FI59023C - FRAMEWORK FOR FLAMMING FORM AND EXTENSION OF CHARACTERISTICS - Google Patents

Description

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Sweden-Sverige (SE) 7606256-1 (Tl) AB Hässle, Fack, S-U31 20 Mölndal 1, Sweden-Sverige (SE) (72) Conny Börje Bogentoft, Mölndal, Sweden-Sverige (SE) (7U) Berggren Oy The present invention relates to a process for the preparation of a clear-soluble gastric acid neutralizing agent in a liquid form.

It is an object of the present invention to provide a gastric acid neutralizing solution which reacts rapidly with an acid having a high acid neutralizing capacity, is not absorbed and does not provide pharmacological systemic effects which are well tolerated and which taste good and have a good consistency.

The acid neutralizing agent becomes e.g. have a high reaction rate with dilute acid and a high acid-binding capacity. Hitherto known acid-neutralizing preparations which best meet these requirements contain aluminum hydroxide or the like, either alone or in combination with magnesium salts. Aluminum hydroxide and the like have the advantage of reacting relatively rapidly with acids at low pH. However, the reaction stops when the pH rises to about four. Other compounds that have been used as relatively neutralizing agents are magnesium silicate and calcium carbonate. Both of these compounds buffer at a slightly higher pH than aluminum hydroxide and are partially absorbed. Other magnesium compounds, such as hydroxide and carbonate, are used only to a limited extent as such. However, they have often been used in combination with aluminum hydroxide due to the fact that these compounds themselves give a strong laxative effect which is reversed by aluminum hydroxide. Sodium bicarbonate is a completely water-soluble compound that has also been used as an acid neutralizing agent to some extent. However, this compound raises the pH above the neutral point, which can excite and thus increase gastric acid secretion. In addition, it is completely absorbed and can cause base overgrowth or base poisoning.

Thus, most of the acid neutralizing compounds used to date are compounds that are difficult to dissolve in water, but which are soluble in gastric acid while reacting with hydrochloric acid. The reaction is not instantaneous, like the reaction between an acid and a base in solution. In the reaction between the solid and liquid phases, as in the case here, the reaction rate depends e.g. particle size (or actually interphase interface), solid phase solubility, crystal structure, possible hydration, etc. It is a known clinical finding that a liquid preparation of aluminum hydroxide, for example, gives a better effect than tablets (e.g. Krantz and Carr, Pharmacol. Principles Med. Pract. Williams and Wilk , Baltimore 1961, page 391). One of the main reasons for this is that liquid preparations react more rapidly with acid than tablets (Sjögren, Farm. Revy. 62, 735, 1963).

However, these previously known substances used as acid neutralizing agents, which contain a combination of Al and Mg salts, have certain drawbacks such as poor taste and chalky consistency and react relatively slowly with the acid. Another disadvantage associated with the use of substances of this type as acid neutralizing agents is that the pH of the urine may increase, which may lead to a faster excretion of co-administered acidic therapeutic agents. Similarly, there may be interactions with other drugs such as anticholinergics and tetracyclines in the gastrointestinal tract, with the latter being absorbed to a lesser extent than intended.

U.S. Patent No. 5,9023,332,841 discloses a method of treating excess gastric acid using a cross-linked polyethyleneimine. However, said substance can only provide a flowable preparation in the form of a suspension of solid particles, which is not acceptable in the case of large groups of patients.

It has now surprisingly been found possible to eliminate the above drawbacks by the present invention, which is characterized in that an aqueous solution of polyethyleneimine is added from 10-60% of the finished product solution to one or more taste-improving acids such as alginic acid, polygalacturonic acid, galacturonic acid, pectic acid, pectic acid -nine, arabic acid, galactaric acid or glutaric acid, followed by reacting the polyethyleneimine with one or more acids, such as tartaric acid, fumaric acid, phosphoric acid, acetic acid, citric acid, succinic acid and nitric acid, to change the pH. that the pH of the aqueous solution of the formed product is 4-11.

