with cefalexin. The following assay (experimental methods) was performed to determine the desired blood level relationship for common cefalexin:

K. Seiga, Chemotherapy (Japan), 18 (6); 899, 1970;

H. Nishimura, Saishin lgaku, 24 (9); 1983, 1969;

R. S. Griffith et al., Cin Med, 75; 15, 1968;

P. Brawn, Applied Microbiology, 16 (11); 1684, 1968 and T. S. Thornhiil, Applied Microbiology, 17 (3); 457,

1969)

Experiment 3 (Figure 3)

I. Oral cephalexin formulations containing 200 mg (curve C), 300 mg (curve B) and 400 mg (curve A) were orally administered to 6 apparently healthy subjects immediately after food.

2. The blood levels of cefalexin were measured by the antimicrobial efficacy of the blood sample as determined by the usual method.

3. The average blood level of the 6 subjects is 0-6 after administration. hours each hour.

Results

1. Blood levels increased rapidly and peaked in 1-2 hours.

2. After 3 to 4 hours it decreased to half of the level and after 5 to 6 hours it decreased to a tenth of the peak.

3. Peak K at 4 pg / ml at 200 mg, 6 pg / ml at 300 mg and 7 Pg / ml at 400 mg.

From the results obtained, it is expected that at an extraordinary dose of 1000 mg or more, the desired inhibitory concentration of 3.13 pg / ml cannot be achieved for more than 6 hours and cannot be achieved with a single administration of a conventional cephalexin formulation.

The minimum inhibitory concentration (3.13 pg / ml) reported herein is for clinically isolated Staphylococcus aureus. Value determined with Strep-41 tococcus haemolyticus and Streptococcus pneumoniae.

This confirms that the prolonged effect of the minimum inhibitory concentration is unlikely and some method needs to be developed for this purpose.

Attempts to suppress the effects of cefalexin

After careful consideration of the results described above, it was considered necessary to provide a prolonged effect of cefalexin. Such a handle can provide a safe and effective clinical treatment for certain infectious diseases.

Although chemical (structural modification) and physiological (metabolic control by the concomitant administration of probenecid) attempts have been made to prolong the effect, they have not been used in clinical practice.

Therefore, the only method seemed to be to provide prolonged absorption by pharmacokinetic methods.

A) Time-dependent absorption of cefalexin coating

To develop a sustained release or slow release formulation, four types of cephalexing granules were coated with ethylcellulose to dissolve 5O 9 Na in 0.5, 1.5, 2.5 and 3.5 hours in U.S. Pharmacopeia XIX. (pH: 2.2 and 7.0; speed: 100).

The coated granules were administered to healthy subjects and the urine excretion rate was determined.

The results of the experiments lead to the following conclusions:

(a) Dissolution for each granule and each solution was time dependent. There was only a slight difference at different pH values.

b) The diffusion of the drug is made more difficult by dissolution through the coating layer.

c) Only minor differences in urinary excretion were observed, but there were significant differences in the amount selected, which is related to the coating of the granules.

d) The amount excreted in the urine decreases with increasing thickness of the coating layers, in other words, the longer the dissolution delayed due to the layer, the greater the amount excreted in the urine.

The detailed results are not presented here due to their length.

It is known that cefalexin is mainly absorbed in the upper part of the small intestine (duodenum and jejunum, J. S. Wells et al., Antiinicrobial Agent and Chemotherapy, 489, 1968).

Consideration of the established facts and the prior art suggests that the biological efficacy of such a formulation is extremely poor, even if the thickness of the coating layer is sufficient to prolong absorption and absorption.

Specifically, it has been found that a sustained release formulation cannot be achieved with a pH-independent coating to prolong degradation, i.e., any time-dependent coating is not effective in treating infectious diseases. The remainder of the drug dissolves from the coated granules only after the upper gastrointestinal tract and is excreted in the faeces.

