GB2186797A - Injectable amoxicillin suspensions - Google Patents

Abstract

Amoxicillin trihydrate is formulated in a solvent for administration by injection. Water can be used as solvent.

Description

SPECIFICATION Pharmaceutical injectable amoxicillin preparation The present invention relates to a new injectable amoxicillin preparation.

Amoxicillin is an antibiotic of the betalactamine family, the therapeutic interest of which has long been known.

Pharmaceutical amoxicillin preparations for oral administration can be prepared easily in all the usual forms such as for example capsules, tablets or other drinkable forms.

On the contrary, the injectable forms of such preparations require the use of soluble amoxicillin derivatives and of an appropriate solvent, which may be water. For this reason, the soluble amoxicillin salts, such as particularly the sodium salt, have hitherto been used for obtaining injectable preparations.

However, such solutions have limited stability and are therefore difficult to prepare on a massproducion scale with a sufficient purity because the salts are degradable.

Moreover, intramuscular injections of the aqueous preparations are painful and irritant to the tissue. It has therefore been necessary to add an anaesthetic to such solutions. However, the choice of a local anaesthetic for rendering the injection bearable is very limited in view particu larly of the incompatibility of the amoxicillin salts with certain types of anaesthetics.

For example, there is known an injectable amoxicillin preparation containing benzyl alcohol as a local anaesthetic. This preparation must be injected immediately after reconstitution.

However, this product is low in titer and its total decomposition-products and impurities content is high and can reach 10%. Moreover, several antibiotic injections must be effected daily in order to maintain the necessary serum concentration.

Furthermore, benzyl alcohol, while effective as a pain reliever, gives rise to local irritations during the intramuscular injection.

In view of the difficulties encountered with the known injectable solutions, particularly the sodium amoxicillin solutions, the use of an alternative composition had to be contemplated.

The present invention has as its purpose to solve the aforementioned problems by providing a pharmaceutical preparation which can be injected easily, has a high purity and stability in time and is capable of efficiently relieving local pain during the injection without giving rise to irritation.

The solution proposed by the present invention to solve this problem consists of a pharmaceutical injectable amoxicillin preparation, characterized in that it includes amoxicillin trihydrate suspended in an appropriate solvent.

Indeed, it has surprisingly been found that the local tolerance to the injection of an amoxicillin trihydrate suspension is higher than that of a water solution of sodium amoxicillin.

This discovery runs counter to a double preconception. It is indeed widely considered that parenteral administration of a suspension must be avoided in view of the poor tolerance during the injection. Furthermore, parenteral administration is generally reserved for products which cannot be solubilized in usual solvents. Now, this is not at all the case with the amoxicillin derivatives. For this reason, use has hitherto been made of only the soluble derivatives of amoxicillin, and there was no reason for anybody conversant with the art to direct his efforts towards the amoxiciilin derivatives, such as amoxicillin trihydrate, suspended in a solvent, all the more so as the injection of such a suspension must a priori be avoided.

According to a particular feature of the invention, the size of the amoxicillin trihydrate particles in the suspension is so selected as to allow the injection of the preparation. Advantageously, this size ranges from about 1 to about 25 microns and is preferably of the order of 5 microns.

According to another specific feature, the amoxicillin trihydrate concentration in the suspension ranges from about 100 mg activity/ml to about 1000 mg activity/ml and preferably from 200 to 500 mg activity/ml.

According to still another feature of the invention, the amoxicillin trihydrate in the solvent is in micronized form. Micronization is particularly advantageous in view of the fact that the conformation of the particles obtained is fully compatible with the requirements of the injection method of administration.

The invention will be better understood as the following explanatory description proceeds with reference to the experiments and observations set forth hereafter by way of example only.

The local pain after subplantar injection in the rat, the local tolerance to intramuscular injection in the rabbit and the bioavailability in the dog of a water suspension of micronized amoxicillin trihydrate according to the invention were studied comparatively to a water solution of sodium amoxicillin.

Water was used for the comparative study because it is the most simple and also the less expensive solvent. However, any other appropriate usual solvent can be used without departing from the scope of the invention.

The amoxicillin trihydrate was micronized by passing on a Christo Jet Mili apparatus under strictly defined and reproductible conditions. This known technique is described for example by G. BOULLAY (APGI Symposium, Dec. 1984).

The powder obtained was subjected to a particle-size analysis which revealed the following granulometric composition: 80% of the particles were less than 5 microns in size; 10% of the particles were of a size ranging from 5 to 10 microns; 10% of the particles ranged from 10 to 20 microns.

