DK145712B - PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL TABLES CONTAINING A BETA-LACTAM ANTIBIOTIC AND SOIL CALCIUM CARBONATE - Google Patents

Description

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The present invention relates to a process for the preparation of pharmaceutical tablets containing β-lactam antibiotic and alkaline earth metal carbonate by mixing the ingredients and pressing of the tablets, which process is characterized by a) 30 - 85% β-lactam antibiotic fc) -70% heavy magnesium carbonate corresponding to the formula 3MgCC> 3,

Mg (OH) 2, 4H 2 O or 8 - 70% heavy magnesium carbonate and 2 - 35% calcium carbonate, the weight of heavy magnesium carbonate being at least equal to the weight of calcium carbonate present and c) 0 - 40% usual tableting auxiliaries being mixed and pressed direct compression. The rate of solubility of water-soluble, slightly acid-soluble drugs can be increased at low pHs by the addition of an agent capable of raising the pH of the medium. There are e.g. carried out attempts to formulate benzylpenicillin in tablets containing calcium carbonate in the hope that the partial neutralization of the gastric acids induced by the effect of the calcium carbonate would increase the solubility rate of the benzylpenicillin.

Unfortunately, it has not been possible to prepare a tablet with various other penicillins such as isoxazolylpenicillins together with significant amounts of calcium carbonate without a) using a wet granulation process which may result in possible stability problems, b) including significant amounts of tableting auxiliaries, or c) reducing the proportion of penicillin to an unacceptable amount.

It has now been found that, if excipients are used as heavy magnesium carbonate BP (British Pharmacopoeia), hard tablets can be made from a penicillin or other drug containing a large proportion of penicillin, and such tablets are further rapidly dispersed in the stomach acid. . It has also been found that these tablets can be prepared by direct compression without the need to add large amounts of tableting agents. This is especially surprising given those of Jaffe and Foss, [J. Amer.

Pharm. Assoc., Sci. Ed., XLVIII, 26 (1959)] made claims that "those substances containing the carbonate radical show a poor tendency to form tablets upon direct compression".

The direct compression method, which consists essentially of only mixing and compression steps, is particularly economical in terms of time, work, space, equipment and power when compared to conventional tabletting methods such as wet granulation or dual compression. Magnesium carbonate appears to be a unique pH modifier which can be used for incorporation into tablets formed by direct compression. Usual pH modifiers such as sodium citrate, sodium acetate, sodium carbonate, potassium carbonate, calcium citrate and calcium carbonate are not directly compressible. Heavy magnesium carbonate has no synergistic effect on the β-lactara antibiotics, but allows direct compression to the tablets and modifies the pH locally by partially neutralizing the gastric acid.

The discovery that heavy magnesium carbonate BP is a direct compressible buffer enables more simplified preparation of drug tablets which are distinguished by the presence of an acid reducing or degrading agent.

Heavy magnesium carbonate is also known as Magnesii Subcarbonas Ponderosus and is a hydrated basic magnesium carbonate of varying composition similar to the formula 3MgCC> 3, Mg (OH)

Magnesium carbonate per se [i.e. MgCO ^] is not sufficiently compressible for use as the sole buffer in the compositions of the present invention, and light magnesium carbonate BP [i.e. 3MgCO 3, MgtOH 2, SI 2 O] have disadvantageous flow properties which do not use it as the only buffer in the present compositions.

All percentages used in this specification and claims are on a weight / weight basis.

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Suitable usual tableting agents for use in the present tablets are lubricants, preservatives, dyes, flavors, fillers, binders, solid organic acids and other conventional agents. Most often fillers and binders are not needed to form acceptable tablets. Preservatives and dyes are usually found only in very small quantities, e.g. usually less than 1% in total. The amounts of binders, fillers and flavorings depend on the nature of the drug; eg. for very powerful drugs, the use of more filler and similar substances is often needed than with weak drugs. Typical fillers are calcium phosphate, sodium sulfate, starch, silica, lactose and dextrose.

Typical binders are natural and synthetic resins such as polyvinylpyrrolidone, starches and gums such as acacia and tragacanth.

The β-Lactam antibiotic (which may be in the form of a salt or ester) is usually poorly soluble, meaning that its solubility is less than 3% in aqueous hydrochloric acid at pH 1.3 at 37 ° C.

Such tablets preferably contain 40-60% of slightly soluble penicillin or cephalosporin or a salt or ester thereof, 30-60% heavy magnesium carbonate, and 2-10% of conventional tableting medium.

However, if two or more penicillins or cephalosporins are used in the same tablet, it is often advantageous to use larger total amounts of antibiotics and smaller total quantities of other drugs. Eg. contains particularly suitable tablets of this type 60 - 85% β-lactam antibiotics, 8-20% heavy magnesium carbonate and 2-15% usual tableting agents.

A useful group of penicillins for use in the present tablets are isoxazolylpenicillins and their salts, e.g. clo-xacillin, flucloxacillin, dicloxacillin, and the alkali metal and alkaline earth metal salts thereof. Tablets containing carbenicillin esters and ticarcillin esters may also advantageously be used with heavy magnesium carbonate.

