FI56772C - FOERFARANDE FOER FRAMSTAELLNING AV EN BEREDNING FOER BEHANDLING AV ONORMALA TARMTILLSTAOND - Google Patents

Description

«Fr - I Γβ1 .... ADVERTISEMENT _ _„ _ ^ [B] O1) UTLÄGG NI NGSSKRI FT 56772 C (45) Patent myonn- ity 10 04 1930 j Patent ineddelat '(51) Kv.ik. * / Int.ci. » A 61 K 35/78 A 61 K 31/74 A 61 K 31/715 FINLAND - FINLAND (21) Pu * nttlh »k« mu * - P «* nun« öknln | 7609 ^ 8 (22) Hakcmispiivi - Ansöknlngtdig · OU .76 ^ (23) Alkupilvl —Glltlghtttdag O7.Oil.76 (41) Has become public - Bllvlt offentllg 10.10.76

Patent and Registry Administrator, -. . . , (44) Date of the letter of formal notice and the date of publication. -

Patent and registration authorities in the United Kingdom and the United Kingdom. » publlcerad 31.12.79 (32) (33) (31) Privilege requested —Begird priorltet 09.0i + .75

Sweden-Sweden (SE) 750 ^ 0 ^ 9-3 (71) AB Hässle, Fack, S — U31 20 Mölndal 1, Sweden-Sweden (SE) (72) Curt Henry Appelgren, V Frölunda, Conny Börje Bogentoft, Mölndal,

John Albert Sjögren, Mölnlycke, Sweden-Sverige (SE) (7 M Berggren Oy Ab (5 * 0 Method for the preparation of a preparation for the treatment of abnormal intestinal conditions - Förfarande för framställning av en beredning för behandling av onormala tarmtillständ for the treatment of abnormal intestinal conditions, in particular Colon irritabile, containing bran of various cereals as a carrier component with a rigid macromorphological structure.

The appendix of the colon is easily inflamed, causing diverculitis, which causes a very painful feeling, which in many cases can only be cured by removing the inflamed parts of the colon.

Colon irritabile is a disease typical of the population of western industrialized countries. The spastic state with increased motor functions in the colon is part of the pathological picture. This leads to an increase in the pressure inside the colon, which leads to the formation of appendicitis, so-called diverticulosis, with possible subsequent inflammation, so-called diverculitis, as described above. The occurrence of sacs is common and has been reported in 56% of the population with an average age of 70 years. Symptoms of colon irritability vary. The most common are changes in the defecation event, in which case both constipation and diarrhea may occur along with abdominal distension and gas formation. Colon irritabile is the most common gastrointestinal disease. It is 2-5 times as common as gastric ulcer due to gastric acid in patients with an internal medicine clinic.

Although the mechanism of birth is complex and in some respects unknown, it is generally accepted that nutrients with too little bulky substance are probably the most common and also the most important cause of appendicitis. For this reason, the amount of defecation is reduced and the transit time through the gastrointestinal tract is prolonged, which in turn results in a spastic state with increased motor functions in the colon.

The treatment has in the past been a modified diet, i.e., foods that contain more bulky substance have been fed, along with therapeutic agents such as diarrhea-improving agents and antispasmodics and peristalsis-suppressing agents. However, this type of treatment is difficult to perform and has not been shown to be effective enough.

Recently, results have been obtained showing that wheat bran has a positive effect on appendicitis. The amount of faeces and the transit time through the gastrointestinal tract increase when a daily dose of bran of about 20 g is administered. In addition, the pressure inside the colon decreases. The beneficial effect of bran is probably due to the water-binding capacity of the bran fibers. This ability is independent of ambient pH.

The disadvantage of bran, however, is that it is difficult to take as much as is needed for effective treatment. This is because the bran is difficult to handle and small doses are not effective enough to prevent a spastic condition in the colon caused by Colon irritability. It has also been found that ingestion of the required amount of bran causes irritation due to a feeling of stretching in the stomach, as the swallowed bran immediately swells.

It is equally difficult for patients to use other types of bulking agents, such as sterhulum gum, psyllium seeds, and cellulose derivatives.

Thus, an ideal preparation for the treatment of appendicitis would be a substance that is not absorbed or broken down in the gastrointestinal tract and that absorbs water and swells to a much larger volume in the intestine, especially the colon, than in the stomach. In addition, such a 3,56772 formulation should be in a form that is easy to administer without causing discomfort.

Fecal agents consisting of a swelling agent such as bassorin or chitosan and a fecal agent such as francula shell are known. However, the frangula shell does not act as a carrier component with a rigid macromorphological structure, but as a chemically active fecal agent.

Feces are also known which contain psyllium seed husks as a swelling component together with glucose. However, such preparations already swell in the stomach, so they have the same disadvantage as "bran alone".

