CN1074134A - Pharmaceutical granulated composition and its preparation method - Google Patents

Abstract

A granulated composition for direct compression which comprises a water-soluble crystalline drug which cannot be compressed or is difficult to compress, a binder, a lubricant and water, and which contains the pharmaceutically active ingredient in an amount of up to 98% by weight. The tablet compressed by the composition has high hardness, and adjustable dissolution time.

The preparation method of the mixture comprises pre-granulating the medicinal powder with water or aqueous solution of the medicinal powder, further granulating the obtained granule with binder solution, drying, and spraying lubricant.

Description

The present invention belongs to the field of pharmaceutical technology, and more specifically relates to a new granulated composition that is easy to compress, contains water-soluble crystalline drugs that cannot or cannot be easily compressed, and a preparation method thereof.

Granulated compositions for tableting and containing water-soluble, non- or poorly compressible crystalline drug substances are known in which the content of excipients amounts to 40-90% (EP 342106, EP 108218).

In the above composition, the content of auxiliary components is very high, which reduces the bioavailability of the active ingredients and also changes the kinetics of the drug. In addition, adding a large amount of auxiliary materials to the tablet composition leads to additional power and material consumption.

Methods for preparing granulated pharmaceutical compositions are known (Remington's Pharmaceutical sciences, 17th Edition, 1985, Mack Publishing company, Easton Pennsylvania, p. 1610-1612). According to the method described above, the pharmaceutical granulated composition is prepared by putting the drug powder in an ebullating bed, granulating it with a binder solution, drying it, and then spraying it with a lubricant. However, this method cannot be used to produce granulated compositions containing water-soluble, incapable or difficult-to-tablet crystalline pharmaceutical ingredients when the content of excipients is extremely low.

The granulated composition of the present application and its method of preparation are new and have not been reported in the literature.

The task of the invention is to create a new granulated composition that is easy to compress and contains water-soluble crystalline pharmaceutical ingredients that cannot or cannot be easily compressed, and the content of auxiliary materials is very small, and its preparation method.

The above tasks are accomplished as follows, according to the invention, the granulated composition of the present application contains the following components:

a) pharmaceutical active substances, accounting for 96.0 to 98.0% (weight) of the total weight of the mixture;

) can be used as a medicinal adhesive, the effective amount is 0.5-2.0% (weight)

B) It can be used as a pharmaceutical lubricant, the effective amount is 0.5-1.0% (weight)

) water in an effective amount of 1-3% by weight.

The granulated composition of the present application contains a minimum amount of excipients, which ensures maximum bioavailability and optimal pharmacokinetics of the active pharmaceutical ingredient. In addition, the granulated composition of the present application can be compressed into good tablets with the desired strength, and the dissolution time can be adjusted, which prevents local irritation of the pharmaceutical active ingredient.

According to the invention, the preparation method of the granulated composition of the present application comprises the following steps:

a) The drug powder is preformed into granules with water or a concentrated solution of the drug. The particle size of most of the drug powders is preferably not greater than 0.3 mm. The preformation of the drug powder into granules is preferably carried out in an ebullating bed.

b) The prefabricated drug granules are further granulated in an ebullating bed with an aqueous solution of a binder or an organic solvent solution of a binder or a mixed solution of water and an organic solvent of a binder.

B) drying the obtained granules, preferably to a moisture content of 1-3% by weight of the granules

г) Spray dry granules with lubricant.

The preparation method of the granulated composition of the present application improves the plasticity of the granule and reduces the cost of the tablet made of the granule due to changing the shape and structure of the granule.

Pharmaceutical ingredients (glycine, mannitol, histidine), adhesive ingredients polyvinylpyrrolidone, organic solvents and water must meet the quality requirements of the Soviet Pharmacopoeia, adhesive ingredients are starch, cellulose ether and lubricating ingredients are stearic acid And its salt must comply with the requirements of the Soviet technical standard documents.

The pharmaceutical ingredients contain more than 99% of the matrix, and the particle size of most of the pharmaceutical ingredient powders is preferably not greater than 0.3 mm. The surface of the tablets obtained in this way is smooth and uniform, which conforms to the Soviet Pharmacopoeia, XI, Volume 2, pages 154-155 on the appearance of tablets requirements.

