SK279744B6 - Pharmaceutical preparation for use in peritoneal dialysis - Google Patents

Abstract

Described is a pharmaceutical preparation for use in peritoneal dialysis, in particular continuous ambulant peritoneal dialysis (CAPD). Also described is the use of a starch ester to prepare such a pharmaceutical preparation. Particularly suitable starch esters are acetyl starch with a mean molecular weight of 100,000 to 200,000 Daltons and a molar substitution ratio of 0.3 to 0.5. There is further described the use of starch ester, wherein starch is substituted by the acyl groups of carboxylic acids with 2 - 6 carbons, for the preparation of a pharmaceutical composition for use in peritoneal dialysis.

Description

Technical field

The invention relates to a pharmaceutical composition for peritoneal dialysis and to the use of starch esters for the manufacture of such composition.

BACKGROUND OF THE INVENTION

Peritoneal dialysis (PD) is a procedure for washing the blood in case of temporary or permanent renal insufficiency. The function of the kidneys is to eliminate metabolic products such as urea or uric acid, or some of the dietary substances, such as potassium, from the body. In renal failure, poisoning of the organism by accumulation of the above-mentioned substances occurs until they are removed by substitution. In addition to peritoneal dialysis, hemofiltration and hemodialysis (blood washing) are used as a surrogate procedure for partial or complete renal failure. These alternative options, compared to peritoneal dialysis, need to be performed using a large device and must be connected to the blood vessels, which presents disadvantages for the patient.

On the other hand, peritoneal dialysis, especially in the form of continuous peritoneal dialysis (CAPD), has the advantage that it imposes a relatively low burden on the patient, moreover, the patient is not dependent on a complex apparatus. A disadvantage of conventional hyperosmolar peritoneal dialysis is the damage to the peritoneal epithelium when using solutions with high osmotic pressure in order to achieve the secretion of harmful substances from the blood into the peritoneal cavity. In conventional peritoneal dialysis, this goal is achieved by adding 1 to 5% by weight of glucose or other osmotic agent, for example sorbitol, to the flushing solution. Glucose, however, gets from the abdominal cavity into the body with its nutritional effect, especially under certain conditions, very undesirable.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a pharmaceutical composition for peritoneal dialysis which overcomes the known disadvantages of this process, especially in continuous outpatient dialysis.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a peritoneal dialysis pharmaceutical composition containing a starch ester as a colloidal osmotic agent, which ester is substituted with acyl groups of monocarboxylic or dicarboxylic acids or mixtures of C 2 -C 6 mono- and dicarboxylic acids in an amount of 1-12% by weight in combination with a physiologically acceptable electrolyte and / or one or more other osmotically active substances.

It is known to use starch derivatives, dextran and gelatin, preferably having a molecular weight of at least 40,000 as blood plasma substitutes, for example according to US 3,937,821, DE 33 13 6000 and Römpp Chemielexikon, 9, edition, p. 919, 1509.

It has now been found that starch esters, as mentioned, have a very good water binding capacity and are therefore suitable for use in peritoneal dialysis.

According to the invention, it is thus possible to completely dispense with solutions of higher osmotic pressure or, in combination with starch esters with conventional osmotically active substances, to substantially reduce the osmotic pressure of the wash solution, in particular to avoid glucose or to reduce its concentration so substantially that dialysis is possible. without causing damage to the peritoneal epithelium and with little nutritional effect. The effective force to eliminate metabolic products into the peritoneal cavity of the invention is not the difference in osmotic pressure or colloidal osmotic pressure, but the ability of the starch ester to bind water in the peritoneal cavity. In this way, other substances are excreted with the solvent in the peritoneal cavity to produce an effect that is comparable to that of an osmotic pressure difference and is often referred to as solvent drag ¹ '. This effect leads to the excretion of metabolic products into the abdominal cavity and thus produces a dialysis effect.

The molecular weight Mw is preferably on average greater than 1000. The upper limit of the mean molecular weight of the ester is not critical and depends in particular on the fact that there is no deposition in the body. As a rule, the average molecular weight also depends on the type of ester and its upper limit is about 1,000,000. Preferably, the average molecular weight is in the range of 100,000 to 200,000.

Preferred starch esters are esters with a molar substitution of 0.1 to 0.5. These are esters of organic carboxylic acids, especially aliphatic mono- and dicarboxylic acids having 2 to 6 carbon atoms, such as acetic acid. The molar substitution of MS is preferably 0.3 to 0.5. A preferred starch ester is acetyl starch with an average molecular weight of 100,000 to 200,000 and a substitution of 0.3 to 0.5.

The peritoneal dialysis pharmaceutical composition according to the invention comprises a physiologically acceptable electrolyte and / or another substance having an osmotic action. The concentration of the starch ester is in the range of 1 to 12, preferably 2 to 6 g / 100 ml, based on the whole composition.

Among the physiologically acceptable electrolytes, it is possible to use electrolytes and mixtures thereof, as are commonly used in peritoneal dialysis agents, in particular, for example, sodium chloride, calcium chloride and salts of lower carboxylic acids having 2 to 4 carbon atoms, in particular acetic acid.

