CS227324B2 - Method of preparing laxatives on the basis of plantago seed and senna pods - Google Patents

Abstract

A laxative composition, comprising ground psyllium seeds and senna fruits, the senna fruit being in a form substantially enveloped by swollen psyllium seeds is prepared by mixing separately ground psyllium seeds and senna fruits in a dry state, moistening the resulting ground mixture rapidly and uniformly with barely sufficient water, quickly granulating the resulting mixture and drying the same in a manner preventing substantial swelling to give a product having a residual moisture content of no more than 3.5% by weight of water and then coating the composition with a pharmacologically acceptable material.

Description

The present invention relates to a process for the manufacture of a laxative based on plantain seeds and senesian pods. The use of plantain seeds (Plantaginis ovataš seeds) as a medicament for the regulation of bowel activity is known. These seeds are able to swell considerably and cause physical dilatation irritation to sensitive intestinal wall receptors. According to one known method (German Patent 1,103,520), the seeds are finely ground, ground with a viscous slurry with water and dried in the form of strands, ground and finally auctioned.

The effect of senne pods (Senne engustifolia) as a plant laxative is also known. Laxatives are also known which contain both effective principles, in which the physical effect of plantain seeds is therefore supported by the pharmacologically stimulating effect of the substances contained in the senesan pods, in order to obtain a better overall effect.

However, when using such combination preparations, undesirable side effects can often be observed, which can be inferred from too much mucosal irritation in the massage effect of seneside sensitive substances, non-alkali sensitive and susceptible to oxidation, and the harmful effects of sennoside degradation products.

In order to eliminate such harmful side effects as much as possible, a form of preparation has now been developed in which the ground product of the senesian pods (Fructus Sennae) is protected from premature contact and the delayed release of sennosides achieves a longer lasting milder effect.

On the other hand, the laxative developed according to the invention, based on ground plantain seeds and senesian pods, is essentially characterized in that the senesium pod particles are surrounded as much as possible by the dried mucilage of the ground product - plantain seeds.

Thus, in the laxative according to the invention, both drug components are not mechanically isolated from each other, but the particles of the milled senesium pods are surrounded by a protective layer of mucilage from the milled plantain seeds. With this coating, the sennosides are protected as much as possible against undesirable changes and their release is considerably delayed so that a sustained retarding effect is achieved.

This protective effect can be additionally stabilized and intensified when small amounts of plank seed husk are added to the mixture of the two milled ingredients, the plantain seeds of Plantaginis ovatae and the Saiinae sngistifoliss seed pods to replace those lost during planting of plantain seeds.

These plantain seed husks are capable of being meeiva compared to ground plantain seeds with respect to the higher concentration of mucilaginous ones. Thus, the measurement of the swelling number according to DAB, page 24, gave an average value of 57 ml per gram of plantain seed husk, while a value of 15 ml per gram was found for ground plantain seeds. '

In accordance with this greater swelling of the milled plank seed husks, the tendency to form the desired sheath of the senesium pod dispersion particles is increased, which is particularly advantageous for medical ingestion.

The molar ratio of the difference between plantain seeds and the proportion of senesian pods in the laxative according to the invention is about 4-5: 1, in particular the molar ratio of plantain seeds, plantain seed husks and senesium husks as the meeiva proportions is in the range of about 52: 2.2: 12.4.

SUMMARY OF THE INVENTION Accordingly, the present invention provides a method for producing a laxative based on plantain and senesian legumes, characterized in that plantain and senesian seeds are milled separately to a grain size of less than 500 µm finer than 400 µm finer than 200 µm. in a ratio of about 4 to 5: 1, mixed from dryness, the mixture is spun quickly and evenly and with as much water as possible, the granulated mixture is granulated and dried to a residual moisture content of at most 3.5% by weight and the dried granulate is finally dre ^ je.

The ground plantain seeds and senesian pods are preferably processed in a weight ratio of 4: 1 to 5: 1 with an additional addition of about 3 to 4% metallurgical plants, ground plantain seeds of plantain with 30 to 40% water, with only limited swelling.

In this swollen state, the licking substances of the ground husk of the plantago ovate species are capable of being dispersed in the swollen layers in the swollen layers of the plantago ovate species, but the material can be further processed appropriately. Larger amounts of water, on the other hand, lead to problems in further processing, while the lyospheres, when added to insufficient amounts of water, only show a sufficient amount so that the desired distribution is not achieved. ·

Prior to milling, the plantain and senesium seeds are preferably dried at 80 ° C to a moisture content of 3.5% and the settoids content of the senesium component to about 2.0 to 2.5% by weight, preferably to 2.2%. The temperature of the ground product should not exceed 80 ° C during milling.

