RU2205630C1 - Methods for tabletting biologically active substances (variants) - Google Patents

Abstract

FIELD: medicine, technology for tablets production. SUBSTANCE: methods for tabletting biologically active substances are suggested including preparation of raw material - medicinal substances, fillers and shape-forming substances, reducing, sieving and sieve classification, dosing and dry mixing of prepared powders, moistening and mixing of wet mass, granulating of wet mass, drying, fragmentation and sieve calibration of dried granules, pressing of granulated mass to obtain tablets and cover them with membranes. Moreover, in addition to a filler and a shape-forming substance represented by sugar, lactose, china clay, etc., one should dose the flour of cereal grains as shape-forming substance. Moreover, raw material mass is moistened with tinctures - extracts of substances containing biologically active components prepared at desired necessary quantity of moisture. The suggested innovation enables to obtain tablets with accelerated assimilation in gastrointestinal tract. Tablets obtained due to the above-mentioned method do not stimulate mucous gastric membrane. EFFECT: higher efficiency. 10 cl

Description

 The invention relates to medicine, in particular to technology for the production of tablets, and can be used in the manufacture of tablet dosage forms.

 A known method of tabletting (Nosovitskaya S.A. et al. Production of tablets. M .: Medicine, 1969, p. 64-94), including the preparation of raw materials - medicinal substances, fillers in case the dose of the medicinal substance is small, grinding, sieving and sieve classification, dosing and mixing the prepared powders, the introduction of formative substances - binding or gluing - water, alcohol, sugar or sugar syrup, starch paste, the introduction of disintegrants - mainly starch, moistening and mixing the wet mass, granules wet mass, drying to a residual moisture content of 1-2%, crushing and sieve calibration of dried granules, the introduction of sliding or lubricating agents, for example talc, magnesium stearates, calcium, liquid paraffin, etc., to prevent the mass from sticking when pressing tablets, pressing the granular mass into tablets.

 A known method of tabletting (Muravyov I.A. Technology of drugs. M .: Medicine, 1971, S. 590-616), including the preparation of raw materials - medicinal substances, fillers and excipients, grinding, sifting and sieve classification, dosing and dry mixing prepared powders, moistening and mixing the wet mass, granulating the wet mass, drying to a residual moisture content of 1-2%, crushing and screening the dried granules, compressing the granular mass into tablets. The manufactured tablets are coated with shells to protect the contents from adverse external influences, to improve the taste - conceal the unpleasant taste of drugs, to give the tablets a more beautiful appearance, to transfer the site of action of drugs outside the stomach in the case of the manufacture of intestinal tablets.

 In the production of specific drugs in each case, laboratory tests determine the optimal amount of moisture. With optimum moisture, the tablets have the greatest strength, with excess moisture, the material sticks to the press equipment.

 The disadvantage of tablets made in a known manner is the use of sugar and starch as disintegrants. Sugar and starch are refined carbohydrates that are quickly and completely absorbed by the stomach. Almost the entire dose of the drug is absorbed immediately, quickly. To ensure long-term continuous exposure to the drug, tablets have to be taken often at short intervals. In addition, in the manufacture of tablets of alkaline drugs, for example, such as sodium salt of paraaminosalicylic acid or sodium salicylate, the disintegration of the tablets is delayed, since the alkalinity of the tableted substances causes gelatinization of starch.

 In addition, the disadvantage of tablets made in a known manner is the need to use water to moisten the drug mixture. Solutions of extracts of substances containing biologically active components used as a drug substance are colloidal solutions. When diluted with water, such solutions lose their physicochemical properties, and the therapeutic effectiveness of the diluted extracts decreases, in addition, the need to dose water reduces the dose of the drug substance.

 The objective of the invention is to develop a method for the preparation of tablets, in which the dose of extracts of biologically active substances would be maximum and their medicinal properties would be used as efficiently as possible, as well as a tablet method in which the produced tablets would disintegrate faster, but would be absorbed in the patient’s stomach for a long time time.

 The technical result obtained by using the proposed method is the provision of long-term continuous therapeutic effects on the patient. To solve this problem, a group of inventions is proposed, united by a common inventive concept.

 The proposed method of tabletting as well as the known method includes the preparation of raw materials - medicinal substances, fillers in case the dose of the medicinal substance is small, grinding, sieving and sieving classification, dosing and mixing the prepared powders, the introduction of formative substances, moistening and mixing the wet mass, granulation of the wet mass, drying to a residual moisture content of 1-2%, crushing and sieve calibration of the dried granules, the introduction of sliding or lubricating substances to prevent flushing anija mass during the pressing of tablets, pressing the granular mass into tablets.