According to a preferred embodiment of the invention, a water-soluble polyethyleneimine having a molecular weight of 500 to 5,000 and preferably having a viscosity of about 200 cp as a 50% aqueous solution is used.

In another preferred embodiment of the invention, the aqueous solution preferably contains 10 to 40% by weight of polyethyleneimine when preparing a solution to be administered directly.

The prepared substance is able to neutralize gastric acid in the stomach to the desired pH without giving undue side effects.

The polyethyleneimines used in accordance with the present invention are water-soluble polyethyleneimines of the formula h2n- (ch2ch2n-) x- (ch2ch2nh) - CH0 I 2 CH0 I 2 -N- 59023 of which suitable grades are sold under the designation G35 and G50 (Badische Aniline und Soda Fabriken), the Federal Republic of Germany, and under the designation PEI 6, PEI 12 and PEI 18 (Dow Chemicals, USA).

However, in order to provide a gastric acid neutralizing agent, at least one organic acid must be added to such polyethyleneimines to lower the pH, which is tartaric acid, fumaric acid, phosphoric acid, citric acid, acetic acid, succinic acid and / or malic acid, preferably citric acid, citric acid.

In order to improve the taste, at least one flavor-improving acid, alginic acid, polygalacturonic acid, galacturonic acid, pectin, tannic acid, arabic acid, galactaric acid and / or glutaric acid, galacturic acid, preferably alginic acid, preferably alginic acid, must be added to the acid-polyethyleneimine solution. The amount of flavor enhancing acid is 1-10, preferably 1-5% by weight of the substance.

In order to obtain the best taste, in a preferred embodiment of the invention, polyethyleneimine is added as an aqueous solution to a solution of a taste-improving acid, after which the pH-adjusting acid is added until the desired pH is reached.

The invention is described in more detail below by means of examples.

Example 1

Polyethyleneimine 100% (G35, BASF) 250 g

Alginic acid 20 g

Citric acid 100 g

Water ad 1000 g

Alginic acid was dissolved in 380 ml of water. Polyethyleneimine was then added as a 50% aqueous solution. After thorough mixing, the pH was adjusted to 7.3 by the addition of citric acid. The resulting solution was a clear pale yellow solution.

Example 2

Polyethyleneimine 100 S (G35, BASF) 250 g

Galacturonic acid 20 g

Acetic acid 160 g

Water ad 1000 g 5 59023

Galacturonic acid was dissolved in 320 ml of water, after which polyethyleneimine was added as a 50% solution. After thorough mixing, acetic acid was added to give a clear, slightly orange solution with a pH of 7.5.

Example 3

Polyethyleneimine G35, 100% 240 g

Polygalacturonic acid 16 g

Phosphoric acid 200 g

Water ad 1000 g

The preparation was carried out according to Example 1 above to give a final pH of 6.0.

Example 4

Polyethyleneimine G 35 210 g

Polygalacturonic acid 14 g

Phosphoric acid 205 g

Acetic acid 90 g

Water ad 1000 g

The preparation was performed as in Example 1 above to give a final pH of 5.0.

Example 5

Polyethyleneimine (100%) 250 g

Pectin 20 g

Acetic acid 150 g

Water ad 1000 g

The preparation was carried out according to Example 1 above. The pH was about 7.

Example 6

Polyethyleneimine (100%) 230 g

Arabic acid 13 g

Phosphoric acid 230 g

Water ad 1000 g

The preparation was carried out according to Example 1 above. The final pH was 6.4.

6 59023

an example

Polyethyleneimine (100%) 260 g

Tannic acid 17 g

Acetic acid 130 g

Water ad 1000 g

The preparation was carried out according to Example 1 above. The final pH was 7/6.

Example 8

Polyethyleneimine 250 g

Alginic acid 17 g

Succinic acid 170 g

Water ad 1000 g

The preparation was carried out according to Example 1 above. Final pH 7.1.

