EP1124538A2

EP1124538A2 - Composition for the parenteral administration of active agents

Info

Publication number: EP1124538A2
Application number: EP99948917A
Authority: EP
Inventors: Jürgen Grande; Silke Schuth; Gitte Böhm; Holger Bengs
Original assignee: Celanese GmbH
Current assignee: Suedzucker AG
Priority date: 1998-10-15
Filing date: 1999-10-02
Publication date: 2001-08-22
Also published as: WO2000021505A3; PL347770A1; AU6198999A; CA2346670A1; NO20011670L; NO20011670D0; WO2000021505A2; DE19847593A1; JP2002527376A

Abstract

The invention relates to a composition for the parenteral administration of active agents, containing a support material and at least one active agent. The support material contains spherical microparticles with an average diameter of 1 nm to 100 νm, said particles consisting entirely or partially of at least one water-insoluble linear polysaccharide, especially a linear polyglucan. The invention also relates to a suspension containing this composition, and to the use of the composition.

Description

Composition for the parenteral application of active ingredients

description

The present invention relates to a composition for the parenteral application of active ingredients comprising a particulate carrier material based on polysaccharide and a stable suspension thereof.

In particular for pharmaceutical or medical applications, active substance carriers are of importance which meet the requirements of the respective

Administration form are optimally adapted, which can be applied gently and which can have a targeted influence on the biodistribution, bioavailability or absorption of an active ingredient.

Furthermore, the active substance carriers in the organism should disintegrate in a controlled manner, on the one hand to enable controlled release of the active substance over a longer period of time if necessary and on the other hand to ensure the biocompatible degradation of the carrier.

For parenteral application e.g. B. by means of injection, an active ingredient carrier must be selected which can form a stable suspension and has excellent cannula mobility, in particular with a very small cannula diameter. From the point of view of biocompatibility, the suspension stability should also be guaranteed without the addition of dispersing agents.

US Pat. No. 4,451,452 describes a composition for parenteral administration, the polymer used being a biodegradable carrier material which is naturally water-soluble and contains hydroxyl groups and which has been rendered water-insoluble by partial esterification. Various compounds such as polyvinyl alcohol or amylose are mentioned as examples of the water-soluble polymer. For the injection as a suspension it is proposed to use the carrier material in the form of particles together with an emulsifying aid such as low molecular weight polyvinyl alcohol. WO 96/39464 describes suspensions of particles made of a crosslinked water-soluble polymer suitable for injection, which can still pass cannulas with a comparatively small diameter of 20 gauge (corresponding to a diameter of 0.9 mm and a length of 40 mm).

Examples of the water-soluble polymers include a. called natural polysaccharides like amylose.

The disadvantage here, however, is the need to use crosslinking agents and emulsifying auxiliaries which can have a negative effect on the biocompatibility and degradability and, moreover, make the production process more complex.

US Patent No. 1, 143,219 describes a process for making a stable suspension from an amylose material obtained from an amylose-rich starch. Here, the amylose-rich starch is first degraded by acid hydrolysis and the water-insoluble degradation products obtained are then mechanically comminuted until the material is distributed so finely that it can form a stable suspension.

However, the particles obtained are very inconsistent in size and shape and therefore have to be subjected to additional classification processes. There is also no indication of a potential suitability for parenteral use.

It was an object of the present invention to provide a composition for parenteral administration which contains a carrier material which can form a stable suspension even without the addition of appropriate auxiliaries, has a high cannula compatibility and has excellent biocompatibility.

Furthermore, the carrier material should have a depot effect and be suitable for the controlled release of active ingredient.

This object is achieved by a composition for the parenteral administration of active substances, which is a carrier material and at least one Contains active ingredient, wherein the carrier material contains spherical microparticles with an average diameter of 1 nm to 100 microns, which consist entirely or partially of at least one water-insoluble linear polysaccharide.

The use of spherical microparticles according to the invention which consist wholly or partly of water-insoluble linear polysaccharides is essential for solving this problem.

Microparticles of this type are distinguished by a high degree of uniformity in size and shape and therefore have excellent cannula mobility even with a very small cannula diameter. In addition, they form slightly stable suspensions even without the addition of dispersing agents.

Furthermore, the microparticles used according to the invention are distinguished by high biocompatibility.