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Heavy magnesium carbonate can advantageously be used when an isoxazolyl or other slightly soluble penicillin is combined in a tablet with other more easily soluble penicillins.

Suitable penicillins for use in the present tablets are those having general formulas I and II

/ Cl ___. — S S CH3 \ _ / i «'7 | —C0_NH ^ ch3 \ 0 S i

R1 CO 2 H

r2-ch-co-nh —- (^ s 3 I CH3 R3 N-k

0 CO 2 H

II

Wherein R is hydrogen, fluoro or chloro, R is phenyl or thienyl, and R is hydrocarbon such as phenyl, toluyl or indanyl; and the alkali metal and alkaline earth metal salts thereof.

Such compounds may occur with other penicillins such as ampicillin or amoxycillin or pivaloyloxymethyl or phthalyl esters thereof.

Other β-lactam antibiotics which may be used in the present tablets are e.g. phenethicillin, propacillin, azidocillin, hetacillin (a form of ampicillin), metampicillin (a form of ampicillin), cyclacillin, epicillin, pivampicillin, thalampicillin, cephaloxin and cephradin.

The use of CaCO 2 in the tablets is advantageous, since the presence of 2 + J

the Ca-ions room counteracts the slightly laxative properties of 2+

Mg ions in the preparation. However, there must be at least 8% heavy magnesium carbonate in the tablet.

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In a very valuable embodiment, tablets containing 30 - 85% of a β-lactam antibiotic, 8 - 70% heavy magnesium carbonate, 2 - 35% calcium carbonate and 0 - 40% conventional tableting agents are prepared; the weight amount of heavy magnesium carbonate in the tablet is at least as great as the weight amount of calcium carbonate present.

When 2 β-lactam antibiotics are present, it is preferred to prepare tablets containing 60 - 85% β-lactam antibiotics, 8-20% heavy magnesium carbonate, 2-10% calcium carbonate and 2-15% usual tableting agents; the weight amount of heavy magnesium carbonate in the tablets is at least as large as the weight amount of calcium carbonate present.

The drug may be encapsulated in microcapsules or dispersed in a filler prior to formulation of the tablets.

In some cases, besides heavy magnesium carbonate, additional fillers may be added. Suitable fillers for such tablets are starch, cellulose, urea (described in Danish Patent Application No. 3746/74), glycine, calcium phosphate or sodium sulfate. Glycine, urea and calcium carbonate are particularly valuable fillers which are used if the intention is to use more than 10% fillers in addition to the heavy magnesium carbonate.

The present tablets may be prepared by mixing the ingredients together in the usual manner and directly compressing the resulting mixture into a tablet press machine.

Conventional single or multiple piston presses may be used, generally at conventional pressures.

The method of the present invention has considerable commercial utility, with its advantages being that the use of the direct compression technique largely means saving labor, time and equipment.

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The process according to the invention is further illustrated by the following examples:

Example 1.

Sodium cloxacillin microencapsulated with 1% "Plasdone K29 / 33" ®.

"Plasdone" ® (consists of polyvinylpyrrolidone) / has appropriate compression properties when mixed with 1/2% Aerosil® (as a liquid / consists of more than 99.8% pure SiO2), 1 1/2% magnesium stearate (as lubricant), 4% "Primojel" ® (as disintegrant, consists of starch glycollate) and 15% "Avicel" ® (as compression agent, microcrystalline cellulose), but the resulting tablet containing 250 mg of sodium cloxacillin is difficult to dissolve at an appropriate rate at pH 1.3 (cf. the table). Using heavy magnesium carbonate, the following composition is compressed:

Sodium cloxacillin, microcapsules 53.6%

Heavy Magnesium Carbonate 40.0%

Sodium lauryl sulfate 1.7%

0.7% magnesium stearate

Primojel® 4.0%.

at a direct pressure of 1200 kg / cm 2, giving tablets with a short dissolution time (see table below) and good hardness properties (14 by Erweka scale).

Solubility rates of 250 mg tablets of Example 1 at pH 1.3 and 37 ° C, measured by the "flask and stirrer method" at 60 rpm.

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Minutes Tablet with Avicel Tablet with MgCO ^ 10 10 4 1 20 12 2 55 20 6 65 30 8 77 60 12 95

Example 2.

Phenethicillin microencapsulated with 1% "Plasdone" ^ - "K29 / 33" is pressed 2 into tablets by direct compression at 820 kg / cm. The composition used is:

Phenethicillin, microcapsules 49% (equivalent to 250 mg phenethicillin)

Heavy Magnesium Carbonate BP 39%

Magnesium gearate 2%

Primojel 'S' 8%

Sodium lauryl sulfate 2%

The time taken for 50% dissolution of the tablets at pH 1.5, 37 ° C and stirring at 60 rpm. the minute is 7 1/2 minutes.

In similar tablets, where phenethicillin and magnesium carbonate have been replaced by 88% microencapsulated phenethicillin, the solubility time under the same conditions is 12 1/2 minutes. The direct compression of similarity between the two systems is the same.

