FI75095B - FOERFARANDE FOER FRAMSTAELLNING AVFOERINGSMEDEL BASERAT PAO RATAMONFROEN OCH SENNAFRUKTER. - Google Patents

Description

1 75095

The present invention relates to a process for the preparation of a web-based seed and fungus-based fecal agent and to a method for producing a web-based seed and fungus-based fungicide.

Plantain (plantaginis ovatae) the use of seeds for the active substances to regulate intestinal activity is known.

These seeds have a substantial swelling capacity, and they provide a physical venytysärsytyksen intestinal walls sensitive receptors. According to a known method (German Pat. No. 11 03 520), the seeds are finely ground, kneaded with water to a viscous mass, dried in the form of a rod, chopped and finally granulated.

The effect of Senna angustifolia fruit as a plant propagating agent is also known. Feces are also known which have two principles of action, in which the physical action of the track seeds is supported by the pharmacologically stimulating action factor of the senna fruit ingredients in order to achieve a better overall effect.

A laxative preparation produced from senna fruit is also known from GB-A-856 351, GB-A-1,135,528, DE-B-10 03 916 and DE-B-11 72 655.

When such combination preparations are used, it is observed; however, often adverse side effects that restore excessive mucosal irritation in the case of the interaction of senna fruit, alkali-sensitive and oxidatively susceptible content (sennosides), and adverse effects of sennoside degradation results.

2 75095 In order to essentially eliminate these adverse side effects, a method has now been developed which protects the milling product of senna fruit from premature action and in which the delayed release of sennosides provides a longer-lasting, milder effect.

The method according to the invention is characterized in that the separately ground track seeds and senna fruits are dry-mixed, the mixture is kneaded with as little water as possible quickly and evenly, the doughy mixture is granulated, dried to a residual moisture content of up to 3.5% by weight and then granulated.

The fecal agent prepared according to the invention thus contains two drug components which are not mechanically isolable from each other, but the "protective layer" formed by the adhesives of the seed products of the track plant surrounds the particles of the ground hay fruit. Thanks to this coating, the sennosides become substantially protected from undesired changes and the release of the sennosides is greatly retarded, thus achieving a longer continuous, slow and milder effect.

This protective effect can be further stabilized and enhanced by adding very small amounts of seed coatings to the mixture of the two ground components, Plantaginis Semen ovatae and Fructus Sennae angustifoliae, during the grinding of the track seed. These shells have a much higher swelling capacity compared to ground web seeds due to the higher concentration of mucus in them. Thus, the DAB 8 (Deutsche Arzneibuch), swelling index measurements on page 24 gave an average of 57 ml / g of ground web seed pellets for 30 samples, while an average of 15 ml / g was obtained for ground web seed.

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Correspondingly, this high swelling capacity of the ground seedlings of the ground web also increases the tendency to form the desired coating or coating of the dispersed senna fruit particles, which seems to be very advantageous for use as a medicine.

The weight ratio of the amount of web seed to the amount of senna fruit in the extender according to the invention is preferably about 4 to 5: 1, in which case the weight ratio of mill seeds, web seed husks and milled fruit grinding products is in particular about 52: 2.2: 12.4.

Preferably, the milled web seeds and senna fruits are thoroughly mixed in a weight ratio of 4: 1 to 5: 1, supplemented by the addition of about 3-4% by weight of ground web seeds and 30-40% water, with only slight swelling. In this state of swelling, the mucilages of the ground web seed grains are able to spread to the swelling layers due to the sufficient stability of the water, in which case, however, there is a suitable further processability of the pulp. In contrast, higher amounts of water lead to processing or treatment problems, while bullets with too little swelling are evident when adding insufficient amounts of water, whereby dispersion is not achieved in the desired amount.

Prior to grinding, the seeds and senna fruits of the track are suitably dried at 80 ° C to a moisture content of 3.5% and the sennoside content of the senna component is adjusted by varying amounts to about 2.0 to 2.5% by weight, preferably 2.2% by weight. During grinding, the temperature of the substance to be ground must not exceed 80 ° C.

In order to adjust the necessary internal equilibria between the poly-molecular protective layers formed by the mucilage layers of ground track seeds and seed coats 4,75095 and the dispersed Senna fruit particles in their vicinity, it is expedient not to further process the mixture in an extruder immediately after about 1-2 hours.