Example 9

Polyethyleneimine (100%) 250 g

Galactaric acid 17 g

Acetic acid 130 g

Water ad 1000 g

The preparation was carried out according to Example 1 above. The final pH was about 7.5.

Example 10

Polyethyleneimine (100%) 250 g

Glutaric acid 17 g

Acetic acid 130 g

Water ad 1000 g

The preparation was carried out according to Example 1 above. The final pH was about 7.5.

Example 11

Polyethyleneimine (100%) 250 g

Alginic acid 20 g

Malic acid 170 g

Water ad 1000 g 7 59023

The preparation was carried out according to Example 1 above. The final pH was about 7.3. Fumaric acid and tartaric acid can be used equally well.

Example 12

Polyethyleneimine (100%) 250 g

Polygalacturonic acid 50 g

Alginic acid 25 g

Phosphoric acid 100 g

Water ad 1000 g

The preparation was carried out by dissolving polygalacturonic acid and alginic acid in 325 ml of water. Polyethyleneimine was then added as a 50% aqueous solution. After thorough mixing, phosphoric acid was added. Final pH 7.5.

Example 13

Polyethyleneimine (100%) 250 g

Alginic acid 50 g

Arabic acid 25 g

Succinic acid 80 g

Water ad 1000 g

Alginic acid and arabic acid were dissolved in 345 g of water. Polyethyleneimine was then added as a 50% aqueous solution. After thorough mixing, succinic acid was added. Final pH 7.6.

Example 14

Polyethyleneimine (100%) 250 g

Alginic acid 30 g

Galactaric acid 30 g

Phosphoric acid 100 g

Water ad 1000 g

The preparation was carried out according to Examples 12-13. The final pH was 7.6.

Example 15

Polyethyleneimine (100%) 100 g

Alginic acid 12 g 8 59023

Fumaric acid 80 g

1000 g of water

The preparation was performed according to Example 11.

Example 16

Polyethyleneimine (100%) 400 g

Alginic acid 25 g

Tartaric acid 175 g

Water ad 1000 g

Alginic acid was added to a 50% aqueous solution of polyethyleneimine, which was mixed thoroughly. Tartaric acid was then added.

The acid neutralizing capacities of the above preparations are 40-50 ml of 0.1% HCl / g of a 25% aqueous solution of polyethyleneimine.

The daily dose of the preparation according to the invention depends very much on the degree of hyperacidity from which the patient suffers. Usually, however, 8-40 g of preparation per 24 hours is required when the preparation contains 25% polyethyleneimine. Single doses are 2-4 g administered 4-10 times a day. The specific weight of the above preparations is about 1.25 g / ml.

Comparative experiments performed to determine the acid-binding capacity and its duration using preparations containing water-soluble polyethyleneimine, cross-linked polyethyleneimine and a reference preparation containing aluminum hydroxide and magnesium hydroxide____

Two experiments were performed, one to determine the gastric acid neutralizing ability of the preparations in rats in vivo and in vitro, and the duration of the second effect in vivo in rats.

Substances and methods

Female Sprague-Dawley rats weighing 200-220 g were fasted for 20 hours before use. However, 9,59023 of water was freely available. The animals were in cages with floors of wire mesh to prevent feces from being eaten.

a) Rat with gastric portal ligament

An incision was made along the midline and a dressing was placed around the gastric port using light ether anesthesia. Once the bandage was attached, the animal was allowed to wake up under anesthesia. Test compounds or vehicle were administered intraperitoneally by gastric tube at the time of dressing. Two hours after making the bandage, the animals were killed by striking them on the head.

b) Rat without gastric port binding

Test compounds were administered intragastrically using a gastric tube and the animals were sacrificed two hours later.

In both experimental models, the stomach was closed after the experiment and excised. Gastric volume was measured and its contents were collected by rinsing accurately with water to a final volume of 12 ml. The pH was measured and the sample was titrated to pH 3.0 with 0.5 M HCl using an automatic titrator (ABU 12, Radiometer, Copenhagen). The acid binding capacity of each sample was determined and averaged for all rats treated with the same treatment.

