LU83058A1 - LIQUIDATORS BASED ON PLANTAGOSAME AND SENNA FRUIT AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

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Dr.Madaus & Co. Cologne-Merheim

Laxatives based on plantago seeds and senna fruits and process for producing the same

The invention relates to a laxative based on plantago seeds and senna fruits and to a method for producing the same.

The use of plantago seeds (Plantaginis ovatae Semen) for medicines to regulate bowel activity is known. These seeds have a considerable ability to swell and exert a physical stretch on the sensitive receptors of the intestinal walls. According to a known method (DE-PS 1 103 520), the seeds are finely ground, pasted with water to a viscous paste and dried in strand form, crushed and finally coated.

The effect of the fruits of Senna angustifolia as a herbal laxative is also known. Laxatives are also known, which contain both principles of action, in which the physical effect of the plantago seeds is supported by the pharmacologically stimulating principle of action of the ingredients of the senna fruits in order to achieve a better overall effect.

When such combination preparations are used, however, undesirable side effects are often observed, which are due to an excessive irritation of the mucous membranes when the alkali-sensitive and oxidation-prone ingredients of the senna fruits (sennosides) are massively affected, and the adverse effects of sennoside degradation products.

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In order to largely rule out such adverse side effects, a preparation has now been developed in which the ground product of Fructus Sennae is protected from premature attack and a longer-lasting milder effect is achieved by delayed release of the sennosides.

The laxative according to the invention developed accordingly on the basis of ground plantago seeds and senna fruits is essentially characterized in that the senna fruit particles largely from dried on planta. gosamen ground product slime are enclosed.

In the laxative according to the invention, therefore, the two pharmaceutical components are not mechanically isolated next to one another, but the particles of the ground senna fruit are surrounded by a “protective layer” made from the mucilages of the plantagos seed products. By means of this coating, the sennosides are largely protected from undesired changes and their release is greatly delayed, so that a longer-lasting, retarding, milder effect is achieved.

This protective effect can be further stabilized and strengthened if the mixture of the two ground components, Plantaginis Semen ovatae and Fructus *

Sennae angustifoliae, in the course of grinding plantago seeds, adds small portions of seed shells that have been lost for restitution. These husks have a far greater swellability compared to ground plantago seeds as a grinding product due to the higher concentration of mucilages in them: Measurements of the swelling number according to DAB 8, page 24, gave an average * of 57 samples per gram * for 30 samples ground plantago seed husks, while an average of 15 ml per gram was found for the ground plantago seeds.

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In accordance with this greater swelling capacity of the ground plantago seed shells, the tendency to form the desired coating of the disperse Fructus Sennae particles increases when they are added, which appears to be particularly advantageous for medicinal use.

The weight ratio of the plantago seed portion to the senna fruit portion in the laxative according to the invention is preferably about 4 to 5: 1, a weight ratio of the plantago seed, plantago seed husk and senna fruit ground product portions of approximately 52: 2.2: 12.4 being chosen in particular.

The laxatives according to the invention are produced by a process which is characterized in that the separately ground plantago seeds and senna fruits are dry-mixed, the mixture is pasted quickly and uniformly with as little water as possible, the pasted mixture is granulated and to a residual moisture content of at most 3 , 5% dries and the dried granules are finally coated.

The ground plantago seeds and senna fruits are preferably in a weight ratio of 4: 1 to 5 s 1 with the additional addition of about 3 to 4% by weight of ground plantago seeds! , Seed husks worked through with 30 to 40% water, whereby.

only limited swelling occurs. In this swollen state, the mucilages of the milled Plantago ovata seed husks (husks) are capable of spreading due to the sufficient immobilization of the water in the swelling layers, although there is adequate further processability of the mass. Larger amounts of water, on the other hand, lead to processing problems, while the lyospheres are only subliminally pronounced when insufficient amounts of water are added, so that the spreading is not achieved to the desired extent.

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Before grinding, the plantago seeds and senna fruits are expediently dried at 80 ° C. to a moisture content of 3.5% and the senna oil content of the sena component by mixing different lots to about 2.0 to 2.5% by weight, preferably 2 , 2 # set. During grinding, the temperature of the material to be ground should not rise above 80 ° C.