 However, in contrast to the known method according to the proposed method of tableting as an additional excipient to the filler used and the excipient, which may be sugar, lactose, kaolin clay, carboxylmethyl cellulose (CMC), the flour of cereal plant grains is dosed in the ratio (1: 0.7 ) - (1: 1,3), and the granulation mass is moistened with extracts of biologically active substances.

 Tablets made by the proposed method have the same strength and, therefore, easily disintegrate in the stomach, however, they are absorbed in the stomach much more slowly, i.e. they stay there much longer. The flour impregnated with the drug substance gives it more slowly, therefore there is no direct contact of the drug substance with the gastric mucosa and it does not irritate the mucous membrane, while at the same time providing a long-term continuous therapeutic effect on the patient.

 The second variant of the proposed method of tabletting involves adding to the fillers 5-10% of crushed bran grains of cereal plants, while the moisture is dosed to the threshold of maximum moisture content, the granulation mass is dried to a residual moisture content of 2.5-10%, and to prevent sticking of the wet mass to the punches press equipment they are lubricated with a lubricating solution, such as white paraffin oil.

 Tablets made by the proposed method have less strength and, therefore, easily disintegrate in the stomach, are absorbed faster and do not have time to irritate the mucous membrane, and coating tablets with water-insoluble membranes does not worsen the storage conditions of tablets with increased moisture content.

 The invention is illustrated by the following examples.

 Example 1. The production of tablets of biologically active food additives - "Hypertonic" by a known method.

Raw materials:
Lemon acid
Aronia chokeberry
Pharmacopoeia tincture of hawthorn
Pharmacopoeia tincture of motherwort
Potassium asparaginate
Magnesium asparaginate
Sugar
Starch
Calcium stearate
Talc
Bearberry grass
Lemon balm herb
Distilled water
1) Sugar is ground in a mill, sieved and dosed in an amount of 80.8 kg.

 2) From the crushed fruits of chokeberry 0.37 kg, bearberry leaves 0.185 kg, lemon balm herbs 0.185 kg and 9 kg of water, an infusion of 7.4 kg is prepared.

 3) 0.93 kg of citric acid is introduced into 1 kg of cooked infusion of herbs and 1.93 kg of solution is obtained.

 4) From 6.4 kg of herbal infusion, 10 kg of sugar and 1.0 starch, 17.2 kg of starch paste in syrup is prepared.

 5) The remaining crushed sugar, starch, potassium aspartate, magnesium aspartate are sieved on a vibrator through a sieve with 1 mm holes.

 6) 70.8 kg of sugar, 14.4 kg of starch, 0.93 kg of potassium aspartate, 0.93 kg of magnesium aspartate are loaded into the mixer, mixed and, during the mixing, tincture of hawthorn 1.85 kg, motherwort tincture 1.85 kg, citric acid solution 1.93 kg, starch paste in syrup 17.2 kg.

 The yield of the product is 109.89 kg.

 7) A wet mass of 109.89 kg is passed through a granulator. Wet granulate with a granule size of 4-5 mm, the output of which is 109.89 kg, is transferred to drying.

8) The granulate is laid out in trays with a layer of 1.5-2 cm and dried in an oven at a temperature of 40-45 ^o C to a moisture content of 1.5-2%. The output of dry granulate 98,43 kg

 9) Dry granulate is crushed to a granule size of 1.5 mm. The output is 97.84 kg.

 10) Sieved talcum powder 2.04 kg and sieved calcium stearate 1.02 kg are added to the dry granular mixture and mixed in a mixer. The yield of finished granulate is 101.00 kg.

11) The finished granulate is sent to press tableting in a tablet machine, at the output of which tablets are obtained:
diameter - 12.0 ± 0.2 mm
height - 3.8 ± 0.2 mm
average weight - 0.55 ± 0.02 g
Every 30 minutes of operation of the machine, the resulting tablets are checked for disintegration, strength and weight. The product yield is 100.5 kg.

 12) The resulting tablets are sieved on a vibrating screen with holes of 8 mm, separating them from crumbs and debris. The output of the finished tablets is 100 kg.

 13) The finished tablets are coated with a waterproof acid-soluble coating, packaged and packaged.

 Example 2. According to the proposed method, all operation technologies are performed in a similar manner, only at stage 4) oatmeal paste is prepared, at stage 5) is sifted, dosed and mixed instead of starch oatmeal, at stage 6) sugar and flour are dosed in the ratio: a) 1 : 0.7 - 46.6 kg and 38.6 kg, b) 1: 1 - 38.1 kg and 47.1 kg, c) 1: 1.3 - 30.8 kg and 53.4 kg.

