DE2163864A1 - Auxiliary material for the manufacture of solid molded medicaments - Google Patents

Description

PATENT LAWYER J Λ e OO G. I

DR. HANS ULRICH MAY D 8 MÖNCHEN 2, OTTOSTRASSE 1 a TELEGRAMS; MAYPATENT MONKS TELEPHONE CO81O βΟ3ββ2

S-19-P-25 / 1O17

Munich, December 22, 1971 GPA 136 Dr .M. / ro

Shinetsu Chemical Company in Tokyo, Japan

Auxiliary material for the manufacture of solid molded medicaments.

Brief summary (abstract) of the invention:

According to the invention vird as an auxiliary for the production of shaped solid Medicines hydroxyalkyl-alkyl cellulose proposed to be included in the Average number of hydroxyalkyl groups and alkoxy groups which are substituted per anhydroglucose unit in the cellulose 0.05 to 1.00 present and the total number of these groups 0.1 to 1.30. When the excipient is mixed with a drug and the obtained mixture is molded, solid pharmaceutical dosage forms are obtained which are easily contained in the human body disintegrate *

Description of the invention:

The invention relates to an adjuvant (Exeipien ”) for shaping medicaments into solid bodies, which easily disintegrate in the human body.

209831/1059

When molding drugs into tablets, pills, or granules Compresses (pellets) usually contain a certain amount of a drug with one or more types of additives mixed, which are used as form or fillers (excipients), binders, Disintegrants or lubricants work. None of the known auxiliaries of this type is free from disadvantages, and satisfactory auxiliaries, in particular disintegrants, have not yet been found. For example, the products primarily used as additives lactose, microcrystalline cellulose and starch only work then as an explosive when in proportion to the amount

_{fc of} the drug can be used in large amounts, while binders such as gelatin, methyl cellulose, hydroxypropyl cellulose, sodium * carboxymethyl cellulose and polyvinylpyrrolidone never improve or even worsen the disintegration of solid pharmaceutical dosage forms when used in large amounts. The explosives currently in use, ζ.B. Carboxymethyl cellulose and its calcium salt, formic acid gelatin, alginic acid and its salts are inadequate in terms of compressibility and malleability when tableting and easily cause lids to form. In addition, because of their acidity or dissociating properties, they are

w gen types of medications incompatible. Methyl cellulose with a low degree of substitution is better in compressibility and moldability, but inferior in disintegration, while hydroxypropyl cellulose with a low degree of substitution is inferior in compressibility and moldability.

The object of the invention is to provide an adjuvant for the manufacture of solid molded medicaments other than the above mentioned disadvantage · has. Further fine should be erfindungigemäö Auxiliary material to be created, which is the su of a solid pharstaseu -

aoti3i / iosa

BATH

table dosage molded powdered drug an excellent Imparts disintegration properties, as well as an auxiliary substance that increases the hardness of the tablets and at the same time promotes the penetration of water into the tablets * so that it can be used as an adjuvant as well as a disintegrant. Furthermore, according to the invention, solid shaped medicaments are to be created during their production the above-mentioned excipient is used.

The adjuvant according to the invention consists of hydroxyalkyl-alkyl cellulose, wherein the average number of substituted hydroxyalkosgroups in the cellulose per anhydroglucose unit and Alkoxy groups from 0.05 to 1.00 each and the total number of these groups 0.1 to 1.30.

The invention is based on the observation of the inventors that the Ordinary hydroxyalkyl-alkyl cellulose hitherto used as a binder is soluble in water. Therefore, when in the course of disintegration drugs containing this binder come into contact come with water, the hydroxyalkyl-alkyl cellulose dissolves on the surface of the pharmaceutical preparation present in solid, dosed form, gelatinizes and forms a film, which prevents further penetration of water into the inner part of the solid pharmaceutical product. As a result, lasts it takes a long time for the latter to disintegrate. In contrast, hydroxyalkyl-alkyl cellulose, in which the number of hydroxyalkoxy groups and the alkoxy groups in the cellulose per anhydroglycose unit are substituted, are in the range given above, are hardly or not soluble in water. Therefore, water penetrates more easily a solid dosed pharmaceutical product that contains this Contains hydroxyalkyl-alkylcallulose as an auxiliary, and causes its quelXung, Dadirch will be a rapid disintegration of the solid

209831/1059

BATH ORIGINAL

pharmaceutical product. In addition, because of its content of hydroxyalkoxy- and alkoxy groups in the molecule of the solid molded pharmaceutical Product has a high hardness that cannot be achieved with other cellulose ethers is. This is based on the fact found by the inventors that this substance is both an excellent excipient as also acts as a binder.

