IE45415B1 - Long acting preparation of cefalexin - 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

This invention relates to a long acting preparation of cefalexin.

Cefalexin [7 - (D - 2 - amino - 2 - phenylacetamido)- [ - methyl - 3 *· eephem - 4 - carboxylic acid monohydrate] has been used widely because it is one of a few oral cephalosporins ever marketed. It is effective against many infections, and is rapidly and mostly absorbed through the digestive organs, the major portion of the drug being excreted in the urine without being subjected to any biotransformation in the body. Unfortunately, the rapid decrease in its blood level 1 or 2 hours after its administration usually requires a patient to take the drug more than four times a day for efficient therapy.

This problem is solved by the present invention by formulating a long acting preparation of cefalexin comprising a mixture of a normal cefalexin and a coated cefalexin which is effective, safe, and convenient for a patient, thus enabling twice daily administration of the drug, i.e. after 12 hour intervals, and effectively avoiding interruption of patient's sleep.- In other words, it has now been found that the necessary blood level of cefalexin can be retained in man for the required period by the administration of normal and slowly releasing cefalexin preparations substantially simultaneously.

.. The preparation of the present invention accordingly comprises a mixture of a cefalexin preparation coated with a coatbase material the solubility of whioh is pH-dependent and which dissolves in the upper intestine and a normal cefalexin preparation.

Preferred preparations of this invention comprise the following constituents: (1) from 60 to 15% (preferably 30%) in potency ratio of a cefalexin preparation? (2) fro;’. 40 to 85% (preferably 70%) in potency ratio of a cefalexin preparation which is coated with a pH-dependent coating material having a dissolution pH of from 5.5 to 6,5 (preferably about 6.0); and, if required, (3) one or more pharmaceutically or veterinarily acceptable carriers or additives in addition to cefalexin preparations (1) and (2).

Each cefalexin preparation (1) and (2) may be in the form of granules or powder. The coated preparation is preferably in particle form and, when administered orally, exists in the coated form in the stomach.

The preparations of this invention can be in unit dosage form, e.g as capsules or tablets containing the two cefalexin preparations in the amounts specified in (1) and (2) above.

Unit dosage form is defined herein as a single prescription dose or a fraction thereof.

The coated cefalexin preparation in the form of beads may be compressed into a tablet with a suitable binding agent. In such cases, portions of the coating layer of the beads may be broken to expose core cefalexin and, when disintegrated in the gastric juice, a portion (about 25—40% of the total tablet) of the cefalexin diffuses out, the - 4 retained portion of the beads passing gradually to the intestine.

Normal cefalexin specified above and referred to throughout this specification means any quick releasing cefalexin preparation conventionally used clinically.

Usually, such a cefalexin preparation is in the form of crystals, powdered crystals, granules, or beads of cefalexin, or if required, mixture with a pharmaceutical or veterinary carrier, additive, or like excipient. The preparation may be coated with a layer which is soluble in gastric juice.

In the following description reference will be made to the accompanying drawings . in which:Each of Figures 1 and 2 is a graph representing the bactericidal action of cefalexin in vitro in terms of its dependence upon exposure time; the hatched traversing bars in Figure 2 indicate exposure levels of cefalexin and their duration; Figure 3 is a graph representing blood levels of cefalexin in man vs. time after oral administration of a normal preparation; Figure 4A is a graph indicating percentages dissolved for one hour of granules coated with enteric layers of various dissolution pHs; Figure 4B is a graph indicating the temporal transition 25 of urinary excretion rates of the same granules; Figure 5 is a graph similar to Figure 3, wherein enteric-coated cefalexin preparations are administered; Figure S is a graph wherein the plots are derived from Figures 3 and 5 indicating blood levels corresponding to 1 mg in potency of cefalexin, and two curves are delineated by - 5 model equations devised by mathematical simulation; Each of Figures 7A, 7B and 7C'Ts a graph derivedfrom the information contained in figure 6, indicating the duration of the standard inhibitory conditions: Figure 8 contains curves A and B, the former indicating the duration of the effective blood levels and the latter indicating the time lag required for attaining the effective blood levels obtained by combined dosage forms in various mixing ratios in full range; Figure 9 is a graph indicating the temporal transitions of blood levels after administration of the combined preparations at a preferred mixing ratio as compared with those after administrations of the normal preparations but with additional administrations; and Figure 10 is a graph indicating the temporal transitions in the number of viable cells of bacteria in the urine of patients suffering from asymptomatic bacteriuria who were administered three types of oefalexin preparations. 1. Time-Dependency of Bactericidal Action in Vitro In contrast to the presently prevailing belief that the bactericidal action of an antibiotic agent is proportional to its concentration or at least the concentration integrated by its exposure time, the present inventors have confirmed the undermentioned facts peculiar to cefalexin as a result of a series of bacterial growth inhibitory experiments, typioal of the results of which are those summarized in Figures 1 and 2.