An aqueous solution of the invention containing 25% polyethyleneimine (PEI 12) and 1% alginic acid was adjusted to pH 8.0 with citric acid and administered orally at 1.0 or 0.5 ml / rat, corresponding to a polyethyleneimine dose of 1 , 25 g / kg or 0.625 g / kg body weight. An aqueous suspension was prepared containing 23% cross-linked polyethyleneimine prepared according to Example 1 of U.S. Pat. No. 3,332,841 in 0.4% methylcellulose (Methocel ® 90HG) and adjusted to pH 8.5 with lemon. and was administered orally at 1.0 ml per rat, corresponding to a dose of 1.15 g per kg body weight.

For comparison, a commercial antacid suspension containing 6% aluminum hydroxide and 2.5% magnesium hydroxide was used and administered in the same volumes as the other substances. All percentages mentioned are percentages by weight. Control animals 10 59023 received 0.75% methylcellulose solution (Methocel®). The composition of the polyethyleneimine used was chosen to correspond to the commercial antacid in terms of its acid-binding capacity, i.e. it neutralized 32 ml of 0.1 μl HCl / g. Upon neutralization, the acid-binding capacity of the cross-linked polyethyleneimine preparation was found to be 17 ml of 0.1 M HCl / g suspension, i.e. about half the corresponding capacity of polyethyleneimine (PEI 12) and commercial antacid.

In vitro titration was performed on all three preparations using the same dilution procedure as when gastric acid samples were collected in vivo.

The residual acid-binding capacity is the amount of hydrogen ions consumed by the stomach contents when titrated with 0.5 M HCl to pH 3.0.

Results and Conclusions 1. Efficiency study

The results of the efficacy study are summarized in Figure 1. In in vitro experiments, the water-soluble polyethyleneimine and the commercial antacid were almost equally effective, while the efficacy of the cross-linked polyethyleneimine was less than half that of the above preparations. In vivo, the residual acid binding capacity of freshly killed animals was 1480 + 181, 3290 + 87 and 662 + 60 μmol in rats receiving 1.0 ml of commercial antacid, polyethyleneimine and cross-linked polyethyleneimine. The total acid binding capacity was calculated by adding to the residual acid binding capacity the amount of hydrogen ions produced by the control rats and was 370 + 37 μmol for the control group of rats receiving commercial antacid and water-soluble polyethyleneimine and 622 + 90 μmol for cross-linked polyethylene of the control group.

The results thus show that the water-soluble polyethyleneimine has a residual acid-binding capacity in vivo of about 5-fold greater than that of the cross-linked polyethyleneimine and about 2-fold that of a commercial antacid. The difference in the doses of polyethyleneimine and cross-linked polyethyleneimine (1.25 vs. 1.15 g / kg) can only be considered to have a minor effect on the results obtained. The preparations according to the invention thus surprisingly show an improved acid neutralizing capacity in vitro and in vivo.

2. Duration of effect study 0.5 ml of a commercial antacid suspension, 0.5 ml of a polyethyleneimine solution and 1.0 ml of a cross-linked polyethyleneimine suspension were administered to rats without bound gastric ports.

An open gastric port allows the contents of the stomach to flow freely into the lower intestine for 2 hours after dosing of the preparations to be determined. The results (Table 1) show that there was virtually no acid binding capacity remaining 2 hours after dosing using a cross-linked polyethyleneimine suspension in an open system, indicating that this suspension migrated very rapidly in the intestine.

After administration of the commercial antacid suspension under the same conditions, only weak acid binding capacity remained. When the polyethyleneimine solution according to the invention is used, rats without a gastric port were left with about half of the acid binding capacity measured in rats with a gastric port bound 2 hours after dosing. This strongly indicates that the polyethyleneimine solution remains in the stomach for significantly longer than the commercial antacid and cross-linked polyethyleneimine suspension, and that the polyethyleneimine solution has a longer duration of action in vivo than the commercial antacid suspension and a very much better duration than the crosslinked polyethylene suspension.