For examples of the present invention as an adjuvant hydroxy alkyl-sdkylcellulose are hydroxypropylmethylcellulose, Hydroxypropyläthylcellulose, Hydroxyäthylmethylcellulose, hydroxyethyl w ethylcellulose, hydroxybutyl methylcellulose, Hydroxybutyläthylcellulose and mixtures thereof. In order to fulfill the above mentioned object of the invention, the mean number is the substituted in the cellulose per anhydroglucose unit hydroxyalkoxy groups of 0 05 to 1.00 _t 'is the average number of anhydroglucose unit in the Cellulosepro substituted alkoxy groups from 0.05 to 1.00 and the total number of both groups is 0.1 to 1.30.

In order to achieve the purposes of the invention more advantageously, the hydroxyalkyl-alkyl cellulose is preferably in the form of a 2 percent strength aqueous jtenatron solution used (weight of hydroxyalkylalkylcellulose based on the weight of a 10 percent aqueous Caustic soda solution), which has a viscosity of 2 to 300 cps, preferably 5 to 100 cps, at 20 ° C.

If the dry compression method (or the so-called direct pressing method) is used in forming the medicament into a solid body), the particle size of the hydroxyalkyl-alkyl cellulose should not exceed 150 yum or less. preferably at most 100 µm

209831/1059

at an apparent density of at least 0.4 g / cm ³ or preferably at least 0.5 g / cm 3, since such hydroxyalkyl-alkyl cellulose has better flowability. The molded products obtained are superior in press formability and disintegrability and hardly show abrasion.

The hydroxyalkyl-alkyicellulose used according to the invention is produced by the known, customary process by (I) dipping pulp into a 10- to 50-percent aqueous caustic soda solution, pressing it and, if necessary, aging it by heat treatment, (II) the product strings alkyl chloride and alkylene oxide simultaneously or placed one after the other in a reaction vessel and the substances are reacted with one another at 20 to 90 ° C for 2 to 8 hours, (III) then the crude hydroxyalkyl-alkyl cellulose produced in this way is neutralized if it is alkaline »(IV) the hydroxyalkyl-alkyl cellulose then washed with hot or cold water, dried and pulverized or, before drying, the hydrous hydroxyalkyl-alkyl cellulose is cooled to 0 to 10 ° C., shaped into pellets in an extruder, dried and then pulverized. In order to set the desired particle size and apparent density, the pulverized cellulose can be further ground in an atomizer, a ball mill or a vibration mill.The hydroxyalkyl-alkyl cellulose powder obtained in this way is neutral, white and odorless and does not contain any physiologically harmful substances. Bs is therefore free from all the disadvantages with which the usual disintegrants are afflicted.

The molding of the medications into a solid body using the invention may be by the known methods values was carried out except that the hydroxyalkyl alkylcellulosepulver mentioned above is v 'r- applies'. This powder is the drug in a ratio of 1 to 50 %, preferably 5 - 30 %, based on the weight of dtr

201 * 11/101

added to solid pharmaceutical dosage form. The mixture can then be shaped by known methods, such as the dry process, the wet process, etc., ^ u tablets, pills or granules.For example, when using the wet method, the drug can first be formed into granules to which the cellulose ether is added (subsequent addition) »Or the mixture of the powdered medicament and cellulose ether can be formed into granules (previous addition). In any case, the tablets produced from the mixture show satisfactory disintegration properties) When mixing the cellulose ether and medicament, lubricants, for example talc, wax or a metal salt of. , Stearic acid are added, and well-known binders, for example polyvinylpyrrolidone, Hydro3cypropylcellulose _# methylcellulose and polypropylene glycol. Known auxiliaries, for example starch, lactose, cane sugar, gum gum, tragacanth gum, gelatin and microcrystalline cellulose, can also be added in such amounts that the effects and properties of the hydroxyalkyl-alkyl cellulose are not impaired. The solid pharmaceutical dosage forms produced according to the invention can for specific purposes on with coating agents such as sugar or to dissolve in the intestine t certain coating compositions are coated ·

In the following examples, all parts and percentages are parts by weight and percentages by weight. The viscosity, grain size and apparent density of the cellulose ether powders, the disintegration (disintegration) measured as time, the hardness and the compression ratio of the tablets were measured under the following conditions.

