AU6198999A - Composition for the parenteral administration of active agents - Google Patents

Description

WO 00/21505 - 1 - PCT/EP99/07300 Composition for the parenteral administration of active compounds Description The present invention relates to a composition for the 5 parenteral administration of active compounds, which composition comprises a particulate, polysaccharide based carrier material and a stable suspension thereof. Active compound carriers which are optimally matched to 10 the requirements of the respective administration form, which can be administered in an innocuous manner and which can specifically influence the biodistribution, bioavailability or absorption of an active compound are of particular importance for pharmaceutical or medical 15 applications. Furthermore, in the body, the active compound carriers should decompose in a controlled manner in order, on the one hand, to enable the active compound to be 20 released in a controlled manner, if required over a relatively long period as well, and, on the other hand, to ensure that the carrier is broken down in a biocompatible manner. 25 For parenteral administration, e.g. by means of injection, it is necessary to select an active compound carrier which can form a stable suspension and which possesses outstanding needle traversability, in particular in the case of a very small needle diameter. 30 From the point of view of biocompatibility, the stability of the suspension should be guaranteed even without adding dispersion aids. US patent No. 4,451,452 describes a composition for 35 parenteral administration, with a hydroxyl group containing polymer, which is by nature water-soluble - 2 and which has been made water-insoluble by being partially esterified, being used as the biodegradable carrier material. For this, various compounds, such as polyvinyl alcohol or amylose, are mentioned as examples 5 of the water-soluble polymer. For injection as a suspension, it is proposed that the carrier material be used in the form of particles together with an emulsification aid such as low molecular weight polyvinyl alcohol. 10 WO 96/39464 describes injection-suitable suspensions of particles composed of a crosslinked, water-soluble polymer which is still able to pass through needles having a comparatively small diameter of 20 gauge 15 (corresponding to a diameter of 0.9 mm and a length of 40 mm). Natural polysaccharides, such as amylose, are mentioned, inter alia, as examples of the water-soluble 20 polymers. However, in this connection, a disadvantage is the necessary employment of crosslinking agents and emulsification aids, which can exert a negative effect on biocompatibility and degradability and can 25 furthermore make the preparation process more elaborate. US patent No. 1,143,219 describes a process for preparing a stable suspension composed of an amylose 30 material which is isolated from an amylose-rich starch. In this process, the amylose-rich starch is first of all degraded by acid hydrolysis and the resulting, water-insoluble degradation products are then comminuted mechanically until the material is so finely 35 divided that it is able to form a stable suspension. However, the particles which are obtained in this connection are very inhomogeneous in size and form and have therefore to undergo additional grading - 3 procedures. Furthermore, the patent does not give any indication of any potential suitability for parenteral use. 5 The object of the present invention was to make available a composition for parenteral administration, which composition comprises a carrier material which is able to form a stable suspension, even without the addition of appropriate adjuvants, which exhibits a 10 high degree of needle traversability and which possesses outstanding biocompatibility. Furthermore, the carrier material should possess a retardant effect and be suitable for the controlled release of active compound. 15 This object is achieved by means of a composition for the parenteral administration of active compounds, which composition comprises a carrier material and at least one active compound, with the carrier material 20 comprising spherical microparticles which have a mean diameter of from 1 nm to 100 pn and which are composed entirely or partially, of at least one water-insoluble, linear polysaccharide. 25 The use, according to the invention, of spherical microparticles which are composed entirely or partially of water-insoluble, linear polysaccharides is of fundamental importance for achieving this object. 30 These microparticles are distinguished by a high degree of uniformity in size and shape and therefore possess outstanding needle traversability even when the needle diameter is very small. Furthermore, they readily form stable suspensions even without the addition of 35 dispersion aids.