The material fed to the extruder is then extruded at a pressure of about 50 aty and, on leaving the press, is broken with rotating blades into grains of about 2.1 to 2.2 mm in length. Also in this state, the moisture content of the product must be about 35%.

Subsequent drying takes place in about 25 minutes in a vortex bed dryer with a vibrating feed to a residual moisture, which very expediently does not exceed 3.5%, using an air temperature of 125 ° C and an air volume of about 8000 m 2 / h. Dry grains are screened to remove grains smaller than 1 mm and larger than 3 mm. They have a vibration weight of 510 to 530 g / l. Finally, this granulate is brought into contact with the granulation suspension and processed into small sugar-layer granules, so that the excipients which are generally customary in the granulation technique can be added to the granulation suspension.

A highly preferred embodiment of the above product is known from the following ingredients: 5,75095

Plantago Semen has 52,000 parts by weight

Plantago Semen ovata (shells) 2 * 200 "

Sennae Fructus angustifoliae 12,400 "

Talc 12,459 »

Arabicum 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 drug granules.

According to another preferred embodiment, the product comprises:

Plantago Semen contains 54,200 parts by weight

Sennae Fructus angustifoliae 12,400 "

The other ingredients are as stated above

The bacterial count is constantly monitored throughout the manufacturing process.

Due to this method of preparation, the quality and the quantity of the ingredients, the defecation agent according to the invention has advantageous properties compared to known defecation agents of this quality. These advantages are that the product physiologically tolerated due to swelling of the intestine may be optimal for natural gut function necessary for filling, and adverse side effects, such as gastric and intestinal mucous membrane irritation is closed off and secured intact Sennoside careful suppressed release. These specific pharmacologically and clinically remarkable advantages will become apparent from model experiments on the kinetics of sennoside release.

To demonstrate the protective coating effect of the dried mucilages of the ground products of the seed (seed husks) of the ratamo, soaking experiments were performed in water at 23 ° C and in artificial gastrointestinal fluid (37 ° C in each case) using 12.4 g of ground senenne fractions, Sennae Fructus (I), mixtures (II) containing 12.4 g of ground senna herbs and 54.2 g of ground track seeds and faeces according to the invention containing 12.4 g of milled fruit and 54.2 g of track seed milling products (III) .

To this end, the above-mentioned powders were mixed for 10 minutes and 30 minutes in 300 ml of soaking liquid, the liquid was separated from the insoluble matter by centrifugation, and lyophilized. The weighing results were used to determine the concentration of sennosides according to the modified method according to EuAB 2 (Europäische Arzneibuch) and were set in proportion to the amount of sennoside in the amount of herbs used. The following table shows the values obtained in these experiments.

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Percentage of Lion Sennosides_

Eri ai · Water Artificial. Artificially, nekset gastric intestinal fluid 10 min. 30 min. 10 min. 30 min. 10 min. 30 min.

I 83.2? 88.9% 55.6% 59.3% 74.1% 74.1%

II 55.6% 59.3% 40.7 «44.4% 48.2% 59.3 S

III 13.0¾ 8.9¾ 6.7¾ 2.2¾ 3.2¾ 5.6¾ These values clearly indicate the delayed release of sennosides from the fecal agent according to the invention.

However, this prolonged release of sennosides from the excipient according to the invention does not lead to complete absorption or interruption of the action of the active substances, which, on the contrary, are practically completely released over a longer period of time, as the following in vitro experiment shows.

The excipient of the invention was allowed to swell overnight. The swollen material was then mixed with water and extracted five times, with the aqueous phase being repeated every one hour. After five hours of extraction, about 84% of the expected sennosides could be isolated from the aqueous phase. The values obtained are shown in the following table.

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Regulation of the rate of release of sennosides from swollen faeces

Mixture Solid Sennoside Dissolved sennos (extraction) (g) (g) Amount (? O) 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 fluid and artificial intestinal fluid, approximately the same values are obtained.

These experiments, which approximate the average residence time of the herbs in the gastrointestinal tract, clearly show that the sennosides of the fecal component of the fecal agent according to the invention, even when slowed down as desired, can act virtually completely.

