KR20030078105A - The novel composition of excipient for solid dosage form - Google Patents

Abstract

PURPOSE: A novel composition of the dilutant for direct tableting for a solid formulation is provided which improves the fluidity of powder and prevents viscosity while tableting. Therefore, it is useful in the field of pharmaceutical industry. CONSTITUTION: A novel composition of the dilutant for direct tableting for a solid formulation is characterized by containing 80-96% of lactose, and 6-14% of starch and using 1-10% of a water-soluble polymer as a linking agent.

Description

Improvement of the fluidity of the powder mixture for tableting in the tableting process, which is an essential step in the manufacturing of tablets in the pharmaceutical and food industries, and among tableting disorders caused by the tableting process, especially tablets stuck to tableting machines or tablet punches. The novel composition of excipients for solid dosage forms for solid preparations that can be used in the pharmaceutical industry without the occurrence of phosphorous adhesion.

Microcrystalline cellulose or powdered cellulose, starch, lactose, dicalcium phosphate and sorbitol are widely used as excipients for the manufacture of internal solids in the pharmaceutical and food industries. Such excipients for internal solids are sticking, which is a phenomenon in which tablets adhere to the surface of tablets due to the flowability of tableting mixtures, mixing with the main components, tableting properties and rapid disintegration during tablet manufacturing, and the surface of tablets. there should be no tableting disorders such as sticking, capping where the upper part of the tablet is peeled off like a hat, laminating when the tablet is peeling off as a symptom, and also suitable tablet hardness and fast disintegration time. It should be suitable for various conditions, such as the conflicting conditions must be met. Examples include pharmaceutical formulations with good flowability (liquidity), good tableting properties obtained by low pressure application of tableting machines during tablet manufacturing, sufficient tablet hardness, external coating impact during tablet coating, and packaging during transport. Low abrasion and abrasion resistance, no change in product properties during long-term storage or distribution after manufacture, and the surface of the tablet adheres to the tablets (plates in contact with the tableting mixture) and tableting punches during rapid disintegration, especially at high-speed tableting It should be suitable for many conditions such that there should be no sticking phenomenon. These various conditions can be somewhat resolved by commercial excipients, in particular direct aids. Typically, lubricants, binders, disintegrating agents that promote disintegration of tablets, and the like are added to the auxiliary adjuvant when preparing the mixture for tableting. In general, when excipients such as lactose, cellulose, starch, inorganic salts are used as excipients for the tableting process, the excipients and the main ingredients are mixed and, if necessary, insoluble carboxymethylcellulose calcium salt, crosslinked carboxymethylcellulose, crosslinked Disintegrants such as polyvinylpyrrolidone or crosslinked carboxymethyl starch, and aqueous solutions or pharmaceuticals such as hydroxypropylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, methylcellulose, ethylcellulose, starch, gelatin, etc. A production process is used that mixes with binders dissolved in an organic solvent acceptable to the industry, wherein the mixtures, associations and granules mixed together are dried, further mixed with lubricant and compressed into tablets. Although such a conventional wet preparation method can provide excellent tableting granules, it is difficult to satisfy the above conditions, and this method has a complicated process, requires a large number of workers, and requires use of an organic solvent. . In addition, these preparation methods often show problems in the formulation process. For example, the main component may cause instability in heat, moisture, and organic solvents, and may cause changes in physicochemical properties, resulting in changes in crystallinity, dissolution and melting of the main component, resulting in tableting disorders or changes in dissolution rate and bioavailability. May be caused. It is an object of the present invention to provide a tablet for the tablets which meets the above conditions and makes it possible to produce tablets directly after mixing with the main ingredient, and also minimizes the amount of the tablet for the tablets.