Example 3. According to the proposed method, all technological operations are performed similarly, only at stage 4) they prepare rice flour paste, at stage 5) sift, dose and mix rice flour instead of starch, at stage 6) sugar and flour are dosed in the ratio:
a) 1: 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 4. According to the proposed method, all technological operations are performed similarly, only at stage 4) they prepare buckwheat flour paste, at stage 5) sift, dose and mix buckwheat flour instead of starch, at stage 6) sugar and flour are dosed in the ratio: a) 1 : 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 5. According to the proposed method, all technological operations are performed similarly, only at stage 4) oatmeal paste is prepared, at stage 5) are sifted, dosed and mixed instead of starch, oatmeal, at stage 6) are dosed lactose and flour in the ratio: a) 1 : 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 6. According to the proposed method, all technological operations are carried out similarly, only at stage 4) oatmeal paste is prepared, at stage 5) are sifted, dosed and mixed oatmeal instead of starch, at stage 6) kaolin clay and flour are dosed in the ratio: a) 1: 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 7. According to the proposed method, all technological operations are performed similarly, only at stage 4) oatmeal paste is prepared, at stage 5) are sifted, dosed and mixed instead of starch oatmeal, at stage 6) the CMC and flour are dosed in the ratio: a) 1 : 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 The disintegration of tablets made by the proposed method is the same as in the prototype method. Comparative experimental leaching of tablets made by the known and proposed methods in 0.1 normal hydrochloric acid solution (imitation of gastric juice) showed that the leaching of tablets made by the proposed method lasts 1.5-2 times longer.

 Example 8. According to the proposed method, all technological operations are performed similarly, only at the mixing stage 6) when dosing instead of part of the sugar, 4.04 kg of crushed and sifted wheat bran are additionally dosed into the raw mix, 6-8 kg of water are gradually introduced until the water begins to exfoliate thereby providing a moisture content up to the threshold of maximum water retention. At the drying stage, the process is brought only to a moisture content of 2.5-4.0%. The yield of the finished product increases to 107-110 kg.

 Example 9. According to the proposed method, all technological operations are performed similarly, only at the mixing stage 6) when dosing instead of part of the sugar, 6.06 kg of crushed and sifted wheat bran are additionally dosed into the raw mix, 7-9 kg of water are gradually introduced until the water begins exfoliate, thereby ensuring moisture content to the threshold of maximum water retention. At the drying stage, the process is brought only to a moisture content of 4.0-7%. The yield of the finished product increases to 107-110 kg.

 Example 10. According to the proposed method, all technological operations are performed similarly, only at the mixing stage 6) when dosing instead of part of the sugar, 8.08 kg of crushed and sifted wheat bran are additionally dosed into the raw mix, 8-10 kg of water are gradually introduced until the water starts exfoliate, thereby ensuring moisture content to the threshold of maximum water retention. At the drying stage, the process is brought only to a moisture content of 6-10%. The yield of the finished product increases to 107-110 kg.

 Examples 11-13. According to the proposed method, all technological operations are performed similarly to examples 1-4, only buckwheat bran is used as part of the filler.

 Examples 14-16. According to the proposed method, all technological operations are performed similarly to examples 1-4, only rice bran is used as part of the filler.

 Examples 17-19. According to the proposed method, all technological operations are performed similarly to examples 1-4, only oat bran is used as part of the filler.

 The punches of the matrix machine were additionally carefully polished and lubricated with white paraffin oil during tabletting.

 The disintegration of tablets manufactured by the proposed method, accelerated to 5-7 minutes compared with 15-20 minutes by the known method, the strength of the tablets decreased by 30-40%. However, due to the applied coating, the dependence of the quality of the tablets on the storage conditions did not appear.

 Example 20. The production of tablets of biologically active food additives "Propovit".

Raw materials:
Propolis 10% alcohol tincture
Lemon acid
Vitamin C
Calcium stearate
Sugar
1) Sugar is ground in a mill, sieved, dosed in an amount of 97.97 kg.

 2) Prepare a solution of citric acid 1.68 kg in a 10% propolis tincture of 16.83 kg, obtaining 18.51 kg of solution.

 3) 97.97 kg of crushed and sifted sugar is loaded into the mixer, moistened with a solution of citric acid in tincture of propolis in the amount of 18.51 kg, mixed and 114.48 kg of moistened mass are obtained.

 4) The wetted mass of 114.48 kg is dried to a residual moisture content of 2%, obtaining a raw material mass for granulation of 100.49 kg.

 5) A dried mixture of 100.49 kg is passed through a granulator. 1.01 kg of sieved calcium stearate and 0.84 kg of ascorbic acid are added to the granular mass and mixed to obtain 101 kg of dry granulate.

