JP2521612B2 - Direct tablet forming aid - Google Patents

Description

Detailed Description of the Invention

[0001] The present invention is preferably a tablet fib such as microcrystalline cellulose (MCC).
direct tableting aids (dire) and preferably binders such as β-cyclodextrin.
ct tableting auxiliary). This auxiliary is manufactured by a wet mixing method.

In the pharmaceutical industry at present, for the direct tableting, ie the dry mixing and compression of the tableting aid with the active substance, a number of carrier substances such as cellulose powder, dicalcium phosphate, sorbitol, MCC, dextrose, lactose or It uses lactose / cellulose.

The main conditions required for this type of direct tableting aid are high flowability, sufficient compressibility at low pressure, and loading capacity.
y) is large.

Tablets produced with this type of auxiliaries should exhibit sufficient hardness, low friability, good disintegration properties and solubility.

Commercially available products only partially meet these requirements.

The direct tableting method is a particularly advantageous method for the pharmaceutical industry because it allows stress-free processing of the active substance and low tablet processing and manufacturing costs.

Microcrystalline cellulose has been used worldwide for many years as an aid in direct tableting (eg,
Avicel (R) PH101 and PH10
2). This is especially true for USP XXII / NF
See XVII, page 1915.

The object of the present invention is to meet the aforementioned requirements and to further increase the filling capacity, ie active substance content 70-75%.
To provide a direct tableting aid which does not require the addition of disintegrants.

For this purpose the following main components were selected: A) selected from microcrystalline cellulose, corn starch, mannitol, lactose, sorbitol, cellulose powder, calcium sulphate, calcium phosphate, calcium carbonate, sodium starch glycolate or carboxymethylcellulose calcium. Excipients for tablets, preferably microcrystalline cellulose (60-98% by weight of direct tableting aid, preferably 80-98% by weight) and B) hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, A binder selected from pre-gelatinized starch maltodextrin, polyvinylpyrrolidone, gelatin and α-, β- or γ-cyclodextrin, preferably β-cyclodextrin (direct tablet formation 2 of agent
˜40% by weight, preferably 2-20% by weight) and homogenously in the presence of water using a wet mixing method, in particular wet granulation, spray granulation or spray drying and simultaneous or subsequent drying. It has been found to be achieved with new tableting aids, including

A suitable binder B) is hydroxypropyl methylcellulose, such as PHARMACOAT®, commercially available from Shinetsu, Japan.
Type A, USPXXI, or Dow Chemica
METHOCEL (R), type B; hydroxypropyl cellulose, such as Hercule, USA
s company KLUCEL (registered trademark), gelatin NF X
It is a polyvinylpyrrolidone having a VI and k value of 20 to 95, preferably 28 to 32. This type of polyvinylpyrrolidone is described, for example, in R.P. Vieweg, M .; Reiher and H.A. Scheuerlen, Kunststoff-
Handbuck, 1971, volume II, 5
Page 58, Carl Hanser-Verlag,
Munch or Ullmann, 4th edition, volume
e 19, pages 385-386. k
For definition of values, see Povidone Monograph USP XX
I, 1985.

However, the preferred binders are α-, β
-And γ-cyclodextrin, preferably Roque
β such as KLEPTOSE (registered on the market) manufactured by tte
-Cyclodextrin.

The wet mixing method means that components A and B moistened with water or an alcohol / water mixture, that is, usually with an amount of water insufficient to completely dissolve the binder, are homogenized in a mixing device. And the method of mixing with and drying at the same time or thereafter.

Spray granulation consists, for example, of introducing a mixture of MCC and binder into the fluidized bed at a rather elevated temperature, for example 40-60 ° C., and spraying water to obtain a dry product. Wet granulation is, for example, by mixing the MCC with the binder in a suitable mixer, injecting water with continuous stirring, screening the wet material and then drying, or adding a tableting excipient to the binder. It consists of wetting with an aqueous solution or suspension, screening the wetted material and drying.

Spray-drying usually involves excipient A for tablets and ingredient B.
The suspension water of (1) is sprayed in a suitable spraying device, for example, at the injection temperature of the drying air or at a high temperature of 120 ° C. or lower in the same direction or the opposite direction to the drying air.

The method described above forms a powder having a narrow particle size distribution, for example, a powder having a particle size distribution of about 25 to 250 microns and 60 to 70% of which is in the particle size range of 40 to 75 microns, using finely ground MCC as a starting material. It is advantageous to use it for Of the above-mentioned methods, wet granulation is preferable, and particularly good results are obtained.

The mixture of the present invention thus prepared exhibits excellent tablet-forming properties, particularly high fluidity, high compressibility under low pressure, excellent disintegration properties, and tablet hardness. It differs from known direct tableting aids in that it enhances and reduces friability.

[0017]

The following examples illustrate the preparation of the blends of the present invention and the manufacture of tablets and compare them with direct tablet aids prepared by physical mixing.

Example I Wet MCC (solid content 51%) 5.0 kg β-cyclodextrin 670 g Distilled water 2.9 kg 380 g β-cyclodextrin was suspended in 2.9 kg water, and this suspended water was placed in a kneader. Add to wet MCC at. After thorough mixing for 5 minutes, the material is sieved (0.
5 mm) and dried at 80 ° C. After drying, it is sieved again (0.250 mm) (water content 6% or less).

