CS218412B1 - Medicinal products for oral use - Google Patents

Abstract

The invention relates to medicinal preparations for oral administration in solid lump or powder form, stabilized against the proliferation of undesirable microflora, conditioned by the presence of moisture, by the addition of an activated anhydrous molecular sieve based on a synthetic alkali metal or alkaline earth metal aluminosilicate.

Description

The invention relates to medicinal preparations for oral administration in solid piece or powder form, for example tablets, dragees or granules, stabilized against external influences, in particular against the proliferation of undesirable microflora, conditioned by the presence of moisture.

Although the aforementioned medicinal products of the above forms have a number of advantages, there are still cases in some species where undesirable microflora grow or multiply, and they do not meet the criteria of the pharmacopoeia, i.e. that microbially safe medicinal products must not contain pathogenic microorganisms or indicators of fecal contamination. The total number of other live germs, unless otherwise specified, must not exceed 10,000 bacteria and 100 fungi and yeasts in ml or 1 g, and for mass-produced preparations it must not exceed 1,000 bacteria and 100 fungi or yeasts in 1 ml or 1 g.

In addition to some factors, such as pH value, temperature, presence of inhibitory or nutritional components, etc., the most common condition for the possibility of extraordinary reproduction of microorganisms is excessive water content, created both by the exceptionally increased humidity of the surrounding environment (wetting) and by the influence of so-called technological water, for example in wet technological processes, in which the intermediate products produced in this way have significantly better pressing properties than in dry technological processes. Pressed products usually contain technological water in the range of 0.1 to 3.0 wt. %, but these values may be exceeded. It is also known that in some cases the presence of even a minimal amount of water in a solid dosage form can result in undesirable decomposition reactions of drugs or interactions with other drugs, or even inadmissible reproduction of microorganisms. In the case of medicinal products containing an unacceptable amount of microorganisms, in addition to not meeting the requirements of the pharmacopoeia for microbial safety, other changes may also occur, such as the appearance of spots, unpleasant odors, changes in color, etc. (biodeterioration). Removing moisture from medicinal products eliminates one of the most important factors that determine the possibility of reproduction of microorganisms. In view of the above, a satisfactory and complete solution to these issues is still a current problem.

Since the ingredients traditionally used so far have not been able to solve this problem comprehensively, it was necessary to reach for materials whose properties would enable their multipurpose use and from which, in addition to the basic properties, other beneficial effects could be expected.

These principles have been applied to medicinal preparations for oral administration in solid lump or powder form, for example tablets, dragees or granules, stabilized against external influences, in particular against the growth of undesirable microflora, conditioned by the presence of moisture, according to the invention. Its essence lies in the fact that the preparations contain as a stabilizer an activated anhydrous molecular sieve based on a synthetic alkali metal or alkaline earth metal aluminosilicate, with a particle size of 0.08 to 0.3 mm, in an amount that is 1.5 to 3 times the amount theoretically necessary to bind the water present.

Molecular sieves (synthetic zeolites) are highly effective selective adsorbents. They are composed of aluminosilicates of alkali metals or alkaline earth metals; they are very similar to substances commonly used so far, such as bentonite, talc, etc. Like these substances, molecular sieves are also practically non-toxic, but they are also characterized by their excellent selective adsorption properties. The cavities in the particles of synthetic zeolites are filled with water molecules in the hydrated state. After dehydration, activated molecular sieves are again capable of adsorbing either water or other substances whose molecules have a critical diameter smaller than the diameter of the entrance opening into the intracrystalline cavity of the synthetic zeolite.

Medicinal preparations for oral administration according to the invention, stabilized against external influences, whether tablets, dragees, granules, powders, etc., are prepared by conventional technology in such a way that a powdered molecular sieve (synthetic zeolite) in the required grain size and quantity, based on the determined water content, or on the expected transport or storage conditions, is added to the mixture of conventional components of the preparation as one of the components before final processing into the dosage form. Activated molecular sieves (synthetic zeolites) thus become a direct part of the finished drug.