As mentioned above, the micronization of the amoxicillin trihydrate is advantageous in that it allows meeting most of the requirements of the injection method of administration of the suspension of the invention. It is of course understood, however, that other techniques can be used, such as for example microgrinding or prolonged grinding.

The integrity of the active principle after this treatment was checked conventionally by quantitative analysis and impurity determination. The powder obtained was suspended in the water by mere agitation. The suspension obtained was homogeneous and easily delivered from a syringe.

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

Experiment 1: Pain during injection.

A study was carried out of pain during injection of OFA strain in female rats according to the E. CELOZZI, V. J. LOTTI, E. O. STAPLAY and A. K. MILLER technique described in J. of Pharmaceutical Methods 1980, volume 4, pages 285 to 289.

The weight of the rats ranged from 60 to 80g.

Use was made, for this experiment, of the following four preparations: -amoxicillin trihydrate/water for an injectable preparation (500 mg activity/ml); -amoxicillin trihydrate/water for an injectable preparation (200 mg activity/ml); sodium amoxicillin/water for an injectable preparation (500mg activity/ml); sodium amoxicillin/3% benzyl alcohol (500 mg activity/ml).

Benzyl alcohol is used here as a local anaesthetic.

0.1 ml of each of the aforementioned solutions and suspensions was injected into the paw subplantar tissue. The pain caused by the injection is evaluated by the rat paw licking reflex test The number of paw lickings, consecutive to the injection, is counted during time lengths of 3 minutes over a total period of 15 minutes. Paw licking is defined as follows: licking followed by turning away of the head, or 5 seconds of uninterrupted licking. The results obtained are set forth in Table 1.

Table 1.

Local pain after subplantar injection into the rat

Average number of lickings during time lengths of 3 minutes.

N 0-3 3-6 6-9 9-12 12-15 0-15 Amoxicillin Na 1 g + 2 ml distilled water 25 15.3 7.6 1.4 1.2 0.7 26.2 Amixicillin Na 1 g + 2 ml 3% benzyl alcohol 9 0 0.1 0 0 0 0.1 Micronized amoxicillin + 2 ml distilled water 10 0.2 0.1 0 0 0 0.3 Micronized amoxicillin + 5 ml distilled water 5 0.2 0.2 0 0 0 0.4 N = Number of animals.

As appears from the results obtained, the injection of sodium amoxicillin in water solution is painful especially during the three first minutes. Thereafter, the pain decreases. In contrast, the injection of trihydrate amoxicillin suspended in water is painless whatever its concentration and the score obtained is fully comparable with that obtained with a local anaesthetic/ Experiment 2: Tolerance to intramuscular injection.

The purpose of these experiments was to study the muscular irritation caused at the site of injection and the cause of the lesions in time.

The test was carried out on 12 adult New-Zealand rabbits (froxfield stock farms, Hampshire).

The rabbits were divided into three groups of four; the dorso-lombar region is shaved and they each are administered six simultaneous intramuscular injections, into the sacro-spiral muscles, of 0.5 ml of the following compositions: water for injectable preparation (E) 3% benzyl alcohol (B) sodium amoxicillin/3% benzyl alcohol (C+B) (concentration of 200 mg activity/ml) -trihydrate amoxicillin/water (200 mg activity/ml) (A+E) -trihydrate amoxicillin/3% benzyl alcohol (A+B) (200 mg activity/ml).

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

Thereafter, the injection sites were subjected to microscopic examination. The lesions were measured and were given a score according to their intensity as follows: 0: no modification 1: very slight affection 2: moderate affection 3: marked affection.

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

Samples representative of each injection site were thereafter taken, included in paraffin, cut to 5 micrometres, colored with hemalum-phloxin-saffron and subjected to a usual histological examination, the results of which are summarized in the following comparative Table 3.

Table 2

48 hours 5 days 14 days Lesion Lesion Lesion Lesion Lesion size Lesion size (mm) intensity size (mm) intensity (mm) intensity Composition Rabbit 1 Rabbit 5 Rabbit 9 Dead D + 4 A + E 3 x 3 1 15 x 10 3 10 x 5 1 A + B 20 x 5 1 12 x 5 3 0 0 C + B 0 0 10 x 5 3 6 x 5 2 B 20 x 10 3 10 x 5 1 0 0 E 8 x 4 1 15 x 8 2 15 x 10 1 Rabbit 2 Rabbit 6 Rabbit 10 A + E 8 x 8 1 3 x 2 1 17 x 8 2 A + B 12 x 7 2 not measurable 1 not measurable 1 C + B 20 x 15 2 18 x 15 2 6 x 3 1 B 20 x 15 3 12 x 5 2 10 x 5 2 E 0 0 8 x 5 2 10 x 5 1 Rabbit 3 Rabbit 7 Rabbit 11 A + E 10 x 5 1 0 0 0 0 A + B 25 x 5 2 10 x 4 1 0 0 C + B 20 x 12 3 12 x 6 2 22 x 4 2 B 15 x 3 1 15 x 4 2 18 x 2 1 E 1 x 1 1 0 0 0 0 Rabbit 4 Rabbit 9 Rabbit 12 Deed D+7 A + E 9 x 4 1 6 x 3 1 15 x 5 2 A + B 20 x 5 3 12 x 10 1 25 x 3 2 C + B 15 x 9 3 8 x 2 2 10 x 5 2 B + 13 x 4 2 15 x 13 2 15 x 5 2 E + 10 x 1 1 3 x 2 1 5 x 4 1 Table 3 HISTOLOGICAL EXAMINATION- Comparative results.

