DD231796A5 - ANTIBIOTIC COMPOUNDS, MANUFACTURING METHOD AND COMPOSITIONS CONTAINING SUCH SUBSTANCES - Google Patents

Abstract

The invention relates to a process for the preparation of acetylerythromycin stearate for use as a medicament. The aim of the invention is to provide a new Erythromycinderivates that does not have the disadvantages of the known Erythromycinpraeparate. According to the invention, acetylerythromycin stearate of the formula I is prepared by reacting erythromycin base with an acetyl halide in an organic solvent in the presence of a acid acceptor and preparing a stearate salt from the resulting ester without isolating it.

Description

AP C 07 H / 272 428/5 64 837/11

Process for the preparation of acetyl erythromycin stearate Field of application of the invention

The application of the present invention is in the field of the synthesis of new drugs, especially those with antibiotic activity.

characteristics the known technical solutions

GB-PS S34 397 describes a process for the preparation of Erythromycinacetatesters. In the reaction in question, the acylation reaction is carried out in acetone and the resulting ester is isolated by adding water to the reaction mixture. In practice, however, it has been found that the acetate ester is very difficult to crystallize from an aqueous solution, and therefore the overall yield of the reaction is quite moderate. Further, the product is difficult to filter, and the one molecule of water of crystallization present in the product can be removed only by the use of very troublesome procedures.

The erythromycin preparations currently on the market include erythromycin base, erythromycin lactobionate, erythromycin stearate (salt) and erythromycin stolate, which is the lauryl sulfate salt of the propionyl ester of erythromycin. The stearate salt is poorly absorbed. Absorbance continues to decrease as the patient ingests or consumes food at or near the time of taking the medication.

The major disadvantage of the preparations in the form of bases is that gastric acid converts them into ineffective compounds.

The conversion can be avoided by making tablets that dissolve only in the intestine. However, these so-called enteric tablets are more costly to produce than conventional tablets and, in addition, their production is associated with some uncertainty since it is difficult to prepare preparations which always dissolve in exactly the same way. This results in varying concentrations of the active ingredient in the blood.

Erythromycin estolate is hepatotoxic. For this reason, its use is of course avoided whenever possible

Object of the invention:

The aim of the invention is the production of a new Ery-

15thromycin derivative which does not have the above disadvantages. Explanation of the essence of the invention:

The present invention has for its object to provide a novel derivative of erythromycin, the

  does not possess the above disadvantages.

20. The invention relates to a process for the preparation of acetylerythromycin stearate of the formula I.

CH ₃ H ₃ C OH Oh '

18 ^H 36 ° 2

This compound is obtained by reacting erythromycin base with acetyl chloride in the presence of sodium bicarbonate using ethyl acetate as the solvent. From the erythromycin acetate ester thus obtained, the stearate salt is then prepared without intermediate isolation of the ester.

According to the invention, an acetate ester in which the acetyl group is in the 2'-position is first prepared in ethyl acetate, whereupon the resulting ester is azeotroped by distilling off

₅ lieren a portion of the ethyl acetate is dried. To the mixture thus obtained, a directly equivalent amount of stearic acid is added. The stearate salt is isolated from the solution by distilling off a portion of the ethyl acetate (bp. 76-77 ° C) and replacing it simultaneously with petroleum ether, which has a higher boiling point (bp. 12O ⁰ C). The solution is cooled slowly to room temperature and further to 0 ^° C., then distilled, and the resulting salt is washed and dried. The yield from this process is very high, about 90%.

It has been found that about 40 ⁰ C is the most advantageous temperature for the preparation of Erythromycinacetatesters. A decrease in temperature causes precipitation, and raising the temperature causes at least some hydrolysis.

Ethyl acetate has been found to be the most convenient solvent. Also suitable for this purpose are chlorinated hydrocarbons and toluene, but not as well as ethyl acetate. For isolation of the salt is suitably chosen a solvent having a boiling point above 100 ⁰ C, since one

²⁵ with the help of which all water and the previously used solvent, such as ethyl acetate, can easily be removed from the solution.

The alkaline earth metal or alkali metal carbonate or bicarbonate used is suitable because of its weakly basic intrinsic

³⁰ a suitable acid acceptor.

If one were to prepare the new compound according to the process of GB-B-834 397 mentioned above, production and isolation would be very difficult.

When using the new connection will be the disadvantages

other Erythromycxnderivate successfully avoided, and you get a product that does not need to be prepared as Enterotabletten or enterocapsules,

to ensure full effectiveness. In addition, the absorption of the compound is good; therefore, a smaller amount of the active ingredient than hitherto is sufficient to give a concentration in the blood which previously required a greater amount of the active ingredient. For this reason, are made with acetylerythromycin stearate. Tablets smaller and therefore more pleasant to take. Large tablets have e.g. the disadvantage that they are relatively often stuck in the esophagus and can cause a local injury.