Other osmotically active agents may be low molecular weight organic compounds, particularly those commonly used in conventional peritoneal dialysis performed at higher osmotic pressure, such as polyhydric alcohols, monosaccharides, disaccharides such as glycerol, sorbitol, maltose, and especially glucose and / or an amino acid.

The pharmaceutical compositions of the invention may comprise one or more starch esters in combination with one or more osmotically active substances in water.

Starch esters can be obtained by the method described in co-pending Laevosan Gesellsachan mbH under the name Verfahren zur Herstellung von Stärkeestem fur Klinische, Insbesondere Parenterale Andwendung, P 4123000.0. The pharmaceutical compositions may be prepared in a known manner, for example by mixing the ingredients with a pharmaceutical carrier, the starch esters preferably being used in dry form, for example after spray-drying, in a drum or in a vacuum followed by milling.

SK 279744-6

Starch esters in which starch is substituted with acyl groups of monocarboxylic or dicarboxylic acids or mixtures of mono- and dicarboxylic acids having 2 to 6 carbon atoms can thus be used for the manufacture of pharmaceutical compositions for peritoneal dialysis. This use is also part of the invention.

During dialysis, hydrocolloids in the flushing solution from the peritoneal cavity also enter the blood. For this reason, starch esters which are degraded in the body and are not stored in the body during long treatment are suitable.

A preferred ester is acetylated starch. Said starch esters are degraded by natural enzymes in the body and are metabolized. In addition to oligosaccharides, isomaltose and maltose, glucose is also formed, so that peritoneal dialysis can also be carried out without the use of glucose. Part of the glucose produced by the degradation of the ester, for example acetylated starch, is excreted into the peritoneal cavity during dialysis, thereby limiting the nutritional effect. The effect of peritoneal dialysis by starch esters on fat metabolism has not been established. However, it is clear that this type of dialysis has significant advantages over a conventional process using a solution containing a significant amount of glucose. Due to the degradation there is also no deposition of starch esters in the body. In peritoneal dialysis lasting 5 days, no higher polysaccharide could be detected in the organs of the test animals when using acetylated starch as opposed to hydroxyethylated starch.

The results obtained were verified in experiments in rats in which both kidneys were removed. The urea was removed from the blood of these animals using a 3% solution of acetylated starch together with the addition of electrolytes, or the electrolyte (e.g. potassium) was removed from the blood. In the case of daily peritoneal dialysis, a sufficiently good animal health was observed within 5 days. Comparative experiments were performed with solutions containing 2 g glucose / 100 ml. In addition, experiments were carried out using solutions containing a combination of acetylated starch with a glucose solution at a concentration of 1% by weight as another osmotic active ingredient. In all cases, a dialysis effect was observed which could not be explained solely by the difference in osmotic or colloidal osmotic pressure. Also, when using the hydrocolloid solutions of the invention without an osmotically effective gradient, an equalization of plasma and wash solution concentrations was observed. Thus, it is apparent that the hydrocolloid efficacy is due to the binding of water in the peritoneal cavity and the so-called solvent drag effect that produces a dialysis effect corresponding to the effect of the difference in osmotic pressure.

After peritoneal dialysis using 5-day starch ester solutions, only traces of acetylated starch in the serum of the test animals could be detected, as shown in FIG. 1. It was not possible to detect acetylated starches in the spleen, liver or lungs during organ examination. Thus, it can be concluded that the acetylated starches that penetrate into the bloodstream during peritoneal dialysis are rapidly and completely degraded by enzymes in the body.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of Acetylated Starch Solutions (AST) for Continuous Ambulatory Peritoneal Dialysis (CAPD)

250 ml of CAPD solutions were prepared in each case, as shown in Table 2. The electrolyte mixture shown in Table 1 was used. filled into 20 ml bottles.

It can be seen from Table 2 that the solutions thus prepared have good stability. Even after sterilization, only slight saponification of the ester groups was observed.

Table 1

Electrolyte mixtures for CAPD and AST solutions

M nmol / 1 g / 1 58,443 sodium chloride 120 7,013 136,080 sodium acetate. 3Η2θ 25 3,402 Calcium chloride. 2 ^ 0 2 0,294 60,053 acetic acid 5 0,303 Osmolarity mOsmol / 1 301

Table 2

CAPD solutions with AST

about. * sn »lu * r. eol / l pH octo. icexyl. ΊΓ ».U * '' ΚηΛΟ ' ³ | / 1 j / 1 vorn» e «t« r. of the group «Hulžl • Nuty'l roI / wV

x Higher Mw and Mn values prior to sterilization are likely due to aggregate formation.

All solutions were almost colorless even after sterilization. Sterilization, as expected, resulted in a small cleavage of the acetyl groups. The residual acetyl content was about 96% after gentle sterilization at 100 ° C for 30 minutes, and about 85% after sterilization at 121 ° C for 8 minutes. Thus, gentle sterilization is expedient.

In a similar manner, the following peritoneal dialysis solutions were prepared using an electrolyte whose composition is shown in Table 1.