- 4 The microparticles employed in accordance with the invention are also distinguished by a high degree of biocompatibility. Furthermore, they can be completely biodegraded and are 5 not concentrated in an animal, in particular human, body. In this context, biodegradation is understood as being any process which takes place in vivo and which leads to degradation or destruction of the compounds, in particular the polysaccharides. These processes 10 include, for example, hydrolytic or enzymic processes. The fact that the water-insoluble, linear polysaccharides which are used for the preparation, and their degradation products, are identical to the equivalent natural products is, in particular, of great 15 importance for the biocompatibility of the microparticles employed in accordance with the invention. The spherical microparticles which are employed as 20 carrier material have a mean diameter dn (number average value) of from 1 nm to 100 pm, preferably of from 100 nm to 10 pm, and particularly preferably of from 1 pm to 5 m. 25 Spherical microparticles are to be understood as being microparticles which have an approximately spherical shape. When describing a sphere by means of axes of equal length which proceed from a common origin, which are directed into space and which define the radius of 30 the sphere in all spatial directions, it is possible, in the case of the spherical particles, for the lengths of the axes to deviate from the ideal state of the sphere by from 1% to 40%. Preference is given to the deviation being 25% or less, with 15% or less being 35 particularly preferred. The surface of the spherical particles can be compared macroscopically to a raspberry, with the depth of the - 5 irregularities on the particle surface, such as indentations or clefts being at most 20%, preferably 10%, of the mean diameter of the spherical microparticles. 5 The specific surface of the microparticles is generally from 1 m 2 /g to 100 m2/g, preferably from 1.5 m2/g to 20 m 2 /g, and particularly preferably from 3 m2/g to 10 m 2 /g. 10 In addition, the particles according to the invention preferably exhibit a dispersity D = weight average value of the diameter (d,)/number average value of the diameter (d.) of from 1.0 to 10.0, in particular of from 1.5 to 5.0, and particularly preferably of from 2.0 to 15 3.0. The average values which are used here are defined as follows: d = sum of n, x d/sum of ni = number average value 20 d. = sum of n, x d 2 /sum of n 1 x d' = weight average value ni = number of particles having a diameter d,, di = a given diameter, 25 j = continuous parameter. In this connection, the term weight notes a weighted average, as a result of which the larger diameters are given a greater relative importance. 30 The spherical microparticles are prepared by dissolving the water-insoluble linear polysaccharide or a mixture of several thereof and also, where appropriate, other biocompatible polymers in a solvent, e.g. DMSO, 35 introducing the solution into a precipitating agent, e.g. water, preferably at a temperature of from 200C to 60 0 C, if required, cooling the solution down to a - 6 temperature of from -10 0 C to +10 0 C, and separating off the particles which are formed in this context. In this connection, the process of dissolving the 5 polysaccharide used as starting material can take place at room temperature or at higher temperatures. By using suitable additives at the same time, it is possible to influence the properties of the microparticles, such as size, surface structure, 10 porosity, etc., and also to influence process control. Examples of suitable additives are surface-active substances, such as sodium dodecyl sulfate, N-methylgluconamide, polysorbates (e.g. Tween 15 (registered trademark)), alkyl polyglycol ether, ethylene oxide-propylene oxide block polymers (e.g. Pluronic (registered trademark)), alkyl polyglycol ether sulfates, generally alkyl sulfates and fatty acid glycol esters, and sugars, such as fructose, sucrose, 20 glucose, water-soluble cellulose or hot-water-soluble poly-alpha-D-glucan, such as native or chemically modified starches, or poly-alpha-D-glucans which are obtained from the starches, and also starch-like compounds. 25 Usually, these additives are added to the precipitating agent. The quantity employed depends on the particular individual case and on the desired particle properties, with the skilled person knowing how to determine the advantageous quantity in each case. 30 However, in contrast to WO 96/39464, for example, which was cited at the outset, there is no need to use crosslinking agents when preparing the particles. 35 Within the meaning of the present invention, linear, water-insoluble polysaccharides are polysaccharides which are composed of monosaccharides, disaccharides or other monomeric building blocks such that the - 7 individual building blocks are always linked together in the same way. Each basic unit or building block which is thus defined has precisely two linkages, with each of these being to another monomer. The only 5 exceptions to this are the two basic units which form the beginning and end, respectively, of the polysaccharide. These basic units only have one linkage to another monomer and form the end groups of the linear polysaccharide. 10 If the basic units possess three or more linkages, this is then referred to as branching. In this connection, the degree of branching follows from the number of hydroxyl groups per 100 basic units which are not 15 involved in the construction of the linear polymer backbone and form the branchings. According to the invention, the linear, water-insoluble polysaccharides exhibit a degree of branching of at 20 most 8%, i.e. they have at most 8 branches per 100 basic units. Preference is given to the degree of branching being less than 4% and, in particular, at most 2.5%. 25 If the water-insoluble linear polysaccharide is a polyglucan, e.g. poly-(1,4-alpha-D-glucan), the degree of branching in the 6 position is less than 4%, preferably at most 2% and, in particular, at most 0.5%, and the degree of branching in the other positions, for 30 example in the 2 or 3 position, is preferably in each case at most 2%, and in particular 1%. Particular preference is given to polysaccharides, in particular polyglucans, such as poly-alpha-D-glucans, 35 which do not exhibit any branchings, or whose degree of branching is so slight that it can no longer be detected using conventional methods.

