CH650403A5 - LIQUIDATORS BASED ON PLANTAGOSAME AND SENNA FRUIT AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

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 stimulus 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.

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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 fruit (sennosides) are massively affected, and the adverse effects of sennoside decomposition products.

In order to largely rule out such adverse side effects, a form of 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 characterized in that the senna fruit particles are surrounded by dried-on plantago seed grinding product slime.

In the laxative according to the invention, therefore, the two medicament components are not mechanically isolated next to one another, but the particles of the ground senna are surrounded by a “protective layer” made from the mucilages of the plantago seed products. With this coating, the sennosides are largely protected against 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, is re-added in the course of the grinding of Plantago seeds to the extent that small portions of seed shells that have been lost are added for restitution. These husks have a far greater swellability compared to the milled 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 ml per gram for 30 samples of ground plantago seed pods , while an average of 15 ml per gram was found for the ground plantago seeds.

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, with a weight ratio of the plantago seed, plantago seed husk and senna fruit 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 quickly and uniformly pasted with as little water as possible, the pasted mixture is granulated and to a residual moisture content of not more than 3.5 % dries and the dried granules are finally coated.

Preferably the ground plantago seeds

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and senna fruits in a weight ratio of 4: 1 to 5: 1 with the additional addition of about 3 to 4% by weight of ground plantago seed shells worked through with 30 to 40% water, with only a limited swelling occurring. 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.

Before grinding, the plantago seeds and senna fruits are expediently dried at 80 ° C. to a moisture content of 3.5% and the sennoside content of the senna component is adjusted to about 2.0 to 2.5% by weight, preferably 2.2%, by mixing different batches . 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 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 carry out the further processing of the mixture in the extruder, but preferably Intermediate waiting times of 1 to 2 hours.

The material fed to the extrusion press is then usually 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 is usually carried out in a fluidized bed dryer with vibration feed within about 25 minutes to residual moisture of not more than 3.5%, with an air temperature of 125 ° C and an air volume of approx. 8000 cbm 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 / 1. Finally, these granules are 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

Parts by weight

Plantago Semen ovata 52,000

Plantago semen ovata (shells) 2,200

Sennae fructus angustifoliae 12,400

Talcum 12,459

Gum arabic 1,400

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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

per 100 parts by weight of coated granules.

Another preferred embodiment

consists

Plantago semen ovata

54,200

Sennae fructus angustifoliae

12,400

Other components as previously stated.

Lower material

Percentage of leached sennosides

water

Art. Gastric juice

Art. Intestinal juice

10 min. 30 min.

10 min. 30 min.

10 min.

30 min.

I.

II

III

85.2% 88.9% 55.6% 59.3% 13.0% 8.9%

55.6% 59.3% 40.7% 44.4% 6.7% 2.2%

74.1% 48.2% 3.2%

74.1% 59.3% 5.6%

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 ingredients, which are rather practically completely released over long periods of time, as the following in vitro experiment shows:

A laxative according to the invention was allowed to swell overnight. The swollen material was then mixed with water and extracted five times, the io 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 rate of sennoside release from swollen

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

The method of manufacture and the type and amount of the constituents impart advantageous properties to the laxative according to the invention compared to 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 how irritation of the gastric and intestinal mucous membranes is 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 senoside release:

To demonstrate the shielding effect of the dried mucilage from plantago seeds (peel) ground products, leaching tests were carried out in water at 23 ° C and artificial gastric and intestinal juice (each at 37 ° C) on 12.4 g of powdered Sennes drug, Sennae Fructus angustifoliae (I) , on mixtures of 12.4 g of powdered Senna drug and 54.2 g of ground plantago seeds (II) and on laxative according to the invention with 12.4 g of Senna fruit and 54.2 g of plantago seed products (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 insoluble material by centrifugation and lyophilized. After determining the balance, the sennoside content was determined using the modified method in accordance with 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.

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laxative

Execution

Solid (g)

Sennoside (g)

solved

(Extraction)

Sennoside content (%)

1.

20.73

0.126

46.67

2nd

6.56

0.051

18.89

3rd

2.98

0.026

9.63

4th

1.53

0.014

5.18

5.

1.15

0.009

3.33

total

0.226

83.7

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

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When using artificial gastric juice or artificial intestinal juice, the values are approximately the same.