1. A 3% solution of acetylated starch (molar substitution of 0.3 or 0.5).

2. Combination solution containing 1,5% acetylated starch and 1% glucose as osmotic agent.

3. 3% hydroxyethylated starch solution HES with 200 / 0.5 (molecular weight 200,000, molar substitution 0.5 mol), HES 100 / 0.7, HES 40 / 0.5, HES 70 / 0.7 and HES 450 / 0.7.

4. 3% hydroxyethylated starch solution (HES 40 / 0.5 and HES 200 / 0.5 with 1% glucose).

Example 2

Performing peritoneal dialysis

Wistar rats weighing 250-350 g were anesthetized and both kidneys were removed. Further, two permanent coils extending into the abdominal cavity were introduced into the abdominal cavity. To replace kidney function, the abdominal cavities were rinsed 6 to 8 times each day using 60 to 100 ml flushing solution. The solution was drained again within 30 to 60 minutes.

In this method of treatment, despite missing kidneys, the animals could be kept alive in good health for an extended period of time. Dialysis was performed for 5 days. On the fifth day, immediately before dialysis, blood was taken from the orbit, and after the last dialysis, the animals were anesthetized by bleeding from the abdominal aorta. The following organs were then removed for examination: spleen, liver and lungs.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows the mg / ml content of individual substances after the fifth day of dialysis. In FIG. 2 shows the spleen hydrocolloid content in mg / g after the fifth day of dialysis. In FIG. 3 shows the urea content in blood serum before and after the fifth dialysis on day 5 and the content of the same substance in the dialysate.

In FIG. 1 and 2, each column has the following meanings:

A, B, C: solution containing 3% acetylated starch (acetylaminopectin) without the addition of glucose.

D to H: 3% glucose-free hydroxyethylated starch solution with HES 100 / 0.7 (D), HES 40 / 0.45 (E), HES 70 / 0.7 (F), HES 200 / 0.5 ( G) and HES 450 / 0.7 (H).

The individual columns in FIG. 3 have the following meanings: I, J, K: solution containing 3% glucose-free acetylated starch (extract 36%), serum pre-dialysis (I), post-dialysis (J) and dialysate (K) content.

L, M, N: solution containing 3% HES 40 / 0.5 with 1% glucose (39.4% extraction), serum pre-dialysis (L), post-dialysis (M) and dialysate (N) content.

O, P, R: solution containing 3% HES 200 / 0.5 with 1% glucose (extraction 42%), serum pre-dialysis (O), post-dialysis (P) and dialysate (R) content.

Claims (15)

PATENT CLAIMS Pharmaceutical composition for peritoneal dialysis, comprising a starch ester as a colloidal osmotically active substance, characterized in that the starch is substituted with acyl groups of monocarboxylic or dicarboxylic acids of 2 to 6% by weight in combination with a physiologically acceptable electrolyte and / or one or more other osmotically active agents. Pharmaceutical composition according to claim 1, characterized in that the starch ester has an average molecular weight Mw of more than 1000, preferably 100 to 200 thousand and a molar substitution of 0.1 to 1.5, preferably 0.3 to 0.5. Pharmaceutical composition according to claim 1 or 2, characterized in that the starch ester is acetylated starch. Pharmaceutical composition according to claim 2 or 3, characterized in that as acetylated starch it comprises acetylated starch with an average molecular weight of 100,000 to 200,000 with a molar substitution of 0.1 to 0.7, preferably 0.3 to 0.5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that it contains 2 to 6% by weight of a starch ester. Pharmaceutical composition according to Claim 5, characterized in that it contains polyhydric alcohols, monosaccharides, disaccharides and / or amino acids as an additional osmotic agent. A pharmaceutical composition according to claim 6, characterized in that it contains glucose as an additional osmotically active substance. Use of a pharmaceutical composition as defined in any one of claims 1 to 7 for performing peritoneal dialysis. Use of a starch ester in which starch is substituted with acyl groups of monocarboxylic acids or mixtures of mono- and dicarboxylic acids of 2 to 6 carbon atoms for the manufacture of a pharmaceutical composition for peritoneal dialysis. Use according to claim 9, characterized in that a starch ester having a molecular weight higher than 1000, preferably 100 000 and 200 000 and a molar substitution MS of 0.1 to 1.5, preferably 0, is used for the preparation of the pharmaceutical composition. 3 to 0.5. Use according to claim 10, characterized in that acetylated starch is used as the ester for the manufacture of the pharmaceutical composition. Use according to claim 11, characterized in that acetylated starch having a molecular weight of 100,000 to 200,000 and a molar substitution of 0.1 to 0.7, preferably 0.3 to 0.5, is used for the preparation of the pharmaceutical composition. Use according to any one of claims 10 to 12, characterized in that a physiologically acceptable electrolyte and / or other osmotically active substance is added to the pharmaceutical composition. Use according to Claim 13, characterized in that a polyhydric alcohol, a monosaccharide, a disaccharide and / or an amino acid are added to the pharmaceutical composition as an additional substance with an osmotic action. Use according to claim 14, characterized in that glucose is added to the pharmaceutical composition as another osmotically active substance.