In addition, they can be completely biodegraded and there is no accumulation in an animal, especially human, organism. Biodegradation is understood to mean any process that takes place in vivo, which leads to a degradation or destruction of the compounds, in particular the polysaccharides. This includes z. B. hydrolytic or enzymatic

Processes. For the biocompatibility of the microparticles used according to the invention, the nature-identical character of the water-insoluble linear polysaccharides used for the preparation and of their degradation products is of particular importance.

The spherical microparticles used as carrier material have an average diameter dn (number average) of 1 nm to 100 μm, preferably 100 nm to 10 μm, and particularly preferably 1 μm to 5 μm.

Spherical microparticles are to be understood as microparticles which have approximately spherical shape. When a sphere is described by axes of the same length that start from a common origin and are directed into space Define the radius of the sphere in all spatial directions, the spherical particles can deviate from the ideal length of the sphere by 1% to 40%. The deviation is preferably 25% or less, particularly preferably 15% or less.

The surface of the spherical particles can be compared macroscopically with a raspberry, the depth of irregularities on the particle surface, such as indentations or cuts, being at most 20%, preferably 10%, of the mean diameter of the spherical microparticles.

The specific surface area of the microparticles is generally from 1 m ² / g to 100 m ² / g, preferably 1.5 m ² / g to 20 m ² / g and particularly preferably 3 m ² / g to 10 m ² / g.

Furthermore, the particles according to the invention preferably have a dispersity D = weight average value of the diameter (d _w ) / number average value of the diameter (d _n ) from 1.0 to 10.0, in particular from 1.5 to 5.0 and particularly preferably from 2.0 to 3.0. The mean values used here are defined as follows:

d _n = sum ri _j xd _j / sum n _j = number average

d _w = sum n-, xd _j ² / sum n-, xd _j = weight mean

n-, = number of particles with diameter d _j , d _j = a certain diameter, i = continuous parameter.

In this context, the term weight means a weighted average, which means that the larger diameters are more important. The spherical microparticles are prepared by dissolving the water-insoluble linear polysaccharide or a mixture of several of these and, if appropriate, further biocompatible polymers in a solvent, for. B. DMSO, introducing the solution into a precipitant, e.g. B. water, preferably at a temperature of 20 ° C to 60 ° C, if necessary cooling the solution to a temperature of minus 10 ° C to plus 10 ° C and separating the particles formed.

Here, the dissolving process of the poiysaccharide used as the starting material can take place at room temperature or higher temperatures.

By using suitable additives, the properties of the microparticles, such as size, surface structure, porosity, etc., as well as the process control can be influenced.

Suitable additives are e.g. surfactants such as sodium dodecyl sulfate,

N-methylgluconamide, poiysorbate (e.g. Tween (registered trademark)),

Alkyl polyglycol ether, ethylene oxide-propylene oxide block copolymers (e.g. Pluronic

(registered trademark)), alkyl polyglycol ether sulfates, generally alkyl sulfates and fatty acid glycol esters, and sugars such as e.g. Fructose, sucrose, glucose, water-soluble cellulose or hot-water-soluble poly-alpha-D-glucan such as e.g. native or chemically modified starches, poly-alpha-D-glucans obtained from these starches and starch-analogous compounds.

These additives are usually added to the precipitant. The amount used depends on the individual case and the desired

Particle properties, the determination of the advantageous amount in each case being familiar to the person skilled in the art.

Unlike e.g. in WO 96/39464 cited at the outset, however, the use of crosslinking agents in the production of the particles can be dispensed with.

Linear water-insoluble polysaccharides for the purposes of the present invention Polysaccharides, which are made up of Monosaccharideπ, Disacchariden or other monomeric building blocks in such a way that the individual building blocks are always linked in the same way. Each basic unit or building block defined in this way has exactly two links, one each to a different monomer. The only exception are the two basic units that form the beginning and the end of the polyaccharide. These have only one link to another monomer and form the end groups of the linear polyaccharide.

If the basic units have three or more links, this is referred to as branching. The number of hydroxyl groups per 100 results

Basic units that are not involved in the construction of the linear polymer backbone and form the branches, the so-called degree of branching.