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

40 The above-mentioned and further results, which are listed in the examples below, show that the laxatives according to the invention are notable for their particularly good tolerability owing to a gentle action which is free from unpleasant side effects 45 and thus in particular as a support for eliminating hemorrhoid - or fissure patients are suitable before and after surgery. They can be used for long-term clinical regulation for patients who are confined to the bed, and can therefore be administered safely during pregnancy.

Manufacturing example

The seeds of Plantago ovata were freed from impurities and foreign seeds, dried to a moisture content of 3.5% at about 80 ° C and ground to a grain size distribution that corresponds approximately to the following sieve analysis:

99% finer than 500 [in 60 85% finer than 400 (in 50% finer than 200 (y, m

The material was not heated above 80 ° C during grinding.

65 Senna fruits (Sennae Fructus angustifoliae) were adjusted to a sennoside content of 2.2% if necessary by mixing different batches. Grinding to that corresponding to the above sieve analysis

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Grain size 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 medium in the following proportions:

104.0 kg plantago seeds (ground product) 24.8 kg senna fruits (ground product)

4.4 kg plantago seed pods (ground product)

1.5 kg tragacanth 134.7 kg

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 m3 / h.

The dry granules were finally processed into sugar-coated pills with the use of a coating suspension, and the coating suspension, apart from 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:

Plantaginis Semen ovatae ground product

Plantaginis Semen ovatae bowls ground product

Fructus Sennae angustifoliae ground product

Saccharum

Oleum Carvi

Oleum Salviae

Oleum Menthae piperitae

Talcum

Gum arabic tragacanth

Paraffinum subliquidum Paraffinum durum Ferrum oxydatum per 100 kg of coated granules.

52,000 kg 2,200 kg 12,400 kg 17,600 kg 0.035 kg 0.035 kg 0.070 kg 12,459 kg 1,400 kg 0.750 kg 0.240 kg 0.110 kg 0.697 kg

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 Sennosidge 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 s Other ingredients as previously stated.

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

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

Examination of toxicity and side effects

Acute toxicity was tested in rats and mice of the same sex, including 40 animals each. The powdered laxative with the special composition given above was administered to them in freshly suspended form by water. The animals were then observed for 8 days. 20 An exact determination of the DLso 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. This means that only the following minimum values can be specified:

DL50 (per os) in the rat:> 5 g / kg in the mouse:> 10 g / kg.

30 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.

To test the chronic toxicity, the Laxa-35 tivum 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 number, leukocyte number, differential blood count, blood sugar, prothrombin value, 40 transaminases and residual nitrogen were tested before and after the treatment. No noticeable changes were found compared to an untreated control group of animals.

After completion of the investigations, all animals were killed 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, adenomatal hyperplasia of the thyroid gland and cell infiltration of the spleen and testis.

55 In further toxicity test series, the subacute toxicity of the composition according to the invention was tested by administering to rats and dogs for 30 days on 30 consecutive days. Oral administration of 5 and 10 times the dose recommended for human use 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 2V and 5X higher dose than that recommended for human use was administered to Sprague-Dawley rats and Bestard dogs of both sexes, which the animals tolerated well. During and after

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No changes were observed during treatment with the following parameters: development of body weight, haematological, blood chemical and urinological parameters, macroscopic and microscopic examination of the main organs. It is particularly noteworthy that there was 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 to male and female animals showed no harmful effects in terms of body weight, erythrocyte and leukocyte count, differential blood count, residual nitrogen and blood sugar .

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

Examination of the laxative effect

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

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 sexes with a weight of 240 g. 22 ml / kg of an aqueous suspension with 10% animal charcoal and 0.5% car-boxymethyl cellulose as well as 2.5 or 5 g / kg of the laxative to be tested were administered to groups of 10 animals 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:

treatment

Dose (g / kg)

Casing 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 test procedure was used:

For the studies, the same number of male and female mice (strain: Swiss) with an average body weight of 24 g and the same amount of male and female Sprague-Dawley rats with an average body weight of 230 g were used.

After 3 hours of food deprivation, the animals were housed 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 experimental 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 pellets that were excreted by the animals were noted. The results are summarized in the tables below (in which “Lax.” Denotes the administration of the laxative according to the invention).

