Method of producing solid pharmaceutical composition of prolonged action

专利摘要:
A process for the preparation of sustained release solid pharmaceutical compositions having an active ingredient content of at least 80% and possessing a structure which loosens in aqueous medium but does not disintegrate to discrete particles within 4 hours which comprises coating the particles of the active ingredient in a liquid medium with a water insoluble polymer- preferably with an ethyl cellulose polymer film- and thereafter admixing the coated crystals with at least one disintegrating agent being capable of swelling in aqueous medium and other auxiliary agents conventionally used in pharmaceutical industry and pressing the mixture into tablets. The advantage of the process of the present invention is that it is readily feasible with a very wide range of active ingredients and provides sustained release tablets having a high active ingredient content.
公开号:SU1535369A3
申请号:SU843792253
申请日:1984-09-21
公开日:1990-01-07
发明作者:Фекете Пал；Ковач Тибор；Беззег Денеш；Бор Илона；Тот Золтан；Зукович Каталин；Тамаш Ева
申请人:Эдьт Дьедьсерведьесети Дьяр (Инопредприятие)；
IPC主号:

专利说明:

The invention relates to medicine, in particular) to methods for the preparation of long-release pharmaceutical compositions having a high content of the active ingredient.
The purpose of the invention is to increase the prolonging effect of the composition and simplify the method.
Example 1: Preparation of long-term release tablets, including L-c / methyldopa (L-c (meth-3,4-dioxyphenylalanine) as an active ingredient.
In a round bottom flask with a capacity of 2 liters, equipped with a reflux condenser and
with a stirrer, 200 g L-o (α-methyldopa (particle size less than 50 µm) and 20 g ethyl cellulose (quality N-100, ethoxygroup content 47.5–49%, viscosity 100 MPa, measured at 25 ° C in 5% by weight solution in a mixture of 80:20 toluene and ethanol) and 1000 ml of cyclohexane,
The powder is suspended at a constant stirring speed (200-250 rpm), the system is heated to 80 G using a water bath. The mixture was heated under reflux with stirring at 80 ° C for 30 minutes and allowed to cool to 40 ° C.
sd oo
SP
with
Oi
with

G4
for I h with constant stirring. When cooled, the particles acquire a coating of ethyl cellulose. The system is cooled below 20 ° C with cold water, the microcapsules are isolated by filtration and dried at room temperature on a tray. When sifting the product thus obtained on a 1 mm sieve, free flowing, non-sticking and non-sticking granules are obtained. Under the microscope, this product consists mainly of agglomerates of almost equal 100 to 300 microns in diameter, which do not possess any crystalline characteristics in polarized light. If L-d-metaldopa particles with a size greater than 100 µm are used for microcapsulation, the peaks of the crystalline particles are not covered with ethyl cellulose. In a double cone mixing apparatus of these microcapsules, the powder mixtures shown in Table 2 are prepared by homogenization for 20 minutes. 1 o
Table 1
five
0
five
The rhenium begins at the first hour in artificial gastric fluid, with half of the dissolving medium being replaced every hour with artificial intestinal fluid.
Use artificial gastric fluid composition: sodium chloride 2 g; 1 n. hydrochloric acid 80 ml; distilled water up to 1000 ml, and artificial intestinal liquid composition: disodium hydrogen phosphate 8.05 g; sodium dihydrogen phosphate 1.56 g; distilled water up to 1000 ml.
During the test, 6 tablets are placed in each container of the apparatus. The containers are vertically moved with an amplitude of 2.5 cm and a speed of 30 cm / s in a beaker thermostatted at 37 ° C and containing 800 ml of dissolving medium. After replacing half of the dissolution medium, the concentration of L-o-methyldopa in the residual liquid is determined spectrophotometrically.
The results of the experiment on the selection are given in table. 2
table 2
L-o (-methyl-dopa (microcapsules) microcrystalline cellulose
Potato starch
Sodium Carboxymethyl Cellulose (Nimsel)
88.7 88.7 88.7 88.7
10.3 6.3 6.3 9.4 4.0 4, 0 0, 9
Magnesium stearate 1.0 1.0 1.0 1.0
Powdered mixtures are given in table. 1 formulations are compressed into tablets containing 500 mg of L-c -methyl-dopa and having a diameter of 12 mm and a breaking strength of 100-120 kN.
The release of the active component is determined by the half replacement method using a fragmentation test apparatus,
45