According to the invention, the linear water-insoluble polysaccharides have a maximum degree of branching of 8%, i.e. they have a maximum of 8 branches per 100 basic units. The degree of branching is preferably less than 4% and in particular a maximum of 2.5%.

If the water-insoluble linear polysaccharide is a polyglucan, e.g. B. poly (1, 4-alpha-D-glucan), the degree of branching in the 6-position is less than 4%, preferably a maximum of 2% and in particular a maximum of 0.5% and the degree of branching in the other positions, e.g. B. in 2- or 3-position, is preferably a maximum of 2% and in particular 1%.

Particularly preferred are polysaccharides, in particular polyglycans such as poly-alpha-D-glucans, which have no branches or whose degree of branching is so minimal that it can no longer be detected using conventional methods

Examples of preferred water-insoluble linear polysaccharides are linear poly-D-glucans, the type of linkage being immaterial as long as there is linearity in the sense of the invention. Examples are poly (1 _! 4-alpha-D-glucan) and poly (1, 3- beta-D-glucan), with poly (1,4-alpha-D-glucan) being particularly preferred.

According to the invention, the prefixes "alpha", "beta" or "D" relate solely to the linkages which form the polymer backbone and not to the branches.

For the present invention, the term “water-insoluble polysaccharides” is understood to mean compounds which, according to the definition of the German Medicinal Products Book (DAB = German Medicinal Products Book, Scientific Publishing House mbH, Stuttgart, Govi-Verlag, Frankfurt, edition, 1987) correspond to classes 4 to 7 fall under the categories "sparingly soluble", "sparingly soluble", "very sparingly soluble" or "practically insoluble".

In the case of the polysaccharides used according to the invention, this means that at least 98% of the amount used, in particular at least 99.5%, under normal conditions (T = 25 ° C. +/- 20%, p = 101325 Pascal +/- 20%) in water is insoluble (according to classes 4 and 5).

For the present invention, sparingly soluble to practically insoluble compounds, in particular very sparingly soluble to practically insoluble compounds, are preferred.

"Very poorly soluble" according to class 6 can be illustrated by the following description of the experiment: One gram of the polyglucan / saccharide to be examined is heated in 1 l of deionized water to 130 ° C. under a pressure of 1 bar. The resulting solution only remains stable for a short time over a few minutes. When cooling under normal conditions, the substance precipitates again. After cooling to room temperature and separation by centrifugation, taking into account the experimental losses, at least 66% of the amount used can be recovered. The polysaccharides used according to the invention can be of any origin, as long as the conditions given above with respect to the terms "linear" and "water-insoluble" are met. They can be obtained naturally or by biotechnological means.

For example, they can be obtained from natural plant or animal sources by isolation and / or purification.

Sources can also be used which have been genetically manipulated in such a way that they contain a higher proportion of unbranched or comparatively slightly branched polysaccharides compared to the unmanipulated source.

They can have been produced from non-linear polysaccharides by enzymatic or chemical branching.

Biotechnical methods include biocatalytic, also biotransformatory, or fermentative processes.

An advantageous method for biotechnological extraction is e.g. B. described in WO 95/31553.

Modified water-insoluble linear polysaccharides can also be used, it being possible for the polysaccharides to have been chemically modified, for example by esterification and / or etherification, in one or more positions which are not involved in the linear linkage. In the case of the preferred 1,4 linked polyglucans, the modification can take place in the 2-, 3- and / or 6-position. Measures for such modifications are well known to the person skilled in the art.

Linear polysaccharides such as pullulans, pectins, mannans or polyfructans, which are water-soluble per se, can be water-insoluble by modification be made.

Furthermore, so-called alpha-amylase-resistant polysaccharides can be used, such as, B. are described in German Patent Application No. 19830618.0.

For the present invention, water-insoluble linear polysaccharides are preferably used which have been produced in a biotechnical, in particular in a biocatalytic or a fermentative, process. In contrast to polysaccharides, which are isolated from natural sources, such as plants, the polysaccharides obtained in this way have a particularly homogeneous profile of properties, e.g. B. in relation to the molecular weight distribution, they contain no or at most only in very small amounts of unwanted by-products that have to be separated in a complex manner, and can be reproduced in a precisely specified manner.