The dry-ground milled products are still combined in small proportions with water to achieve uniform wetting and swelling and are subjected to intensive mixing in a series of mixing stages. This is preferably done in a plurality of downstream screw mixers. In this way, even swelling and swelling are achieved in a few minutes.

In order to adjust the necessary internal equilibrium between the polymolecular protective layers which are formed by the layers of mucclaga ground Plantago ovata seeds and its seed husks and adjacent senesian pods, it is advantageous not to carry out further processing of the mixture in the extruders, but preferably after 1 to 2 hours ·

The melt fed to the extruder is then extruded at a pressure of about 5 MPa and chopped into granules having a length of 2.1 to 2.2 mm at the outlet of the press with a rotating knife. In this state, the product should contain a moisture content of about 35%.

The subsequent drying is preferably carried out in fluidized-bed dryers with a vibration shift of about 25 minutes to a residual moisture of not more than 3.5%, operating at an air temperature of ¹²⁵ ° C and an air volume of about 8,000 m ^J per ^hour. odinu. The dry grande is sieved to remove granules that are less than 1 mm or greater than 3 mm. Their bulk density is 510-530 g / L. Finally, the granulate is combined with a dragee suspension and processed into small dragees coated with a sugar layer and may be added to the dragee suspension. auxiliary substances customary in the auction technique.

A particularly preferred embodiment of the product described above consists of plantain seeds of Plantago ovata husk of the plantain seeds of Plantago ovata senesan pods of Sennae species of gum arabic iron oxide (ferrum oxydatum). E 172 color index (1956) 77492> 77499

77491 gum tragacanth

Oleum Carvi (Caraway Essential Oil)

Oleum SalviM X (^ d ^ Lj ^ cj sage)

Oleum Menthae Pipe (paraffin oil) Paraffiuum Subliquidim (liquid paraffin) Paraffin Durum (solid paraffin) S-charum (sugar) per 100 parts by weight of the granulate to be auctioned.

52,000 parts by weight

2,200 parts by weight 12,400 parts by weight 12.459 parts by weight

1,400 parts by weight

0.697 parts by weight

0.750 parts by weight

0,035 parts by weight

0,035 parts hmoo ,.

0.070 parts by weight

0.240 parts by weight

0.110 parts by weight

17,604 parts by weight

Another preferred embodiment consists of

Plantain seeds of the species Plantago ovata of Senna tngctifslit

54,200 parts by weight

12,400 parts hmoot.

and other aforementioned ssuCás ·

The number of beats is constantly checked throughout the production cycle.

The method of manufacture, as well as the type and wear of the components, provide suitable vltstioots in comparison with the known laxatives of this type of laxative according to the invention. These properties are that the physiologically appropriate swelling of the product gives the intestine the necessary fillings necessary for optimal bowel function and that undesirable side effects such as the irritation of the mucous stomach and intestine are avoided as much as possible and a careful, delayed release is guaranteed.

227324 4 integer aennoids. These fermecologlees and clinically observed particular foresters can be elucidated by model experiments to monitor the kinetics of sennoeid release: to test the shading effect of the ellootic milled seed product (husk seed) of the tulle seed, experiments with leaching in water at 23 ° C and artificial acorns intestinal Glory (at 37 ° C) for 12.4 g of powdered senesium drug, senesan pods of Sennae axngsaifoliee (I), mixtures of 12.4 g of powdered senesium drug and 54.2 g of ground plantain seeds (II) as well as laxative according to An invention comprising ground products (III) consisting of 12.4 g senes pods and 54.2 g plantain seeds.

For this, the front mentioned powders which míchaaí 10 popřípadS 30 minutes in 300 ml of digestion of ^] ^ S ^ 3 l: ₉ ins e oddUí fluid from the undissolved residue, and lyophilized. After determining _the yield ae aennoaidů content - determined according to the modified procedure of EuAB 2 and in relation thereto shall abut množaví aennoaidů contained in the used amount of the drug. The following table shows the values found in these experiments.

Tested atheros Amounts of excluded dreams Water Artificial gastric juice Urnmiá intestinal Glory 10 min 30 min 10 min 30 min 10 min 30 min AND 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 show a clearly delayed release of the aennoids from the laxative of the invention.