To achieve uniform moistening and swelling, the dry-mixed ground products are continuously brought together with water in small proportions and subjected to intensive mixing in a number of mixing stages. This is preferably done in a number of screw mixers connected in series.

In this way, an even rise and swell is achieved within a few minutes.

For the purpose of establishing the necessary internal equilibria between the polymolecular protective layers, which are formed by mucilage layers of ground Plantago ovata seeds and seed husks, and the dispersed Senna fruit particles located in their vicinity, it is advisable not to immediately process the mixture in the extruder, but preferably to interpose waiting times of 1 to 2 hours.

The material fed to the extrusion press is then extruded at a pressure of about 50 atm and chopped into granules of 2.1 to 2.2 mm in length at the outlet of the press with a rotating knife. Even in this condition, the product should have a moisture content in the region of 35%.

The subsequent drying takes place in a fluidized bed dryer with vibration feed within about /, / ii · # - 9 - 25 minutes to residual moisture of not more than 3.5%, which is particularly expedient, with an air temperature of 125 ° C. and an air volume of approx. 8000 cbm is worked per hour. The dry granules are sieved to remove granules that are smaller than 1 mm or larger than 3 mm. Their bulk density is 510 to 530 g / l. Finally, this granulate is brought together with a coating suspension and processed into small sugar-layer coated tablets, it being possible to add auxiliaries which are customary in coating technology to the coating suspension.

*

A particularly preferred embodiment of the product described above consists of

Plantago Semen ovata 52,000 parts by weight

Plantago Semen ovata (bowls) 2,200 "

Sennae Fructus angustifoliae 12.400 "

Talcum 12.459 "

Gum arabic 1,400 "

Ferrum Oxydatum. E 172 0.697 ”

Color index (1956) 77492 77499 77491

Tragacanth 0.750 "

Oleum Carvi 0.035 "

Oleum Salviae 0.035 ”

* Y

Oleum Menthae Piperitae 0.070 "

Paraffinum subliquidum 0.240 n

Paraffinum Durum 0.110 n

Saccharum 17.604 "per 100 parts by weight of coated granules.

• / Ls - »f - 10 - s

Another preferred embodiment consists of

Plantago Semen ovata 54,200 parts by weight

Sennae Fructus angustifoliae 12,400 ”Other ingredients as previously stated.

The number of bacteria is constantly monitored during the entire production process.

• The method of production and the type and amount of the constituents give the laxative according to the invention advantageous properties in comparison with the known laxatives of this type. These advantages consist in the fact that the physiologically adequate swelling of the product gives the intestine the filling necessary for optimal natural intestinal activity and undesirable Side effects such as irritation of the gastric and intestinal mucosa are largely eliminated and a careful, subdued release of the intact sennosides is guaranteed. These pharmacologically and clinically observed special advantages can be understood on the basis of model experiments on the kinetics of sennoside release:

To demonstrate the shielding effect of the dried-on mucilage from plantago seeds (peel) ground products, leaching tests were carried out in water at 23 ° C as well as artificial gastric and intestinal juice (each at 37 ° C) on 12.4 g powdered senna drug, Sennae Fructus angustifoliae (I), on mixtures of 12.4 g of powdered Sennes drug and 54.2 g of ground Plantago seeds (II) and on laxative according to the invention with 12.4 g of Sennes fruit and 54.2 g of Plantagosa seeds (III).

For this purpose, the powders mentioned above were each stirred in 300 ml of leaching liquid for 10 minutes or 30 minutes, the liquid was separated from the original leaching by centrifugation and lyophilized. After determining the weight, the content of sennosides was determined using the modified method according to EuAB 2 and related to the amount of sennoside present in the amount of drugs used. The table below shows the values determined in these tests.

Percentage of leached Sennoside_ subs. Water__art. Gastric juice artificial intestinal juice M & tefί ο 1 1 10 min 3® min 10 min 30 min 10 min 30 min I 85.2? 88.9? 55.6? 59.3? 74.1? 74.1? II 55.6? 59.3? 40.7? 44.4? 48.2? 59.3? III 13.0? 8.9? 6.7? 2.2? 3.2? 5.6?

These values clearly show the delayed release of the sennosides from the laxative according to the invention.