Examination of the laxative effect in the rat treatment g / kg observation time (hours after administration)

2nd

4th

6

8th

H

w

H

w

H

w

H

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;

W = soft faeces;

the number of fecal beads / rat is indicated

Examination of the laxative effect on the mouse n treatment g / kg observation time (hours after administration)

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H

W

H

w

H

w

H

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 rats or mice was also determined.

n Treatment g / kg hours after administration of the 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 of effectiveness is obviously reached at a dose above 2.5 g / kg.

n Treatment g / kg hours after administration of the mice

2 4 6 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 fecal globules compared to the hard fecal globules.

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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 cholesteric effect. s

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 the endogenous 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 found.

In summary, it can be determined from the test results that the composition according to the invention has an extraordinarily low toxicity, 20 which is so low that an in vivo measurement of the DL 50 values fails, since even the hundred times the dose recommended for human use by the test animals is still well tolerated.

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 tract of animals treated or treated with a long dose of the laxative were observed. 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 control animals.

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 intake was also not influenced by the administration of the laxative according to the invention.

B

Claims (17)

650403 2nd PATENT CLAIMS 1. Laxatives based on ground plantago seeds and senna fruits, characterized by senna fruit particles, which are surrounded by dried-up plantago seed mucilage. 2. Laxative according to claim 1, characterized in that the plantagos seed ground product slime comes from a mixture of ground plantagos seeds and plan tagosame husks. 3. Laxative according to claim 1 or 2, characterized by a weight ratio of the plantago seed portion to the senna fruit portion of 4 to 5: 1. 4. Laxative according to one of claims 1 to 3, characterized in that the plantago seed, plantago seed husk and senna fruit ground product portions are contained in a weight ratio of 52: 2.2: 12.4. 5. Laxative according to claim 4, characterized by the following components: Parts by weight Plantago semen ovata 52,000 Bowls from Plantago Semen ovata 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 Oleum Menthae Piperitae 0.070 Paraffinum subliquidum 0.240 Paraffinum Durum 0.110 Saccharum 17.604 per 100 parts by weight of coated granules. 6. Laxative according to claim 1, characterized by the following components: Parts by weight Plantago semen ovata 54,200 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 Oleum Menthae Piperitae 0.070 Paraffinum subliquidum 0.240 Paraffinum Durum 0.110 Saccharum 17.604 per 100 parts by weight of coated granules. 7. A method for producing a laxative according to claim 1 based on plantago seeds and senna fruits, characterized in that the separately ground plantago seeds and senna fruits are dry-mixed, the mixture quickly and evenly pastes with as little water as possible, the pasted mixture is granulated and mixed on one Residual moisture content of a maximum of 3.5% by weight of water dries and the dried granules are finally coated. 8. The method according to claim 7, characterized in that the water content of the pasted mass makes up 30 to 40% by weight, based on the total moist mass. 9. The method according to claim 7 or 8, characterized in that the pasting takes place with the constant bringing together of relatively small amounts of ground product mixture and water in several successive mixing stages in several screw mixers. 10. The method according to any one of claims 7 to 9, characterized in that the granulation takes place in an extruder with a large D ratio and a separately controllable chopping knife at the outlet of the press. 11. The method according to any one of claims 7 to 10, characterized in that the granulation takes place at 50 atm and on particle sizes in the range from 2 to 2.5 mm. 12. The method according to any one of claims 7 to 11, characterized in that the granules are dried in a fluidized bed in an air stream for 0.5 hours. 13. The method according to any one of claims 7 to 12, characterized in that the plantago seeds and senna fruits separately with a grain size distribution 99% finer than 500 by 85% finer than 400 [xm 50% finer than 200 14. The method according to any one of claims 7 to 13, characterized in that the ground plantago seeds (I) and senna fruits (II) are mixed in a mixing ratio of 4 to 5: 1 (1:11). 15. The method according to any one of claims 7 to 14, characterized in that the sennoside content of the senna fruits before grinding by mixing different batches to a standard value in the range of 2.0-2.5% by weight, preferably 2.2%. % is set. 16. The method according to any one of claims 7 to 15, characterized in that the grinding products are mixed with the addition of ground plantago seed shells, in particular in amounts of 3 to 4% by weight of the mixture. 17. The method according to any one of claims 7 to 16, characterized in that the pasted mass is deposited in the extruder for 1 to 2 hours before extrusion.