- 8 Examples of preferred water-insoluble, linear polysaccharides are linear poly-D-glucans, with the nature of the linkage being of no importance as long as there is linearity within the meaning of the invention. 5 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", 10 "beta" or "D" refer solely to the linkages which form the polymer backbone and not to the branchings. For the present invention, the term "water-insoluble polysaccharides" is understood as meaning compounds 15 which, corresponding to classes 4 to 7, come within the categories "not particularly soluble", "difficultly soluble", "very difficultly soluble" and "virtually insoluble", respectively, in accordance with the definition in the German Pharmacopeia (DAB = Deutsches 20 Arzneimittelbuch, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Govi-Verlag, Frankfurt, 1987 edition). In the case of the polysaccharides used in accordance with the invention, this means that at least 98% of the 25 quantity employed, in particular at least 99.5%, is insoluble in water (corresponding to classes 4 and 5, respectively) under normal conditions (T = 25 0 C +/ 20%, p = 101325 Pascals +/- 20%). 30 For the present invention, preference is given to compounds which are difficultly soluble to virtually insoluble, in particular compounds which are very difficultly soluble to virtually insoluble. 35 "Very difficultly soluble", corresponding to class 6, can be illustrated by the following experimental description: - 9 One gram of the polyglucan/saccharide to be investigated is heated in 1 1 of deionized water at 130 0 C and under a pressure of 1 bar. The resulting solution remains stable for only a brief period of a 5 few minutes. On cooling under normal conditions, the substance precipitates out once again. After cooling down to room temperature, and separating off by means of centrifugation, at least 66% of the quantity employed is recovered, taking into consideration 10 experimental losses. The polysaccharides employed in accordance with the invention can be of any origin as long as the abovementioned conditions regarding the terms "linear" 15 and "water-insoluble" are fulfilled. They can be obtained naturally or by means of biotechnology. For example, they can be obtained from natural plant or 20 animal sources by isolation and/or purification. It is also possible to use sources which have been recombinantly manipulated such that they contain a higher proportion of unbranched polysaccharides, or of 25 polysaccharides which are only branched to a comparatively minor extent, compared with the unmanipulated source. They can have been prepared from nonlinear 30 polysaccharides by means of enzymic or chemical debranching. Biotechnological methods comprise biocatalytical, including biotransformational, or fermentative 35 processes.

- 10 An advantageous method for obtaining them biotechnologically is described, for example, in WO 95/31553. 5 It is also possible to use modified water-insoluble, linear polysaccharides, with it being possible, for example, for the polysaccharides to have been chemically modified, for example, by esterification and/or etherification in one or more positions which 10 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(s). The skilled person is sufficiently familiar with measures for carrying out such modifications. 15 Thus, linear polysaccharides, such as pullulans, pectins, mannans or polyfructans, which are water soluble per se, can be made water-insoluble by being modified. 20 In addition, use can be made of so-called alpha amylase-resistant polysaccharides, as are described, for example, in German patent application No. 198 30 618.0. 25 For the present invention, preference is given to using water-insoluble, linear polysaccharides which have been prepared in a biotechnological process, in particular in a biocatalytical process or a fermentative process. 30 In contrast to polysaccharides which are isolated from natural sources, such as plants, the polysaccharides which are obtained in such a process exhibit a particularly homogeneous profile of properties, e.g. with regard to the molecular weight distribution; 35 furthermore, they do not contain any undesirable incidental products, which have to be separated off in an elaborate manner, or at most only contain such - 11 products in very small quantities, and can be reproduced in a precisely specified manner. In particular, it is possible to use biotechnological methods to obtain water-insoluble, linear 5 polysaccharides, such as poly-1,4-alpha-D-glucans, which do not contain any branchings or whose degree of branching is below the detection limit of conventional analytical methods. 10 The molecular weights M. (weight average, determined by means of gel permeation chromatography as compared with standardizing with a pullulan standard) of the linear polysaccharides which are used in accordance with the invention can vary in a wide range from 0.75 x 102 g/mol 15 to 10' g/mol. The molecular weight Mw is preferably in a range from 10' g/mol to 10' g/mol, and is particularly preferably from 10' g/mol to 10' g/mol. Another advantageous range is from 2 x 10 3 to 8 x 10'. Corresponding ranges apply for the poly(1,4-D-glucan) 20 which is preferably employed. The molecular weight distribution or polydispersity M,/M. may also vary in wide ranges depending on the method used for preparing the polysaccharide. Preferred 25 values are from 1.01 to 50, in particular from 1.5 to 15. In this connection, the polydispersity increases with a bimodal distribution of the molecular weights. It is possible to use a single linear polysaccharide 30 substance, in particular linear poly(1,4-D-glucan), or mixtures which are composed of two or more representatives. In another embodiment, it is possible to add a water 35 insoluble, branched polysaccharide, preferably a polyglucan, in particular a poly(1,4-alpha-D-glucan) or a poly(1,3-beta-D-glucan).

