LU86781A1 - INJECTABLE PHARMACEUTICAL COMPOSITION BASED ON AMOXICILLIN - Google Patents

Description

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The present invention relates to a new injectable preparation based on amoxicillin.

Amoxicillin is an antibiotic of the beta-lactam family, the therapeutic benefit of which has been known for a long time.

Pharmaceutical compositions based on amoxicillin for oral administration can be easily prepared in all the usual forms such as, for example, capsules, tablets or other compositions intended for oral absorption.

Unlike this, the injectable preparations of such compositions require the use of soluble amoxicillin derivatives and an appropriate solvent, which may be water. Also, the soluble salts of amoxicillin, such as in particular the sodium salt, have hitherto been used for the preparation of injections.

However, such solutions have limited stability and are therefore difficult to prepare industrially with satisfactory purity because the salts are degradable.

In addition, intramuscular injection of preparations in aqueous solution is painful and irritating to the tissue. It has therefore been found necessary to add an anesthetic to these solutions. However, the choice of a local anesthetic to be used to make the injection tolerable is very limited, in particular because of the incompatibility of the amoxicillin salts with certain types of anesthetics.

Thus, an injectable preparation based on amoxicillin containing benzyl alcohol is known as a local anesthetic. This preparation should be injected immediately after reconstitution.

\ 2 ’However, this product has a low titer and the overall content of decomposition products and impurities is high, and can reach 10%. In addition, several injections of antibiotics must be administered per day 5 to maintain the necessary serum concentrations.

In addition, benzyl alcohol, although effective against pain, nevertheless causes local irritation during intramuscular injection.

Because of the difficulties encountered with the 10 known injectable solutions, in particular based on sodium salt of amoxicillin, it was therefore necessary to consider an alternative formula.

The object of the present invention is to solve the abovementioned problems by providing a pharmaceutical composition which is easy to inject, which has good purity and stability over time and which effectively combats local pain during injection without causing irritation.

The solution proposed by the present invention to solve this problem consists of an injectable pharmaceutical composition based on amoxicillin, characterized in that it comprises amoxicillin trihydrate in suspension in a suitable vehicle or liquid medium.

It has indeed been surprisingly found that the local tolerance to the injection of an amoxicillin trihydrate suspension is better than that of an aqueous solution of amoxicillin sodium salt.

30 The parenteral administration of suspensions meets a priori unfavorable opinion and is generally reserved for products which cannot be dissolved in conventional vehicles, the objection relating to poor local tolerance to injection.

♦ 3 This is why until now, only soluble derivatives of amoxicillin have been used, and there was no reason for those skilled in the art to turn to amoxicillin derivatives, such as the trihydrate. , suspended 5 in a liquid medium.

According to a particular characteristic of the invention, the particle size of the amoxicillin trihydrate in the suspension is chosen so as to allow the injection of the composition. Advantageously, this size is between approximately 1 and 25 microns and is preferably of the order of 5 microns.

According to another particular characteristic, the concentration of amoxicillin trihydrate in the suspension is between approximately 100 mg activity / ml and 15,700 mg activity / ml and is preferably between 200 and 500 mg activity / ml.

According to yet another characteristic of the invention, the amoxicillin trihydrate is in micronized form in the solvent. Micronization is particularly advantageous because the conformation of the particles obtained is entirely compatible with the constraints of the injection.

The invention will be better illustrated on reading the explanatory description which follows, given with reference to the experiments and observations given below only by way of example.

Local cluster headache after subplantar injection in rats, local tolerance to intramuscular injection in rabbits and bioavailability in dogs of an aqueous suspension of micronized amoxicillin trihydrate, according to the invention, were studied in comparison with an aqueous solution of sodium salt of amoxicillin.

4

The vehicle chosen for the comparison is water, which is the simplest liquid medium, and also the least expensive. However, any other suitable conventional liquid medium can be used without departing from the scope of the invention.

Amoxicillin trihydrate was micronized by passage through a Christo Jet Mill device under strictly defined and reproducible conditions. This known technique is described for example by G. BOULLAY

10 (APGI conference Dec. 1984).

The particle size analysis of the powder obtained reveals the following particle size distribution: approximately 80¾ of the particles have a size less than 5 microns; About 10¾ of the particles have a size between 5 and 10 microns; about 10¾ of the particles have a size between 10 and 20 microns.

As mentioned previously, the micronization of amoxicillin trihydrate is advantageous because it overcomes most of the constraints of the injection of the suspension according to the invention. It is however understood that other techniques can be used, such as for example micro-grinding or prolonged grinding.

The integrity of the active principle, after this treatment, has been verified, in a conventional manner, by assaying and looking for impurities. The powder obtained was suspended in water by simple stirring. The suspension obtained is homogeneous and easily administered by a syringe.