Facts a) Exposure to cefalexin over a period of more than 3 hours is necessary for decreasing the number of viable cells 48415 - 6 of Staphylococcus aureus 2O9P (ATCC 6538P), Minimum Inhibitory Concentration (MIC) of cefalexin against this strain is 3.13 hg/ml, according to the standard method recommended by Japan Society of Chemotherapy. b) Exposure of the bacteria to 3.13 u,g/ml of cefalexin for up to 3 hours is much less effective than that for 4 hours or more. Critical exposure time has therefore been found to be befc-aen 4 and 6 hours (Figure 1). c) Similar observations were experienced in an experiment with a cefalexin concentration of 12.5 |ig/ml (4 x MIC). d) Concurrently performed experiments indicated similar results with 9 other strains which belong to S. aureus including Staphylococcus aureus No. 120160 (a clinical isolate) and with 6 strains which belong to Escherichia coli. These results are, however, considered to be ancillary and are therefore omitted from the present description for brevity. e) In a short exposure period (up to 6 hours), the decrease in the number of viable cells did not show the expected clear response to the concentration of cefalexin. f) The (intermittent) exposure of the bacteria to 12.5 jig/ml of cefalexin, each exposure being for 2 hours, i.e., from 0 to 2 hours and from 6 to 8 hours, resulted in no remarkable decrease in the number of viable cells, while a continuous exposure for 6 hours to a 3.13 μg/ml cefalexin concentration reduced the number of viable cells significantly down to 1% or lass (Figure 2). g) Thus, it is concluded that the bactericidal action of cefalexin depends on exposure time rather than the blood - 7 level of the drug, provided that the required MIC is maintained during the exposure.

Experiment 1 (Figure 1) Method 1. Staphylococcus aureus 209 P (ATCC 6538P) in the logarithmic growth period was inoculated into AMB3 (Difco, registered Trade Mark broth at an inoculum size of 10 cells/ ml. 2. Cefalexin was added to the broth at the concentra1O tion of 3.13 μg/ml, and allowed to stand for a predetermined exposure time [O hour i.e., control (Line 0), 2 hours (Line D), 3 hours (C), 4 hours (B) or 6 hours (A)]. 3. The broth was centrifuged to collect bacteria, which was washed to remove cefalexin, inoculated again in the said medium and cultured for a given time. 4) The broth medium containing the viable cells was diluted, and a part of the bacterial suspension was spread over a nutrient agar plate. After 24 hours propagation, the number of colonies was counted and plotted in terms of the number of viable cells in the original broth medium.

Results 1) Cefalexin killed a definite number of the bacteria, but after removing the drug, the surviving bacteria began to increase. 2) Minimum number of viable cells and increasing rate of viable cells (recovery) varied depending on exposure time (2 hour exposure showed no minimum, while 6 hours exposure showed minimum of less than 1%). 3) Remarkable difference was observed between the 4 hour exposure and that of the 6 hour. - 8 Experiment 2 (Figure 2) The same test microorganism was employed and a generally similar procedure was followed in this experiment as described in Experiment 1, except for: 1) Cefalexin was added to the broth at the concentration of i) 0 qg/ml (Line 0, Control) ii) 3.13 μο/ΰΐΐ (Line A) for 6 hours continuously. iii) 12.5 lig/ml (Line B) intermittently for 2x2 hours, i.e., 0 to 2 hours and 6 to 8 hours.

(Exposures are indicated by hatched traversing bars in the Figure ).