6) The finished granulate is sent to press tableting in a tablet machine, at the output of which tablets are obtained:
Diameter - 12 ± 0.2 mm
Height - 3.8 ± 0.2 mm
Average weight 0.55 ± 0.02 g
7) Every 30 minutes of operation of the machine, the resulting tablets are checked for disintegration, strength and weight.

 During the preparation of tablets, the prepared infusion of substances containing biologically active components was not diluted with water, so their dose is higher, and the physicochemical and therapeutic properties of the extracts have not changed.

 Example 21. According to the invention, technological operations are carried out similarly, only at stage 4) oat flour paste is prepared, at stage 5) are sifted, dosed and mixed instead of starch oat flour, at stage 6) sugar and flour are dosed in the ratio: a) 1: 0 7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 22. According to the invention, all technological operations are carried out similarly, only at stage 4) they prepare rice flour paste, at stage 5) sift, dose and mix rice flour instead of starch, at stage 6) sugar and flour are dosed in the ratio: a) 1: 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 23. According to the invention, all technological operations are performed similarly, only at stage 4) they prepare buckwheat flour paste, at stage 5) sift, dose and mix buckwheat flour instead of starch, at stage 6) sugar and flour are dosed in the ratio: a) 1: 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 24. According to the invention, all technological operations are carried out similarly, only at stage 5) are sifted, dosed and mixed oatmeal instead of starch, at stage 6) are dosed lactose and flour in the ratio: a) 1: 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 Example 25. According to the invention, all technological operations are performed in a similar way, only at stage 4) oatmeal paste is prepared, at stage 5) are sifted, dosed and mixed instead of starch oatmeal, at stage 6) the CMC and flour are dosed in the ratio: a) 1: 0.7 - 46.6 kg and 38.6 kg; b) 1: 1 - 38.1 kg and 47.1 kg; c) 1: 1.3 - 30.8 kg and 53.4 kg.

 The disintegration of tablets made according to the invention is the same as in the prototype method. Comparative experimental leaching of tablets made according to the known method and the invention in 0.1 normal hydrochloric acid solution (imitation of gastric juice) showed that the leaching of tablets made according to the invention lasts 1.5-2 times longer.

 These tablets have the same strength and, therefore, easily disintegrate in the stomach, but they are absorbed in the stomach much more slowly, that is, they stay there much longer. The flour impregnated with the drug substance gives it more slowly, therefore there is no direct contact of the drug substance with the gastric mucosa and it does not irritate the mucous membrane.

Claims (10)

 1. A method of tabletting biologically active substances, including grinding the active components, mixing them with fillers and excipients, followed by moistening, granulating, drying and tabletting, characterized in that the granulation mass is moistened with extracts of biologically active substances.  2. A method of tabletting biologically active substances, including grinding the active components, mixing them with fillers and excipients, followed by wetting, granulation, drying and tabletting, characterized in that the excipients and excipients are pre-mixed in the ratio (1: 0.7) - (1: 1.3) with flour of cereal grains selected from the group of oat, rice, buckwheat grains, and the granulation mass is moistened with extracts of biologically active substances.  3. The method according to claim 2, characterized in that as fillers and forming substances use sugar, lactose, kaolin or carboxymethyl cellulose.  4. The method according to claim 2, characterized in that as biologically active substances use citric acid, fruits of Aronica aronia, bearberry leaves, lemon balm grass.  5. The method according to claim 2, characterized in that the granulation mass is moistened with tinctures of hawthorn and motherwort and a solution of citric acid.  6. A method of tabletting biologically active substances, including grinding of medicinal substances, fillers and excipients, sieving and sieving classification, dosing and dry mixing of prepared powders, moistening and mixing the wet mass, granulation of the wet mass, drying, crushing and sieve calibration of dried granules, pressing granular mass into tablets, coating the tablets with shells, characterized in that as part of the filler in the amount of 5-10% dosed ground grains of cereal plants, the granulation mass is moistened with extracts of biologically active substances, while the moisture is dosed to the maximum moisture retention threshold of the prepared mixture of substances, the granular mass is dried to a residual moisture content of 2.5-10%, and to prevent sticking of the wet mass to the punches of the press equipment they are lubricated with a lubricant.  7. The method according to p. 6, characterized in that wheat bran is dosed as part of the filler.  8. The method according to p. 6, characterized in that buckwheat bran is dosed as part of the filler.  9. The method according to p. 6, characterized in that as part of the filler dosed oat bran.  10. The method according to claim 6, characterized in that rice bran is dosed as part of the filler.