However, this delayed release of the sennosides from the laxative according to the invention in no way leads to a complete blocking of the active substances, which are rather practically completely released over longer periods of time, as the following in vitro experiment shows:

Laxative according to the invention was allowed to swell overnight. The swollen material was then mixed with water and extracted five times, the water phase being renewed every hour. After five hours of extraction, around 84% of the expected sennosides could be isolated from the aqueous phases. The individual values are shown in the table below.

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Determination of the sennoside release rate from swollen _____nem_Laxativum_______________________

Stirring solid (g) Sennoside (g) dissolved Sen (extraction) ___ noside content QQ

1. 20.73 0.126 46.67 2. 6.56 0.051 18.89 3. 2.98 0.026 9.63 4. 1.53 0.014 5.18 5. 1.15 0.009 3.33

Total 0.226 83.7

When using artificial gastric juice or artificial intestinal juice, you get approximately the same verte.

These experiments, which approximate the length of time the drugs remain in the gastrointestinal tract, clearly show that the sennosides of the senna fruit component of the laxative according to the invention can have a practically complete effect, albeit delayed in the desired amount. ,

The above and other results, which are listed in the examples below, show that the laxatives according to the invention are notable for their particularly good tolerability as a result of a gentle action which is free from unpleasant side effects, and thus in particular as a support for eliminating hemorrhoid or Fissure patients are suitable before and after surgery. You can go to clinical j ΊΤ '- 13 -

Regulation for patients who are confined to bed, used for long periods of time and can be safely administered during pregnancy.

Manufacturing example

The seeds of Plantago ovata were freed of impurities and foreign seeds, dried to a moisture content of 3.5% at about 80 ° C. and ground to a grain size distribution which roughly corresponds to the following sieve analysis; 99% finer than 500 um 85% finer than 400 um 50% finer than 200 um The material was not heated above 80 ° C during grinding.

Senna fruits (Sennae Fructus angusti-foliae) were adjusted separately to a sennoside content of 2.2% if necessary by mixing different batches. The grinding to the grain size corresponding to the above sieve analysis was carried out in two stages with a pre-grinding and a fine grinding.

The two ground products were mixed dry with the addition of ground Plantago ovata seed husks with a tragacanth carrier medium in the following proportions: 104.0 kg plantago seeds (ground product) 24.8 kg senna fruits "4.4 kg plantago seed husks" 1.5 kg tragacanth 134.7 kg / x ~ \! ly t - 14 -

This powder mixture was transferred from the mixing container to the mixing section of an extruder and continuously mixed with 30 to 40% water. In this moist state, the mass was left to stand for 1 to 2 hours in order to promote spreading of the mucilage layers around the senna fruit particles.

The material was then pressed in an extruder with a large D ratio at a pressure of approx. 50 atm and was chopped into granules of 2.1 to 2.2 mm in length at the outlet of the press with a separately controllable rotating knife. The moist granules showed a desired moisture content of 35

The subsequent drying was carried out in a fluidized bed dryer with vibration feed to a moisture content of not more than 3.5% within about 25 minutes at an air temperature of 125 ° C and an air throughput of 8000 m ^ / h

The dry granules were finally processed with the use of a coating suspension to form sugar-coated dragées, where the coating suspension, in addition to sucrose, can contain aromatic essences customary in pharmaceutical technology, such as peppermint oil, caraway oil and sage oil, and pigments.

The laxative obtained is used in daily doses of 1 to 5 g in patients with constipation and for stool regulation. A particularly preferred embodiment of the laxatives according to the invention has the following composition: U '(I-15 -

Plantaginis Semen ovatae ground product 52,000 kg Plantaginis Semen ovatae bowls "2,200 kg

Fructus Sennae angustifoliae * »12.400 kg

Saccharum 17.600 kg

Oleum Carvi '0.035 kg

Oleum Salviae 0.035 kg

Oleum Menthae piperitae 0.070 kg

Talcum 12.459 kg

Gum arabic 1,400 kg

Tragacanth 0.750 kg

Paraffinum subliquidum 0.240 kg

Paraffinum durum * 0.110 kg

Ferrum oxydatum 0.697 kg per 100 kg of coated granules.

This product has a swelling number of approx. 7.50 (at least 6.0) (determination according to DAB 8), a bulk density of 0.765 to 0.905 g / ml (determination according to DIN 53912), granule diameter of 1-3 mm and one Sennoside content from 0.25% to 0.31, preferably 0.27% · These parameters ensure a particularly good overall effect.