Results 1) Even at a high exposure concentration of 12.5 p,g/ml, discrete exposures for 2 hours with a 4 hour interval i.e , from 0 to 2 and from 6 to 8 hours, were almost ineffective in decreasing the number of viable cells. 2) Continuous exposure for 6 hours at a concentration of 3.13 p.g/ml effectively reduced the number of viable cells to a minimum at the 8 hour time. 3) The bactericidal action cf cefalexin depended on the exposure time rather than on the concentration under the experimental conditions employed. 2. Blood Level of Cefalexin in Man 25 An excessively high peak in the blood level, observable only after administrating a very high dose, may possibly cause unfavourable side effects which are negligible at a low concentration.

In order to avoid unfavourable side effects, it is 30 preferred to keep the blood level at the minimum necessary 115 - 9 value for the required period to give an effective and safe treatment of any particular infection with cefalexin. For the purpose of confirming the reported blood level-time relationships of normal cefalexin, the following experiment was performed. (See, for instance: K. Seiga, Chemotherapy (Japan), 18(6);899, 1970; H. Nishimura, Saishin igaku, 24(9); 1983, 1969; R.S. Griffith et al., Clin, Med. 75; 14, 1968; P. Brawn, Applied Microbiology, 16(11); 1684, 1968; and T. s. Thornhill, Applied Microbiology, 17(3); 457, 1969. Experiment 3 (Figure 3) 1) Normal cefalexin granules comprising 200 mg (Line C of the Figure), 300 mg (Line B) or 400 mg (Line A) of active ingredient were given orally to 6 apparently healthy volunteers immediately after a meal. 2) The blood level of cefalexin was measured by assaying the antibacterial potency of a blood sample according to a conventional method. 3) Mean blood levels calculated from the data obtained from each of the 6 men were plotted against time (every hour) from 0 to 6 hours, after the administration.

Results 1) The blood level rose rapidly to reach a maximum after about 1 to 2 hours. 2) After 3—4 hours, the level fell by 1/2, and after —6 hours, by 1/10 of the peak value. 3) Peak values were about 4 [ig/ml for a 200 mg dose, about 6 ug/ml for a 300 mg dose and about 7 μ-g/ml for a 400 mg dose, respectively.

From the above results, it is presumed that even with an exceptional high dosage of 1000 mg or more, the «ί * ** - 10 required standard inhibitory conditions of 3.13 ug/ml for more than 6 hours, would never be attainable by single administration of a normal cefalexin preparation.

The MIC given here (3.13 pg/ml) is the value of almost all clinically isolated strains belonging to Staphylococcus aureus, Streptococcus haemolyticus and Streptococcus pneumoniae.

Therefore, it is confirmed that this means of extending the duration of the MIC is not realistic and an alternative method for the purpose is needed. 3. Attempt to make Cefalexin Long Acting As a result of careful scrutinizetion of the previously described views and discoveries, the necessity for a long acting preparation of cefalexin can be deduced. With such a preparation, safe and effective clinical treatment of an infectious disease would be possible.

Although chemical (structural modification) or physiological (e.g. controlling excretion by concurrent use of probenecid) retardation of the action of the drug has been contemplated, it has never succeeded in the clinical field. Pharmacokinetic methods of retarding absorption are investigated herein.

A) Time-Dependent Coating of Cefalexin In an attempt to develop a prolonged releasing or slowly absorbable preparation, 4 kinds of cefalexin granules were coated with ethyl cellulose so as to show 5050 dissolution times of 0.5, 1.5, 2.5, and 3,5 hours, respectively, when determined by the use of an apparatus as described in U.S. Pharmacopeia XIX (pH 2.2 and 7.0; 100 r.p.m.).

The coated granules were given to healthy volunteers •*5413 - 11 and the urine excretion rates were measured. From the thusobtained data, the following facts were found: a) Time dependency of the dissolution rates was observed with each of the groups of granules tested in either of the solutions (i.e. the solutions of different pH). Only slight differences in the rates were found as a result of differing pH value. b) With the increase in difficulty of diffusion of the core drug through the coating layer the dissolution rate decreased. c) Only slight differences were observed in the times when the peaks appear in the urinary excretion rates, but significant differences were observed in urinary excretion itself (attributable to the differences in the abovementioned difficulties of the respective granules). d) Total amounts of urinary excretion decreased with the increase in the above-mentioned difficulty of the coated layers. In other words, the more the dissolution rates were delayed in this manner, the more the total amount of urinary excretion decreased.

Details of these results are however omitted from the description for the sake of brevity.

