DE2544881A1 - TABLET - Google Patents

Description

NIPPON KAYAKU KABUSHIKI KAISHA, Tokyo, Japan

HAYASHIBARA BIOCHEMICAL LATORATORIES INC., Okayama-shi, Japan

tablet

The invention relates to a tablet produced by the direct pre ^ process.

The tableting processes are divided into three groups. A first method is the liaßgranulierverfahren, in which a pharmacologically active substance with a binder (Tablet base) is mixed. Then water is mixed in or an organic solvent and the resulting Mixture is kneaded, granulated and dried and sieved. Thereafter, the granules obtained are coated with a lubricant added and the mixture is compressed into tablets.

The second method is a dry granulation method in which a pharmacologically active substance is mixed with a binder for tablets is mixed. Then the mixture is granulated in a dry granulator and the granules obtained is compressed into tablets. The compression properties of the tablets are usually worse because the properties of the Granules vary.

A third method is the direct compression method, in which a pharmacologically active substance is added to a tablet base (Binder) is mixed, whereupon the obtained

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Mixture is compressed into tablets without prior granulation. Recently, the direct pressing method has gained importance increased and the other procedures partially replaced. In the direct pressing process, you can use the kneading stage, avoid the granulation stage, drying stage and screening stage of the wet granulation process. This "offers substantial Advantages in terms of time and costs. Further there are advantages with regard to the stability of the pharmacologically active substance.

The wet granulation method, however, has the advantage that the flowability of a powder with poor flowability by the granulation is improved and that the grain strength is increased, whereby the tabletting is made easier. on the other hand does the direct pressing process have the disadvantage that for this only a few binders come into question, which have satisfactory compression properties and satisfactory compatibility and have stability (stability against loss of enzyme activity at high pressure of the pressing process) (Yakuzaigaku 33 (1) 1-5, 1973 and 33 (1) 5-9, 1973; pressure inactivation of digestive enzymes (II) (III). Tsuneo Uchida, et al (Chugai Pharmaceutical Co., Ltd., Ukima Factory)). Furthermore, the physical stability of the tablet is lost with aging.

So far, microcrystalline cellulose has mainly been used as a binder for the direct compression process. A tablet with a content of microcrystalline cellulose as a binder, produced by the direct compression process, however, shows a high coefficient of expansion in a high humidity atmosphere. Hence it disadvantageously arises in the case of tablets with a sugar coating and a content of microcrystalline cellulose to cracks. In addition, the disintegration of a tablet containing microcrystalline cellulose depends to a large extent on the Pressing force. The disintegration is very slow when the tablet is pressed with a pressure above a certain limit value

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becomes so that the dissolution of the 'active substance is too slow he follows. Such a tablet is therefore quite ineffective.

It is therefore the object of the present invention to create a tablet which can be produced by the direct compression process and meets the stated requirements. In particular, the tablet should have excellent compression properties and a have excellent hardness similar to a microcrystalline cellulose tablet and moreover in an atmosphere high humidity has an expansion coefficient which is significantly lower than the corresponding expansion coefficient in the case of a tablet with microcrystalline cellulose and which, in addition, no reduction in activity when pressed shows and disintegrates well and has a sweet taste.

According to the invention, this object is achieved by a tablet with a content produced by the direct compression process dissolved in maltose as a binder.

Maltose is obtained by separating the α-1,6-glucosidic Binding of starch using α-1,6-glucosidase, straight-chain connections being obtained, which are subsequently treated with ß-amylase.

When a tablet is made by the direct compression method using maltose as a binder, one can Mixing in lubricants and other additives as well as disintegrants for conventional pharmaceutical preparations. the The type of pharmacologically active substance is not subject to any restrictions as long as it is suitable for tableting. The content of the pharmacologically active substance can be in the range from 0.1 to 85% by weight. The content of maltose can be in the range of 5-99 wt .- $ and preferably in the range from 10 to 99 wt. If the fluidity and the When the pressing properties of the pharmacologically active substance are good, the content of maltose may be low and if otherwise the flowability and the compression properties of the

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active substance are small, the content of maltose is preferably large. In general, it is "preferred to have a to provide high maltose content if pills with a sweet taste are to be made. One can do more Add additives which are conventionally used for the production of tablets by the direct compression method be e.g. B. crystalline lactose, mannitol, sorbitol, calcium sulfate, anhydrous calcium phosphate or the like. The The content of further additives is preferably in the range from 0-30% by weight. Typical disintegrants include corn starch, potato starch, calcium carboxymethyl cellulose, hydroxypropyl starch or the like. The content of the disintegrant is preferably in the range of 0-20% by weight. Typical lubricants are talc, silica fine powder, magnesium stearate, stearic acid, palmitic acid or the like. The lubricant content is preferably in the range from 0.1 to 2.0 wt .- ^. In the method for producing tablets according to the present invention, a pharmacologically active substance is mixed with maltose and if desired with other additives, a lubricant and a disintegrant mixed. The mixture is pressed directly with a tablet machine. One can in particular Use eccentric presses or rotary tablet machines.