From the above and other results shown in the example below, it can be seen that the faeces according to the invention are excellent due to their mild adverse side effects due to their very good tolerability and are therefore particularly suitable for hemorrhoids or post-surgical patients before and after surgery.

They can be used for long periods of time for clinical regulation in bedridden patients and can no doubt also be administered during pregnancy.

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Preparation Example

Plantago sera seeds were cleaned of impurities and foreign seeds, dried at about 80 ° C to a moisture content of 3.5% and ground to a grain size distribution corresponding to approximately the following screening analysis: 99% finer than 500 μm 85% finer than 400 μm 50% finer than 200 pm

During grinding, the material was not heated above 80 ° C.

Senna fruits (Sennae Fructus angusti-foliae) were separately adjusted, if necessary, by mixing different amounts with a sennoside content of 2.2%. Grinding was performed to a grain size corresponding to the screening analysis described above in two steps, namely pre-grinding and fine grinding.

Both mill products were mixed dry, adding ground track seed hulls together with tragacanth carrier medium in the following volume ratios: 104.0 kg track plant seeds (milled product) 24.8 kg of senna fruit "4.4 kg track seed hulls" 1.5 kg of tragacanth and stirred continuously with 30-40 7ό water. In this thoroughly moist state, the pulp was allowed to stand for 1-2 hours to cause the layers of plant mucus to spread around the senna fruit particles.

The material was then pressed in an extruder at a pressure ίο 7 50 9 5 of about 50 aty and chopped at the outlet of the press with separately controlled rotating blades into grains 2.1 to 2.2 mm in length. The wet granulate had a desired moisture content of 35%.

Subsequent drying was performed in a vortex bed dryer with a vibratory feed to a moisture content of up to 3.5% in about 25 minutes at an air temperature of 125 ° C and an air permeability of 8000 m 2 / h.

Finally, the dry granules were processed using the granulation suspension into sugar layer granules, whereby the granulation suspension may contain, in addition to sucrose, aromatic essences customary in pharmaceutical technology, such as peppermint oil, cumin oil and sage oil, and pigments.

The resulting fecal agent is used in daily doses of 1-5 g for constipation patients and to regulate defecation. The composition of a highly preferred embodiment of the faecal agent according to the invention is as follows:

Plantaginis Semen ovatae, ground product 52,000 kg

Plataginis Semen ovatae, shells "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

Talc 12,459 kg

Arabicum 1,400 kg

Tragacanth 0.750 kg

Paraffinum subliquidum 0.240 kg

Paraffin durum 0.110 kg

Ferrum oxydatum 0.697 kg per 100 kg of granulated product 11 75095 This product has a swelling number of about 7.50 (minimum 6.0) (regulation according to DAB 8), vibration weight 0.765 - 0.905 g / ml (regulation according to DIN 53912), grain diameter 1-3 mm and a sennoside content of 0.25 to 0.31 S, preferably 0.27 S. These parameters ensure a very good overall effect.

Another preferred embodiment includes:

Plantaginis Semen ovantae, ground product 54,200 kg Fructus Sennae angustifoliae 12,400 kg

The other ingredients are the same as above. The parameters of this second preferred embodiment are in the above ranges.

In order to investigate the pharmacological properties of the fecal agent according to the invention, the following studies were performed.

Investigation of toxicity and side effects

Acute toxicity was studied in rat and mouse in both sexes.

The animals were orally administered a powdered fecal agent having the above composition in a freshly suspended form with water. The animals were then observed for 8 days.

The exact regulation of LDjgs proved impossible because the toxicity of the fecal agent is too low. Even a hundred times the recommended daily dose for humans did not result in any adverse effects in animals. Therefore, only the following minimum values can be reported: DL ^ q (oral rat:> 5 g / kg mouse: £ 10 g / kg 12 75095.

In addition, subacute toxicity was studied in rats and mice by administration (daily) 0.5; 1.0 and 2.0 g / kg (oral) for 15 days. There was no mortality at that time.

To investigate long-term toxicity, fecal agent was administered to two groups of 150 g Sprague-Dau / ley rats of both sexes at doses of 0.5 g / kg and 1.0 g / kg. Animals were examined before and after treatment for weight, red blood cell count, white blood cell count, blood count, blood glucose, prothrombin value, amino group transfer enzymes, and residue type. In this case, no significant changes were observed compared to the untreated control group of animals.