- 12 It is also possible to add mixtures composed of two or more branched polysaccharides. The branched polysaccharides may be of any arbitrary 5 origin. In this connection, the reader is referred to the comments in this regard which were made in the case of the linear polysaccharides. Preferred sources are starch and starch analogs, such as glycogen. If necessary, the proportion of linear structures in the 10 branched polysaccharides can be increased using suitable enrichment methods. The same specifications as for the linear polysaccharide apply as regards the water-insolubility; 15 in the case of the branched polysaccharides, the molecular weight can also be higher and, for example, have values of up to preferably 10' g/mol and more. It is also possible for other biocompatible or 20 biodegradable polymers to be admixed. In this connection, the quantity of the other polymer(s) which is/are admixed, without the spherical shape and/or other properties of the microparticles to be prepared being altered, always depends on the polymer added. 25 In order to ensure that the microparticles have the desired properties, the proportion of linear polysaccharide should be at least 70% by weight, in particular 80% by weight, and preferably 90% by weight, 30 based on the total content of polysaccharide and, where appropriate, other polymers. According to a particularly preferred embodiment, 100% by weight of the microparticles consist of linear 35 polysaccharide. A detailed description of the microparticles which are used in the present instance, and of their preparation - 13 and of the water-insoluble, linear polysaccharides which can be used for this preparation, can be found in the applicant's German patent applications which are of earlier priority but not prepublished and which have 5 the references 197 37 481.6, 198 03 415.6, 198 16 070.4, 198 30 618.0 and 198 27 978.7, which applications are hereby incorporated into the present description by reference. 10 The microparticles which are employed, as carrier material, for parenteral use can furthermore comprise other adjuvants which are customary for this purpose in the usual quantities. 15 The active compound or the active substance for the composition according to the invention can be any solid, liquid or gaseous substance which is to be administered parentally, in particular by means of injection, to a living organism or else to an 20 inanimnate object. In particular when being administered to living organisms, the active compound or active substance is also understood to meaning biologically active substances or substance combinations in the widest 25 possible sense. An example of the broad application range for parenteral administration which may be mentioned is pharmacy or medicine in the human and veterinary areas, 30 for example in therapy, diagnosis or prophylaxis. Examples of active compounds which can be administered using the microparticles employed in accordance with the invention are so-called LHRH analogs, such as 35 Buserelin (a Hoechst Marrion Roussel registered trademark) for use against prostate cancer, endometriosis and other tumorous diseases of the sex organs; erythropoietin (EPO) for stimulating the growth - 14 of red blood cells, pain-alleviating active compounds, antiallergic agents, growth hormones, steroids for hormone treatment and birth control, biphosphonates, calcitonin (e.g. Cibacalcin from Ciba-Geigy) for 5 treating osteoporosis, psychotropic drugs and, quite generally, active compounds, e.g. proteins or peptides, which are decomposed in the gastrointestinal tract and cannot therefore be administered orally, or active compounds which require to be administered parentally, 10 etc. The active compounds or active compound combinations which can be employed can be selected at will for the desired area of application and are not subject, as 15 long as they can be administered parenterally, to any restrictions with regard to the nature of the active compound, to the way in which the active compound is prepared or to the area of application. So-called macromolecules, in particular peptides, proteins or 20 nucleotides which can be prepared or synthesized, for example, by means of biotechnological methods or methods which depend on modern biotechnology are particularly suitable. 25 It goes without saying that the quantity of active compound to be employed varies depending on the application field and the purpose, and is to be determined for each individual case. Thus, quantities in the microgram range are generally sufficient for 30 Buserelin, EPO and many other active compounds. In order to prepare the composition according to the invention, the active compound or the active compound combination is brought into contact, in the requisite 35 quantity, with the carrier material. For this, the active compound can be added to the starting compounds used for preparing the - 15 microparticles, such as the water-insoluble, linear polysaccharide, such that the microparticles comprise a mixture consisting of starting compound and active compound. 5 The active compound can be encapsulated in the microparticles, with it being possible to employ customary encapsulation techniques. Suitable examples are emulsion processes or spray drying processes. In 10 this connection, spraying processes, in which the particles are sprayed with a solution of the active compound in a fluidized bed or analogous processes, are also included in the latter term. 15 Furthermore, the active compound can be absorbed and/or adsorbed on the microparticle surface by the active compound and the microparticles being, for example, suspended in a suitable medium and left to stand until equilibrium has been reached, after which the active 20 compound-loaded particles are separated off. The composition according to the invention is particularly suitable for the controlled release of active compound, without, however, being restricted 25 thereto. Controlled release of active compound is understood as meaning that the active compound is not released immediately and at once; instead, the release takes 30 place over a given period of time and/or after a given period of time has elapsed. The rate of release can be changed at will depending on the desired purpose. It can be constant over the given period of time or it can be high at the beginning, with this being followed by a 35 slower rate of release. It goes without saying that the rate of release, and the rate of degradation of the microparticles, in an - 16 organism is highly dependent on the nature of the starting materials, on the nature of the active compound employed, on the size of the particles and on the preparation method employed. The skilled person 5 can, as required, produce a system which is tailor-made for his special purpose by varying these parameters in a simple manner, with which he is per se familiar. Parenteral administration is understood as meaning the 10 administration of any arbitrary active compound by means of injection or infusion, for which it is particularly advantageous if the composition to be administered is readily dispersible and exhibits good needle traversability. 15 Because of the outstanding needle traversability of the microparticles used in accordance with the invention, the composition according to the invention is particular suitable for administration by means of 20 injections. The injection can take place in any arbitrary manner; it can be administered intravenously, intramuscularly, intraarterially, subcutaneously or intralumbarlly. 25 A high degree of needle traversability means that the composition according to the invention is also able to readily pass through injection needles such as hypodermic needles having small needle diameters. 30 For the administration, the composition is suspended in a suitable medium. It has been found that, even without the addition of further adjuvants, such as dispersing agents, the composition according to the invention forms a stable suspension which remains unaltered even 35 over a relatively long period of time.