Another preferred embodiment consists of:

Plantaginis Semen ovatae ground product 54,200 kg

Fructus Sennae angustifoliae 12.400 kg Other ingredients as previously stated.

The parameters of this further preferred embodiment relate to the same areas.

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The following tests were carried out to test the pharmacological properties of the laxative according to the invention.

DUT of toxicity and side effects

Acute toxicity was tested in rats and mice of both sexes, including 40 animals each. The powdered laxative with the special composition given above was administered to them in a freshly suspended form with water. The animals were then observed for 8 days.

An exact determination of the DL ^ q turned out to be impossible because the toxicity of the laxative is too low. Even a hundred times the recommended daily dose for humans did not have any harmful effect on the animals. Thus only the following minimum values can be given: DL ^ o (per os) in the rat:> 5 g / kg in the mouse:> 10 g / kg.

In addition, subacute toxicity in rats and mice was controlled by (daily) administration of 0.5; 1.0 and 2.0 g / kg (per os) were examined over a period of 15 days. No mortality was observed.

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To test the chronic toxicity, the laxative was administered to two groups of Sprague-Dawley rats of both sexes with a body weight of 150 g in a dose of 0.5 g / kg and 1.0 g / kg. In the animals, weight gain, erythrocyte count, leukocyte count, diff. rential blood count, blood sugar, prothrombin value, transaminases and residual nitrogen before and after treatment g ^ rüffc. There were no noticeable changes compared to an untreated control group of animals.

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After completion of the investigations, all animals were sacrificed and subjected to a complete autopsy: the weight of the spleen, liver, heart, kidney, brain, adrenal gland, thyroid, testis and pituitary showed no noticeable abnormalities compared to the control animals. Histologically, no deviations were observed with regard to cell infiltration, fat infiltration and adenomatous hyperplasia of the liver, nephrosis, sinusoidal dilatation of the adrenal gland, cell infiltration of the heart, adenomatous hyperplasia of the thyroid gland and cell infiltration * of the spleen and testis.

In further toxicity test series, the subacute toxicity of the composition according to the invention was tested by administration to rats and customers for 30 days on 30 consecutive days. Oral administration 5 and 10 times that recommended for human use. A dose was well tolerated by rats and dogs of both sexes.

For further validation, the chronic toxicity when administered orally to rats and dogs was determined over a period of 180 days. In these studies, a 2 1/2 and 5-fold higher dose than recommended for human use was administered to Sprague-Dawley rats and bastard dogs of both sexes, which the animals tolerated well. No changes were observed during and after treatment for the following parameters: body weight development, hematological, blood chemical and urinological parameters, macroscopic and microscopic examination of the main. -organs. It should be noted that there is no bleeding or ulceration in the gastrointestinal tract.

Studies in rabbits with a daily administration of 1.0 g / kg (per os) over 6 weeks / male and female animals showed no harmful Wfc »- / S \ - 18 - reductions in terms of body weight, erythrocyte and leukocyte count , the differential blood count, residual nitrogen and blood sugar.

The teratogenic effect of the invention according to en Laxati-vum was tested in rats and rabbits with daily doses of 1 g / kg (per os), from the 7th to the 21st day of gestation in the rat and from 7- "to 15 The gestation was administered to the rabbit, and the fetuses were removed from the animals and examined on day 21 and 27. A specific teratogenic effect of the laxative according to the invention was not ascertained, and the laxative apparently has no effect on embryonic development .

Examination of the laxative effect

To investigate the laxative effect, individual doses of 2.5 or 5 g / kg (per o) of the laxative according to the invention were administered to mice or rats. 3 to 4 sti. after administration, a clear, dose-dependent effect with an increase and softening of the faeces was observed.

The influence of the laxative on intestinal motility and on the passage time of the intestinal contents was tested on Sprague-Dawley rats of both types with a weight of 240 g. 22 ml / kg of an aqueous suspension with 10 animal charcoal and 0.5% carboxy methyl cellulose as well as 2.5 or 5 g / kg of the laxative to be tested were administered to groups of 10 animals each after a 24-hour withdrawal of food. The animals were sacrificed 40 minutes after the administration and the total length of the small intestine and the length thereof filled with suspension were measured. The following results were obtained: / - 19 -

Treatment dose (g / kg) intestinal filling length (cm) --- - 56 + 4-, 4-

Laxative 2.5 79 ± 6.2

Laxative 5 86 ± 6.8

In further test series, the laxative effect of the laxative according to the invention was investigated by administration in different doses to mice or rats. The following I * of the test method was used: For the investigations, the same number of male and female lice (strain: Swiss) with an average body weight of 2 h g and the same number of male and female Sprague-Dawley rats with an average body weight of 230 g were used used.