Martindale: The Extra Pharmacopoeia 26. p. (1972) pp. 987-991 discloses several ion exchange resins, among them Calcium Polycarbophil. Pages 1070-1093 of the same book disclose several natural or synthetic swelling agents, including acacia (gum arabic), polyacrylic acids such as Carbopol® (Biesterfeld), sodium alginate, sodium carboxymethylcellulose and Sterculia.

Meller K.O., Pharmakologie 1966, pp. 167-169 discloses several mucolytic agents, including gum arabic and sodium carboxymethylcellulose. Pages 207-211 of the same book provide an overview of different laxatives, e.g. chemically / musculoskeletal, lubricating and bulking agents.

The study of the effect of wheat bran and cellulose used as a dietary supplement on intestinal function is described in British Medical Journal 4, pp. 392-394 (1973).

These known substances, which are thus either substances with a rigid macromorphological structure or swellable substances, have also been used separately as excipients. However, they have considerable disadvantages in this case, because e.g. they must be administered in very large quantities, are technically difficult to handle or have a swelling effect on the wrong part of the gastrointestinal tract. The latter is particularly disadvantageous in the case of colon irritability.

4,56772

Preparations for binding bile acids are also known, which preparations contain anion exchange resins and additives such as acacia gum. Further preparations are known which have a protective effect on the gastric mucosa and which e.g. contain a small amount of microcrystalline cellulose. However, this amount is so small that cellulose cannot act as a carrier component. These preparations do not have advantageous swelling properties and have not been used to treat abnormal intestinal conditions.

It is an object of the present invention to provide a formulation which meets the above requirements and which does not have the disadvantages of previously known similar formulations. The invention therefore relates to a process for the preparation of a preparation for the treatment of abnormal intestinal conditions, in particular Colon irritable disease, containing bran as a carrier component with a rigid macromorphological structure, and the process according to the invention is characterized in that bran is mixed in a weight ratio of 98: 2-20: 80 in water at a pH above 4 with a swellable water-binding carboxyl group-containing polymer or a salt thereof, and that a solution of the binder in an organic solvent is added to the mixture, followed by drying.

According to the invention, polyacrylic acid or carboxypolysaccharide or a salt thereof is preferably used as the water-binding compound.

According to the invention, a lipophilic substance such as cetanol, wax, fatty acid esters, glycerol esters and the like can also be dissolved in the organic solvent of the binder. Other lipophilic agents may be used to coat the solid preparation to facilitate its administration when the preparation is in granular form.

The preparation according to the invention thus contains bran of various cereals as a water-binding, swellable carrier component with a rigid macromorphological structure and inert to gastrointestinal processes, and a compound which swells insignificantly at the acidic pH of the stomach but which increases significantly and absorbs water when the pH rises above 4, i.e. when the preparation enters the intestine. At the intestinal pH, the volume of the compound has increased significantly (2-20 times to 5,56772) compared to the volume in the stomach. This compound is preferably polyacrylic acid (Carbopor® type, Biesterfeld) or a carboxypolysaccharide such as karaja gum (Sterculia gum), ghatic gum (Indian gum), acacia gum or a salt thereof such as calcium polyacrylate, sodium carbosymethyl calcium alginate.

According to the invention, the preparation can be prepared as a granulate, in which case the granules can be coated with lipophilic substances to facilitate ingestion. The granules can be ingested as such or suspended in solution as a slurry or suspension. They can also be compressed into tablets.

The daily dose effective for the treatment of appendicitis is 2-10 g, which is considerably lower than with conventional edema agents.

The invention is illustrated below with reference to the following examples.

A suitable method for determining the water absorption capacity of the present preparation is as follows: 0.5 g of the preparation is combined with 40 ml of gastric or intestinal fluid for 24 hours. The mixture is then centrifuged at 4000 rpm for 5 minutes and the centrifuge is removed. The remaining part corresponds to the water absorption capacity of the preparation.

Example 1 50 g of wheat bran and 20 g of Carbopo] ® 934 are mixed and 7 g of Vinnapas® B 100 (Wacker-Chemie: polyvinyl acetate) and 18 g of glyceryl monostearate dissolved in a methylene chloride / isopropanol mixture (9 + 1) are added. The granules are dried and ground through a 2.4 mm sieve.

0.5 g absorbs 2.7 g of I 2 O in gastric fluid 0.5 g absorbs 18 g of I 2 O in intestinal fluid

Example 2 50 g of wheat bran are mixed with 20 g of calcium alginate and 13.4 g of Kollidon® K 90 (BASF: polyvinylpyrrolidone) dissolved in isopropanol are added. The granules are dried and ground through a 2.4 mm sieve.