Any pharmaceutically acceptable binder can be used as the binding component, such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, acetyl ortho Phthaloyl cellulose, polyvinylpyrrolidone, starch, sugar, natural gum, gelatin, dextrin, shellac, pectin, alginic acid derivative, polyglucosamine.

Cellulose ethers, starches and polyvinylpyrrolidone are preferred because they are non-toxic and widely used in the pharmaceutical industry.

The amount of binder in the composition of the present application determines the dissolution time of the tablet, and the amount is 0.5% to 2% (by weight) based on the total weight of the composition.

Any medicinal lubricant can be used, such as stearic acid and its salt, polyethylene glycol, hydrogenated vegetable oil, talcum powder, sodium lauryl sulfate or a mixture formed by their reasonable combination as the lubricant component.

Preferably, stearic acid, calcium stearate or magnesium stearate is used to hydrophobize the surface of the water-soluble pharmaceutical ingredient particles, and the lubricant is used in an amount of 0.5% to 1.0% by weight of the total composition.

In order to be able to directly compress tablets, the composition of the present application also contains required moisture, and its content is 1% to 3% of the total amount of the composition.

Like this, according to the invention, the ratio of the above-mentioned components contained in the composition of the present application is as follows, by the total weight of the composition:

Table 1

Ingredient Tolerance,% by weight

Drug 96.0-98.0

Adhesive 0.5-2.0

Lubricant 0.5-1.0

Water 1.0-3.0

The optimum composition of the composition of the application depends on the nature of the pharmaceutical ingredients and the dissolution time of the tablet in each particular case.

The granulated composition of the present application can be directly compressed into tablets, the hardness of the tablet is 13 to 138 Newton, and the dissolution time is 1 to 55 minutes.

According to the present invention, the preparation method of the composition of the present application is as follows:

The drug powder is pre-granulated. In order to make the water evenly distributed on the drug ingredients and speed up the process, the powder pre-granulation is best carried out in an ebullating bed.

For this purpose, the calculated amount of drug powder is placed in an ebullating bed granulator, moistened with water or a concentrated solution of the drug, and the resulting granules are dried to a moisture content of 3% to 5%. In the same granulator, granulate again with the aqueous solution of binder or organic solvent solution or the mixed solvent solution of water and organic solvent, and the obtained granules are dried. In order to ensure the best plasticity of granules, it is best Dry until the remaining moisture is 1%-3% (weight) and then take out the granules from the fluidized bed, sieve through a sieve with an aperture of 0.5 mm, and spray lubricant in the mixer.

The granulation prefabrication of the drug powder can also be carried out in the wet granulation granulator. For this purpose, the calculated amount of the drug powder is placed in the wet granulation granulator, wetted with water or a concentrated aqueous solution of the drug and stirred carefully, and then removed from the granulator. Take out the granulated soft material from the granulator, rub it into granules with a sieve with an aperture of 1 mm, dry until the remaining moisture is 3%-5%, and then rub the dried granules into small particles with a sieve with an aperture of 0.5 mm. Into the ebullating bed, carry out the operation of following process with above-mentioned similar method.

The finally obtained granulated composition can be directly compressed into tablets, that is, without adding any auxiliary agent, it can be compressed into tablets under different pressures, the pressures are in MPa: 98 MPa, 196 MPa and 294 MPa.

The hardness of the tablet is measured by Erweka Tablet Hardness Tester, expressed in Newton, the international unit of force, N

In order to evaluate the dissolution time of the tablet, T100% is used as an index, indicating the time required for the drug ingredients to completely dissolve in the solution, expressed in minutes, and the determination of T100% is carried out according to Soviet Pharmacopoeia XI, Volume 2, pages 159-160 of.

In order to evaluate the abrasion resistance of the tablet, the weight lost during the test is used as an index, expressed as a percentage. The determination of the abrasion resistance of the tablet is carried out according to Soviet Pharmacopoeia XI, volume 2, pages 157-158, with the application The composition is prepared into tablets with a diameter of 9 mm and a weight of 300 mg.

The invention is illustrated by the following examples.