Further details of the nature of the invention and its consequences result from the following exemplary embodiments, which only illustrate the invention but do not limit it in any way.

An obvious condition for the usability of molecular sieves in medicinal products according to the invention, in addition to maintaining a low content of microflora, is that they are physiologically harmless, chemically indifferent substances that must not affect the action of the active ingredient itself and that must also not be used in any adverse way in the final pharmaceutical form throughout its shelf life.

Example 1

Sample No. (quantity in g)

A mixture of bismuth tannate and albumin tannate in the form of commercial granules with a water content of 6.1% by weight.

anhydrous molecular sieve microcrystalline cellulose aluminum stearate

Workflow:

Granulate with a particle size of no more than 1.2 mm and other substances after screening through a sieve with a mesh size of 0.125 mm were homogenized in

Intestinal astringent

21 22

0.500 0.500 0.500 — 0.050 0.075 —. 0.008 0.010 — 0.002 0.005

mixer for 30 minutes. Granulate containing 0.300 g albumin tannate, 0.100 g bismuth tannate and 0.100 g common tableting ingredients including a preservative was used to prepare the tablets.

The prepared tablets had the following properties: Sample No. 20 diameter in mm 12 weight _(in g) 0.50 strength (_x) MPa 0.44 disintegration (x) sec. 786

0.56

0.49

732

0.59

0.51

617

The evaluation of samples stored at room temperature in standardized packaging is evident from Table 1 (effect of molecular sieve on mold growth in the previous preparation):

Day

Sample No. 1 21 40 20 4500 4500 4360 21 4450 2070 1180 22 4510 1470 430 Example 2 Enzymes matic preparation (dragees) Sample No. (quantity in g) 23 24 25 26 Granulated protease mixture, amylase and lipase, water content 2.3% by weight 0.250 0.250 0.250 0.250 neutral granulate, content vi rows 1.9% mass 0.165 0.157 0.112 0.134 talc 0.009 0.015 0.015 0.015 calcium stearate 0.004 0.006 0.006 0.006 ultraamylopectin 0.022 — —- — molecular sieve — 0.022 0.067 0.045

Workflow:

The granulated enzyme mixture was added to the neutral granulate (a mixture of lactose and starch in a ratio of 2:1, treated with 5% gelatin hydrogel) with a particle size of 0.8 mm after screening through a sieve with a mesh size of 0.125 mm. Other excipients were added to the perfectly homogenized mixture in a mixer and after 39 minutes of mixing, tablets were pressed. Sample No. 26 was prepared by pre-briquetting with 50% by weight of excipients. The second part of the excipients was added to the granulate obtained from the briquettes (1.2 millimeters). After re-homogenization, the mixture was pressed. The prepared tablets had the following properties:

Sample No. 23 24 25 26 diameter in mm 10 10 10 10 mass (in g) 0.45 0.45 0.45 0.45 strength (x) MPa 0.49 0.43 0.38 0.41 decay (x) sec. 968 1092 1227 1110 It was applied to the tablets ethanol solution the forged tablets were filled to normal- polyacrylate flow at a concentration of 5.5% by weight. used packaged and stored at temperature fluid technique. Solubility of the formed rooms. Influence molecular growth screen film at pH 1.2 was 123 up to 128 min. La- microflora in the previous preparation: Microbes — day Mold - - day Sample No. 1 15 75 1 15 75 23 680 690 2100 1100 — 1860 24 690 295 430 1150 290 370 25 685 165 100 1100 25 10 26 670 10 10 1050 10 85

SUBJECT

Claims (1)

Medicinal preparations for oral administration, in solid lump or powder form, for example tablets, dragees or granules, stabilized against the effects of external influences, in particular against the multiplication of undesirable microflora due to the presence of moisture, characterized in that they contain activated anhydrous molecular sieves based on an alkali metal or alkaline earth metal synthetic aluminosilicate, with a particle size of from 0.08 to 0.3 mm, in an amount that is 1.5 to 3 times the amount theoretically needed to bind the water present.