The following are the advantages of the tablets according to the invention explained on the basis of experiments.

Attempt 1

Maximum hardness and disintegration properties (1) Test method:

99.5 parts by weight of maltose are mixed with 0.5 parts by weight of magnesium stearate mixed. One with a punch (tablet punch) with a diameter of 10 mm and a curvature of 7.5 R equipped tablet machine, the punch of which is equipped with a tension meter,

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is used for the production of tablets with a weight of 270 mg, a hardness of 6 kg and a thickness of 5.00 mm. The mixture is pressed directly into tablets with this tabletting machine, the pressure being varied. The average pressure of the upper punch and the lower punch are measured and the hardness of the pressure produced The tablet is eaten with an Erweka hardness tester. The maximum hardness is determined (tablet A according to the invention). The term "maximum hardness" means the maximum hardness value not obtained by increasing the pressure is changed or the hardness at the top of the curve. The disintegration test is carried out according to Pharmacopoeia of Japan, Volume 8, pages 824-846. For comparison, microcrystalline cellulose is used instead of maltose and tableting is repeated under the same conditions, the weight of the tablet being 235 mg (tablet B, comparison).

97.5 parts by weight of a mixture of lactose and corn starch (3: 1) are mixed with 2 parts by weight of polyvinylpyrrolidone, whereupon a granulate is produced from this mixture according to the hate granulation process. The granulate is 0.5 Parts by weight of magnesium stearate mixed. The above tableting process is repeated, but the mixture obtained is used and tablets with a weight of 290 mg can be produced (tablet C, comparison).

(2) Test result:

(a) Fig. 1 shows the dependence of hardness on pressure (Maximum hardness test): Curve A shows the hardness of a tablet made with maltose according to the present invention. The hardness is plotted on the ordinate and the pressure on the abscissa. Curve B relates to a tablet with microcrystalline cellulose and curve C relates to a tablet with lactose and corn starch.

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From Pig. 1 it can be clearly seen that the tablet made using maltose is essentially the same Has pressing properties like one using microcrystalline Cellulose made tablet. In contrast, the maximum hardness is one using lactose and corn starch manufactured tablet low. The maximum hardness value is around 12.5 kg.

(b) Influence of pressure on tablet disintegration (disintegration test:

The test results are in Pig. 2 shown. Curve A ¹ shows the dependence of the time taken for the tablet with maltose to disintegrate according to the present invention (ordinate) on the compression pressure (abscissa);

Curve B 'shows the dependency of the disintegration time of a tablet with microcrystalline cellulose and curve C. shows the dependence of the disintegration time of a tablet with Lactose and corn starch from the press. From Fig. 2 it can be clearly seen that the inventive using maltose tablet produced at a typical pressure of 1000-2000 kg disintegrates within a short time, the time until disintegration does not depend significantly on the pressure. In this In terms of the tablet of the present invention, it is essential to a tablet made with microcrystalline cellulose think. A tablet made with lactose and corn starch has a relatively low dependence of the disintegration time on the pressure, but it has the disadvantage described above a low maximum hardness. The tablet produced according to the invention using maltose shows both in the experiment (a) as well as in the experiment (b), excellent properties.

Attempt 2

Weariness test and weight gain test

and the thickness at different relative humidity:

(1) Making the sample:

99.5 parts by weight of maltose are mixed with 0.5 parts by weight of magnesium

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mixed stearate. One uses a tablet machine with a punch with a diameter of 10 mm and a curvature of 7.5 R (7.5 mm). There will be tablets with a Hardness of 5 kg directly pressed (tablets according to the invention). For comparison, this procedure is repeated using microcrystalline cellulose instead of maltose.

(2) Test method:

(i) The friability test is performed with a friability test facility carried out by Roche.

(ii) The test of the increase in thickness and weight at different relative humidity is carried out ^{at 25 ° C.}

(3) Test result:

The test results are summarized in Tables 1 and 2.

Table 1
(Residual friability in wt .-? £)

Invention comparison test duration 10 min 99.95 i ° 99.90 #

Table 2

(Increase in the weight and thickness of the tablets at different relative humidity and at 25 C after 2 days)

weight Tablet currently
d.Creation 52 $ r • τ? 74 $ r.h. 84 io rF Invent
manure thickness 280 mg +0.43 * + $ 2.21 +2.16 io Ver
same weight 5.07 mm +0. mm + O, O35mm +0.036 mm thickness 240 mg +0. * +2.38 io + $ 0.29 5.17 mm +0, mm +0.118 mm +0.110 mm , 01 , 30 , 006

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It can be clearly seen from Table 1 that there is no difference between the tablet according to the invention and the comparative tablet with regard to the fragility of more than 74 ° . The weight gain of the tablet according to the invention is essentially equal to the weight gain of the comparison tablet. This is a considerable advantage of the tablet according to the invention. The large coefficient of expansion of a tablet with microcrystalline cellulose leads to the formation of cracks in a sugar coating on such a tablet.