In particular, water-insoluble linear polysaccharides can be obtained with biotechnological methods, such as. B. poly-1, 4-alpha-D-glucans, which contain no branches, or whose degree of branching is below the detection limit of conventional analytical methods.

The molecular weights M _w (weight average, determined by means of gel permeation chromatography in comparison with a calibration using pullulan standard) of the linear polysaccharides used according to the invention can vary within a wide range from 0.75 × 10 ² g / mol to 10 ⁷ g / mol. The molecular weight M _w is preferably in a range from 10 ³ g / mol to 10 ⁶ g / mol and particularly preferably from 10 ³ g / mol to 10 ⁵ g / mol. Another advantageous range is from 2 x 10 ³ to 8 x 10 ³ . Corresponding ranges apply to the preferred poly (1,4-D-glucan).

The molecular weight distribution or polydispersity M _w / M _π can also vary widely depending on the production process of the polysaccharide. Preferred values are from 1.01 to 50, in particular from 1.5 to 15. The Polydispersity with a bimodal distribution of molecular weights.

A single linear polysaccharide substance, in particular linear poly (1,4-D-glucan), or mixtures of two or more representatives can be used.

In a further embodiment, a water-insoluble branched polysaccharide, preferably a polyglucan, in particular a poly (1, 4-alpha-D-glucan) or a poly (1, 3-beta-D-glucan), can be added. Mixtures of two or more branched polysaccharides can also be added.

The branched polysaccharides can be of any origin. In this context, reference is made to the relevant explanations for the linear polysaccharides. Preferred sources are starch and starch analogs such as glycogen. If necessary, the proportion of linear structures in the branched polysaccharides can be increased by suitable enrichment processes.

For the water insolubility the same information applies as for the linear polysaccharide, the molecular weight can also be higher for the branched polysaccharides, e.g. B. values up to preferably 10 ⁹ g / mol and more.

Other biocompatible or biodegradable polymers can also be added. The amount of the other polymer (s) that are added without changing the spherical shape and / or other properties of the microparticles to be produced always depends on the polymer added.

To ensure the desired properties of the microparticles, the proportion of linear polysaccharide should be at least 70% by weight, in particular 80% by weight and preferably 90% by weight, based on the total content of polysaccharide and optionally further polymer. According to a particularly preferred embodiment, the microparticles consist of 100% by weight of linear polysaccharide.

A detailed description of the microparticles used here, their production and the water-insoluble linear polysaccharides that can be used for this purpose can be found in the applicant's earlier, unpublished German patent applications with file numbers 197 37 481.6, 198 03 415.6, 198 16 070.4, 19830 618.0 and 198 27 978.7 which is referred to for the present description.

The microparticles used according to the invention as carrier material for parenteral use can also contain other auxiliaries customary for this purpose in customary amounts.

The active substance or the active substance for the composition according to the invention can be any solid, liquid or gaseous substance which is to be administered parenterally, in particular by means of injection, to a living organism or to an inanimate object. In particular when administered to living organisms, biologically active substances or combinations of substances are also understood in the broadest sense.

Pharmacy or medicine in the human and veterinary field can be cited as an example of a broad field of application for parenteral administration, e.g. in therapy, diagnostics or prophylaxis.

Examples of active substances which can be administered with the microparticles used according to the invention are so-called LHRH analogs, such as Busereiin (registered trademark of Hoechst Marrion Roussel) for use against prostate cancer, endometriosis and other tumor-like diseases of the genital organs; Erythropoietin (EPO) to stimulate the growth of red blood cells, analgesic agents, antiallergics, growth hormones, Steroids for hormone treatment and birth control, biphosphonates, calcitonin (e.g. cibacalcin from Ciba-Geigy) for the treatment of osteoporosis, psychotropic drugs, generally active substances, e.g. proteins or peptides, which are broken down in the gastrointestinal tract and therefore not orally can be administered, or active ingredients that require parenteral administration, etc.

The active substances or combinations of active substances which can be used can be chosen as desired for the desired field of use and, insofar as they can be administered parenterally, are not subject to any restrictions either with regard to the nature of the active substance, with regard to the preparation of the active substance or with the field of use. So-called macromolecules, in particular peptides, proteins or nucleotides, which z. B. by biotechnical or by modern biotechnology based methods can be produced or synthesized.