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After 3 hours of food deprivation, the animals were placed in a cage with individual compartments, the bottom of which was lined with filter paper in order to collect the faeces of the individual animals. The animals that eliminated soft stool were removed from the trial program. The remaining animals were placed in the treatment cage. They were given 2.5 or 5 g / kg of the laxative orally (using an oral syringe).

At regular intervals of up to 8 hours after the administration, the number and type of faeces or faecal spheres which were excreted by the animals were noted. The results are * summarized in the following tables * (in which "Lax." Denotes the administration of the laxative according to the invention).

A

/

K

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Examination of the laxative effect in the rat n treatment. g / kg observation time (hours after administration) 2 4 6 8

H WH W H WH W

10 control - 2.4 0.1 3.8 0.1 4.5 0.1 4.5 0.1 10 Lax. 2.5 3.1 0.2 3.8 2.2 4.2 6.2 5.4 ’6.8 10 Lax. 5 3.3 4.1 3.9 6.1 4.4 7.2 4.9 9.1 * »H = hard faeces; the number of faeces W = soft faeces are given; globules / rat.

Examination of the laxative effect on the mouse n treatment, g / kg observation time (hours after administration) 2 4 6 8

H W H WH W E W

20 control - 3.1 0.1 4.2 0.1 4.4 0.2 4.5 0.2 20 Lax. 2.5 2.4 0.2 4.2 2.1 5.1 3.3 5.3 3.8 20 Lax. 5 2.6. 3.4 4.4 5.6 4.6 8.2 4.6 9.8)

The ratio of the number of animals with soft faeces to the total number of treated rites or muses was also determined.

n treatment G / kg hours after administration of rats___2_4_6_8_ 10 control - 0/10 0/10 2/10 2/10 10 lax. 2.5 3/10 5/10 5/10 6/10 10 Lax. 5 3/10 7/10 10/10 10/10

In these animals the upper limit in terms of effect is obviously reached at a dose above 2.5 g / kg.

- 21 - n treatment g / kg hours after administration of the mice 2 4 5 8 20 control - 0/20 1/20 4/20 4/20 20 Lax. 2.5 4/20 8/20 10/20 17/20 20 Lax. 5 8/20 17/20 20/20 20/20

The results show the clear laxative effect of the laxative according to the invention, which manifests itself in an increase in defecation and a considerable increase in the number of soft fecalization spheres in comparison to the hard faecal spheres.

Finally, when the choleretic effect of the laxative according to the invention was checked, practically no significant effect was found, from which it is concluded that the product according to the invention has no choleretic effect.

Daily food intake was also examined; practically no change was found.

A decrease in kidney secretion was observed in a diuresis test, which seems to be related to the increase in enteral fluid excretion.

The product administered in doses of 1.0 and 2.0 g / kg to male rats of 280 g body weight showed no noticeable changes in arterial blood pressure and cardiac activity. No inflammatory changes in the gastrointestinal area were also found.

In summary, it can be determined on the basis of the test results that the composition according to the invention has an extraordinarily low toxicity, which is so low that an in vivo measurement of the DL ^ values chartered, since even hundreds of times that for the human dose recommended dose is still well tolerated by the experimental animals.

No toxic effects or intolerances were observed, only the desired laxative effect, i.e. the main pharmacological property. In addition, no inflammatory changes in the gastrointestinal region of the animals treated with a high dose of the laxative or long-term treatment with the same were found. This is considered surprising since inflammatory changes are often observed in animals that have received laxatives.

In pregnant animals, the administration of the laxative according to the invention does not lead to any changes in the normal development of the fetuses, the number, weight and appearance of which completely matched the corresponding data and findings of the confronters.

The laxative effect of the agent is evident 3 to 4 hours after administration to the test animals. It is directly dose-dependent and manifests itself in an acceleration of the passage time of the intestinal contents as well as an increase and softening of the stools.