59023

table 1

Durability study in rats with unbound gastric gates Compounds given 2 hours before assay

Compound Acid-binding pH of the stomach contents

Commercial antacid 0.5 ml / rat 4.19 + 0.18 172 + 68 11

Polyethyleneimine (PEI 12) 0.5 ml / rat 7.24 + 0.16 1172 + 94 10

Cross-linked polyethyleneimine 1.0 ml / rat 3.35 + 0.06 25 + 3 g

Numbers denote the mean + SEM (standard error of the mean values) 13 59023 For example, the upper limit of the upper limit of the upper limit of the maximum level of the polyurethane is shown to be the same as that of the polyurethane.

In particular, the use of uptake in a high-performance, high-reactive form, which has a negligible neutralization capacity, absorbs and improves the pharmacological systemic effect, and is tolerated outside the environment.

That syraneutraliserande medel bör bl.a. if the reaction time is limited to the size and the syrup capacity. Hittills kända syraneutraliserande preparat, som bäst uppfyller dessa fordringar inne-häller aluminiumydroxid eller dylika föreningar, antingen ensamma eller i combination with magnesium salt. Aluminiumhydroxid ocl dylika föreningar har den fördelen, att de relatat snabbt reagerar med syror vid lägt pH. The reaction is preferably carried out, the pH of which is determined by the action of Figure 4. The reaction is preferably carried out using a syrane-neutral solution with magnesium hydroxide and calcium carbonate. This means that the pH of the aluminium hydroxide and the resorbent batches are high. Andra magnesium compounds, hydroxides and carbonates are added to the mixture. The above-mentioned combination of aluminium hydroxide can be used to reduce the effect of the laxative effect, which neutralizes the combination with aluminum hydroxide. Sodium carbonate is present in the water, in which case it is considered to be pure. The pH is measured by the pH of the neutral point, the cell stimulator and the secretion of the nucleus. The desiccants are completely full and alkaline.

The fixture has been shown to be neutral in the form of a mixture of water, which can be treated with water, but also reacted with water. Reactions are not present at the moment of reaction and are inherent in the environment.

In the case of reactions with a high temperature and a low pressure, the reaction time is reduced, the reaction time is bl.a. p £ particle form, (or, in the case of a single contact), a solid, crystalline structure, eventual hydration o.s.v. En flash 14 59023 clinical observation is not included in t.ex. Aluminum hydroxide is effective on tablets (e.g. Krantz and Carr, Pharmacol. Principles Med. Practic. Williams and Wilkins, Baltimore 1961, sid 391). In the case of a compound which has been prepared, it is possible to prepare a reactive solution with a syringe (Sjögren, Farm. Revy. 62, 735, 1963).

Dessa hittills kända och använda syraneutraliserande medel inne-hällande en kombination av Al- och Mg-salter uppvisar emellertid vissa nackdelar, säsom dälig smak ocen en kritaktig consistency and de reagerar relativt slängsamt med syra. In addition to the use of the drug in the form of a syrane-neutral formulation, the pH of the urine can be adjusted to the secretion of the same therapeutic agent. In addition to the anticholinergic medication and tetracycline, the compound can be used in the gastrointestinal tract, which can be described as such.

U.S. Pat. No. 3,332,841 discloses the use of a polyethylene core. In this case, the emellants can be used to prepare a suspension, the best of which can be used, and the patient can be accepted as well.

In particular, it is possible to use the same or more than 10% to 60% of the yield of the product concerned. smakförbättrande syra, som är alginsyra, polygalacturonsyra, galacturonsyra, pectin tannin, arabinsyra, galactarsyra eller glutar-syra, toe, i avsikt att ändra pH, polyethyleneimation omsätts med en eller flera syror, som är vinsy citronsyra, bärnstenssyra eller äppelsyra i en sadan mängd att den bildade produkten i vattenlösning har pH 4-11.