B) pH dependent coating

Based on previous work by two inventors of the present invention [H. Maekawa et al., Yakuzaigaku, 30 (2) 94-101 and 102-110 (1970) disclose that externally applied granules, taken immediately after a meal, are continuously and gradually released from the stomach into the upper intestine within a few hours, and here the granules are disintegrated], further pharmacokinetic studies were conducted to prepare a sustained release cefalexin formulation, which included coating and testing the pH dependent layer of the cefalexingrenulates.

4. Ghost (Figures 4A and 4B)

Hydroxypropylmethylcellulose phthalate (HPMCP), Eudragit L and Eudragit S (trademark of coating material made from a copolymer of methyl methacrylate and methacrylic acid) were used as the coating material, which is soluble in an alkaline medium, i.e. the intestinal tract.

The outer coatings were characterized by their dissolution pH. This is the pH at or above which the layer rapidly dissolves and the coated composition disintegrates (Fig. 4A).

Three types of coated granules were prepared by coating ordinary granules with HPMCP, Eudragit L and S, which were soluble at pH 5.0, 6.0 and 7.0, designated E, F, and G, respectively.

Dissolution in buffer solutions at different pHs and the time course of urinary excretion in humans was determined as described previously. and the results obtained are illustrated in Figures 4A and 4B.

Results (Figure 4B)

(a) For granule F soluble at pH 6, the amount of urine excreted over time is approximately 5 hours after administration.

b) A significant proportion (approximately 83%) of the drug is recovered in the urine, indicating satisfactory absorption and excretion.

c) The peak of granule G (solubility pH 7) is 9 hours after administration, but the amount excreted in urine is significantly reduced.

d) The curve of granule E, which dissolves around 5 pl / cr, increases relatively rapidly and then decreases rapidly.

e) Neither of the latter two appeared to be suitable for the preparation of a cefalexin sustained release formulation.

f) In these cases, the thickness of the coating layers played a minor role in the disintegration rate compared to the time-dependent properties of the coating layer.

According to the results, the optimal solubility is between pH 5.5 and 6.5, preferably around 6 ρΗ, and the blood levels have been maintained at a sufficiently high level for a sufficient period of time, and the biological efficiency is also quite high.

C) Blood levels of cefalexin as a result of the preferred formulation

Experiments have been conducted to determine the blood levels achievable by administering the above preferred formulation, which

-5184 196 i

results are summarized in Figure 5 and compared with the curve in Figure 3 obtained in Experiment 3.

Experiment 5 (Figure 5)

1. Coated granules containing 300 mg (curve C), 600 mg (curve B) and 900 mg (curve A) of cefalexin, soluble at pH 6.0, were administered orally immediately after a meal to 6 healthy subjects.

2. Blood levels were measured and plotted against time as described in Experiment 3.

Results

a) The peak occurred 6 hours after administration.

b) Blood levels above the peak were maintained for 6 hours (curve B).

c) The time to reach half of the peak was approximately 3 hours (curve B).

d) These results can be applied to the other two doses (300 mg and 900 mg).

D) Time and reduction to reach the desired blood level

The blood levels of said enteric coated cefalexin formulation are only 5 to 6 hours after administration and the time required to reach the desired blood level is too long (e.g. 3 hours) to be effective.

Because a patient with an infectious disease usually requires urgent antibiotic treatment, the long time it takes to reach the desired blood level can be fatal.

In order to accelerate the absorption time of the enteric coated formulation and thereby eliminate the aforementioned disadvantages, a rapid absorption dose is administered simultaneously with the formulation. However, the physician prescribing the drug is not always aware of the use of the two formulations, especially in determining the ratio needed to achieve the desired blood levels and maintain them for a certain time.

With this in mind, it is most advantageous and most appropriate to prepare the enteric coated formulation and the common formulation in the most advantageous combination unit dosage form.

E) Determining the optimum mixing ratio

The results of Experiments 3 and 5, illustrated in Figures 3 and 5, also provide a proportional relationship between blood levels and time during the experiment and the amount of drug administered. As a basis for determining the preferred formulation, the information in Figures 3 and 5 was studied to determine the amount of cephalexin in the blood based on the effective amount of 1 shirt for each granule and is shown in Figure 6.