In the following, the invention is explained in more detail with the aid of exemplary embodiments.

example 1

50 g aspirin are mixed with 14 g maltose and 4 g corn starch. A tablet machine is used with a punch with a diameter of 12 mm and a curvature of 20 R. The resulting mixture is continuously made into tablets, each weighing 680 mg and having a thickness of 5.25 mm and with a hardness of 8 kg - 1 kg, namely 70 tablets per minute. Excellent Tablets with a weight fluctuation coefficient (n = 50) of 1.6 ^ and with a disintegration time (n = 6) from 2 -3 minutes.

Example 2

50 g of 2,4'-dimethyl-3-piperidinopropiophenone v / earth with 1 g Silica anhydride powder is mixed and then 150 g are added Add maltose and 42 g corn starch. Then add 2 g of magnesium stearate. A tablet machine is used with a punch with a diameter of 9.0 mm and one

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Curvature of 7.0 R. This machine continuously produces tablets from the mixture obtained, each weighing 245 mg and having a thickness of 2.65 mm. 70 tablets / min are produced. The tablets show a coefficient of weight fluctuation (n = 50) of 1.3 $, a hardness (n = 20) of 5.5 kg - 1 kg and a disintegration time (n = 6) of 2-3 min and a friability residue of 99.95 / ö. The maximum hardness of the mixture is above 15 kg. These tablets have been sugar-coated in a conventional manner. The tablets obtained in this way are stored at a relative humidity of 74 λ> at 50 ^° C. and the formation of cracks is examined.

50 g of 2,4'-dimethyl-3-piperidinopropiophenone are mixed with 1 g mixed with fine silicon dioxide powder and then 50 g of microcrystalline cellulose and 117 g of crystalline lactose are added, before adding 2 g of magnesium stearate. Then the same tabletting machine is used with a punch with a diameter of 9.0 mm and a curvature of 7.0 R for the continuous production of tablets weighing 220 mg, a thickness of 2.65 mm and a Hardness of 5.5 kg - 1 kg from the mixture obtained. The tablets obtained in this way are used in a conventional manner provided with a sugar coating. The cracking of the sugar coating is examined.

Within 3 days it comes to $ 100 of the sugar-coated Tablets with a content in microcrystalline cellulose for cracking. In contrast, it occurs within 14 days the sugar-coated tablets according to the invention with a maltose content of only 30% lead to the formation of cracks.

Example 3

A mixture of 15 g of blomelain (10,000 blomelain units = about 15 mg) and 30 g of corn starch are mixed with 98.5 g of maltose and then 1.5 g of magnesium tearate are added.

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A tablet machine with a punch with a diameter of 7.5 mm and a curvature of 5.5 R is used for the continuous production of tablets weighing 145 mg, a thickness of 3.7 mm, a hardness of 4 to 5 kg and a disintegration time of 2-3 min. 70 tablets / min are produced. The activity of the blomelain is 10,300 units in the powder mixture and 10,300 units in the tablet. Thus, no change is found. On the other hand, tablets are made by conventional granulation using lactose instead of maltose. 145 mg of the granules show a blomelain activity of 9800 units. A tablet produced from the granules shows a blomelain activity of 9250 units. This corresponds to a reduction compared to the granulate of about 6 fo.

The tablets are coated with a coating solution of 10 wt. Parts of cellulose acetate phthalate, 3 parts by weight of purified sesame oil, 30 parts by weight of acetone and 53 parts by weight of 2-ethoxyethanol coated. Blomelain tablets are obtained, which are soluble in the intestine.

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Claims (7)

7544881 PATENT CLAIMS \ Λ \ Tablet made by the direct compression process with a pharmacologically active substance and maltose. 2. Tablet according to claim 1, characterized by 5 to 99.8 wt .- ^ maltose and 0.1 -. 85 wt -4 "of the pharmacologically active substance. 3. Tablet according to one of claims 1 or 2, characterized by 0.5-2 wt .- ^ of a lubricant, 0-30 wt .- ^ of an auxiliary and 0-20 wt .- ^ of a disintegrant. 4. Tablet according to claim 3, characterized in that the lubricant talc, fine silicon dioxide powder, Is magnesium stearate, stearic acid or palmitic acid. 5. Tablet according to claim 3, characterized in that the excipient is crystalline lactose, mannitol, sorbitol, calcium sulfate or calcium phosphate anhydrous. 6. Tablet according to claim 3, characterized in that the disintegrant is corn starch, potato starch, calcium carboxymethyl cellulose or is hydroxypropyl starch. 7. Tablet according to one of claims 1 to 6, characterized by a coating. 609817/1210 Blank page