In addition, it is already known that cefalexin is absorbed mainly through the limited upper portion of the small intestines (duodenum and jejunum: J. S. Wells et. al., Antimicrobial Agent and Chemotherapy, 489, 1968, and the present inventors' confirmation in the course of this work).

Thus, very poor bioavailability of this type of preparation is suggested if the thickness of the coated layer is sufficient to retard absorption and excretion.

Thus, it is confirmed that a-long acting preparation cannot be realized by means of merely delaying the disintegration rate with coating layers having pH-independency. In other words, preparations with time-dependent coating do not contribute to the effective treatment of infectious diseases. The portion of the drug remaining in the core granules which dissolve after the passage of the granules through the upper intestine is probably wasted in the faeces.

S) PH-Dspendent Coatings On the basis or an experience of two of the present inventors (H. Maekawa et. al., Yakuzaigaku, 30 [2] 94—101 and 102—llo (1970) reports that enteric coated granules, when administered immediately after a meal, travel continuously and gradually from the stomach to the upper intestine for several hours after administration, and the granules placed there disintegrate rapidly, another pharmacokinetic measure for making cefalexin long acting is envisaged. In the following series of experiments, the coating of cefalexin granules with materials having pH dependent solubility was investigated and evaluated.

Experiment 4 (Figures 4A and 4B) As coating base materials which dissolve in an alkaline medium, i.e., in the intestine, hydroxypropylmethyl-cellulose phthalate (HPI4CP), Eudragit I> and Eudragit S (Trade names of coating materials comprising copolymers of methylmethacrylate and methacrylic acid) were picked to be tested.

The enteric coatings are characterized by their dissolution pH. This term, as used herein, is defined as the pH value at which, or higher than which, the coating dissolves rapidly to disintegrate the coated preparation (Figure 4A). 3 413 - 13 The three kinds of enteric granules having dissolution pH's of about 5.0, 6.0 and 7.0, designated by E, F and G,were prepared by coating normal granules with HPMCP, Eudragit L and S, as base coating materials, respectively.

The dissolution rates in various buffer solutions of varying pH and the temporal transition in the human urinary excretion rates of these three are measured in a manner substantially as previously described to obtain the results in Figures 4A and 4B (summarized below).

Results (Figure 4B) a) Granules F having a dissolution pH around 6 show an urinary excretion rate-time curve having a peak value at approximately five hours after administration. b) A high recovery (average 83% of the given dose) of the drug from urine was observed, suggesting efficient absorption and excretion. c) Granules G (dissolution pH around 7) have a peak at 9 hours after administration but with a remarkable decrease in the total amount of urinary excretion. d) The curve for Granules E (dissolution pH around 5) rises comparatively rapidly and falls quickly. e) Neither Granules G nor Granules E were found to be suited for a long acting preparation of cefalexin. f) In these two cases, the thickness of the coating layers had less influence on the velocity of disintegration than the time-dependent properties of the coating material.

These results suggest that the optimum dissolution pH is between 5.5 and 6.5, more preferably around 6, in order to keep the blood level at a sufficiently high value for the required period of time and to reserve the relatively high 4S41S bio-availability of the cefalexin.

C) Actual Blood Level of Cefalexin obtainable with this Preparation In order to confirm the actual blood level obtainable by administering this preferred dosage form, a series of experiments were performed to obtain the results summarized in Figure 5, which were compared with those of Experiment 3 and the curves in Figure 3.

Experiment 5 (Figure 5) 1) Enteric-coated granules containing 300 mg (curve C), 600 mg (Curve B) or 900 mg (Curve A) of cefalexin having a dissolution pH of 6.0 were given orally to 6 apparently healthy volunteers immediately after a meal in a cross-over way. 2) Measurement of the blood level and delineation of the mean blood level vs. time curve were made in accordance with the methods described in Experiment 3.

Results a) The peak appeared at 6 hours after administration b) A blood level exceeding half of the peak value extended over 6 hours (Curve B). c) The time lag (rise-up time) required to reach half of the peak value was about 3 hours (Curve B). d) The above properties are applicable to the two other dosages (300 mg and 900 mg).

D) Time Lag for reaching the required Blood Level (Rise-Up Time) and its Reduction The above-described enteric-coated cefalexin shows a peak of blood level after five to si:: hours from administra30 tion, the time spent for reaching the required blood level <»3415 being too long (e.g., 3 hours) to expect an effective clinical response since the patient who required an antibacterial agent is suffering from an infectious disease and an urgent action of the agent is imperative, this long time lag might sometimes be a lethal disadvantage.