Example 1

292.5 grams of glycine powder, most of which have a particle size of not more than 0.2 mm, were placed in a fluidized bed dryer (Aeromatic AG, Model STREA-1), granulated with 100 ml of water, and the obtained granules were dried to a residual moisture content of 5% (weight ), then in the same machine, use 150 ml of 2% aqueous solution of methylcellulose M-100 to continue granulation, and the obtained granules are dried to a residual moisture weight of 1%, taken out from the ebullating bed, and granulated with a hole diameter of 0.5 mm sieve and spray 1.5 g of magnesium stearate in a cube blender (Erweka Model KB20/UG).

The finally obtained granulated composition contains the ratio of the above-mentioned ingredients as follows, calculated with the total weight of the composition:

Table 2

Composition Weight %

Glycine 97.5

Methylcellulose 1.0

Magnesium stearate 0.5

water 1.0

The granulated mixture was directly compressed using an eccentric tablet press (Erwerka, Model EKO). The physical properties of the obtained tablets are listed in Table 3.

table 3 Tablet Physical Properties Tablet pressure, MPa 98 196 294 Hardness, Newton 18 35 55 Dissolution time, T100%, min 20 28 30 Abrasion resistance, % 35 0.3 0.3

Example 2

292.5 g of glycine powder, the majority of which has a particle size of not more than 0.5 mm, was placed in a laboratory wet granulation mixer (Erweka, Model SW 1/S), granulated with 90 ml of water, and the resulting soft material was transferred to wet granulation In a machine (Erweka, Model FGS), rub it into granules with a sieve with a pore size of 1 mm, and dry it in an oven (B & T "Stabilec" Oven, Model 322/0205) at 60°C until the remaining moisture is 5% by weight. The granules were placed in a fluidized bed drier (Aeromatic AG, Model STREA-1), granulated with 300 ml of 1% aqueous solution of methylcellulose M-100, and the following operations were carried out according to the method described in Example 1.

The composition of the granulated composition finally obtained is as shown in table 2

The granulated composition was directly compressed with an eccentric tablet press (Erweka, Nodel EKO), and the physical properties of the obtained tablets are listed in Table 4.

Table 4 Tablet Physical Properties Tablet pressure, MPa 98 196 294 Hardness, Newton 17 25 33 Dissolution time, T100%, min 12 18 0 22 Abrasion resistance, % 0 2 0.2 0.25

Example 3

276 grams of glycine powder, most of which have a particle size of not more than 0.2 mm, are placed in a laboratory wet granulation mixer (Erweka, Model SW1/S) to granulate with 90 grams of 20% glycine aqueous solution, and the following operations are carried out according to examples 2, with one exception, the preformed granules were further granulated in an ebullating bed with 300 ml of a 0.5% aqueous solution of methylcellulose M-100.

The finally obtained granulated composition contains the following proportions of components, calculated on the basis of the total weight of the composition:

table 5

Component Weight %

Glycine 98.0

Methylcellulose 0.5

Magnesium stearate 0.5

water 1.0

The granulated composition was directly compressed using an eccentric tablet press (Erweka, Model EKO). The physical properties of the obtained tablets are listed in Table 6.

Table 6 Tablet Physical Properties Tablet pressure, MPa 98 196 294 Hardness, Newton 41 64 82 Dissolution time, T100%, min 9 13 16 Abrasion resistance, % 0.2 0.1

Example 4

292.5 grams of D-mannitol (Chemapol company) powder, most of which have a particle size of not more than 0.2 mm, were placed in a laboratory wet granulation mixer (Erweka, Model SW1/S), granulated with 100 ml of water, and The following operation is carried out according to the method described in Example 2, but with one exception, the prefabricated granules of mannitol are further granulated in an ebullating bed with 150 ml of 1% starch paste aqueous solution, and then the granules are dried to residual moisture 1.5% by weight, with calcium stearate as lubricant.

The finally obtained granulated composition contains the following proportions of components, calculated on the basis of the total weight of the composition:

Table 7

Component Weight %

Mannitol 97.5

Starch 0.5

Calcium stearate 0.5

water 1.5

The granulated composition was directly compressed using an eccentric tablet press (Erweka, Model EKO). The physical properties of the obtained tablets are listed in Table 8.