It aims to improve the product quality and reduce the manufacturing cost by shortening the manufacturing process by simplifying, stabilizing and securing the manufacturing method of the solids in the pharmaceutical and food industries, and combining the pharmaceutical compositions intended by the present invention. To prepare other compositions and to prepare the content solids, especially tablets, without the usual wet granules manufacturing method, by preparing a direct excipient that can be directly driven after mixing the main component and excipients, the high content of the main component of the conventional direct excipient The present invention has been made to solve the flowability (fluidity) and the sticking phenomenon (Sticking) of the tablet generated when mixing.

The inventors have found that the object of the invention is embodied in accordance with the invention by means of excipients for direct hits, which are composed of a mixture of the following three components.

1) a carrier of fine powder pharmaceutically acceptable for tablets of 80 to 96% by weight of the total composition, and 2) polyvinylpyrrolidone (povidone K 25, K having K values of 25, 30, 60, 90). 30, K 60, K 90 F), hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, gelatin, one or more kinds of mixtures such as gelatin starch It is characterized in that it comprises a binder containing 1 to 10% by weight and 3) starch disintegrating in water or artificial 1, 2 liquid by weight 6 to 14% disintegrant by weight. In a preferred embodiment of the present invention, lactose of particle size of 600 micrometers or less is used as the base. However, powdered cellulose may be used, and of course lactose and powdered cellulose, lactose and mannitol, lactose and calcium phosphate, powdered cellulose and mannitol, lactose and starch or mixtures of powdered cellulose and calcium phosphate may also be used. Well mixed mixtures of the three components (1), (2) and (3) can be prepared by pharmaceutically acceptable methods such as dry granules, wet granules or spray drying or fluid bed granulation. The fluidized bed granulation step may be, for example, as follows; The mixture of lactose or the above-mentioned pharmaceutically acceptable excipient and (3) component is first introduced into a fluidized bed granulator container, while the powder mixture is flowed in the chamber while the temperature of the air sucked is warmed to 40 to 80 ° C. The desired dry granules can be obtained by spraying with a dissolved solution of component (2). Among the general wet granulation methods, extrusion granulation through a basket or sieve and high speed rotary granulation or granulation using a ribbon type mixer can be produced as follows; Lactose or the pharmaceutically acceptable pharmaceutical excipients mentioned above are premixed with component (3) and the solution in which component (2) is dissolved is added with homogeneous mixing and stirring. The wetted mixture is then passed through a basket or sieve and dried to obtain granules. It is also possible to obtain a constant dry granule by the spray drying process; Suspension solutions in which each component is dissolved or suspended by a certain amount are sprayed in a suitable nebulizer, for example, in the forward or reverse direction of dry air with a suction temperature of up to 120 degrees Celsius. In a particular spray drying process, for example, 60 to 70% of particles of 100 to 250 micrometers having a narrow particle size distribution starting from the microparticle lactose powder are included in the particle size distribution of approximately 50 to 500 micrometers. You get an assembly. The following example shows the synthesis of a mixture for the novel direct excipient of the present invention, a tableting test using other excipients, and a new vitamin direct excipient composition and a commercial direct excipient using a multivitamin (particularly containing tocopherols). ) Is an example and a test example for the formulation test of the mixture, which does not limit the whole invention.

Example 1) Lactose 88%

Starch 10%

Polyvinylpyrrolidone K 90 2%

Example 2) Lactose 88%

Starch 12%

Example 3) Lactose 86%

Starch 10%

Hydroxypropylcellulose 4%

Example 4 Lactose 82%

Starch 10%

Gelatin 8%

The mixture may be prepared into a tableting mixture by the following procedure. Lactose and disintegrant are mixed in a fluidized bed granulator chamber by a fluid bed granulation method, and the granules are dried by spraying a binder dissolved in water. In addition to this method, lactose and disintegrants are mixed together in horizontal kneaders or extruded conventionals using basket or sieve nets. The binder is dissolved in water and poured into a mixed dispersion of lactose and starch and the wet mixture is passed through a 0.88 millimeter sieve. This wet granule is dried at 40 ° C. and then uniformized using a 0.55 millimeter sieve. Alternatively, a solution of the binder dissolved in a mixed dispersion of lactose and starch is added, mixed and coalesced, dried to 2% or less in a fluidized bed dryer or hot air dryer (105 ° C., 20 minutes), and the 0.55 mm sieve is removed. Sizing to make particles uniform.