In order to overcome this disadvantage of the entericcoated preparation by reducing the time lag, concurrent use of a quickly absorbable dosage form with this preparation may be contemplated. Physicians are not, however, always aware of the proper use of these two types of dosage forms, particularly, of the appropriate ratio to be prescribed to attain the required blood level and to maintain the level for the required period. In view of this, a combined dosage form of an enteric-coated preparation with a normal preparation in a preferred ratio, pre-mixed by a pharmaceutical manufacturer, may be considered to be the most preferred and practical preparation.

E) Determination of Optimum range of the Mixing Ratio The results of Experiments 3 and 5, illustrated in Figures 3 and 5, indicate the proportional relationships between the blood levels at various times during the measurements varying the amounts of the administered drug.

In order to provide a basis for designing a useful preparation, the information contained in Figures 3 and 5 was analyzed to illustrate mean values of cefalexin in blood which correspond to each one milligram of the drug in potency of both types of granules as shown in the respective plots in Figure 6.

Curves A and B are presented in Figure 6 as if they were real representations of the blood levels corresponding 415 - IS to the normal and enteric preparations respectively. The curves are, however, delineated according to model equations devised by mathematical simulation so that both of the curves are in substantial conformity with curves enveloping the respective plots.

From the information contained in figure 6, the temporal transitions in blood level of cefalexin in men who took three typical mixed dosage forms containing 500 mg of cefalexin in varied ratios of normal/enteric cefalexin i.e.. A: normal/enteric = 70/30, B: normal/enteric = 50/50 and C: normal/enteric = 30/70, were also calculated and delineated as shown in Figures 7A, 7B and 7C, respectively.

The duration of the standard inhibitory conditions for preparations containing both ingredients in potency to potency ratios which extend to full range (i.e., from all of one ingredient to all of the other 0—100% vs. 100—0% with 10% increments), were calculated to delineate a curve A shown in Figure 8 from a composite curve derived from Figure 6 in order to confirm the fact that this duration starts to be prolonged with a preparation containing at least 40% of the enteric ingredient and this prolongation becomes remarkable for one containing at least 50% of the enteric ingredient.

The time lags (rise-up times) for reaching the effective blood level for preparations of various ingredient ratios, also extending to full range (i.e. as before 0—100% vs. 100—0% with 10% increments), were also calculated to present a curve B shown in Figure 8 obtained by connecting plots.

From the information contained in Figure 8 (Curve B) £3413 ... - 17 - · confirmed that the rise-up time obtained with a preparation containing at.least 15% of normal quick-releasing ingredient significantly differs from that obtained with a 100% enteric preparation. Furthermore, this advantageous feature is remarkably improved with a preparation containing at least 20% of the normal ingredient. The ingredient may be increased up to 60% with respect to the continual attainment of a short time lag.

As a consequence of a realistic compromise between the just-mentioned time lag aspect and effective prolongation of the duration, it is found that the content of the conventional quick releasing ingredient in the combined preparation desirably must be from 15 to 60%, preferably from 20—50%, and more preferably from 25—40%,and that of the enteric ingredient desirably must be from 40 to 85%, preferably from 50—80%, and more preferably from 60—75% in potency ratio.

F) Confirmation of the Blood Level in Vivo As can be seen from the curve shown in Figure 7C, the duration of the MIC over 6 hours, obtained with the combined preparation of normal/enteric = 30/70, seems to be the most realistic from the both aspects, and this has been confirmed by a clinical investigation on the human subject, the results being illustrated in Figure 9.

When a unit dosage form of 500 mg or 1000 mg of granules having the above-mentioned normal/enteric ingredient ratio was given orally to apparently healthy volunteers immediately after a meal, the desired blood level (3.13 |ig/ml, curve B or 6.25 |ig/ml, curve A; average of 8 men) was maintained over a period of 6 hours continuously, from about 1.5 to about 7.5 hours after administration. <1 ΰ S1 5 - 18 In contrast to the above results, with a prescription involving administrations at intervals of six hours of a conventional preparation containing 250 mg or 500 mg of cefalexin, the same blood levels were attained and kept only intermittently from 2 to 4 hours and from 8 to 10 hours after the first administration as shown by Curves C and D in Figure 9. Even with the additional administration 5 hours after the first one, continuous duration of the desired blood level cannot be attained.