Apparent density t

_; 90 g of the sample (cellulose ether powder) are placed in a 250 ml MeQ cylinder and placed in a shaker for 3 minutes.

BATH ORIGINAL - '

shakes. The volume (cm ³ ) <the sample in the cylinder was then measured * and the value obtained was used to calculate the apparent density of the sample.

Disintegration:.

The disintegration of a tablet made from the drug and the cellulose ether powder was measured according to General Test Method 25 of Japanese Pharmacopoeia.
Hardness:

The hardness of a tablet like the one given above was measured with a Monsanto type tablet hardness tester. Compression ratio:

The difference between the volume of the sample and that of a tablet formed from it (in cm3) was divided by the volume of the powdery sample (in cm ³ ) and the value obtained (in %) was used to indicate the compression ratio. Particle size distribution t

100 g of the sample were placed on a set of three sieves of 0.147 «0 * 074 and 0.037 mm mesh size (100, 200 and 400 mesh Tyler), and after 30 minutes of shaking at a frequency of 128-130 per minute, the distribution of the particle sizes in Weight percent determined.
Viscosity:

2% of the sample was dissolved in a 10 percent aqueous caustic soda solution, the viscosity of which was measured at 200 ° C. with a low-temperature viscometer.
- MS:

With "M.S." (Molar substitution) is an average number of Moles of a hydroxyalkylating agent or an alkylating agent given as substituents in the cellulose per anhydrous glucose unit are present. This number is obtained using the Zeisel-Morgan method certainly.

209831/1059

Example 1 .

2.5 parts of polyvinylpyrrolidone (K-30) are dissolved in 92 parts of lactose in 10 parts of methanol », and after thorough kneading is forced the mixture through a 0.495 mm (32 mesh) screen to granulate it. The granulate produced in this way was dried for 3 hours at 70 ° C and passed through a 0.495 mm sieve again to regulate it. The granules were given 0.5 parts of calcium stearate and 5 parts of the table 1 indicated auxiliary added. The mixture was tabletted, whereby the sample having the properties shown in Table 1 was obtained. When using methyl cellulose showed the tablets obtained have poor disintegration properties, while when hydroxypropyl cellulose is admixed the tablets are insufficient Showed hardness. The use of Hydroao ^ ropylraethylcellulose According to the invention, tablets with a satisfactory hardness and disintegration property were obtained,

Table 1.

1
control 0.6 2
comparison 3
invention 0.2 Auxiliary material (type) i methyl
cellulose HydroxyproiyL- Hydroxypropyl-
^: cellulose methyl cellulose 0.4 Physical Properties 10 15th - of the auxiliary material: 1.5 0.5 Methoxy group (M.S.) Hydroxypropoxy
group (MS) 45 0.6 45 Viscosity (cps) 300 12th 299 Apparent density
(g / cm3) 7.5 0.5 7.0 - tablets ι 80 15th Compression ver
ratio (X) 45 Weight (mg) 298 Hardness (kg) 5.5 Disintegration time (sec) 20th

209131/1059

Example 2

An experiment similar to that of Example 1 was carried out with the only difference that instead of that given in Table 1, the in Table 2 listed auxiliaries were used. The received Tablets had the properties given in Table 2.

Table 2

Control invention

Excipient {type):

HydrO3cyäthyl methyl cellulose Hydroxyethyl
methyl
cellulose

invention

Hydroxyethyl
methyl cellulose

Physical properties - of the auxiliary ι

Methoxy group (M.S.)

Hydroxyethoxy group (M.S.) Viscosity (cps)

Apparent density (g / cm3)

0.03 0.25 0.25 0.05 0.05 0.10 20th 20th 0.4 0.4 0.4

- tablets ι

Compression ratio (%) 42

Weight (mg) 299

Hardness (kg) 90

Disintegration time (sec) over 300

42 42 300 300 9.0 9.0 90 49

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Example 3

94.5 parts of icainite (CaHP03), 0.5 parts of calcium stearate and 5 parts of the excipient given in Table 3 were mixed well and tabletted according to the direct compression method. The properties of the samples obtained are shown in Table 3. In the case of use no tablets with high hardness were obtained from CMC-Ca, since cap formation occurs when the compression ratio is increased would.