Test Example 1) Flowability Test: The flowability of the powder was measured using a powder flow meter (diameter 5 mm, slope 30 °).

Table 1) Flowability of powder

Example 1 Example 2 Example 3 Example 4 Ludipress ^® Fluidity (g / sec) 2.5 5.6 4 5 6

Test Example 2 The particle size distribution of Example (2) is as follows.

595-297 micrometers: less than 32%

297 to 210 micrometers: 30 to 35%

210 to 149 micrometers: 22 to 27%

149 to 105 micrometers: 12 to 17%

Test Example 3) A tableting test to confirm the occurrence of stickiness (sticking)

In addition, commercially available products of Rudy press ^® (Ludipress ^®) as in Example 1 in the lubricant component and the main component by using the mixture according to the method multivitamin (vitamin B ₁ and their salts, vitamin B ₂ and its salts, vitamin B _6, and Its salt, vitamin E and its salts and adsorbates, etc.), and tableted with a rotary tableting machine with an average tableting weight of 530 ± 30 milligrams and an average hardness of 10 ± 3 kg. Whether or not (sticking) was observed and measured.

Prescription

Chiamine Hydrochloride --------------- 10.00%

Naksan Riboflavin ------------ 0.51%

Phosphoric Acid Pyridoxal -------------- 0.69%

Tocopherol Acetate 50% Adsorbate --- 8.00%

Example 1) ----------------- 62.04%

Glidant -------------------- 1.94%

Table 2) Tableting test result with commercial item

Example (1) Ludipress ^® Average hardness (kp) 7 to 13 7 to 13 Average tablet weight (mg) 540 540 Disintegration time (minutes) 6 to 8 6 to 8 Adhesion X Occurs after 3-5 minutes after tableting Wear and tear (%) 0.01 or less 0.01 or less

These new granules have the properties of good tableting at low pressures, high hardness and low wear / wear and rapid disintegration of tablets during tableting, which are much better than conventional tableting excipients. Starch and lactose or other water-insoluble excipients are prepared by wet granulation, compared to spraying or adding a solution of a binder such as polyvinylpyrrolidone, hydroxypropyl cellulose, modified starch, polyvinyl alcohol, etc. Preparation and direct preparation of the excipients for direct use of tablets is advantageous not only to reduce the process but also to the physical properties of the tablet manufacturer, which prevents sticking problems, ie sticking, of the most problematic tablets. It is available in significantly improved excipients, and surprisingly good results can be obtained in terms of rapid disintegration time of tablets and improved workability of the tableting process.

Claims (7)

Pharmaceutically acceptable excipients comprising lactose, starch, and water-soluble polymers as binders for the preparation of direct excipient compositions for the production of solid preparations in the pharmaceutical or food industry The excipient composition for direct stroke according to claim 1, which contains 80 to 96% of lactose as an excipient. The excipient composition for direct rudder according to claim 1, which contains 6 to 14% of starch as an excipient. Polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatinized starch, gelatin, polyvinyl alcohol, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose as binders of water-soluble or water-swellable polymers Excipient composition for direct hitting is prepared from a binder that uses a mixture of one or more polymer materials having water-soluble or water swellable properties, such as The amount of the binder used in claim 1 is an excipient composition for direct hits, characterized in that it contains 1 to 10%. Direct excipient composition prepared so as to have a particle size of 50 to 500 micrometers of the direct excipient prepared according to claim 1 Excipient compositions wherein the composition prepared according to claim 1 may be used in the production of solid preparations of pharmaceuticals or foods