Preferably, the refining formulation is carried out with the addition of polyethylene having a molecular weight of 500-5000 and a viscosity of up to 200 cp up to 50% of water.

I give a total of 10 to 40% by weight of polyethylene in the form of a water-based solution, so that a maximum of 15 59023 fractions is obtained from the administration directly.

The effect is to neutralize the magnesia and the magenta to its own pH after the effect of the binding effect.

The polyethyleneimine is preferably used in the form of a polyethyleneimine with the formula h2n- (ch2ch2n-) χ- (ch2ch2nh) - CH- I 2 CH ~ I 2 -N- and a vigorously heated quality sulfur according to the designation G35 and G50 (Badische Aniline) , Förbundsrepubliken Tyskland, och under notes PEI 6, PEI 12 and PEI 18 (Dow Chemicals, USA).

For the purposes of the entry into force of this Regulation, the polyethylene glycol content of the organic matter is determined by the pH of the wine, the fatty acid, the phosphorus acid, the citric acid, the citric acid, the fatty acid, the fatty acid

For use in the manufacture of syrups, polyurethylenic acid, galacturic acid, galactic acid, galactic acid, galactic acid and galacturic acid The game size is 1-10%, the average yield 1-5% av medlets vikt.

For the purposes of this Regulation, the odoriferous substances in the form of a mixture of water and polyethylene in the form of polyethylene in the form of a syrup, the pH of the syrup and the pH of the syrup are adjusted to pH.

The application of this Regulation does not affect the nature of the exemptions.

Exempt 1

Polyethyleneimine 100% (G35, BASF) 250 g

Alginsyra 20 g

Lemon 100 g

Watts give 1000 g of 16,59023

Alginsyran was added to 380 ml of water. Därefter tillfördes polyethylene is made up to 50% by weight. After that, the pH was adjusted to 7.3 by adding the genome to the lemon. The resultant solution is a clear-cut solution.

Exempel 2

Polyethyleneimine 100% (G35, BASF) 250 g

Galacturon syrup 20 g Acetyl syrup 160 g

Watts give 1000 g

The galacturonic acid is poured into 320 ml of cotton, with a polyethylene content of up to 50%. After complete application of the mixture, the color of the orange oranges is adjusted to pH 7.5.

Exempel 3

Polyethyleneimine G35, 100% 240 g

Polygalacturon is 16 g

Phosphorus 200 g

Watts give 1000 g

Framställningen utfördes i enlighet med ovanstäende exempel 1, varvid erhölls ett slutgiltigt pH av 6,0.

Exempel 4

Polyethyleneimine G35 210 g

Polygalacturon is 14 g

Phosphorus 205 g Acetic acid 90 g

Watts give 1000 g

Framställningen utvördes i magnimate with exemplet 1 ovan, varvid som sutgiltigt pH erhölls 5,0.

Exempel 5

Polyethyleneimine (100%) 250 g

Pectin 20 g Acetic acid 150 g

Watts give 1000 g 17,59023

Framställningen utfördes i enlighet med exemplet 1 ovan. The pH can be about 7.

Exempel 6

Polyethyleneimine (100%) 230 g

Arabinsyra 13 6

Phosphorus 230 g

Watts give 1000 g

Framställningen utfördes i enlighet med exemplet 1 ovan. The pH can be 6.4.

Exempel 7

Polyethyleneimine (100%) 260 g

Tannin syrup 17 g Acetic acid 130 g

Watts give 1000 g

Framställningen utfördes i enlighet med exemplet 1 ovan. The pH can be 7.6.

Exempel 8

Polyethyleneimine 250 g

Alginia syrup 17 g Bärnstenssyra 170 g

Watts give 1000 g

Framställning utfördes i enlighet med exemplet 1 ovan. The pH is 7.1.

Exempel 9

Polyethyleneimine (100%) 250 g

Galactic syrup 17 g Acetic acid 130 g

Watts give 1000 g

Framställningen utfördes i enlighet med exemplet 1 ovan. The pH can be about 7.5.