Muscle fiber Muscle fiber Cellular Fibrosis Bleeding Total degeneration regeneration infiltrate Micronited amoxicillin + water flo (fDr injectable preparation) J + 2 4/4 (2-3) 0/4 4/4 (1-2) 0/4 0/4 J + 5 3/5 t2-4 2/5 (1-2) 315 (2-3) 0/5 1/5 (1) J + 14 213 (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 J + 14 1/3 (3) 1/3 (2) 113 (3) 1/3 0/3 Total 8/12 4/12 8/12 1/12 3/12 24 Sodium salt + benzyl alcohol J + 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) J + 14 2/3 (3) 2/3 (2) 2/3 (3) 2/3 (1-3) 0/3 Total 10/12 6/12 10/12 2/12 4/12 32 Water fip 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) J + 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 exhibiting the lesion.

(ii) Number of rabbits examined (iii) Intensity of lesion.

Tables 2 and 3 have allowed the preparations to be classified from the most irritant to the best tolerated. This classification is as follows: sodium amoxicillin/3% benzyl alcohol 3% benzyl alcohol -micronized trihydrate amoxicillin/water for injectable preparation and micronized trihydrate amoxicillin/benzyl alcohol water for injectable preparation.

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

Experiment 3: Bioavallability.

By means of the usual tests, the bioavailability of a water suspension of micronized amoxicillin trihydrate was studied in comparison with a water solution of sodium amoxicillin.

The study was conducted in dogs, using, on the one hand, sodium amoxicillin reconstituted with 3% benzyl alcohol as solvent, and on the other hand, the trihydrate form in water suspension for an injectable preparation.

6 Beagle dogs (3 males-3 females) weighing from 10.8 kg to 14.5 kg were administered by intramuscular route (dose: 50 mg/kg) the two following preparations: sodium amoxicillin/3% benzyl alcohol -amoxicillin trihydrate/water for injectabie preparation.

The serum concentrations and the urinary elimination were determined microbiologically applying the disc method (Sarcina Lutea ATCC 9341 strain) in relation to a standard range.

The taking of blood samples was effected at the following times: 30 min, 1 her, 1 her 30, 2hrs, 4hrs, 6hrs, 8hrs, 10hrs, 12hrs, 24hrs, 32hrs, 48hrs after the injection.

The urines were collected from 0 to 6hrs, from 6 to 12hrs, from 12 to 24hrs.

Table 4 indicates the values of the serum concentrations in time for each of the preparations studied.

Table 5 gives the values of urinary elimination in time for each of the preparations studied.

Table 6 gives the areas under the serum concentration-time curve for each composition studied.

These results show that the serum peaks are higher and earlier in the case of the preparation of sodium amoxicillin in solution, whereas there is a persistence of the serum concentrations in the micronized preparation (see Table 4).

There was determined arbitrarily but according to the usual inhibiting antibiotic concentrations a minimum inhibiting concentration threshold at 5mcg/ml.

Table 4 shows that the decrease in serum concentration towards the minimum inhibiting concentration is reached in 5 hours for the sodium amoxicillin and in 10 hours after the administration in the case of the micronized preparation.

From a quantitative viewpoint of the bioavailability concept, Tables 5 and 6 show that the values of total urinary elimination as well as the areas under the serum concentration-time curve are not statistically different.

Urinary elimination is significantly higher during 6 hours in the case of sodium and significantly higher in the case of the micronized preparation starting from the sixth hour, the 24-hour elimination not being significantly different. However, the important elimination during the time interval 12-24 hours observed in the case of the micronized preparation allows forecasting the persistence of the urinary concentrations well beyond 24 hours.