Table 3

Auxiliary substance (type) ι

7 8 9 Comparison comparison invention

CMC-Ca micro-hydroxy, crystalline propyl cellulose raethyl-

cellulose

Physical properties - of the auxiliaries t Methoxy group (MS) Methoxypropoxy group (MS) Viscosity (cps) Apparent density (g / cnr)

- particle size distribution (%)

0.6

0.5

> O, 147 mm 3.1 1.0 0.147-0.074 mm (100 - 200 mesh) 39.0 12.2 0.074-0.037 mm (200 - 400 mesh) 45.0 40.3 <O, O37 »η 12.8 46.6 of tablets j Compression Ratio (%) 50 43 Weight (mg) 294 295 Hardness (kg) 4th 7th Disintegration time (sec) 11 300

0.2 0.3 8.0 0.5

0.5 2.8

44.4 52.3

41

295

15th

209831/1069

Example 4

An experiment similar to that described in Example 3 was carried out, with the difference that only the auxiliaries indicated in Table 4 were used instead of the auxiliaries indicated in Table 3. The properties of the tablets obtained are shown in Table 4.

Tabel Auxiliary material (type) t 4th 11
invention 12th
invention Physical Properties 10
comparison Hydroxy
propyl
methyl-
cellulose Hydroxy
propyl
methyl-
cellulose - the auxiliary materials: Hydroxy
propyl
methyl-
cellulose Methoxy group (M.S.) Hydroicypropo: xy group (M.S.) 0.8 0.3 Viscosity (cps) 0.8 0.1 0.2 Apparent density (g / cm ^) 0.7 15th 17th - particle size distribution (50 16 0.45 0.55 > O, 147 ram 0.55 0.147-0.074 mm
(100 - 200 mesh) 0.3 0.1 0.074-0.037 mm
(200 - 400 mesh) 0.1 1.8 2.3 <O _t mm O37 1 »9 39.5 42.6 - of the tablets: 40.3 58.4 55.0 Compression ratio {%) 57.7 Weight (mg) 39 41 Hardness (kg) 40 319 320 , Decay time (sec) 320 8th 8th 8th 40 20th 240

209831/1059

Example 5

70 parts of mefenecine, 20 parts of lactose, 10 parts of starch and 5 parts of the auxiliary substance shown in Table 5 were thoroughly mixed, and to the mixture 4 parts of polyvinylpyrrolidone were dissolved in Given 20 parts of ethanol. The mixture was kneaded well and then passed through a wire mesh of 0.991 ram mesh size (16 mesh) pressed and dried for 2 hours at 90 ° C, giving a granulate was obtained. The granulate was mixed with 1 part of magnesium stearate and tabletted. The tablets thus obtained had the properties given in Table 5.

Table 5

13 14 15 Comparison invention invention

_Hl IP «otoff HiiJrsstoiri:

Hydroxy- hydroxy- hydroxypropyl- propyl- propylmethyl- methyl-methyl cellulose cellulose cellulose

Physical Properties 1.8 0.4 0.4 - the auxiliaries ι ) 0.3 0.1 0.1 Methoxy group (M.S.) 1500 1000 40 Hydroxypropoxy group (M.S.) 0.4 0.55 0.55 Viscosity (cps) Apparent density (g / cm *) 38 41 42 - tablets j 350 349 350 Compression ratio (%) 8th 8th 8th Weight (mg) over 300 60 30th Hardness (kg) Disintegration time (sec)

209831/1059

Example 6

50 parts of vitamin C (ascorbic acid), 20 parts of lactose, 10 parts Talc and 20 parts of the excipient given in Table 6 were well mixed and tabletted according to the Direktpreßraethode. The properties of the tablets obtained are shown in Table 6.

Tabel

Auxiliary substance (type) ι

16

comparison

Hydroxypropyl ethyl cellulose

17 Invention

Hydroxypropyl ethyl cellulose

18 Invention

Hydroxypropyl ethyl cellulose

Physical properties "of the auxiliary materials:

Ethoxy group (M.S 0 hydroxypropoxy group (M.S.) Viscosity (cps) Apparent density (g / cni3)

- Particle size distribution (%) > 0.147 now 0.147 - 0.074 mm (100 - 200 mesh) 0.074 - 0.037 mm (200 - 400 mesh)

<O, Q37 »TO - tablets t

Compression Ratio (%) Weight (mg)
Hardness (kg)
Disintegration time (sec)

1.2 0.7 0.7 0.4 0.1 0.1 25th 24 26th 0.55 0.40 0.55 0.5 2.5 1.0 4.0 38.4 2.9 49.5 41.3 58.2 46.0 17.8 38.9 33 43 43 201 201 200 9.0 4.0 7 »0 180 40 45