In Fig. 6, curves A and B are represented as real blood levels, which corresponds to the normal and enteric formulations, but are constructed by mathematical modeling and substantially correspond to the original curves.

Figure 6 shows the change in blood levels at three different ratios of common and enteric cefalexin containing 500 mg cefalexin, i.e. A: common / enteric = 70:30, B common / enteric ~ 50:50, and C: common / enteric = 30:70 and is illustrated in Figures 7A, 7B and 7C.

The duration of steady state inhibition for formulations containing both ingredients is illustrated by the curve A in Fig. 8, which is derived from Fig. 6 and shows that the effect over the entire range (0-100% to 100-0-0% with 10% increase) elongates when the composition comprises at least 40% of the enteric component and this sustained action becomes significant when the enteric component is at least 50%.

On the other hand, the time needed to achieve effective blood levels at various ratios was also determined over the entire range (ΟΙ00% to 100-0%, 10% increase) and is illustrated in curve B of Figure 8.

Curve B of FIG. 8 shows that the onset of action of at least 15% of a rapidly absorbed common ingredient composition is significantly different from that of a 100% enteric composition and is preferably increased by at least 20% of a common composition. This ingredient can be increased up to 60% for a very quick effect.

In view of the above-mentioned aspect of actually satisfying the need for effective prolongation of the effect, it has been found that the usual rapid release in the combined preparation! the proportion of the component is 15-60%, preferably 20-50% and particularly preferably 25-40%, and the ratio of the enteric component is 40-85%, preferably 50-80% and particularly preferably 60-70%.

F) Determination of blood levels in vivo

The curve in Fig. 7C shows that the minimum inhibitory concentration at 6: 30 for a normal and intestinal absorption composition is sufficient to meet all requirements, but clinical trials have been conducted in humans to confirm this, and is illustrated in Figure. Following oral administration to healthy subjects of the following oral and intestinal absorption granules of 500 mg and 1000 mg per unit dose, the desired blood level (3.13 µg / ml, curve B or 6.25 pg / ml) , The curve; average of 8 persons) was maintained for 6 hours from 1.5 hours to 7.5 hours after administration.

In contrast to these results, a standard formulation containing 250 mg or 500 mg of cefalexin was administered every 6 hours, with the same blood levels only intermittently in steps 2-4. hours and 8, —10. hours were maintained from the first administration, as shown by curves C and D. Even a further administration 6 hours after the first administration was not sufficient to maintain blood levels continuously.

It will be apparent from Figure 9, with reference to Figures 1 and 2, that the cephalexin composition of the present invention is much more effective than the conventional cephalexin composition at the same dosage.

Gj Determination of efficacy based on viable cells in urine

With a combination composition having a preferred mixing ratio

The bactericidal efficacy (potent inhibitory activity) was examined and the results are shown in Figure 10. The preferred composition was as given in (F).

The 500 mg combined formulation (curve A) and two common formulations (250 mg, curve B and 500 mg curve C) were administered immediately after a meal to 9, 8 and 5 patients, respectively, who had asymptomatic bacterial excretion of Escherchia, Pseudomonas, Streptomyces, KlebsieBa. , Retigeralla, and Enterobacter strains, and the number of viable bacterial cells in the selected urine at defined intervals after oral administration (bold PO indicated in POI of Figure 10) and averaged in Figure 10.

It should be noted that the combination formulation achieved a substantially complete effect 22 hours after administration, whereas none of the conventional formulations were capable of producing a partial effect.

Appropriate tests have also been performed to determine the beneficial properties of the composition according to the invention in animals (dogs and rabbits), but the biological efficacy of the composition in this case was extremely poor. The delay in absorption was undetectable and most of the administered drug was excreted in the faeces prior to absorption, with no increase or prolongation of blood levels. It is believed that the failure in animal administration is due to differences in the gastrointestinal tract of the animals, in particular the sites of absorption and length of the intestine.