- 17 The ability to do without foreign substances such as dispersing agents is particularly advantageous as far as biocompatibility is concerned. 5 Insofar as the microparticles settle when the suspension is left to stand, for example during storage, a stable suspension can be produced once again simply by shaking briefly, with several seconds normally sufficing. 10 The choice of a suitable medium is in turn determined by the specific purpose which is intended. Sterile salt solutions, such as a physiological NaCl solution, are, for example, suitable for medical use. 15 The good to very good suspendibility is substantiated by the large concentration ranges. Thus, up to about 25% solids content can be present in the suspension. This corresponds to a proportion of 250 mg of particles 20 to 1 ml of solvent, e.g. physiological sodium chloride solution. Preferred concentration ranges are from 1% to 18%. A range of from 5% to 10% solids content is particularly preferred. This corresponds to quantities of from 50 mg to 100 mg of active compound-loaded 25 microparticles, a value which, in the case of alternative formulations, even when using a suspension aid, is only achieved at the cost of high experimental input. The very good suspendibility and needle traversability 30 can be supported, in particular, by the observation that 500 mg of particulate carriers are suspended in only 3 ml of water and can be administered without difficulty through a needle having a diameter of 0.6 mm. 35 If a higher concentration of microparticles is desired or required in the suspension, it is, of course, also possible to use auxiliary agents such as Pluronic (a BASF AG trademark), Haemaccel (a Behringwerke - 18 trademark), sodium dodecyl sulfate, etc., that is auxiliary agents which are generally recognized and used for such pharmaceutical administration forms. 5 In certain cases, the microparticles can themselves act as the active compound. Thus, the microparticles used in accordance with the invention can be employed as contrast agents, for example for ultrasonic diagnosis. In this case, the composition according to the 10 invention can be administered with or without an additional active compound. Gases are an example of possible additional active compounds, with it being possible for the nature of the 15 gas to vary widely (e.g. nitrogen, air, argon, helium, fluorochlorinated hydrocarbons and fluorinated hydrocarbons). It is also possible to use aspirin or NO-releasing compounds, which are of particular importance in diseases of the coronary circulation. 20 As explained above, the microparticles which are employed in accordance with the invention are particularly suitable for parenteral administration because of their outstanding dispersibility and high 25 degree of needle traversability. In that which follows, the present invention is explained with the aid of some selected examples. 30 Example 1 Preparing microparticles from poly(1,4-L-D-glucan) 500 mg of poly(1,4-2-D-glucan) are dissolved in 2.5 ml of dimethyl sulfoxide (DMSO, analytical grade, from 35 Riedel-de-Haen) at approx. 70 0 C. The DMSO solution is added dropwise, while stirring, to 100 ml of double distilled water and this solution is stored overnight at 5oC. The fine, milky suspension is centrifuged at - 19 3 500 rpm for 15 minutes and the supernatant is decanted off. The sediment is suspended using double distilled water and centrifuged once again. The procedure is repeated a further two times. The 5 suspension is then freeze-dried. 311 mg of white poly(1,4-aL-D-glucan) particles are obtained. This corresponds to a yield of 62% of colorless microparticles. 10 Example 2 Experiments on the needle traversability of suspensions containing microparticles composed of poly(1,4-alpha-D glucan) 15 A method which is accepted for testing and preparing microparticulate drug delivery systems is used for assessing the quality of the microparticle suspension. 100 mg of microparticles, which have been obtained as described in example 1, are suspended in 1 ml of double 20 distilled water. The individual particles can be separated from each other simply by shaking the sealed vessel by hand. The suspension is drawn up through a septum using a syringe and a needle having a diameter of 0.5 mm (or greater). The particles are then 25 expressed through the needle to be tested. The assessment of the individual needles is summarized in the following tables. A cross symbolizes the needle traversability of the suspension. The needles used are obtained from Braun Petzold GmbH (Melsungen). 30 In contrast to commercially available preparations, the addition of a suspension aid had no effect on the results in the case of microparticles composed of poly(1,4-alpha-D-glucan). In commercial systems and those which are based on a similar technology but use 35 other materials, a stepwise improvement in resuspension, up to a limiting value, is observed as the quantity of the suspension aid (additive) increases.