55
From the table. 2 data shows that when testing for excretion outside the body, the proposed formulations 3 and 4 satisfy the requirements for long-term release compositions. The release from formulation 1, which does not contain a fragmentation agent, proceeds too slowly, while the isolation from formulation 2 containing a large amount of Nimsel, proceeds too quickly, since the tablet is crushed within 5 minutes. However, by reducing the amount of Nimsel, the desired degree of excretion can be achieved.
51
Example 2. Preparation of tablets long-lasting with trimethome (the effect of ethyl cellulose and granulating agent in microcapsules, the effect of the magnitude of the compression force on the release of the active component).
100 ml of cyclohexane is introduced into the apparatus of Example 1, the south of polyisobutylene (Oppanol, mol. Weight 90,000) is dissolved, and 200 g of trimetoprotein (2,4-diamino-5- (3, D) are added to the solution thus obtained. , 5G-trimethoxybenzyl) -pyrimidine, particle size less than 200 µm) and ethyl cellulose in three portions in various quantities (10, 20 and 30 g, respectively) are added in the same manner as in Example 1. The system is mixed at 200 rpm and processed in a manner similar to Example 1 .
Microcapsules are homogenized, with potato starch and magnesium stearate (the amount of these components
From tab. 3 that the release of tablets prepared from microcapsules, in which the ratio of ethyl cellulose to trimethoprim reaches 1:20, is too fast even in the presence of 1% potato starch, while in the case of microcapsules that correspond to the ratio of ethyl cellulose to Trimethopri353696
are given in table. 2). The mixture is pressed on an eccentric machine dl. the production of tablets equipped with a dynamometer, including a pressure gauge in tablets containing 200 mg of trimethoprim and having a diameter of 10 mm, was carried out testing on the release in an apparatus similar to Example 10, but an artificial gastric fluid of a given composition and for spectrophotometric analysis, samples of 10 ml are taken every hour.
15 The composition of the powder mixture, the pressing load and the release of the active component from the tablets are given in table. 3, with the ratio of ethylcellulose and trimethoprim in computations 1-4 equal to 1:20, in compositions 5-8 to 1.5: 20, in compositions 9-12 to 2:20, and the pressing load for compositions 1.2.5 , 6.9 and 10 is 10,000 kN, for compounds 3, A, 7,8,11
25 and 12 - 15000 kN.
Table 3
A ratio of 1:20 requires more than 7% starch to provide a full degree of release.
The results of the experiment demonstrate the effect of some parameters on the degree of excretion, and the optimal composition can be determined by taking into account these effects.
Example 3. Preparation of tablets, which emit potassium chloride for a long time.
Potassium chloride is subjected to micro encapsulation as in Example 1 using 200 g of potassium chloride (particle size less than 71 microns) and 20 ethyl cellulose (No. 100). From the microcapsules get a powder mixture having the following composition, g: potassium chloride in the microcapsule of 98.0; potato starch 1.0; magnesium stearate 1.0. From this homogenizate, tablets with a diameter of 12 mm, a potassium chloride content of 500 mg and a breaking strength of 100-120 N are obtained.
In tab. Table 4 shows the release of potassium chloride from these tablets.
Table 4
Allocation time, h
Isolated potassium chloride,%
The extent of the release is determined on a test apparatus for fragmentation. using distilled water as a dissolving medium, the amount of released potassium chloride being determined by measuring the conductivity,
Example 4. Preparation of tablets, long-lasting theophylline.
The microencapsulation is carried out analogously to example 2, using 200 g of theophylline (particle size less than 500 µm) as the core material and 20 g of ethyl cellulose (ff 100) as the coating material. From these microcapsules a powdered mixture is obtained (total weight 300 g) having the following composition, g: theophylline microcapsules 275.0; microcrystalline a-cellulose 5.5; lactose (monohydrate) 18.0; magnesium stearate 1.5.
From the powder mixture, tablets are pressed having a diameter of 10 mm, breaking strength 80 N, weight 300 mg and including 250 mg of theophylline as an active ingredient. The degree of release is determined analogously to Example 3 and the results shown in Table 5 are obtained.
Table 5
Allotment time
The release of theophylline,%
1 2 3 4 5 6
19.1 29.5 39.0 52.9 68.4 82.7
Example 5. The active component of L-aC-methyldopa.
The microcapsule described in example 1 is undertaken by placing 200 g of L-o (α-methyldopa and 10 g of ethyl cellulose (test A) into the apparatus, or 100 g of L-c / methyldopa and 18 g of ethyl cellulose (test B).
In the process of microencapsulation, a powdery mixture is obtained, which is listed in Table. 6 „
Table 6
Microcapsules of L-methyldopa, g ethylcellulose (5%) 84.0 ethylcellulose (18%) - 94.4 microcrystalline cellulose. 10.0 potato starch 1.9 crospovidones - 0.9 lactose (milk sugar) - 3.0 magnesium stearate 1, 0
Continuation of table 6
stearinova
acid - 2,2
talc 3.5 3.0
colloidal silica 0.6 content of active ingredient,% 80.0 80 Ethylcellulose (in terms of active ingredient),% 518
Loosening agent (in terms of the active ingredient),% 14.9 1.1
Crospovidone is a spatially moistened polyvinylpyrrolidone, which is obtained from GAT (QIIA) under the trade name Polyplasdone XL.
As colloidal silicon oxide, Aerosil 200 obtained by Degussa (HGF) is used.
From the powder mixture, tablets are pressed with a diameter of 12 mm with an active ingredient content of 500 mg and a breakdown strength of 100-120 N.
When studying the release of the active component described in Example 1, the results are shown in Table. 7
Table 7
Example 6. The active component trimetroprim.