18 5 902 3

Exempel 10

Polyethyleneimine (100%) 250 g

Glutar 17 g

Attiksyra 130 g

Watts give 1000 g

Framställning utfördes i enlighet med exemplet 1 ovan. The pH can be about 7.5.

Exempel 11

Polyethyleneimine (100%) 250 g

Alginsyra 20 g Äppelsyra 170 g

Watts give 1000 g

Framställning utfördes i enlighet med exemplet 1 ovan. The pH can be about 7.3. Lika väl kan fumarsyra och vinsyra användas.

Exempel 12

Polyethyleneimine (100%) 250 g

Polygalacturon is 50 g

Alginsyra 25 g

Phosphorus 100 g

Watts give 1000 g

Framställningen utfördes genom att plösa polygalacturonsyra and alginsyra i 325 ml vatten. Därefter tillsattes polyethyleniminen som 50 -% ig vattenlösning. After that, the mixture is treated with phosphorus. The pH is about 7.5.

Exempel 13

Polyethyleneimine (100%) 250 g

Alginsyra 50 g

Arabic syrup 25 g Bärnstenssyra 80 g

Watts give 1000 g

Alginsyran and arabinsyran are added in 345 mg of water. Därefter till sattes polyethyleniminen som 50-% sig vattenlösning. After that, the costs are reduced. Slutligt pH 7.6.

19 59023

Exempel 14

Polyethyleneimine (100%) 250 g

Alginsyra 30 g

Galactarsyra 30 g

Phosphorus 100 g

Watts give 1000 g

Framställningen utfördes enligt exemplen 12-13. The pH is adjusted to 7.6.

Exempel 15

Polyethyleneimine (100%) 100 g

Alginsyra 12 g

Fumarsyra 80 g

Watts give 1000 g

Framställningen utfördes enligt exemplet 11.

Exempel 16

Polyethyleneimine (100%) 400 g

Alginsyra 25 g

Winch 175 g

Watts give 1000 g

The initial color of the mixture is 50 -% up to a polyethylene name, which is completely reduced. Därefter tillsattes vinsyra.

The syrane neutrality capacity of the overnight preparation is 40-50 mg of 0.1% HCl / g 25% by weight of polyethylene.

The preparation of the preparation is further enhanced by the use of hyperacidity, in which the patient is guided. In the same case, 80-40 g of the preparation per 24 timmar, 25% polyethyleneimine, are prepared. The total dosage is 2-4 g, with 4-10 g of dygnet being administered. The specificity of the overnight preparation is 1.25 g / ml.

The study has shown that the capacity and duration are determined by the addition of polyethyleneimine, the polyethyleneimine and the reference hydroxylation and magnesium hydroxide .__________.

20 5 9 0 2 3

These studies are based on the in vitro and in vivo neutralization of the test in vitro and in vivo, and are based on the in vivo duration of the test.

Material and methods

A sprat-Dawley rattan with a weight of 200-220 g is added at a rate of 20 times. Cotton wool frying pan. Djuren hystes i burar med ett et trädnätgolv för att undvika koprofagi.

a) Rätta med pylorusligatur

In this case, the lines and the ligated placenta runt pylorus under the ethers. After that, the sluts will be given anesthesia. Testing or administration of intra-gastric genomic nucleus probes under such a ligature.

This is true after the ligature is exposed to the genome and slag head of fun.

b) Intact rag

Test results are administered intragastrically to the genome of the probe and the test results.

In this case, the model is used to determine the size of the medium and the skin. The volume of magsaft mättes och maginnehället uppsamlades nog-grant genom sköljning med vatten with a total volume of 12 ml.

The pH is measured and titrated to pH 3.0 with 0.5 M HCl using an automatic titrator (ABU 12, Radiometer, Copenhagen). For the purposes of this Regulation, the name of the company shall be the same as that of the group under the same conditions.