209831/1059

Example 7

60 parts of bromovalerylurea, 25 parts of lactose and 3 parts of hydroxypropyl cellulose (M.S .: 3.5), which were dissolved in 10 parts of ethanol, were thoroughly soldered, granulated and kept at 80 ° C for two hours dried. The granules were sieved to have particle sizes ranging from 0.991 to 0.833 mm (16 to 20 mesh), and 2 parts of Carbowax 4000 (protected name of one manufactured by Carbide and Carbon Chemicals) were added to the grains Polyethylene glycol) and 10 parts of the excipient given in Table 7. The mixture was tabletted. on Samples 19, 20 and 21 were produced in this way Properties are given in Table 7.

Tabel Excipient (type): 7th 20th
invention 21
invention • 45 Physical Properties 19th
comparison Hydroxy
butyl
methyl-
cellulose Hydroxy
butyl
ethyl-
cellulose 401 - the auxiliary materials: without 7.0 Hydroxybutoxy group (M.S.) 70 Methoxy group (M.S.) 0.1 0.1 Ethoxy group (M.S.) 0.5 Viscosity (cps) 0.5 - of the tablets: 5.5 15.0 Compression ratio {%) Weight (mg) 45 Hardness (kg) 45 402 Disintegration time (sec) 400 10.0 4.5 50 > 300

209831/1059

Example 8

50 parts acetylsalicylic acid, 5 parts caffeine, 10 parts starch,

5 parts of calcium stearate and 30 parts of that given in Table 8

The excipients were mixed homogeneously and tableted according to the Direktpreßme method. The properties of the samples 22, 23 and 24 thus obtained are shown in Table 8.

Table 8

22nd 23 24 comparison invention invention Hydroxy Hydroxy Excipient (type): none ethyl-
methyl- ethyl-
ethyl- cellulose cellulose Physical Properties - the auxiliary materials: Hydroxyethoxy group (M.S.) 0.2 0.2 Methoxy group (M-S.) 0.1 Ethoxy group (M.S.) 0.1 Viscosity (cps) 100 95 Apparent density (g / cm3) 0.5 0.5 - particle size distribution (%) > 0.147 mm 0.2 1.0 0.147-0.074 mm (100 - 200 mesh) 2.5 2.8 0.074-0.037 mm (200 - 400 mesh) 51.3 49.6 <0.037 mm 46.0 46.6 - of the tablets: Compression ratio (#) 55 40 39 Weight (mg) 500 503 501 Hardness (kg) 3.0 6.0 6.0 Disintegration time (sec) y 300 45 60

209831/1059

Claims (6)

PATENT CLAIMS ' ) Auxiliary material for the production of solid shaped medicaments, consisting of hydroxyalkyl-alkyl cellulose, worrln the average number the hydroxyalkoxy groups and the Alkoay groups included in the Cellulose are present as substituents per anhydroglucose unit, each from 0.05 to 1.00 and the total number of groups from 0.1 to 1.30 be. 2.) adjuvant according to claim 1, characterized in that the Hydroxyalkyl-alkyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, Hydroxyethyl methyl cellulose, hydroxyethyl ethyl cellulose, hydroxybutylmethyl cellulose, hydroxybutylethyl cellulose or a mixture thereof. 3.) adjuvant according to claim 1 or 2 _r, characterized in that the hydroxyalkyl-alkyl cellulose has a viscosity of 2 to 300 cps, preferably 5 to 100 cps at 20 ° C, if 2 percent ~ by weight thereof in a 10 percent by weight solution of Caustic soda are dissolved. 4.) adjuvant according to one of claims 1 to 3, characterized in that the hydroxyalkyl-alkyl cellulose in particles with a size of at most 150 μm, preferably at most lOOyum, and with an apparent density of at least 0.4 g / cm ³ , or preferably at least 0.5 g / cm3. 209831/1059 5.) drug dosage in the form of a solid body, characterized in that 1 to 50 % of its weight consists of an excipient according to one of claims 1 to 4. 6.) Drug dosage in the form of a fixed. Body according to claim 5, characterized in that it additionally contains a known lubricant and / or a known binder. 7 ·) Drug dosage in solid form according to claim 5 or 6, characterized in that it is coated with a known coating agent » vie sugar, and / or a known coating agent dissolvable in the intestine is coated. 209831/1059