The microencapsulation described in Example 2 is undertaken by placing 200 g of trimethoprim and 10 g of ethylcellulose (test C) or 100 g of trimethoprim and 18 g of ethyl cellulose (test D) into the equipment. From the microcapsules receive a powder mixture, the composition of which is given in table. 8. Table 8
Components of trimethoprim microcapsules
The content of the components, g, with experience
15
five
0
five
0
Ethyl cellulose
(5%) 84.0 - ethylcellulose
(18%) - 94.4
Microcrystalline cellulose 9.0 0.4 Potato
starch2.9
Sodiumcarboxylic methylcellulose
(Nimsel) - 0.5
Magnesium stearate 0.5 - Stearic acid 1, 0 2.0 Talc 2.1 2.1 2.7 Colloidal silica (Aerosil 200) 0.5
Tablets with a diameter of 10 mm are compressed from the powder mixture with an effective component content of 200 mg and a fracture strength of 80-100 N. In a study of the release of the active component, the results given in Table 2 are obtained. 9.
Table 9
55
11J5
In the described experiment C, the percentage of ethylcellulose in terms of effective components is 5%, disintegrating agents 14.9%, and in experiment D these values are 18% and 1.1%, respectively
Example 7 “Potassium chloride active ingredient.
The microencapsulation described in Example 3 is undertaken by placing 200 g of potassium chloride and 10 g of ethyl cellulose (test E) or 100 g of potassium chloride and 18 g of ethyl cellulose (test F) into the apparatus.
From the microcapsules receive a powder mixture, the composition of which is given in table. ten.
Table 10
The content of the components, g, with experience
E
Ethylcellulose (5%) 84.0
Ethylcellulose for
(18%)-
Microcrystalline cellulose11, 0 Potato starch0.9 Crospovidone
(Polyplasdone XL) - Stearic acid2, 0 Talc1.5 Colloidal silica 0.6
The blends contain, in terms of the active ingredient, 5% ethylcellulose and 14.9% disintegrating agents (test E) or 18% ethyl cellulose and 1.1% disintegrating agents (experiment F).
Tablets with the content of potassium chloride 500 mg with a diameter of 12 mm and a resistance to destruction of 100-120 N are compressed from the mixtures. The following results are presented in the investigation of the release of an effective component, presented in Table 11
Example 8 The active ingredient theophylline.
Analogously to Example 4, microcapsulation is undertaken by placing 200 g of theophylline and 10 g of ethyl cellulose (test G) or 100 g of theophylline and 18 g of ethyl cellulose (test H) into the equipment.
From the microcapsules receive a powder mixture, the composition of which is given in table. 12
Table 12
The content of the components, g, with experience
35
H
Ethylcellulose (5%) 84.0
Ethyl cellulose
(18%) - 94.4
Microcrystalline cellulose 10.0 Potato
starch1.9 Carboxymethylcellulose (Primoiel) - 0.9, Hydrated castor oil 3.5 2.5 Talc-2.2
Colloidal silicon (Aerosil 200) 0.6
The blends contain, in terms of the active ingredient, 5% ethylcellulose and 14.9% disintegrating agents (test) or 18% ethyl cellulose and 1.1% disintegrating agents (test H).
Tablets with the content of 300 mg of the active component with a diameter of 10 mm and strength to fracture of 80-100 H0 are compressed from the mixtures. In the study of the release of the active component, the results given in Table 2 are obtained. 13.
Table 13
In the described examples, which contain limit amounts of ethylcellulose and concentrations of disintegrating agents, it has been shown that other friction-reducing substances (lubricants) can be used instead of magnesium stearate: hydrogenated castor oil, talc. In addition, other substances, such as flowability improvers: colloidal silica or milk sugar as a filler
In the experiments, the tablets were pressed in a special machine adapted to vary the pressing load, and in example 2 the quality (release of the active component) of the tablets prepared using different pressing loads was examined. (this is the force at which the tablets break in compression in the direction of the diameter). In this quality, the mechanical properties of acetylsalicylic acid tablets are described by a known method also from the point of view Their strength to damage (the above notes to a damage strength of 10.5–12.5 kg correspond to 105–125 N). Since most tablet machines are not equipped with a tool that is suitable
0
0
five
to measure the pressing load, and in the device for tabletting there are appropriate tools for measuring the strength of the tablets to break, then to characterize the mechanical properties of the tablets, their strength to break is the most suitable parameter,
The selection outside the body of crystalline particles (microcapsules), covered with a uniform layer, studied under the microscope. Studies have shown that if the amount of covering 5 substance is 10-18%, the degree of excretion is too large — about 90-100% within 1 hour. This means that the microcapsules are not suitable for obtaining long-lasting pharmaceutical substances. either alone or after filling into hard gelatin capsules, it is therefore necessary to convert the microcapsules into matrix tablets by pressing
The proposed method provides long-lasting solid pharmaceutical compositions that have an active ingredient content of at least 80% and have a structure that breaks down in an aqueous medium but does not disintegrate into separate particles within 4 hours.
five
The proposed method makes it possible to manufacture preparations with a high content of active substances, and in the manufacture of micro capsules, it is not necessary to fulfill special technically difficult conditions due to the grain size or the form of the active substance used. According to the well-known 5 method, to ensure the appropriate rate of release of pharmaceutical compositions, one can apply 1-crystalline grains of 0.25 - 84 microns in size, having approximately isodiametric shape, with the largest grains maximum two times the smallest. The manufacture of such special crystals of acetyl salicylic acid of this type, although possible, however, is associated with increased costs, while in the case of other medicinal active substances, the manufacture of such products is often impossible.
0
five