Therefore, it can be stated that the composition of the invention is for human use only. The details of the animal experiments due to their failure are not included here.

The composition according to the invention may be in the form of powders, granules, granules, microcapsules, preferably in unit dosage form, for example capsules, tablets or granules in blister strips.

In a unit dose formulation, cefalexin is present in an amount of 50 to 2000 mg, preferably 500 to 1000 mg, in the range of 3.13 pg / ml to 6.25 Mg / ml in adults.

Advantages of the composition according to the invention are as follows:

A) The resistance of many bacterial strains to cephalexin is similar in time to the strains used in the practice of the invention, i.e., Staphylococcus aureus 209P and 9 other strains and 6 strains of Escheria coli. Thus, the composition of the invention is effective against a number of infectious diseases that could not be treated with conventional cephalexin formulations. Thus, the present invention opens a new pathway for the clinical use of cefalexin without changing the mode of treatment and ordering.

B) On the other hand, the composition of the invention shortens the treatment time and the required amount of cefalexin, but the antibacterial property is maintained and the adverse side effects of conventional cephalexin preparations can be reduced.

C) In addition, it is sufficient to take the drug twice daily at 12 hour intervals without reducing the effect, so that the patient does not have to interrupt sleep, which is required for conventional cephalexin preparations at 4, 6 hour intervals.

D) Other side effects, such as indigestion due to cefalexin passage through the stomach, cio.

The following example illustrates the preparation of the present invention.

Example

To make a conventional cefalexin granulate (component (a)), a mixture of 117 g of cefalexin, 270 g of milk sugar and 97 g of corncake was kneaded with 500 g of 8% starch paste and granulated on a roller granulator for 60 hours. Dried at 0 ° C. The dry granules are ground and sieved in a Fritzpatrick mill. 0.7-1 mm granules: obtained.

For the preparation of enteric coated granules (component b (b)), from a standard cephalexin granulate prepared as described above, 1000 g of a methacrylic acid methyl ester and methacrylic acid copolymerate (acid number 300-330 mg / potassium hydroxide) are known in the known manner. dry weight; soluble in the pH range of 5.5-6.5) and coated with 52 g of talc in a solution of ethanol in 1000 g. Spraying was performed using a 1.2 mm diameter nozzle at 5 g / sec and 2 bar pressure. Spraying is repeated several times for 20 seconds and the granulate is dried for 25 seconds at 70 ° C with 8 m ³ / min hot air. Uniformly coated granules are obtained.

The antibiotic efficacy of the coated granules and the conventional cephalexin formulation is determined to adjust the exact mixing ratio. 150 mg (based on efficacy) of conventional cefalexing granules and 350 mg (based on efficacy) of enteric coated cefalexin granules, which are effectively 205 and 609 mg respectively, are mixed and blister packed. 125 to 125 mg of the mixture by weight may also be filled into hard gelatine capsules.

Claims (3)

Patent claims CLAIMS 1. A process for the preparation of a partially delayed oral pharmaceutical formulation containing 7- (D-2-amino-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate as an active ingredient, characterized in that it is pelletized in the stomach. soluble 7- (D-2-amino-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate - component (a) - and a soluble methacrylic acid polymerizate at pH 5.5, preferably methyl methacrylate and 7- (D-2-amino-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate coated with a 30: 70 to 70: 30 molar copolymer of methacrylic acid monomers - component (b): 15: 85-60: 40 by weight, which corresponds to 15-60% by weight of the total active ingredient in the first component, 40-85 lbs in the second component, optionally in combination with conventional carrier, excipient / vaginal additives and solid pharmaceutical compositions. preparation of lakítunk. The process of claim 1, wherein the mixture of component (a) and (b) is compressed into a tablet. 184 196 The 7- (D-2-amino-2-phenylacetamido) coated copolymer of the process of claim 1, wherein the component (b) is methyl-3-methyl-3-cephem-4-carboxylic acid. monocyanate, methacrylate and methacrylic acid monomers 50:50 molar