However, this delayed release of sennoeides from the laxative of the present invention does not in any way lead to complete blocking of the active ingredients, which rather are released almost completely over a longer period of time, as shown in the following in vitro experiment;

The laxative according to the invention was left to swell overnight. The tulle was swollen with water and extracted five times, the aqueous phase being renewed every hour. After five hours of extraction, about 84% of the expected sennosides could be isolated from the aqueous phases. Single values are reproduced in the following table.

Determination of sum of released sennosides from non-swollen laxative

Extraction Solid (g) Sennosides (g) Dissolved fraction of sennosides («) 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

By using ummium gastric glory or artificial intestinal glory, approximately the same values are obtained.

these experiments, approaching the average residence time of the drugs in the stomach, will clearly show that the sennosides of the components of the senesium pods contained in the laxative according to the invention - even if their release is delayed in a desirable manner - will practically work perfectly.

The foregoing and other results shown below in the examples show that the laxatives of the present invention have a particularly good tolerability due to the mild and undesirable side effects and are therefore particularly suitable as aid for elimination in patients suffering from haemorrhoids or tear sores ^ m before and after surgery. They can be used for the clinical regulation of bedridden patients for extended periods of time and can be used without objection during pregnancy.

Production example

Plantain species of Plantago ovata got rid of impurities and foreign seeds, at about 80 ° C tulle. dried to a residual moisture content of 3.5% and ground to a grain size corresponding to the following sieve analysis:

% less than 500 / µm 85% mercury than 400 / µm% less than 200 / µm

It was not heated to above 80 ° C during milling.

Separately, senna pods (Sennae Fructus anguSifsline) were not set, if necessary, by mixing different parts to a sennoside content of 2.2%. Growth to a grain size corresponding to the aforementioned sieve analysis was carried out in two stages with pre-grinding and fine grinding.

Both grinding products were dry blended by adding ground seeds - Plantago ova seeds with a traganoo carrier in the following screeds:

227324 6

104.0 kg plantain seeds (milled product) 24.8 kg senes pods (milled product)

4.4 kg plantain seed husk (milled product)

1.5 kg of tregant

134.7 kg

This tulle powder mixture transferred from the mixing tank to the mixing tract of the extruder is continuously mixed with 30-40% water · In this moistened state of the tulle, the mass is left to rest for 1 to 2 hours to allow the mucilages to spread around the senesian pods.

The material was then pressed in an extruder with a high D ratio at a pressure of about 5 KPa and not chopped out of the press by a separately actuated rotating granule blade of 2.1 to 2.2 mm in length.

Subsequent drying was carried out in a fluid bed dryer with a vibration feed to a moisture content not exceeding 3.5% in 25 minutes at an air temperature of 125 ° C and a throughput of ^8,000 m ³ / h ·

The dry tulle granules are then processed with the aid of the dragee suspension into a dragee coated with a layer of sugar, the dragee suspension being able to contain the dragee suspension. in addition to sucrose in pharmacy the usual aroma essences such as peppermint oil, caraway oil and sage oil as well as pigments ·

The laxative obtained in patients with constipation and stool control is used in daily doses of 1 to 5 g. Ingredients:

ground product of plantain seeds of Plantago ova 52,000 kg a ground product of the plantain seeds of the plantago ovata species 2,200 kg ground product of senesian pods of the species Senná and gustícl 12,400 ^kg , sacchanuím 17,600 kg Oleum Cervi (caraway oil) 0,035 kg Oleum Salviae (Sage Essential Oil) 0,035 kg Oleum Menthae Piperitae (Peppermint essential oil) 0,070 kg talc 12,459 kg arabic gum 1, 400 kg tregant 0.750 kg Subliquid paraffins (liquid paraffin) 0.240 kg Durum paraffins (solid paraffin) 0,110 kg Ferrum oKydatum 0,697 kg no 100 kg of coated granulate ·

This product has a swelling number of about 7.50 (at least 6.0) (as determined by DAB 8), a bulk density of 0.765 to 0.905 g / ml (as determined by DIN 53912), a granule diameter of 1 to 3 mm and a selenium content of 0, 25 to 0.31%, preferably 0.27%

Another preferred embodiment of the ground product of plantain seeds of Plantaginis ovetae ground product of Senna pods of Sennae angustifoliae consists of:

54,200 kg

12,400 kg

The other parts are the same as those mentioned above ·

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

The following tests were performed to test the phermacological properties of the laxative according to the invention:

Testing for toxicity and side effects

Acute toxicity was tested in rats and mice of both sexes, each comprising 40 animals. They were administered orally a powdered laxative of the aforementioned special composition, in the form of a fresh suspension with water. The animals were then observed for 8 days.