Two separate suspensions were prepared, at respective concentrations of 200 mg activity / ml and 500 mg activity / ml, expressed in terms of amoxicillin in the form of anhydrous free acid.

5

Experiment 1: Pain at injection.

The injection pain was studied in female OFA rats according to the technique of E. CELOZZI, V.J. LOTTI, E.O. STAPLAY and A.K. MILLER described in J. of 5 Pharmaceutical Methods 1980, Volume 4, pages 285 to 289.

Batches of rats weighing 60 to 80 g received the following four preparations: - amoxicillin trihydrate / water for injection (500 mg activity / ml); 10 - amoxicilin trihydrate / water for injection (200 mg activity / ml); - sodium salt of amoxicillin / water for injection (500 mg activity / ml); - sodium salt of amoxicillin / benzyl alcohol at 3% (500 mg activity / ml).

Benzyl alcohol is used here as a local anesthetic.

0.1 ml of each of the above solutions and suspensions is injected into the subplantar tissue of the paw. The pain caused by the injection is evaluated by the rat paw licking reflex test. The number of lickings of the paw, consecutive to the injection, is counted by intervals of 3 minutes over a period of 15 minutes. We define the licking of the leg as follows: 25 licking followed by the diversion of the head or 5 seconds of uninterrupted licking. The results obtained are presented in Table 1.

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The results obtained show that the injection of the sodium salt of amoxicillin in aqueous solution is painful, in particular during the first three minutes. The pain then subsides. On the contrary, the injection of amoxicillin trihydrate suspended in water is painless whatever its concentration and the score obtained is quite comparable to that obtained with a local anesthetic.

Experiment 2: Tolerance for intramuscular injection

The purpose of these experiments is to study the muscle irritation caused at the injection site and the development over time of the lesions observed.

The test is carried out on 12 rabbits 15 adult New Zealanders (Froxfield Farms Hampshire).

These rabbits are divided into 3 lots of 4; the dorsolumbar region is shaved, and they each undergo 6 simultaneous intramuscular injections into the sacrospiral muscles with a volume of 0.5 ml, of the following compositions: - water for injection (E) - benzyl alcohol at 3% (B) - amoxicillin sodium / 3% benzyl alcohol (C + B) (concentration of 200 mg activity / ml) 25 - amoxicillin trihydrate / water (200 mg activity / ml) (A + E) - amoxicillin trihydrate / benzyl alcohol at 3% ( A + B) (200 mg activity / ml).

The three groups of rabbits are sacrificed 2.5 and 14 days respectively after the injections.

A macroscopic examination of the injection sites is then carried out. Lesions are measured and given a score according to their intensity defined as follows: 0: no change 35 1: very slight damage 8 2: moderate damage 3: marked damage.

The individual results of this gross examination are reported in Table 2.

5 The representative samples of each injection site are then taken, included in paraffin, cut to 5 micrometers, stained with hemalun-phloxine-saffron and are the subject of a usual histological examination, the results of which are given below. -after in comparative table 10 3.

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Table 3.

HISTOLOGICAL EXAMINATION - Results compared Degeneration Regeneration Infiltrate Fibrosis hemorrhage Total

Musk fibers. Musk, cellular fibers

Micronized amoxicillin + ppi water (for injection) (i) (ii) (iii) D + 2 4/4 (2-3) 0/4 4/4 (1-2) 0/4 0/4 D + 5 3/5 (2-4) 2/5 (1-2) 3/5 (2-3) 0/5 1/5 (1) J + 14 2 / 3_ (3) 2/3 (1-2) 2/3 (3) 2/3 (2-3) 0 / 3_

Total 9/12 4/12 9 / 12_2 / 12_1 / 12 25

Micronized amoxicillin + benzyl alcohol J + 2 3/4 (3-4) 0/4 3/4 (2) 0/4 3/4 (1) J + 5 4/5 (3-4) 3/5 (2 ) 4/5 (3) 0/5 0/5 D + 14 1/3 (3) 1/3 (2) 1/3 (3) 1/3 0/3

Total 8/12 4/12 8/12 1/12 3/12 24

Sodium salt + benzyl alcohol D + 2 3/4 (3-4) 0/4 3/4 (1-2) 0/4 2/4 (2-3) J + 5 5/5 (3-4) 5 / 5 (1-3) 5/5 (2-3) 0/5 2/5 (1-2) J + 14 3/3 (2-4) 3/3 (2) 3/3 (3-4 ) 1/3 (3) 0/3

Total 11/12 8/12 11/12 1/12 4/12 35

Benzyl alcohol J + 2 4/4 (3-4) 1/4 (1) 4/4 (2) 0/4 3/4 (1-3) J + 5 4/5 (3-4) 3/5 (1-3) 4/5 (2-3) 0/5 1/5 (2) D + 14 2/3 (3) 2/3 &) _ 2/3 (3) 2/3 (1-3 ) 0 / 3_