At the end of the studies, all animals were sacrificed and necropsied. The weight of the spleen, liver, heart, kidneys, brain, adrenal gland, thyroid, testicles, and pituitary did not show any abnormalities compared to control animals. Histologically, virtually no abnormalities were observed with respect to cell compaction, lipid compaction, and hepatic, glandular proliferation, nephrosis, adrenal capillary dilation, cardiac cell condensation, hyperthyroidism, and splenic and testicular cell compaction.

In other series of toxicity tests, the semi-acute toxicity of a composition of the invention was studied by administration of the drug for 30 consecutive days in rats and dogs. Five and ten times the oral dose for humans was well tolerated in rats and dogs of both sexes.

For further confirmation, long-term toxicity was determined when rats and dogs were administered the drug over 180 days. In these studies, Sprague-Dau / ley rats and mixed breed dogs of both sexes 75095 13 were given 2.5- and 5-fold the human recommended dose, which was well tolerated by the animals. No changes were observed during and after treatment with respect to the following parameters: development of body weight, blood, blood chemistry and urinary tract parameters, visible to the naked eye of the main organs and microscopic examination. In particular, it should be noted that the range of the stomach and bowel showed no bleeding and ulcer formation.

Studies in male and female rabbits at a daily dose of 1.0 g / kg (oral) for 6 weeks showed no adverse effects on body weight, red blood cells, white blood cells, blood counts, residual nitrogen and blood sugar.

The malformative effect of the fecal agent of the invention was studied in rats and rabbits at daily doses of 1 g / kg (oral) administered to rats between days 7 and 21 of gestation and to rabbits between days 7 and 15. The fetuses were removed from the animals on days 21 and 27 and examined. No specific malformative effect of the fecal agent of the invention was observed, and the fecal agent apparently had no effect on fetal development.

Investigation of faecal effects

To study the laxative effect, single doses of 2.5 and 5 g / kg of the fecal agent according to the invention were administered (orally) to mice and rats. A clear dose-dependent effect in the increase and softening of faeces was observed 3-4 hours after administration.

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Purgative effect on bowel movement and passage of the contents of the duration of time were examined in each sex Sprague-Da \ i / Ley rotisssa with a weight of 240 g. In each case, groups of 10 animals were given 22 ml / kg of an aqueous suspension containing 10% bone char, 0.5% carboxymethylcellulose and 2.5 or 5 g / kg of test fecal material after 24 hours of weaning. 40 minutes after the administration, the animals were sacrificed and the small intestine was measured, and the total length of the length of the filled suspension. The following results were obtained: Treatment Dose (g / kg) Intestinal filling height (cm) ---- - 56 + 4.4

Stool 2.5 79 + 6.2

Stool 5 86 + 6.8

In additional experimental series, the excretory effect of the fecal agent of the invention was studied by administering different doses to mice and rats. The following test methods were used:

The studies used an equal number of male and female mice (genus: Swiss) with an average body weight of 24 g and an equal number of male and female Sprague-Dawley rats with an average body weight of 230 g.

After 3 hours of weaning, the animals were placed in individual compartments in a cage lined with filter paper11a to collect feces from individual animals. Those animals that secreted soft feces were excluded from the experimental program. The remaining animals were placed in a treatment cage. They were orally (in the form of a large injection) of 2.5 or 5 g / kg of fecal agent.

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After administration of faeces, the number and quality of faeces or faecal secretions excreted by the animals were recorded at regular intervals up to 8 hours. The results are shown in the following tables, where "administration" means the administration of the faecal agent according to the invention:

Leak test in rats

Num. treatment Observation time (hours after faecal administration) 2 4 6 8

g / kg H WHWH W H W

10 amendments - 2.4 0.1 3.8 0.1 4.5 0.1 4.5 0.1 10 output 2.5 3.1 0.2 3.8 2.2 4.2 6.2 5.4 6.8 10 output 5 3.3 4.1 3.9 6.1 4.4 7.2 4.9 9.1 H = hard result test; The figures are the number of faecal spheres W = soft faeces; volume / rat

Test the effect in mice

Num. treatment Observation time (hours after faecal administration) g / kg 24 6 8

H W H W H W H W

20 amendments - 3.1 0.1 4.2 0.1 4.4 0.2 4.5 0.2 20 output 2.5 2.4 0.2 4.2 2.1 4.1 3.3 5.3 3.8 20 output 5 2.6 3.4 4.4 5.6 4.6 8.2 4.6 9.8

In addition, the ratio of the number of animals excreting soft feces to the total number of rats and mice treated was determined.