The following tests illustrate the absorption and liver toxicity of erythromycin acetate stearate. absorption test

In the absorption tests, the absorption of acetylerythromycin stearate in human patients was compared with the fasting and after a meal with the absorption of erythromycin stearate salt. Thus, the accompanying Figure 1 shows the result of the above-mentioned comparison test in fasting patients; Fig. 2 shows the corresponding result in patients who had taken a usual breakfast. 'j

As can be clearly seen from Figures 1 and 2, fasting absorption of acetyl erythromycin stearate is markedly better than that of erythromycin stearate, and this difference becomes even clearer in patients who have had a meal along with the drug intake. The blood serum concentration of the drug increased much faster when taking the compound according to the invention than in the reference compound, moreover the level increased three-fold than when using the reference compound. Furthermore, it can be seen from the drawings that the concentration in the serum remained significantly higher than in the reference compound, even after 8 hours.

The intake of food together with the drug lowers the maximum concentration in the blood serum even when

³⁵ dungsgemaßen compound, but with erythromycin stearate, the reduction is so large that the obtained mirror would not be sufficient as a therapeutic dose.

Thus, it is clearly demonstrated that the new compound is effectively absorbed regardless of the conditions. Lebertoxi2itatsversuche

To determine liver toxicity of the stearate salt of the erythromycin acetate ester, its effect on liver function descriptive enzymes was compared with the effect of certain other erythromycins on the same enzymes. The reference compounds used in the experiments were the erythromycin stearate salt and erythromycin stolate. As experimental animals, dogs were used in which the enzymes describing the life function were determined before and after the test period of 5 days. The results are shown in Table 1.

As clearly shown by the values in the table, erythromycin stolate is clearly the most toxic of the tested compounds. The increase in ASAT and ALAT values caused by this is clearly the highest; furthermore, it is the only one of the tested compounds that also caused an increase in APHOS and γ-GT values.

Pharmacological studies

To test the pharmacological activity of the new drug acetylerythromycin stearate, the following procedure was used

Bacteria culture test

Diplococcus pneumoniae type 3 cultures were obtained from Helsinki University, Department of Serology and Bacteriology. The bacteria were transferred with a metal loop from the anaerobic culture medium to 50 ml volume blood culture bottles (Hemobact, Orion Diagnostica, Espoo, Finland). The bacteria were incubated for 24 h at 37 ⁰ C and gave about 10 bacteria / ml

test animals

White NMRI mice of both sexes with 20 to 25 g weight. test method

The test mice were divided into 12 groups of 10 mice each. The animals receiving intraperitoneally 100μl of bacterial culture (approximately 10 bacteria / ml) were given subcutaneous erythromycin stearate and acetyl erythromycin stearate as follows:

Erythromycin group ο mg / kg ("untreated r5 " Acetylerythromycinstearat- 0 mg / kg (untreated 5 " 1) Control) Il 7) Control) Il ι, M 1, Il 5 2) 5 Il 8th) 5 Il 3) 15 9) 15 4) 50 10) 50 5) 11)

6) 150 "12) 150

The drugs were suspended in 0.125% carboxymethylcellulose (CMC), the pH was adjusted to 6 and the solution stored in ice to minimize hydrolysis. The drugs were injected subcutaneously at 12 hour intervals.

¹⁵ Results

All animals of the control group died within 48

, Hours after infection. Treatment with erythromycin stearate and acetylerythromycin stearate dose-dependently protected the mice from death. When treated with acetylerythromycin

stearate with 150 mg / kg b.i.d. none of the animals died, "while 1/10 died in the same dose when treated with erythromycin stearate.

As can be seen above, the pharmacological studies clearly show that acetyl erythromycin stearate in subcutaneous

Administration has at least as good an activity as erythromycin stearate.

When administered orally, the activity is even better than that of erythromycin stearate, since the absorption of acetyl erythromycin stearate is 2 to 4 times better than that of erythromycin stearate. This is due to the action of gastric juices on erythromycin stearate.

The following examples demonstrate the preparation of the stearate salt of erythromycin acetate as well as the preparation of suitable pharmaceutical compositions containing acetyl erythromycin stearate as an active ingredient.