[0019]Example II Wet MCC (solid content 51%) 5.0 kg β-cyclodextrin 210 g Ethanol 95% 2.0 liters 190 g β-cyclodextrin 2.0 liters
Suspend in 95% ethanol and add 5 kg
Mix well with wet MCC and place on a sieve (0.5 mm).
And dried at 80 ° C. After that, 0.250 mm
Rui Example III MCC 5.0 kg β-Cyclodextrin 1.25 kg Water 4.5 kg β-Cyclodextrin suspension water under stirring is fluidized bed granulator
Continuously spray the MCC in. Injected air temperature is about 60
℃.

The drying process ends when the water content of the final product is below 6%. The material is then screened through a 250 micron screen.

A mixture having the following composition was prepared in the same manner.

1. MCC 90 parts β-cyclodextrin 10 parts 2. MCC 85 parts β-cyclodextrin 15 parts 3. MCC 70 parts β-cyclodextrin 30 parts 4. MCC 60 parts β-cyclodextrin 40 parts 5. MCC 75 parts β-cyclodextrin 25 parts 6. MCC 92.5 parts PVP-K 30 7.5 parts 7. MCC 80 parts α-cyclodextrin 20 parts 8. MCC 80 parts γ-cyclodextrin 20 parts 9. Corn starch 80 parts Cyclodextrin 20 parts 10. Mannitol 70 parts β-Cyclodextrin 30 parts 11. Sodium starch glycolate 80 parts β-cyclodextrin 20 parts 12. Carboxymethyl cellulose calcium 80
Part β-cyclodextrin 20 parts 13. Calcium phosphate 80 parts β-Cyclodextrin 20 parts The product obtained has the following properties: respiration angle: 38-55 °, bulk density: 278-470 g / l, particle size:> 75 micron, 75%, particle size distribution :> 250 micron maximum, 1%.

Tablet Preparation Example A) Mixture of Example I 99.5 parts Magnesium stearate for lubrication 0.5 parts The above ingredients are mixed for 5 minutes and then medium pressure (5) on a rotary tablet machine.
-10 KN) is added to form a biplanar tablet having a diameter of 12 mm and a weight of 500 mg.
The obtained tablets have a hardness of 180 to 290 N and a disintegration time of 5
Minutes.

The properties of the physical mixture of the powder components are clearly inferior to the new tableting aids.

Filling capacity is important for direct tableting aids. For filling tests it is preferred to use substances known to be difficult to tablet, for example paracetamol or acetylsalicylic acid. Besides the large filling capacity,
Good disintegration properties, hardness and friability are also important.

B) A tablet is produced in the same manner as in A) using the following ingredients.

Paracetamol 350 parts Mixture of Example 1 148 parts Stearic acid powder 2 parts The filling capacity in this case is 70%, but filling up to 80% is possible.

Weight: 500 mg Hardness: 115N Disintegration time: 1-2 minutes Friability: 0.5% In comparison with this, Avicel® pH 101
The results of direct tablet formation using (MCC from FMC) are as follows: Weight: 500 mg Hardness: 95 N Disintegration time: 5 minutes Friability: 0.3% Thus, the novel direct tablet of the present invention If forming aids are used, less pressure is required to achieve the same tablet hardness.

C) The same operation as in Example A) is carried out with the following components: Acetylsalicylic acid 400 parts Mixture of Example 1 60 parts Potato starch 35 parts Stearic acid powder 5 parts This has a filling capacity of 80%. Corresponding to.

Weight: 500 mg Hardness: 97 N Disintegration time: 5 minutes Friability: 0.2% Diameter: 12 mm The results of direct tableting using MCC instead of Mixture 5 are as follows: Weight : 500 mg Hardness: 72 N Disintegration time: 5 to 10 minutes Friability: 0.3% Diameter: 12 mm

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/36 A61K 47/36 B 47/40 47/40 B

Claims (4)

(57) [Claims] 1. A main component selected from the following: A) microcrystalline cellulose, corn starch, mannitol, lactose, sorbitol, cellulose powder, calcium sulfate, calcium phosphate, calcium carbonate, sodium starch glycolate or calcium carboxymethyl cellulose, directly. 60 of tablet forming aid
Excipients for tablets, which account for 98% by weight, B) Hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, pregelatinized starch maltodextrin, polyvinylpyrrolidone, gelatin and α-, β- or γ-cyclo A direct tableting aid selected from dextrins and a binder comprising 2-40% by weight of the direct tableting aid in the form of an intimate mixture, the intimate mixture of A and B being prepared using a wet mixing method and simultaneous or subsequent drying. A direct tableting aid prepared in the presence of 2. A direct tableting aid according to claim 1, wherein the content of component A) is 80-98% by weight and the content of component B) is 2-20% by weight. 3. A direct tableting aid according to claim 1, wherein the binder is β-cyclodextrin. 4. The direct tableting aid according to claim 1, which is prepared by wet granulation.