Table 4 Dose : 50 mg/kg Animal Serum concentration mcg/ml/hour Preparation N . Sex Weight 0.5 1 1.5 2 4 6 8 10 12 24 32 48 (kg) Sodium 1 M 14.5 88.0 70.0 50.0 36.4 7.0 2.3 0.7 amoxicillin 2 M 13.1 102.0 78.0 50.0 33.3 7.0 1.8 0.5 3 M 14.5 83.0 88.0 53.0 34.6 7.0 1.8 0.6 4 F 12.9 102.0 88.0 55.0 37.6 9.7 2.1 0.6 5 F 12.7 83.0 65.0 46.0 25.1 5.0 1.1 0.4 6 F 10.8 92.0 57.0 31.0 17.9 2.2 0.5 0.2 Average 91.6 74.3 47.5 30.8 6.3 1.6 0.5 Micronized 1 M 14.5 6.2 7.6 7.9 9.4 8.7 6.7 4.3 4.2 3.3 2.0 0.6 0.15 amoxicillin 2 M 13.1 7.5 13.0 13.6 15.4 12.6 6.3 6.2 5.6 4.1 1.6 0.3 0.09 trihydrate. 3 M 14.5 7.3 12.0 15.4 15.4 12.6 8.3 5.9 4.9 4.0 2.2 0.4 0.12 4 F 12.9 8.8 12.0 15.5 16.6 14.7 11.8 8.2 6.4 3.5 2.0 0.6 < 0.10 5 F 12.7 7.3 9.2 11.5 13.6 11.2 9.4 6.4 4.2 2.6 1.6 0.4 < 0.10 6 F 10.6 6.2 7.6 9.3 12.0 10.2 9.4 6.2 4.7 3.0 1.6 0.3 < 0.10 Average 7.21 10.23 12.20 3.7311.73 8.98 6.20 5.00 3.41 1.83 0.43 0.10 Table 5 Dose : 50 mg/kg Preparation Dog 0-6 hrs. 6-12 hrs. 12-24 hrs. 24-48hrs. 0-24 hrs.

No. mg/ elimination% mg/elimination % mg/elimination mg/elimination mg/elimination % % % Sodium 1 408.0 56.28 48.0 5.77 15.6 2.15 465.4 64.19 amoxicillin 2 394.0 60.15 23.0 3.51 1.2 0.18 418.2 63.81 3 21.8 3.01 259.2 35.75 39.2 5.41 320.2 44.16 4 355.7 55.15 50.0 7.75 2.9 0.45 Unrecovered 408.6 63.34 5 317.4 49.98 41.9 6.60 4.1 0.65 urine 363.4 57.23 6 267.1 49.46 37.8 7.00 1.5 0.28 306.4 56.74 Average 294.0 45.67 75.6 11.06 10.75 1.68 380.36 58.23 Micronized 1 66.5 9.17 142.6 19.64 68.4 9.43 277.3 38.24 amoxicillin 2 54.9 8.38 174.7 26.67 81.8 12.49 Unrecovered 311.4 47.54 trihydrate 3 53.9 8.62 105.6 16.90 183.6 29.36 urine 343.1 54.89 4 63.4 9.83 150.4 23.32 78.4 12.16 292.2 45.30 5 71.4 11.24 166.5 26.22 83.1 13.09 321.0 50.55 6 92.0 17.04 129.5 23.98 82.0 15.19 303.5 56.20 Average 67.0 10.71 144.86 22.79 96.2 15.28 308.08 48.78 Table 6 Animal NO Preparations sodium trihydrate 1 168.80 120.89 2 174.72 151.11 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 The above results therefore allow considering that the pharmaceutical preparation of the invention can also be successfully administered to man. In this respect, 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 per se been known for a long time.

Claims (9)

1. A pharmaceutical injectable amoxicillin preparation, comprising amoxicillin trihydrate suspended in an appropriate solvent

2. A pharmaceutical preparation according to claim 1, wherein the particle size of the amoxicillin trihydrate in the suspension is so selected as to allow the injection of the said preparation.

3. A preparation according to either of claims 1 and 2 wherein the particle size of the amoxicillin trihydrate ranges from 1 to 25 microns.

4. A preparation according to claim 3 wherein the particle size is in the order of 5 microns.

5. A pharmaceutical preparation according to any one of claims 1 to 4 wherein the concentration of the suspended amoxicillin trihydrate ranges from 100 mg activity/ml to 1000 mg activity/ml.

6. A preparation according to claim 5 wherein the concentration is from 200 mg activity/ml to 500 mg activity/ml.

7. A pharmaceutical preparation according to any one of claims 1 to 6 wherein the amoxicillin trihydrate is in micronized form in the solvent.

8. A pharmaceutical preparation according to any one of claims 1 to 7 wherein the solvent is water.

9. A pharmaceutical preparation according to claim 1 substantially as hereinbefore specifically described.