EMBODIMENTS Example 1

3§ £ § ^ §ίΐΗί} 9_Υ20

200 g (2.38 mol) of sodium bicarbonate became a

Solution containing 400 g (0.545 mol) of erythromycin base in 3.6 l of ethyl acetate. The resulting suspension was

₁₀ to 40 ⁰ C heated, and 46.4 ml (0.65 mol) of acetyl chloride in ml of ethyl acetate were added within 2 to 3 hours. After the addition, a further 2 hours at 4 0 ⁰ C was further stirred, then 1 1 water was added at 0 ⁰ C 4. Stirring was continued for a while, then the ethyl acetate layer was separated, concentrated to 2.5 L and to it was added 155 g (0.545 mol) of stearic acid. The ethyl acetate was distilled off under normal pressure, and the ethyl acetate distilling off was replaced by 2 liters of petroleum ether (bp. 12O ⁰ C). The mixture was cooled slowly to room temperature and further to 0 ^° C. The desired stearate salt was filtered from the solution, washed with petroleum ether and dried. The yield obtained was 520 g of product, which was 90% of theory. corresponded

Analysis: C ₅₇ H ₁₀₅ NO ₁₆ (mol.wt.1060.42)

25 calculated: C 64.56 H 9.98 N 1.32 obtained: C 64.74 H'10.21 N 1.28

Example 2_

Herstellung_von_Tabletten

Using the compound prepared above, a tablet having the following composition was prepared:

393 mg 6 mg 54 mg 80 mg 10 mg 2 mg

Acetyl erythromacinstearate corresponding to 250 mg erythromycin

polyvinylpyrrolidone

Purified water (evaporated from the ⁵ method)

microcrystalline cellulose

modified cellulose gum (Ac-di-Sol '(croscarmellose sodium USP)

Mg stearate

The active ingredient was granulated by means of an aqueous solution of polyvinylpyrrolidone, the granules were dried and sieved, the remaining ingredients were mixed with the granules, and tablets were pressed from the resulting mass The tablets were coated with a conventional pigment / cellulose film coating ,

Example 3_

§§ £ §i: §LIun ^ jvon ^ tablets

Using the ingredients and amounts of Example 2 but omitting polyvinylpyrrolidone and water, tablets were prepared as follows. The active ingredient and the microcrystalline cellulose as well as the modified cellulose gum were mixed together. The powder mixture was dry granulated by compressing and sieving, then the Mg stearate was added and the mixture was compressed into tablets. Further, a conventional film coating was used

Example 4

Acetyl erythromycin stearate accordingly

125 mg erythromycin 196.5 mg

Cornstarch - ~ 50 mg

granulated sugar - 50 mg

Polyvinylpyrrolidone 15 mg

purified water (evaporated from the process)

The round granules were prepared using a suitable CF-360 granulator for this purpose according to the operating instructions of the apparatus.

CO ((Π C table ro o 1 before activity cn O = 4) APHOS (mU / ml) S -GT j (mU / ml) cn Bilirubin (ωηοΐ / ΐ) I VO 5-day toxicity test later ALAT (mU / ml) on liver enzymes (n - SD) 227+ 52.4 3.8 + 2.9 15.0 + 10.4 I before 30.5+ 7.8 on dogs (aft ASAT (mU / ml) 234 + 64.1 2.5 + 1.7 7,5+ 2 _r 7 later 30.0+ 7.8 32.8+ 7.0 214+ 48.3 3.0 + 0.82 13.3+ 5.7 before 27.3+ 6.85 24.8+ 1.7 178+ 38.7 3.3 + 1.3 12.0+ 4.1 later 102.0+ 48.0 25.5+ 8.5 218+ 40.6 2.8 + 1.3 10.0+ 1.8 before, afterwards 24.0+ 7.0 33.3+ 13.9 610 + 582.4 8.0 + 5.7 11.5 + 2.1 285.8 + 218.1 27.3+ 6.4 209+ 39.7 189+ 40.6 2.5 + 1.0 3.3 + 1 _f 5 7,3+ 1 _T 0 10,3+ 3.4 before, afterwards 25.3+ 3.9 90.25+ 51.15 274.5 + 233.8 • 29.0+ 7.0 24.5+ 4.4 • 180+ 70.6 197+ 90.3 3.0 + 0.0 5.5 + 4.4 13.0+ 5.7 8.8+ 4.4 26.5+ 7.3 177.0 + 192.5 27.8+ 9.2 28.0+ 50.9 control erythromycin stearate 278 mg / kg χ 2 erythromycin estolate 14 4 mg / kg χ 2 Acetyleryric acid stearate 14 5 mg / kg χ 2 Acetyl erythromycin stearate. 290 mg / kg χ 2

Claims (4)

invention claim 1. A process for the preparation of acetylerythromycin stearate of the formula I. H, C ^XC 13 ^H 36 ° 2 CH. characterized by reacting erythromycin base with an acetyl halide in an organic solvent in the presence of an acid acceptor and producing a stearate salt from deprotected esters without isolation thereof. 2. The method according to item 1, characterized in that the acid acceptor used is an alkaline earth or alkali metal carbonate or bicarbonate. 3. The method according to item 1, characterized in that the reaction is carried out in the presence of sodium bicarbonate using ethyl acetate as solvent and the reaction temperature is about 40 C. 4. The method according to item I _1, characterized in that for the separation of the salt, the organic solvent by another solvent having a boiling point above 100 ⁰ C, z. As petroleum ether, is replaced.