Precise determination has proved impossible because the laxative toxicity is very low.

The daily doses recommended for humans did not lead to any harm in animals. For this reason, only the following minimum values may be given:

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

Additionally, subacute toxicity in rats and mice was tested by (daily) administration of 0.5; 1.0 and 2.0 g / kg (per os) for 15 days. No mortality was observed.

For chronic toxicity testing, the laxative was administered to two groups of Sprague-Dewley rats, both sexes weighing 150 g, at a dose of 0.5 g / kg and 1.0 g / kg. Animals were measured for weight gain, erythrocyte count, leukocyte count, differential blood count, blood sugar, prothrombin, transaminase and residual nitrogen before and after treatment. There were no remarkable changes compared to the untreated control group.

At the end of the experiments, all animals were sacrificed and subjected to a thorough autopsy (examination): the weight of the spleen, liver, heart, kidney, brain, adrenal gland, thyroid, testis (verlat) and pituitary (pituitary) showed no abnormalities compared to control animals.

Histologically, virtually no deviations were observed with respect to cell infiltration, fat infiltration and adematous hepatic hyperplasia, nephrosis, sinusoid adrenal dilation, heart cell infiltration, thyroid adematous hyperplasia © spleen and testicular cell infiltration.

In other series of toxicity tests, the subacute toxicity of the laxative composition of the invention was tested for 30 days by administration for 30 consecutive days in rats and dogs. Oral administration of 5 to 10 times the doses recommended for humans was well tolerated by rats and dogs of both sexes.

For further insurance, chronic oral toxicity was determined for rats and dogs for 180 days. In these investigations, a dose of 2 1/2 to 5 times the dose recommended for humans, Sprague-Dewley rats and bastard dogs of both sexes, which was well tolerated by the animals, was administered. No changes were observed during and after treatment: body weight development, haematological, blood-chemical and urinological parameters, wet and microscopic examination of the major organs. In particular, it should be noted that there was no bleeding or ulceration in the gastro-thyteostinal tract.

Investigations in rabbits with daily administration of 1.0 g / kg (per os) for 6 weeks showed no harmful effects in either male or female with respect to 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 using decay doses of - 1 g / kg (per os), which were administered to rats from 7 to 21 days of heat and to rabbits from 7 to 15 days of heat. On days 21 and 27, the animals were harvested and examined. The specific teratogenic effect of the laxative according to the invention has not been found and the laxative appears to have no effect on the development of erythromites.

Testing of laxative effect

To investigate the laxative effect of the laxative according to the invention, 2.5 and 5 g / kg (per os) of laxative were administered to rats or rats, respectively. A pronounced dose-dependent effect of laxative was observed 3 to 4 hours after administration, manifesting itself as a multiplication and softening of stool.

The effect of the laxative on intestinal (intestinal) mesh and on the duration of transient intestinal contents was tested in rats of the species. Spregue-Dawley animal sex of 240 gm. Groups of 10 animals were given 22 ml / kg of an aqueous suspension of 10% charcoal and 0.5% carbonic acid carbones, as well as 2.5, after 24 hours of food withdrawal. optionally 5 g / kg of laxative tested. 40 minutes after administration, the animals were sacrificed and the total length of the small intestine, including the length not filled with the suspension, was measured.

The following results were obtained:

Treatment . Dose (g / kg) Length of intestinal filling (cm)  _ 56 ± 4.4 laxative 2.5 79 ± 6.2 laxative 5 86 + 6.8

In another series of experiments, the laxative effect of the laxative of the present invention was investigated by administering it to mice or rats at various doses. The following testing method was used:

For testing, the same number of males as female mice (strain: Swiss) with an average body weight of 24 g and the same number of male and female rats (Spregue-Rawley) with an average body weight of 230 g were used.

After the food was removed for 3 hours, the animals were placed in a cage with single compartments, the floor of which was lined with filter paper to collect the faeces of the individual animals. The animals that softened the soft stools were excluded from the trial program. The remaining animals were housed in the treatment cage. These were administered orally (oral syringe) with 2.5 and 5 g / kg of laxative, respectively.

Severography, n. P., MOST

Price 2,40 Kčs

At regular time intervals of up to 8 hours after administration, the number and type of excrement or faecal beads excreted by the animals was recorded. The results are summarized in the following tables (in which lax is the administration of the laxative according to the invention).