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Lukum kasit- Hour after administration of fecal agent to rats in g / kg 2 4 6 8 10. control - 0/10 0/10 2/10 2/10 10. administration 2.5 3/10 5/10 5/10 6/10 10. administration 5 3/10 7/10 10/10 10/10 In these animals, a dose limit of more than 2.5 g / kg relative to the effect is clearly reached.

Num. Hours after administration of fecal agent to mice in g / kg __2_4 6_8_ 20 control - 0/20 1/20 4/20 4/20 20 administration 2.5 4/20 8/20 10/20 17/20 20 administration 5 8 / 20 17/20 20/20 20/20

The results show a clear defecation effect of the fecal agent according to the invention, manifested in an increase in defecation and a considerable increase in the number of soft fecal spheres compared to hard fecal spheres.

Finally, the study of the bile secretagogue promoting effect of the fecal agent according to the invention found virtually no significant effect, from which it can be concluded that the product according to the invention has no bile secretagogue promoting effect.

In addition, the daily food intake was examined and virtually no change was observed.

In the urinary excretion test, a decrease in renal excretion was observed, which appears to be associated with an increase in intestinal fluid excretion.

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At doses of 1.0 and 2.0 g / kg in male rats weighing 280 g, the product did not cause any significant changes in arterial blood pressure or cardiac function. Similarly, there is no inflammatory changes found in the stomach and intestinal region.

In summary of the results of the study, the composition according to the invention has a very low toxicity, which is so low that the in vivo measurement of DL-g values fails because the experimental animals tolerated well up to 100 times the recommended human dose.

No toxic effects or intolerances were observed, only the desired excretory effect, i.e. the main pharmacological property. Similarly, there is no inflammatory changes found in the animal stomach and intestinal region, which were treated with high doses or purgative that were long-time exposed to these doses. This is considered surprising because inflammatory changes are usually observed in animals that have received fecal agent.

In pregnant animals, administration of the fecal agent according to the invention did not cause any changes in the normal development of the fetuses, but their number, weight and nature were completely consistent with the corresponding values and results of the control animals.

The excretory effect of the defecation agent appears 3-4 hours after administration to the experimental animals. The effect is directly dependent on the dose and is manifested intestinal contents läpikulkuajän shortening and feces, as well as an increase in softening.

Urinary excretion tests in treated animals indicated a decrease in urinary excretion, which may be associated with an increase in intestinal fluid excretion. No changes in biliary excretion, smooth muscle, arterial blood pressure, or cardiac function were also observed. The administration of the rennet according to the invention also did not affect the daily food intake.

Claims (7)

A process for the preparation of a web-based seed and senna-based fecal agent, characterized in that the separately milled web-seed and senna fruit blend is dry-dried, the mixture is kneaded quickly and evenly with as little water as possible, the doughy mixture is granulated, dried to a residual moisture content of 3.5% and then granulating the dried grains. Process according to Claim 1, characterized in that the water content of the doughy mass is brought to a value of 30 to 40% by weight of the total moist mass. A method according to claim 1 or 2, characterized in that the seeds and hay fruits of the track are ground to a grain size distribution of about 99. finer than 500 μm 85% finer than 400 μm 50% finer than 200 μm. Method according to one of the preceding claims, characterized in that the ground web seeds (I) and the hay fruits (II) are mixed in a ratio of about 4-5: 1 (I: II). Process according to one of the preceding claims, characterized in that the sennoside content of the senna fruit before grinding is adjusted by mixing different amounts to a standard value of 2.0 to 2.5% by weight, preferably 2.2% by weight. Method according to one of the preceding claims, characterized in that the mixing of the grinding products takes place by adding ground web seed hulls, in particular in amounts of about 3-4% by weight of the weight of the mixture. Method according to one of the preceding claims, characterized in that the weight ratio of the milled seeds, the milled seed husks and the milled fruit to the milled product is about 52: 2.2: 12.4.