It goes without saying that the amount of active ingredient to be used varies depending on the field of application and purpose and is to be determined in each individual case. For busereiin, EPO and many other active ingredients in general amounts in the microgram range are sufficient.

To produce the composition according to the invention, the active ingredient or combination of active ingredients is brought into contact with the carrier material in the required amount.

For this purpose, the active ingredient can be added to the starting compounds used for the production of the microparticles, such as the water-insoluble linear polysaccharides, so that the microparticles consist of a mixture of starting compounds and active ingredient.

The active substance can be encapsulated in the microparticles, it being possible to use conventional encapsulation techniques. Suitable examples are emulsion processes or spray drying processes. Thereby fall under the last The term also applies to spray processes in which the particles are sprayed with a solution of the active substance in a fluidized bed or in an analogous process.

Furthermore, the active ingredient can be absorbed and / or adsorbed on the microparticle surface by, for. B. the active ingredient and the microparticles suspended in a suitable medium, allowed to stand until equilibrium is reached and then the particles loaded with active ingredient are separated.

The composition according to the invention is particularly suitable for the controlled release of active ingredient, but is not restricted to this.

Controlled release of active substance is understood to mean that the active substance is not released immediately and all at once, but that the release takes place over a certain period of time and / or after a certain period of time has elapsed. The release rate can be chosen arbitrarily depending on the intended use. It can be constant over time or it can be large initially followed by a slower release.

It is understood that the rate of release and the rate of degradation of the microparticles in an organism depend strongly on the type of starting materials, the type of active ingredient used, the particle size and the production process. Depending on requirements, the person skilled in the art can create a system tailored to his specific purpose by simply varying these parameters, which is familiar per se.

Parenteral administration is understood to mean the administration of any active ingredient via injection or infusion, for which good dispersibility and cannulability of the composition to be administered is particularly advantageous.

The composition according to the invention is suitable because of the excellent cannula mobility of the microparticles used according to the invention especially for administration by injection.

The injection can be arbitrary, it can be administered intravenously, intramuscularly, intraarterially, subcutaneously or intralumbally.

A high cannula passage means that the composition according to the invention can also easily pass through injection needles such as syringes with small needle diameters.

For administration, the composition is suspended in a suitable medium. It has been shown that the composition according to the invention, even without the addition of other auxiliaries such as dispersants, forms a stable suspension which remains unchanged even over a longer period of time.

The avoidability of foreign substances such as dispersing agents is particularly advantageous for their biocompatibility.

As far as standing, e.g. B. Storage, the suspension of settling of the microparticles can be generated again by a simple brief shaking, usually several seconds, a stable suspension.

The choice of a suitable medium is in turn determined by the specific one

Purpose.

For medical use, for. B. sterile salt solutions such. B. a physiological NaCI solution.

The good to very good susceptibility is evidenced by the large concentration ranges. Up to 25% solids can be present in the suspension. This corresponds to a proportion of 250 mg particles per 1 ml of solvent, e.g. B. Physiological saline. Preferred concentration ranges are 1% to 18%. A range from 5% to 10% solids content is particularly preferred. This corresponds to amounts of 50 mg to 100 mg drug-loaded microparticles, a value that can only be achieved with alternative formulations even with a suspension aid with great experimental effort becomes.

In particular, the very good suspendability and the ability to pass cannulas can be supported by the observation that 500 mg of the particulate carrier can be suspended in only 3 ml of water and can be applied without problems through a cannula with a diameter of 0.6 mm.

If a higher concentration of microparticles in the suspension is desired or required, it is of course also possible to use auxiliaries such as Pluronic (brand from BASF AG), Haemaccel (brand from Behringwerke), sodium dodecyl sulfate etc., i.e. auxiliaries that are generally suitable for such pharmaceutical application forms are recognized and used.

In certain cases, the microparticles themselves can be effective as an active ingredient. Thus, the microparticles used according to the invention can be used as contrast agents, e.g. B. for ultrasound diagnosis. The composition according to the invention can be applied with or without a further active ingredient.

Possible other active ingredients are e.g. B. gases, the type of gas can vary within wide ranges (z. B. nitrogen, air, argon, helium, chlorofluorocarbons, fluorocarbons). Aspirin or NO-releasing compounds can also be used, which are particularly important in cardiovascular diseases.