Total 10/12 6/12 10/12 2/12 4/12 32

Water ppi J + 2 2/4 (1-2) 0/4 2/4 (1-3) 0/4 1/4 (3) J + 5 1/5 (3) 1/5 (3) 1 / 5 (3) 0/5 1/5 (2) D + 14 1/3 (1) 1/3 (1) 0/3 0/3 0 / 3_

Total 4/12 2/12 3/12 0/12 2/12 11 (i) Number of rabbits with the lesion (ii) Number of rabbits examined (iii) Intensity of the lesion 11

Tables 2 and 3 were used to classify the preparations from the most irritant to the best tolerated. This classification is as follows: - sodium amoxicillin / 3% benzyl alcohol 5 - 3% benzyl alcohol - amoxicillin micronized trihydrate / water for injection and amoxicillin micronized trihydrate / benzyl alcohol - water for injectable preparation.

Table 3 shows in particular the poor results of benzyl alcohol used alone, or as a local anesthetic with a solution of amoxicillin sodium.

Experiment 3: Bioavailability The bioavailability of an aqueous suspension of micronized amoxicillin trihydrate was studied by means of the usual tests in comparison with an aqueous solution of sodium salt of amoxicillin.

The study was carried out in dogs using on the one hand sodium amoxicillin reconstituted with benzyl alcohol at 3% as solvent, and on the other hand the trihydrate form suspended in water for injection. .

5 Beagle dogs (3 males - 3 females) weighing between 10.8 kg and 14.5 kg received intramuscularly (at a dose of 50 mg / kg) the following two preparations: - sodium salt d amoxicillin / 3% benzyl alcohol 30 - amoxicillin trihydrate / water for injection.

Serum levels and urinary excretion were determined microbiologically by the disc method (Sarcina Lutea ATCC 9341 strain) 12

The blood samples were taken at the following times: 30 min, 1 hour, 1 hour 30 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 32 hours 48 hours after the injection.

Urine was collected from 0 to 6 a.m., from 6 to 5 a.m., from 12 to 24 a.m.

Table 4 gives, for each of the compositions studied, the values of the serum levels over time.

Table 5 gives for each composition studied the values of urinary excretion over time.

Table 6 gives for each composition studied the areas under the curve of evolution of serum levels over time.

These results show that the serum peaks are higher and earlier for the preparation of sodium amoxicillin in solution, while serum levels persist in the micronized composition. (see table 4).

A minimum inhibitory concentration threshold of 5 mcg / ml has been defined arbitrarily, but as a function of the usual inhibitory concentrations of amoxicillin.

Table 4 shows that the decrease in serum levels below the threshold of 5 mcg / ml is reached in 5 hours for the sodium salt of amoxicillin, and in 10 hours after administration for the micronized preparation.

The areas under the serum concentration curve (Table 5) are not statistically different for the two preparations.

30 Urinary elimination (Table 6) in 24 hours is not statistically different for the two preparations; during the six hours following the administration of antibiotics, it is significantly higher for the sodium salt, by 13 against between the sixth and the twenty-fourth hour it is significantly higher for the amoxicillin trihydrate.

However, the significant elimination of the antibiotic in the 12-24 hour interval observed for micronized trihydrate makes it possible to predict the persistence of urinary levels well beyond twenty-four hours.

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Areas under the curves mg / ml x h 5 __

Animal No. Administered products sodium salt trihydrate 10 _ 1,168.80 120.89 2,174.72 151.11 15 3 173.45 156.15 4 193.70 172.79 5 140.97 129.19 6 117.97 127.54

Average 161.60 194.94 20 __

The above results therefore suggest that the pharmaceutical composition according to the invention can also be administered to humans successfully.

In this regard, the pharmacological properties of such a suspension need not be described here, since they are those of amoxicillin trihydrate which is a compound whose effects have been known per se for a long time.

Claims (6)

1. Pharmaceutical composition for injection based on amoxicillin, characterized in that it comprises amoxicillin trihydrate in suspension in a suitable vehicle or liquid medium. 2. Pharmaceutical composition according to claim 1, characterized in that the particle size of the amoxicillin trihydrate in the suspension is chosen so as to allow the injection of said composition. 3. Composition according to claim 2, characterized in that the particle size of the amoxicillin trihydrate is between approximately 1 and 25 p and is preferably of the order of 5 d. 4. Pharmaceutical composition according to one of claims 1 to 3, characterized in that the concentration of amoxicillin trihydrate in suspension is between 100 mg activity / ml and 700 mg activity / ml, and preferably between 200 mg activity / ml and 500 mg activity / ml. 5. Pharmaceutical composition according to one of claims 1 to 4, characterized in that the amoxicillin trihydrate is in a micronized form in the abovementioned vehicle or liquid medium. 6. Pharmaceutical composition according to one of claims 1 to 5, characterized in that the aforementioned vehicle is water. »*«