From the information contained in Figure 9 in view of that in Figure 1 and 2, it could be deduced that the cefalexin preparation of the present invention is more effective than a conventional cefalexin preparation when the same total dosage is given. g) Clinical Response in terms of Viable Cells in Urine A comparative clinical investigation was carried out on the bactericidal activity (effective inhibiting ability) of the combined preparation having the preferred mixing ratio mentioned under F above, giving the results summarized in Figure 10.

The combined preparation (500 mg. Curve A) and two normal preparations (250 mg, Curve B and 500 mg, Curve C) were administered immediately after a meal to 9 patients, patients and 5 patients, respectively, who had been suffering from asymptomatic bacteriuria caused by at least one of the various strains which belong to the genera Escherchia, Pseudomonas, Streptomyces, Klebsiella, Retigeralla and Enterobacter. The number of viable cells of bacteria excreted in their urine at predetermined intervals after the oral administration (indicated in figure 10 by a thick arrow vzith the letter P.0.) were counted by a 415 - 19 conventional assaying method to produce the curves in Figure 10 which are mean values obtained from the patients.

It will be noted that virtually complete suppression of viable cells was achieved with the combined preparation even as long as 22 hours after the oral administration. In contrast, the normal preparations failed to attain sufficient suppression.

A series of ancillary experiments conducted to investigate if there was any improved clinical response of the preparation of this invention with respect to animals (dogs and rabbits) disclosed very poor bioavailability of this preparation. There was retarded absorption and a major portion of the administered drug was excreted into the faeces before being absorbed; there was no rise in blood level and no extension in duration of the blood level.

It was presumed that this failure with respect to the preparation's usage in animals was mainly due'to differences between the structures of the digestive organs of these animals and those of humans, particularly attributable to the short lengths of the absorption sites for the drug in the animals examined.

Therefore, it can be concluded that the preparation described is suited for human use only. The details of the animal experiments are omitted from the present description for the sake of brevity.

The preparations of this invention can be in various forms, e.g. powder, beads, granules or microcapsules. The preparations are preferably in unit dosage form, for example, capsules, tablets or granules packed in strippackages. The present unit dosage preparations usually 4-3415 - 20 contain from 50 mg to 2000 mg of cefalexin in potency, preferably between 500 mg to 1000 mg when the desired blood level is 3.13 μg/ml or 6.25 μg/ml for adult use.

The ratio in potency of norma1/enteric ingredients 5 may be from 15:85 to 60:40, preferably between 50:50 and 20:80, more preferably between 40:60 and 25:75, and most preferably 30:70.

The enteric ingredient of the present preparation is coated with material which dissolves to disintegrate the core granules in the upper intestine, i.e. which is soluble in a high pH region. Its dissolution pH is preferably between 5.5 and 6.5, more preferably about 6.0.

A preferred example of the coating base material is a copolymer or methylmethacrylate and methacrylic acid (Eudragit L) which belongs to the group of pH-dependent coatings.

According to this invention, the preparations can be a mixture of normal and enteric dosage forms. Such mixed preparations in unit dosage form are apparently more convenient for a patient than the two dosage forms in separate form, e.g. packed in separate containers, to be mixed before use.

Doctors and druggists can, however, make more accurate prescriptions for specific patients e.g., for children, if they use the two separate dosage forms in separate containers.

Most of the patients suffering from infections caused by almost any bacteria sensitive to cefalexin satisfactorily respond to an effective amount of the present mixed prepara30 tion with the dosage ratio specified above. - 21 The mixed preparations of the present invention can be administered to a patient suffering from bacterial infections caused by sensitive bacteria at 12 hour intervals, each dosage preferably being given immediately after a meal.

The following Examples are given to further illustrate this invention without restricting the scope thereof.

Only Examples D and E are Examples of the invention as such.

Example A Normal cefalexin granules: A mixture of cefalexin (1117g), lactose (270 g), and corn starch (97 g) is Kneaded well with an 8% starch paste (500 g), and the mixture is granulated by a cylindrical granulator, followed by drying at 60°C for 1 hour.

The dried granules are crushed by a Fritzpatrick mill and sieved to give uniform granules of 16 mesh to 24 mesh.