As stated above, the microparticles used according to the invention are particularly suitable for parenteral administration on account of their excellent dispersibility and high cannulability.

In the following, the present invention is explained on the basis of a few selected examples.

example 1

Production of microparticles from poly (1,4-α-D-glucan) 500 mg of poly (1,4-D-glucan) are dissolved in 2.5 ml of dimethyl sulfocide (DMSO, pa from Riedel-de-Haen) at approx. 70 ° C. The DMSO solution is added dropwise in 100 ml of double-distilled water with stirring and the solution is kept at 5 ° C. overnight. The fine milky suspension is centrifuged for 15 minutes at 3500 revolutions per minute and the supernatant is decanted off. The sediment is slurried with double-distilled water and centrifuged again. The process is repeated two more times. The suspension is then freeze-dried. 311 mg of white poly (1,4-α-D-glucan) particles are obtained. This corresponds to a yield of 62% colorless microparticles.

Example 2

Experiments on the cannulability of suspensions with microparticles made of poly (1,4-alpha-D-glucan)

In order to assess the quality of the suspension of microparticles, a method is used that is accepted for the testing and manufacture of microparticulate drug delivery systems.

100 mg of microparticles obtained according to Example 1 are suspended in 1 ml of double-distilled water. The particles can be separated by simply shaking the closed container by hand. The suspension is drawn through a septum using a syringe and a cannula with a diameter of 0.5 mm (or larger). The particles are then pressed out through the cannula to be tested. The assessment of the individual cannulas is summarized in the following tables. A cross symbolizes the cannula passage of the suspension. The cannulas used are from Braun Petzold GmbH (Melsungen).

The addition of a suspension medium did not affect the results for microparticles made of poly (1,4-alpha-D-glucan), in contrast to commercially available preparations. In commercial systems and those based on similar technology but using different materials, a gradual improvement in the resuspension up to a limit value is observed with the increase in the suspension aid (additive). Table 1: Characteristics of cannulas used

Size gauge diameter in mm length in mm

18Gx1 ^_1/2 1.20 40

1 20 G x 1% 0.90 40

2 21 G x ¹ _1/2 0.80 40

12 22 G x 1 ^Λ Ä 0.70 30

14 23 G x 1% 0.60 30

17 24Gx1 0.55 25

18 26Gx1 0.45 25

20 27 G x 4/5 0.40 20

30Gx1 0.30 25

Table 2: Cannula accessibility of microparticles made of poly (1, 4-alpha-D-glucan)

Material cannula diameter (mm)

1.20 0.90 0.80 0.70 0.60 0.55 0.45 0.40 0.30

Poly (1,4-j 3lpha-D- X X X X X X X X X glucan)

Example 3

Attempts to pass suspensions with microparticles

Comparative materials (comparative examples) The experiments with comparative substances, such as those used either commercially or in research for the production of depot systems, were carried out as in Example 1. The systems used are known biodegradable polymers made from lactic and glycolic acid or from tartaric acid or from aspartic acid (see Table 3).

Example 4

Loading the particles with the active ingredient by means of a suspension process

The microparticles, or agglomerates, made of poly (-α-D-glucan) are loaded with active ingredient by a suspension process. 250 mg Busereiin ^* are dissolved in 10 ml distilled water. 100 mg of particles are added. The suspension is stirred for 3 hours. The suspension is centrifuged. The centrifugate is washed with water. The particulate solid is separated off using a centrifuge (3000 rpm) and the centrifugate is freeze-dried. By dissolving an exact amount of the particles in a mixture of water and dimethyl sulfoxide and the spectroscopic measurement in the UV-Vis spectrometer, the loading with Busereiin can be calculated at 3.28% based on the total mass of the particles using a calibration curve. By modifying the solvent, e.g. As alcohol, the solubility and thus the loading of the particles with active ingredients can be influenced.