权利要求:
Claims (1)
[1]
15 claims
"
A method of obtaining a solid pharmaceutical composition of prolonged action by coating the particles of the active component with a water-insoluble polymer film of ethyl cellulose, followed by adding a disintegrant, excipient and pressing into tablets, characterized in that, in order to extend the time of the composition and simplify the process use 5 15

1535369
sixteen
18 mas% ethyl cellulose, as a disintegrating agent - 1.1–14.88 wt.% Microcrystalline cellulose, 1.1– 5.0 wt.% Carboxymethylcellulose and 1.1– 8.4 wt.% Potato starch or their mixtures in a ratio of 1: (15 - l): l, 5, a as an active ingredient - L-oG-methyl-3,4-dioxyLenylalanine, 2,4-diamino-5- (3, 4, 5 - trimetoxibibenzyl) pyrimidine, theophylline and potassium chloride, and pressing under a load of 10,000-15,000 N

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同族专利:

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公开号 | 公开日

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CH661659A5|1987-08-14|

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GB8423339D0|1984-10-17|

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BE898888A|1984-08-13|

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US4748023A|1988-05-31|

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FI843773L|1984-09-26|

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DK457984D0|1984-09-25|

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GB2143734A|1985-02-20|

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FR2559389A1|1985-08-16|

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JPS60500213A|1985-02-21|

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DE3490030T1|1985-02-21|

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FR2559389B1|1986-05-30|

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GB2143734B|1986-07-30|

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NL8420009A|1984-12-03|

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SE8404804L|1984-09-25|

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NO843563L|1984-09-07|

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SE458092B|1989-02-27|

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DK457984A|1984-09-25|

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SE8404804D0|1984-09-25|

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WO1984002843A1|1984-08-02|

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HU187215B|1985-11-28|

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FI843773A0|1984-09-26|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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HU83245A|HU187215B|1983-01-26|1983-01-26|Method for producing pharmaceutical product of high actor content and prolonged effect|

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