- 20 Table 1: Characteristics of needles employed Size Gauge Diameter in Length in mm mm 18 G x 1%/ 1.20 40 1 20 G x 1% 0.90 40 2 21 G x 11/2 0.80 40 12 22 G x 1%A 0.70 30 14 23 G x 1% 0.60 30 17 24 G x 1 0.55 25 18 26 G x 1 0.45 25 20 27 G x 4/5 0.40 20 30 G x 1 0.30 25 5 Table 2: Needle traversability of microparticles composed of poly (1, 4-alpha-D-glucan) Material Needle diameter (mm) 1.2 0.9 0.8 0.7 0.6 0.5 0.4 0.4 0.3 0 0 0 0 0 5 5 0 0 Poly(1,4- x x x x x x x X X alpha-D glucan) Example 3 10 Experiments on the needle traversability of suspensions containing microparticles composed of comparison materials (comparison examples) The experiments using comparison substances, as are 15 used either commercially or in research for preparing sustained release systems, were carried out as in example 1. The systems used are known biodegradable polymers composed of lactic acid and glycolic acid or of tartaric acid or of aspartic acid (cf. table 3). 20 - 21 Example 4 Loading the particles with active compound using a suspension process 5 The microparticles or agglomerates, composed of poly (1, 4-L-D-glucan) , are loaded with active compound using a suspension process. 250 mg of Buserelin* are dissolved in 10 ml of distilled water. 100 mg of particles are added. The suspension is stirred for 3 h. 10 The suspension is centrifuged. The centrifugate is washed with water. The particulate solid is separated off by centrifugation (3 000 rpm) and the centrifugate is freeze-dried. By dissolving an exact quantity of the particles in a mixture of water and dimethylsulf oxide, 15 and measuring spectroscopically in a UV-Vis spectrometer, the loading with Buserelin can be calculated, using a calibration curve, to be 3.28% based on the total mass of the particles. The solubility, and consequently the loading of the 20 particles with active compounds, can be influenced by modifying the solvent, e.g. alcohol. (*5-Oxoprolyl-L-hystidyl-L-tryptophanyl-L-tyrosyl-0 tert-butyl-D-seryl-L-leucyl-L-arginyl-N-ethyl-L 25 prolineamide) Example 5 Loading the particles with active compound by means of spray drying 30 The microparticles are suspended in distilled water or a mixture composed of water and a readily volatile component such as acetone or ethanol. For this, 10 g of the solid are added to 1 000 ml of the solvent. 0.5 g 35 of theophylline had been dissolved in the solvent beforehand. The spray dryer (Minispray dryer 191 from Bchil) is operated as follows: - 22 Atomization air flow 700 liters per hour, inlet temperature 200 0 C, activated nozzle cooling, nozzle diameter 0.5 mm, aspirator 70%, pump 10%. Checking the loading by spectroscopy (for description, see 5 example 4) gives a degree of loading of 4.8%. This value is in agreement with the theoretically achievable value of 5.0% within the limits of experimental error.