Testing of laxative effect in rats

n Nursing. 2 Observation time (hours after administration) 4 t 6 m tm 8 t m t Ш 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

t = stool;

m = soft stool; the number of faeces / rat beads is reported.

Testing of laxative effect in mice n Treatment. g / kg

Observation time (hours after administration)

t m t m t m t m 20 May control 3.1 0.1 4.2 0, ’ 4.3 0.2 4,5 0.2 20 May lax. ² · ⁵ 2.4 0.2 4.2 2.1 5.1 3.3 5.3 3.8 20 May lax. 5 2.6 3.4 4.4 5.6 4.6 8.2 4.6 9.8

Furthermore, the ratio of the number of soft stool animals to the total number of treated rats or mice was determined.

n Nursing. rats g / kg 2 Hours after administration 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 / Ю 7/10 10/10 10/10 These animals shall: reaches apparently with respect to upper effect dosage limits

above 2.5 g / kg.

n ošěeř. mrší g / kg 2 Hours after administration 4 6 8 20 May control - 0/20 1/20 4/20 4/20 20 May 18X. 2.5 4/20 8/20 10/20 17/20 20 May lex. 5 8/20 17/20 20/20 20/20

The results show an apparent laxative effect of the laxative according to the invention, which is manifested by an increase in the secreted faeces of the stool and a considerable increase in the number of soft faecal beads compared to the hard faecal beads.

Finally, virtually no significant effect has been found when examining the choleretic effect of the laxative according to the invention, from which it can be obtained.

Daily food intake was also investigated and practically no fading was found.

In the diures test, a decrease in renal secretion has been observed which appears to be related to an increase in enteral fluid excretion.

The product, administered at doses of 1.0 and 2.0 g / kg to male rats of 280 g body weight, did not produce any noticeable changes in blood pressure and heart rate. Also, no inflammatory changes were found in ges.

In total, on the basis of the results of the examination of kunta to vet, the composition of the laxative according to the invention is extremely low toxicity, the toxicity is so low. the multiple of the dose recommended for humans is still well tolerated by the animals.

Toxic effects or intolerance were not observed, but only the direct effect observed, i.e. logically, as a major property. Furthermore, no inflammatory changes were found in the animal ' s disease which was treated with high doses of the pro-agent or was subjected to long-term treatment with these laxatives. This was observed with surprise, as it was not often altered in animals that received laxative.

In animals in heat, administration of the laxative according to the invention does not lead to any significant change in the normal development of the fetus, its number, mass, and the effect pattern fully agrees with the data and findings of the control animals.

The laxative effect of the composition is manifested 3 and 4 hours after administration to the test animals. It is proportional to the dose of e manifested. by accelerating the passage time of the intestinal contents as a result of the contamination and from the stool.

Dimension tests (urinary excretion tests) in treated animals showed a decrease in urinary excretion, which may be related to enteral fluid excretion. No changes were found in lung spawning, smooth muscle function, blood pressure or cardiac activity. The dietary intake of the laxative of the present invention was also unaffected by dietary intake.

Claims (8)

A method for producing a laxative based on plantain seeds and senesian pods, characterized in that plantain seeds and senesan pods are milled separately for granularity 99% finer than 500 85% finer than 400 µm 50% finer than 200 μη blend in a ratio of about 4 to 5: 1, dry blended, blend rapidly 8 evenly with as little water as possible, granulate the blend and dry to a maximum moisture content of 3.5% by weight and the dried granulate is finally auctioned. The method according to claim 1, characterized in that the water content of the bulk material is 30 to 20 $ 40 weight based on total wet weight · Method according to claim 1 or 2, characterized in that the spinning-off is carried out by permanently joining relatively small amounts of the mixture of the ground product and water in more than ⁴ mixing stages arranged in succession. Process according to one of Claims 1 to 3, characterized in that the granulation is carried out at 5 MPe and a particle size of 2 to 2.5 mm. Method according to any one of the preceding claims, characterized in that the granulate is dried for half an hour in a fluidized bed with a stream of air. Method according to one of the preceding claims, characterized in that the seneside content of senesium pods is adjusted to a standard value of 2.0 to 2.5% by weight, preferably 2.2% by weight, by mixing the different parts before milling. Method according to one of the preceding claims, characterized in that the mixing of the milled product is carried out with the addition of milled plank seed husk, in particular in amounts of 3 to 4% by weight. Method according to one of the preceding claims, characterized in that the kneaded mass is left to rest for 1 to 2 hours before extrusion in a extruder.