Diuresis tests in treated animals showed a decrease in urine output, which may be related to the increase in enteral fluid excretion. No changes in bile secretion, smooth muscle function, arterial blood pressure, or cardiac activity were found. The daily food. uptake was also not affected by the administration of the laxative according to the invention.

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Claims (17)

1. A process for the production of a laxative based on plantago seeds and senna fruits, characterized in that the separately ground plantago seeds and senna fruits are mixed dry, the mixture quickly and evenly pastes with as little water as possible, the pasted mixture is granulated and to a residual moisture content of a maximum of 3 »5% by weight of water dries and the dried granules are finally coated. 2. The method according to claim 1, characterized in that the water content of the pasted mass is 30 to 40 wt. #, Based on the total wet mass. '3 · Method according to claim 1 or 2, characterized in that the pasting takes place with the constant bringing together of relatively small amounts of ground product mixture and water in several rear intermixed mixing stages in several screw mixers. * · * 4. The method according to any one of claims 1 to 3 », characterized in that the granulation takes place in an extruder with a large D ratio and a separately controllable cleaver at the outlet of the press. 5. The method according to any one of claims 1 to 4, characterized in that the granulation takes place at about 50 atü and to particle sizes in the range of about 2 to 2.5 mm. 6. The method according to any one of the preceding claims, characterized in that the granules are dried in a fluidized bed in an air stream for about 0.5 hours. «- 2 -» 7. The method according to any one of the preceding claims, characterized in that the plantago seeds and senna fruits are ground separately to a grain size distribution with about 99. finer than 500 by 85% finer than 400 by 50% finer than 200 µm. * 8. The method according to any one of the preceding claims, characterized in that the ground plantago seeds (I) and senna fruits (II) are mixed in a mixing ratio of about 4 to 5: 1 (I ï II). 9. The method according to any one of the preceding claims, characterized in that the sennoside content of the senna fruits is adjusted to a standard value in the range of 2.0-2.5% by weight, preferably 2.2% by weight, before mixing by mixing different batches becomes. 10. The method according to any one of the preceding claims, characterized in that the mixing of the ground products with the addition of ground Plantagossmenschalen takes place in particular in amounts of about 3 to 4 wt.% Of the mixture. 11. The method according to any one of the preceding claims, characterized in that the pasted mass is deposited in the extruder for 1 to 2 hours before extrusion. 12. Laxatives based on ground plantago seeds and senna fruits characterized by senna fruit particles, which are enclosed by dried-up plantago seed grinding product slime. (y \} - 3 - < 13 · Laxative according to claim 12, characterized in that the PIantagosamen ground product mucilage comes from a mixture - of ground plantago seeds and plantago seed shells. 14. Laxative according to claim 12 or 13 »characterized by a weight ratio of the proportion of plantago seeds; about 4 to 5: 1 senna fruit. 15 · Laxative according to one of claims 12 to 14, characterized in that the plantagosame, plantagosame husk and senna fruit ground product portions are contained in a weight ratio of about 52: 2.2: 12.4. 16. Laxative according to claim 15, characterized by the following components Plantago Semen ovata 52,000 parts by weight Plantago Semen ovata (shells) 2,200 "Sennae Fructus angustifoliae 12,400 n Talcum 12,459" gum arabic 1,400 "Ferrum Oxydatum. E 172 0.697" color index (1956) 77492 77499 77491 tragacanth gum 0.750 "Oleum Carvi 0.035" Oleum Salviae 0.035 n Oleum Menthae Piperitae 0.070 n Paraffinum Subliquidum 0.240 "Paraffinum Durum 0.110" Saccharum -17.604 "per 100 parts by weight of coated granules. C - · - - - 17. Laxative according to claim 12, characterized by the following constituent Plantago Semen ovata 54,200 parts by weight of Sennae Fructus angustifoliae 12,400 n Talcum 12,459 ”gum arabic 1 * 400" · '. Ferrum Oxydatum. E 172 0.697 "color index (1956) 77492 77499 77491 tragacanth 0.750 "Oleum Carvi 0.035" Oleum Salviae 0.035 "Oleum Menthae Piperitae 0.070" Paraffinum Subliquidum 0.240 "Paraffinum Durum 0.110" Saccharum 17.604 w per 100 parts by weight of coated granules. LUXJ "fi Φ