0.5 g absorbs 2 g I ^ O in gastric fluid 0.5 g absorbs 8 g f ^ O in intestinal fluid 56772

The preparation prepared according to the invention was compared with two known preparations and wheat bran. Of the known preparations, Metamucir consists mainly of psyllium husk and glucose and Normalaj consists mainly of frangula husk and bassarin. The water-binding capacity was determined by the method described above.

Water-binding capacity of various preparations

Preparation H20 uptake H20 uptake Percentage of H20 in gastrointestinal fluid uptake,,. t „/„ \ in intestinal fluid / _ ^^ _ in gastric fluid

Metamucil® 14.0 14.0 1.0

Normalaj ^ 8.4 11.8 1.4

Wheat bran 2.8 2.8 1.0

Example 1 3.9 16.0 4.1

The preparation according to the invention can also be used for other abnormal intestinal conditions, such as constipation, whereby the consistency and volume of defecation become more normal, which improves the motor function of the intestine.

56772 A method of preparing a mixture for the preparation of a macromorphological structure with the same macromorphological structure.

Divertiklarna i tjocktarmen blir lätt inflammerade, varvid diver-tikulit uppstär, varvid mycket smärtsamma tillständ erhälles, vilka self, i mänga fall, kan elimineras genom eliminering av de in-flammerade tjocktarmspartierna.

The colon is irritable and has a specific state that is particularly common in other civilizations. This account can be used spatially with other motor vehicles and vehicles. Detta leder account et för-höjt intraluminalt tryck i Colon med imilding av divertiklar s.k. diverticulate med ev. efterföljande infektion s.k. diverticles som ovan nämnts. Divertikelbildning är vanlig och har rapporteats ske billi 56% hos en population medeläldern 70 är. Symptoms of Colon Irritation include variation. However, there are defects in the composition, and in the case of a combination of uptake and gas. The colon is irritable in the gastrointestinal tract of the elderly. The patient is treated with internal medicine for 2-5 years.

The uplink control mechanism is complex and accounts may be based on the fact that the underlying acceptance factor, and whether or not the redundancy factor is present in the divergent account, is not limited to the bulk feed. Därigenom blir mängden avföring mindre och passagetiden genom magtarmkanalen längre, vilket i sin tur leder account ett spastiskt tillständ med ökad motorik i tjocktarmen.

Behandlingen har tidigare gätt ut pä ändrade kostvanor, dvs. mer bulkrik föda i kombination med läkemedel som t.ex. antidiarrheals, antispasmodics and anticholinergics. Such a type of dock is considered to be genome-free and has the potential to be effective.

The results of the present case are based on the results of the in-service report. In the case of passage and passage of the genomic energy channel, a maximum of 20 g per dose is added. Dessutom sänks det intraluminala trycket i Colon. The positive effects of the tracer on the watten are 5 6772 in the case of a cliff. The pH is determined by the pH adjustment.

Nackleden med kli är emellertid bl.a. svärigheten att ta in den stora mängd kli som behövs för en effektiv behandling. This means that there is no effect on the skin and that there is no effect on the effect of the sponge when the skin is irritable. In this case, the game is described above and in the same way as in the case of Magen, the genome of which has been found to be free from the game.

Samma problem upplever patients à og med andra typer av bulkgivande medel säsom sterhulia gummi, psyllium frö, Cellulosa derivat.

The ideal base for the distribution of the divergent volume of the base and the absorption or absorption of the transmission and the supply channel and the supply to the supply and the volume of the supply, the specific operation, and the recovery. If necessary, the product can be stored in the form of a blanket.

Man känner laxermedel, som bestär av ett svällande material, säsom bassorin eller kitosan, och ett laxativ, säsom frangulabark. Framgu-labark verkar emellertid icke som bärarkomponent med stel macromor-fologisk struktur, then somehow chemically verksamt laxermedel.

In the case of a laxermedel, the scales of which are psylliumfrö som svällande component tillsamman med glukos. Sädana preparat sväller dock redan i magsäcken, varför de har samma nackdel som kli använt ensamt för sig.

Martindale: The Extra Pharmacopoeia 26: th ed (1972) sid 987-991 anger et antal jonbytarhartser, däribland Calcium Polycarbophil.

Ibid sid 1070-1093 anger and flertal pellets in natural or synthetic form are treated with acacia (gum arabicum), sodium alginate, sodium carboxymethylcellulose and sterculia.

Meller K.O., Pharmakologie 1966 sid 167-169 anger and anthelmintic amine gum arabicum and sodium carboxymethyl-9 56772 Cellulosa. Ibid sid 207-211 ger en översikt över olika laxermedel däribland kemiskt / neuromuskulärt verkande ämnen, medel med smörjande egenskaper och volymsökande medel.