(* 5-oxo-prolyl-L-histidyl-L-tryptophyl-L-tyrosyl-0-tert-butyl-D-seryl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide)

Example 5

Loading the particles with the active ingredient by means of spray drying

The microparticles are suspended in distilled water or a mixture of water and a volatile component such as acetone or ethanol. For this purpose, 10 g of the solid are added to 1000 ml of the solvent. By doing Solvent had previously been dissolved in 0.5 g of theophylline. The spray dryer (mini spray dryer 191 from Büchi) is operated as follows: atomizing air flow 700 liters per hour, inlet temperature 200 ° C., nozzle cooling switched on, nozzle diameter 0.5 mm, aspirator 70%, pump 10%. The spectroscopic examination of the load (for a description, see Example 4) shows a degree of loading of 4.8%. This value corresponds to the theoretically achievable value of 5.0% within the error limits.

Table 3: Needles for microparticles made from biodegradable polymers

Auxiliary material cannula diameter (mm) (%)

1, 20 0.90 0.80 0.70 0.60 0.55 0.45 0.40 0.30

Poly (1, 4-alpha- - x x x x x x x x x D-glucan)

Polyamide ^{* 1} Hämaccel * x (x) ^{* 6} (x) ^{* 6} (x) ^{* 6} (x) ^{* 6} (x) ^{* 6} (x) ^{* 6} (x) ^{* 6} - (10)

PTA Pluronic F68 x x x x x

Polyvinylic acid ^ ^{* 2} (10)

PLGA Pluroπic F68

Poly milk-co- ^ glycolic acid ^{* 3} (10)

PTA Pluronic F68

Poiyartaric acid * 5

^{* 2} (10)

PLGA Hämaccel ^* xxxxx

Poly milk-co- (1) glycolic acid * ³ '* ⁷ * ¹ according to EP 535387 * ² according to EP 514 790

* 3 according to EP 514790. ** Manufacturer: Fluka

* ⁵ manufacturer from Behringwerke

^ The results in brackets are only achieved if special filters are used to separate the particles or the process is repeated several times with larger diameter cannulas. * ⁷ Manufacturer Medisorb (PLGA = poly milk-co-glycolic acid 65:35, dl)

Claims

claims

1. Composition for the parenteral administration of active substances, comprising a carrier material and at least one active substance, the carrier material containing spherical microparticles with an average diameter of 1 nm to 100 μm, which consist wholly or partly of at least one water-insoluble linear polysaccharide.

2. The composition of claim 1, wherein the water-insoluble linear polysaccharide is a bio-engineered water-insoluble linear

Is polysaccharide.

3. The composition of claim 1 or 2, wherein the water-insoluble linear polysaccharide is a linear polyglucan.

4. Composition according to one of the preceding claims, wherein the polyglucan is poly (1,4-alpha-D-glucan).

5. Composition according to one of the preceding claims, wherein the polyglucan is poly (1, 3-beta-D-glucan).

6. The composition according to any one of the preceding claims, wherein the water-insoluble linear polysaccharide is a chemically modified polysaccharide.

7. The composition according to claim 6, wherein the polysaccharide has been esterified and / or etherified in at least one of the positions 2-, 3- and 6.

8. The composition according to any one of the preceding claims, wherein the depth of irregularities on the surface of the microparticles is at most 20% of the average particle diameter.

9. The composition according to claim 8, wherein the depth of the irregularities on the particle surface is at most 10% of the mean particle diameter.

10. The composition according to any one of the preceding claims, wherein the microparticles have a dipersity D in the range from 1.0 to 10.0.

1 1.Composition according to one of the preceding claims, wherein the active ingredient is present mixed with the carrier material.

^ .Composition according to one of claims 1 to 10, wherein the active ingredient is encapsulated in the carrier material.

13. The composition according to any one of claims 1 to 10, wherein the active ingredient is present absorbed on the carrier material surface.

H. Composition according to one of the preceding claims, wherein the composition has a depot effect with controlled release of active ingredient.

15. Use of a composition according to any one of claims 1 to 14 for human or veterinary purposes.

16. Suspension containing a composition according to any one of claims 1 to 14 and a dispersant.

17. The suspension of claim 16, wherein the dispersant is a sterile saline solution.

18. Use of a suspension according to one of claims 16 and 17 for human or veterinary purposes.

19. Use of a composition according to any one of claims 1 to 14 or a suspension for injection containing this composition.

20. Use of spherical microparticles according to one of claims 1 to 1 for parenteral administration.

21. Use of spherical microparticles according to claim 20, wherein the microparticles are used as contrast agents.