Example B Enteric coated granules: Normal cefalexin granules obtained in Example A (1000 g), placed in a coating pan (40 cm diameter), are coated by a conventional method by spraying an alcoholic solution of Eudragit L (containing 52 g of Eudragit L and 52 g of tale in 1OOO g of ethanol: total 3500 g) to give uniformly coated granules.

Example C Assay of antibacterial potency: The potency of the coated granules and the potency of the normal cefalexin are measured to determine an accurate mixing ratio. ί» «J β - 22 Example D Unit-dosage form in strip-package: The normal cefalexin granules (150 mg in potency) and enteric coated cefalexin granules (350 mg in potency), described in Examples A and B, 205 and 650 mg, respectively in actual amounts, are mixed and filled in a pouch by a conventional strip-packaging machine. This preparation is used to confirm the advantages of this invention.

Example E Unit-dosage form in hard gelatine capsules: The mixture of granules containing respective ingredients in the stated potency ratio as in Example D is filled into hard gelatine capsules (125 mg in total potency). Advantages of this Invention A) Many strains of bacteria have a similar timedependency of response against cefalexin as compared to the bacteria used in this investigation i.e.. Staphylococcus aureus strain 209P, and 9 other strains, and 6 strains of Escheria coli. Thus, the preparation and method of this invention are expected to be clinically effective against other infections which are only insufficiently treated with normal cefalexin preparations. The invention thus opens a new field of clinical use of cefalexin without creating problems in prescription and administration.

B) This invention reduces the therapeutic period and, therefore, the necessary amount of cefalexin, whilst retaining the same bactericidal effect and minimizing the possible dangers of side effects of conventional cefalexin prepara tions.

C) The invention enables twice daily administration of the drug at 12 hour intervals without reducing the effect. 5415 - 23 Thus, a patient's sleep need not be interrupted while the use of conventional cefalexin prescribed 4 times daily, i.e. administration at 6 hour intervals, does involve sleep interruption.

D) Some side effects, for example stomach disorder caused by the passage of cefalexin through the stomach, can be reduced by this invention.

Claims (18)

1. CIAXMS:1. A long acting pharmaceutical cefalexin preparation comprising a mixture of a normal cefalexin preparation which dissolves rapidly in the stomach and a coated cefalexin 5 preparation which does not dissolve in the stomach but which dissolves rapidly in the upper intestine.

2. A preparation as claimed in claim 1, wherein the coated preparation is in coated particle form and, when administered crfj Xv, exists in the coated form in the 10 stomach.

3. A preparation as claimed in claim 1 or claim 2, wherein the potency ratio of the normal preparation to the coated preparation is from 15:85 to 50:40.

4. A preparation as claimed in claim 3, wherein the 15 potency ratio is from 40:50 to 25:75.

5. A preparation as claimed in claim 4 wherein the potency ratio is approximately 30:70.

6. A preparation as claimed in any one of claims 1 to 5, wherein the coating base material of the coated prepara20 tion has a dissolution pH of from 5.5 to 6.5.

7. A preparation as claimed in claim 6, wherein the dissolution pH is approximately 6.0.

8. A preparation as claimed in any one of claims 1 to 7, wherein the coating base material of .the coated 25 preparation is a copolymer of methylmethacrylate and methacrylic acid (Eudragit L).

9. A preparation as claimed in any one of claims 1 to 8, wherein the normal and/or the coated preparation is a powder, beads, granules or microcapsules.

10. A preparation as claimed in any one of claims ASdlo - 25 1 to 9, and in unit dosage form.

11. A preparation as claimed in claim 10, wherein the unit dosage form is finished as capsules.

12. A preparation as claimed in claim 10, wherein 5 the unit dosage form is finished as tablets.

13. A preparation as claimed in claim 10, wherein the unit dosage form is finished as beads, granules or miorocapsules contained in strip-package(s).

14. A preparation as claimed in any one of claims 10 10 to 13, wherein the unit dosage contains from 50 to 2000 mg of cefalexin in potency.

15. A preparation as claimed in claim 14, wherein the unit dosage contains from 500 to 1000 mg of cefalexin in potency. 15

16. A long acting pharmaceutical cefalexin preparation as claimed in claim 1 substantially as hereinbefore described.

17. A long acting pharmaceutical cefalexin preparation substantially as hereinbefore described in Example D or

18. 20 Example E. F. R. KELLY & CO.,