In the case of water, up to 25% polyethyleneimine (PEI 12) and 1% alginium, with a pH of 8.0 with lemon orally 1.0 or 0.5 ml / sheet, weighing 1.25 g / kg and 0.625 g / kg of polyethylene. In suspension in water, 23% by weight of polyethyleneimine is preferably obtained from U.S. Patent No. 3,332,841 Ex 1 to 0.4% methylcellulose (Methocel (2 / 90HG)) and just to a pH of 8.5 with lemon, orally 1.0 ml / rätta, motsvarande en dos av 1,15 g / kg kroppsvikt.

21 59023

Some reference is given to a commercial antacid suspension containing 6% aluminum hydroxide and 2.5% magnesium hydroxide in the same volume. Less than a percentage is not a percentage. The control yields 0.75% of methylcellulose (Methocel). For the formulation of polyethyleneimine, the board is then equipotent with a commercially available antacid and a syrabinating capacity, flashing neutral to 32 ml of 0.1 M HCl / g. The neutralization can be carried out with the aid of a polyethylenimine content of 17 ml of 0. 1 M HCl / g suspension, which is then obtained from the polyethylene (PEI 12) and commercially available antacids.

In vitro titration is performed under the same conditions, in which the same procedure is used to prepare the in vivo samples in vivo.

The use of such substances in the reaction medium is limited to 0.5 ml of HCl at pH 3.0.

Results and comments 1. Potential studies

The results of the potency studies are shown in FIG. 1. In vitro varietal polyethylene and commercially available antacids without equipotent, Medan poteneen hos den tvärbundna polyethylene is varied with the potential of the product. In vivo, the other syrups can be used in addition to 1480 + 181, 3290 + 87 and 662 + 60 .mu.mol in a solution containing 1.0 ml of a commercial antacid, polyethyleneimine or a corresponding polyethyleneimine. In the case of a control group of the genome from which a control group is used, the control of the product is determined by the control of 370 + 37 control group accounts for the use of polyethylene.

The result is that polyethylene in the form of a polyethylene mixture is used in vivo to form a compound in vivo with 5 compounds of polyethylene and a mixture of 2 compounds with a commercial antacid. The weight of the polyethylene is 22 5902 3 imine and the corresponding polyethylene (1.25 or 1.15 g / kg) can be weighed for the purpose of observing the skills. In addition, uptake of the assay is carried out in vitro and in vivo.

2. Durationsstudie 0,5 ml av den kommersiie antacidasuspensionen, 0,5 ml av poly-ethylyleneiminlösningen and 1,0 ml av suspensionen av tvärbunden polyethyleneimine administrerades account intakta rättor. I dessa tilläter den öppna pylorus fri passage av maginnehället ner i tarmen under 2 timmar efter administration av den testade beredning. As a result (Table 1), it can be practically guaranteed that the above-mentioned 2 methods of administration of the polyethylene imine suspensions can be used to indicate a systemic indicator of the suspension.

The self-employed persons in the Member State of origin under liquidated conditions after the administration of the commercial antacids suspension. In the case of polyethylenimines, the use of polyethylenecarbons up to a maximum of 2 years is determined by the administration of the polyurethylated substances. Particular indications for polyethylenimine quartz in the form of a polyethylene quenching agent are used for commercially available polyethylene suspensions, and for polyethylene enrichment in vivo with a long-term effect on the effect.

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Table 1

Durationstudie, intakt rätta Föreningen administrerades 2 timmar före utvärdering Förening Maginnehällets Syrabindande n pH förmäga, ^ umol

Commercial antacid 0.5 ml / rag 4.19 + 0.18 172 + 68 11

Polyethyleneimine (PEI 12) 0.5 ml / rag 7.24 + 0.16 1172 + 94 10

Tvärbunden polyethyleneimine 1.0 ml / rag 3.35 + 0.06 25 + 3 16

Shade siffra ger medelvärde + SEM (medelvärdenas standardiel)