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Example 3

Benzylpenicillin is formulated as follows:

Benzylpenicillin 45% (equivalent to 250 mg benzyl penicillin)

Heavy Magnesium Carbonate BP 45%

Sodium lauryl sulfate. 2%

Magnesium stearate 1%

Primo jel® 7% and pressed into tablets by direct compression at 1300 kg / -2 cm. The hardness of the tablets turns out to be 8 on the Erweka scale. The time to 50% dissolution of the tablets at pH 1.5 is found to be 6 minutes. Hard tablets in which the magnesium carbonate is replaced by calcium carbonate cannot be prepared by direct compression.

By replacing the heavy magnesium carbonate with dicalcium phosphate dihydrate (unpainted), tablets can be made by direct compression 2, but tablets made at a pressure of 1300 kg / cm have only a 5 1/2 hardness on the Erweka scale, and the time for 50% solution under the same conditions as above is 16 minutes.

Example 4

Calcium flucloxacillin is prepared as follows:

Calcium lucloxacin Hin 52.2%

Heavy Magnesium Carbonate 40.8%

Sodium lauryl sulfate 1.6%

0.4% Magnesium Gearate

Primojel ^ 5.0%.

This preparation is directly compressible to obtain hard tablets with a dissolution efficiency (as defined by KA Khan and CT Rhodes, Pharm. Acta Helv. 4 "7, pages 594, 1972) of 31% using a conventional" flask and stirrer. "method" at 60 rpm, pH 1.2 and 37 ° C.

(If other buffers, such as sodium citrate, glycine or calcium carbonate, are used instead of heavy magnesium carbonate, the mixture is no longer directly compressible. The following formulation is pressed into tablets using a double compression method:

Calcium flucloxacillin 52.1%

Sodium citrate 10.4%

Glycine 31.3%

Sodium starch glycolate 3.7%

Sodium lauryl sulfate 1.9%

Magnesium stearate 0.6%.

The resulting tablets have a solubility efficiency of only 13.2% even at 100 rpm. while the other circumstances are as stated above.

If a conventional direct compression excipient, e.g. dicalcium phosphate dihydrate (unpainted), the tablets can be compressed directly, but even with a usual buffer, e.g. of sodium citrate, the solubility is still poor, e.g. has a wording:

Calcium flucloxacillin 61.8%

Sodium citrate 12.3%

Dicalcium phosphate 18.6%

Sodium lauryl sulfate 2.2%

Primo jel® 4.4%

Magnesium stearate 0.7% a solubility efficiency of 3.9% at 100 rpm. minute).

Example 5

Heavy magnesium carbonate BP can advantageously be used in formulations combining two penicillins, one poorly soluble in acid and the other more easily soluble. The presence of heavy magnesium carbonate both greatly improves the formulation's tablet properties and increases the solubility rate of the total penicillin. An example of such a composition is:

Calcium flucloxacillin 32%

Amoxycillin 32%

Heavy Magnesium Carbonate 31%

Magnesium stearate 1% _ · π®> .3.

Primo gel / 4%.

This formulation can be directly compressed. Any other salt of flucloxacillin, e.g. the sodium, potassium, magnesium or aluminum salt can replace the calcium salt in this preparation, but the calcium salt is the easiest to compress.

Example 6

. In certain combination tablets, the total weight of the tablet limits the amount of heavy magnesium carbonate that can be used in the formulation.

However, in such formulations, incorporation of 5-20% heavy magnesium carbonate will greatly improve the tableting properties and disintegration / solubility rate of the composition.

Examples of such tablets are: A,% B,% C,%

Sodium cloxacillin 40 30 33

Ampicillin Trihydrate 40 42 33

Heavy Magnesium Carbonate 12 20 14

Primoj el 'S' 4 5 4

Sodium lauryl sulfate 2 12

Magnesium stearate 2 22

Calcium carbonate 0 08 11 145712

Example 7

The following tablets may be prepared by direct compression: A,% B,%

Carbenicillin Phenyl Ester - Sodium Salt 59 79

Microcrystalline cellulose 0 15

Heavy Magnesium Carbonate BP 35 0

Magnesium stearate 1 1

Sodium lauryl sulfate 1 1

Primo jel'- '4 4

Although both formulations are prepared with acceptable hardness and brittleness, both tablets A have a much higher solubility rate than tablet B. Increasing microcrystalline cellulose content does not improve the solubility rate of tablet B. When given to volunteers, the tablets containing heavy magnesium carbonate induce nearly twice the cumulative urinary excretion of penicillins over the first 6 hours as tablet B.

Incorporation of other buffer substances, e.g. glycine, in sufficient concentrations to achieve the same cumulative urinary excretion of penicillins as tablet A, prevents the tablets from being made by direct compression. Very brittle coated tablets are produced by a single compression.

These results clearly show that heavy magnesium carbonate has unique properties in that it is both a pH modifier, enhances the bioavailability of poorly acid-soluble drugs, and is also a direct compressible tableting aid.