Table 8 Tablet Physical Properties Tablet pressure, MPa 98 196 294 Hardness, Newton 23 56 94 Dissolution time, T100%, min 22 26 29 Abrasion resistance, % 0.2 0.5

Example 5

280.5 g of D-mannitol (Chemapol) powder, most of which have a particle size of no more than 0.3 mm, was placed in a fluidized bed dryer (Aerom-atic AG, Model STREA-1) with 75 g of 10% mannose Alcoholic aqueous solution granulation, the following operation is described in example 1, but one point except that the prefabricated granules of the gained mannitol are further granulated with a mixed solution of 300 milliliters of 2% sodium carboxymethylcellulose, and the mixed solution solvent The composition of water: ethanol: acetone weight ratio is 5: 4: 1, uses 3 grams of stearic acid as lubricant.

The proportions of the finally obtained granulated composition components are as follows, calculated by the total weight of the composition:

Table 9

Composition Weight %

Mannitol 96.0

Sodium Carboxymethyl Cellulose 2.0

Stearic acid 1.0

water 1.0

The granulated composition was directly compressed using an eccentric tablet press (Erweka, Model EKO). The physical constants of the obtained tablets are listed in Table 10.

Table 10 Tablet Physical Properties Tablet pressure, MPa 98 196 294 Hardness, Newton 66 125 138 Dissolution time, T100%, min 42 48 55 Abrasion resistance, % . 1 .1 0.1

Example 6

288 grams of L-histidine hydrochloride (Sigma company) powder, most of the particle size is not greater than 0.3 mm, put into the fluidized bed dryer (AeromaticAG, Model STREA-1), with 75 grams of 10% histidine Aqueous solution granulation, the following operation is carried out as described in Example 1, except that the prefabricated granules of the obtained histidine are further granulated with 0.5% ethanol solution of polyvinylpyrrolidone with a molecular weight of 12600 ± 2700 Carry out, be 3% with granule drying to residual moisture constant weight then, make lubricant with 1 gram of calcium stearate and 0.5 gram of stearic acid.

The proportions of the components contained in the finally obtained granulated composition are as follows, calculated by the total weight of the composition:

Table 11

Composition Weight %

Histidine 96.00

Polyvinylpyrrolidone 0.50

Calcium stearate 0.33

Stearic acid 0.17

Water 3.00

The granulated composition was directly compressed using an eccentric tablet press (Erewka, Model EKO). The physical properties of the resulting tablets are listed in Table 12.

Table 12 Tablet Physical Properties Tablet pressure, MPa 98 196 296 Hardness, Newton 13 30 50 Dissolution time, T100%, min 1 2 0 2 Abrasion resistance, % .2 0.3

The granulated composition of the present application and its preparation method are applied in the production process of preparing granules and tablets from aqueous solution crystalline drugs that cannot be compressed into tablets or are difficult to compress into tablets.

Claims (9)

1, granulated medicinal composition, wherein contain water miscible can not tabletting or the crystallization shape medicine of difficult tabletting, medicinal adhesive, lubricant and water is characterized in that contained each composition contains following ratio, % (weight) is as follows:

Medicine 96.0-98.0

Binding agent 0.5-2.0

Lubricant 0.5-1.0

Water 1.0-3.0

2, the compositions of claim 1 is characterized in that it contains cellulose ether in water-soluble or organic solvent or water and the organic solvent mixed liquor as binding agent.

3, the compositions of claim 1 is characterized in that it contains starch and make binding agent.

4, the compositions of claim 1 is characterized in that it contains molecular weight is that 12600 ± 2700 polyvinylpyrrolidone is made binding agent.

5, the compositions of claim 1 is characterized in that it contains stearic acid or its pharmaceutically useful salt or the mixture of the two and make lubricant.

6, the method for preparing the described granulated medicinal composition of claim 1; this method comprises that the solution with the water of binding agent or organic solvent or water and organic solvent mixed liquor carries out granulation with medicine in ebullated bed; the granule that obtains carries out drying and spraying lubricant, it is characterized in that the prefabricated granulating of the fortified aqueous of drug powder water or medicine.

7, the described method of claim 6 is characterized in that particle drying to the contained humidity weight that obtains is 1-3%.

8, claim 6 and 7 described methods, it is characterized in that the granulation of drug powder is prefabricated carries out in ebullated bed.

9, the described method of claim 6 to 8 is characterized in that the drug powder that prefabricated granulation is used, and its most of particulate granularity is not more than 0.3 millimeter.