British Medical Journal 4, sid 392-394 (1973) redesigns and studies the effects on the function of cells and cellulose in the diet of Scotland.

Salunda kända medel, utgörande ämnen med stel makromorfologisk struktur eller ämnen med svällande förmäga, har även var fig sig kmmit till användning som laxermedel. De uppvisar dock därvid flera nackdelar dä de exempelvis mäste administreras i mycket Stora mängder, är tehniskt ohanterliga eller utövar sin svällande förmäga pä fel ställe i magtarmkanalen. The system is specially formulated to treat the colon irritabile.

The headband is made of a binder with a gyroscope, a bright cut-off of an anionic resin and a torsatsmedel, säsom acacia-gummi. Vidare känner man beredningar med skyddande effekt pä mags-lemhinnan och som bl.a. innehäller en liten games microcrystalline Cellulosa. If the cell is not in the dock, the cellulose is not present in the bark. This measure is based on the same conditions as in the case of imports from one country to another.

For example, the manufacturer of the preparation may be required to prepare the preparation and, if necessary, to prepare the preparation. The application of this Regulation to the preparation of a product for the manufacture of certain macromorphological structures, including the use of certain components of the macromorphological structure 98: 2-20: 80 with a pH of about 4 carboxyl groups of the carboxyl group of the polymer or that of the site of action, and that of the bleaching provision and the addition of the binder and the organic bleaching agent, the blister is pierced.

In addition, the addition of a polyacrylic acid or a carboxylic polysaccharide to a solid having a water content of 10 56772 binders.

In addition to the addition of a lipophilic filler and a binder, organic binders, such as cetanol, wax, fettsyraestrar, glycerolestrar och liknande. This lipophilic form is used for the preparation of a composition for the administration of granules in the form of granules.

In order to increase the cost of the preparation, the preparation of the mixture may have a significant effect on the macromorphological structure and the inherent concentration of the pH of the measurement channel, as well as of the above, Märkbart och som lätt absorberar watten da pH stiger over 4 dvs the preparation is incompatible with the feed channel. In this case, the pH in the feed channel is determined by the volume to the maximum value (2-20 gers) in the volume of the volume. For the production of polyacrylics (Carbopol®-typ, Biesterfeld) or carboxylic polysaccharides, starch gum, ghattigumium (India-gum), gum arabicum ellercarbium

Preferably, the granules can be prepared in the form of granules, the granules of which can be formulated with lipophilic particles for administration. The granules can be administered as a solution or suspension in a solution or suspension. De kan även pressas account tabletter.

The dosage form is preferably effective in the form of a mixture of 2-10 g, with a vigorous fatigue mixture which can be obtained with a vanilla butter.

For the purposes of this Regulation, the Community rules do not apply to exemptions.

In this case, a method is used which can be used for the preparation of the product in the form of a mixture of: 0.5 g of the formulation in a mixture with 40 ml of magnesia oil under 24 Tim. Därefter centrifuges blandningen med en hastighet av 11 56772 4000 varv / min under 5 min and centrifugatet avlägsnas. Den kvar-varande mängden motsvarar beredningsformens vattenbindande förmiga.

Exempel 1 50 g of wax and 20 g of Carbopol® 934 bleach and 7 g of Vinnapas ® B 100 (polyvinyl acetate) and 18 g of glyceryl monostearate are then added in methylene chloride / isopropanol (9 + 1). Granulate throat and rives genome cut 2.4 mm.

0.5 g tar upp 2.7 g Η ,, Ο i magsaft 0.5 g tar upp 81 g Η2 <0 i tarmsaft ^ Exempel 2 50 g vetekli blandas med 20 g calciumalginat och 13.4 g Kollidon ® K 90 ( BASF: polyvinylpyrrolidone) in isopropanol. Granulate throat and rives genome cut 2.4 mm.

0.5 g tar up to 2 g H 2 O in magnesium 0.5 g tar up to 8 g H 2 O in milk

In this case, the preparation of the basic preparation of the preparation is carried out with the preparation of the preparation. Metamucil> 5 / is preferably used in the form of psylliumfrom and glucose and Normalax® is best used in the form of frangularbars and bass. Vat-tenupptagningsförmägan bestämdes med den ovan angivna methods.

Vattenbindande förmaga hos olika beredningar

Preparations H20 upptag H20 upptag Quota Η2 <0 upptag i i magsaft ι tarmsaft tarmsart / magsaft (g / g) (g / g)

Metamucil 14.0 14.0 1.0

Normalax ® 8.4 11.8 1.4

Vetekli 2.8 2.8 1.0

Exempel 1 3.9 16.0 4.1

Preparations for the application of these methods are intended to meet the requirements of this Regulation, in the case of stopping, colors having a consistency consistent with the normal consistency and volume of the main engine.