CD M o 0 0. .04 -I-) U) Q) 0 r oH -H 0 4-4 Q) o C 0) 0) 00 I C)' N U C C 0 I4 0 4-) .1i (a >' ufl -I 0\0H UU Ca40 -0 -H > rH-J 4)U 0 0 0 (a -H r M Ca- T 4 T~ 4~ NO () E C 71~ 03C) zOD )o 0 42 Z :Za -- i r- -I r 1,0 r-i Q0 HHH 5 Co I ~04 z.--a4 r1 Aq-L ro 0) UU 0) UH I r U 4.) 420 -H) .-4 I u aC , 0)~r r-I -o (a Ca> 1 -H-~ .0I 421 04 >, Ho g-- >, s-H 1H >, s ro 0a Osr--1 0 E- 0U .- i 0 0 U E 0 u E 0+, M I D4 P M 4al a- 0U (o N~ 04 Z w r 00 a40 ) - 25 In accordance with EP 535 387 In accordance with EP 514 790 In accordance with EP 514 790 Manufacturer, Fluka 5 Manufacturer, Behringwerke The results in parentheses are only achieved when special filters are additionally used for separating the individual particles or the process is repeated several times using needles of 10 relatively large diameter. Manufacturer, Medisorb (PLGA = polylactic-co glycolic acid 65:35, dl)

Claims (21)

1. A composition for the parenteral administration of active compounds, comprising a carrier material 5 and at least one active compound, with the carrier material comprising spherical microparticles which have a mean diameter of from 1 nm to 100 pm and which are composed, entirely or partially, of at least one water-insoluble, linear polysaccharide. 10

2. The composition as claimed in claim 1, wherein the water-insoluble linear polysaccharide is a biotechnologically produced water-insoluble linear polysaccharide. 15

3. The composition as claimed in claim 1 or 2, wherein the water-insoluble linear polysaccharide is a linear polyglucan. 20

4. The composition as claimed in one of the preceding claims, wherein the polyglucan is poly(1,4-alpha D-glucan).

5. The composition as claimed in one of the preceding 25 claims, wherein the polyglucan is poly(1,3-beta-D glucan).

6. The composition as claimed in one of the preceding claims, wherein the water-insoluble linear 30 polysaccharide is a chemically modified polysaccharide.

7. The composition as claimed in claim 6, wherein the polysaccharide has been esterified and/or 35 etherified in at least one of positions 2, 3 and 6. - 27

8. The composition as claimed in one of the preceding claims, wherein the depth of irregularities on the surface of the microparticles is at most 20% of the mean particle diameter. 5

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

10. The composition as claimed in one of the preceding claims, wherein the microparticles exhibit a dispersity D in the range from 1.0 to 10.0. 15

11. The composition as claimed in one of the preceding claims, wherein the active compound is mixed with carrier material.

12. The composition as claimed in one of claims 1 to 20 10, wherein the active compound is encapsulated in the carrier material.

13. The composition as claimed in one of claims 1 to 10, wherein the active compound is absorbed on the 25 carrier material surface.

14. The composition as claimed in one of the preceding claims, wherein the composition has a retardant effect with controlled release of the active 30 compound.

15. The use of a composition as claimed in one of claims 1 to 14 for human or veterinary medical purposes. 35

16. A suspension, comprising a composition as claimed in one of claims 1 to 14 and a dispersing agent. - 28

17. The suspension as claimed in claim 16, wherein the dispersing agent is a sterile salt solution.

18. The use of a suspension as claimed in claim 16 or 5 17 for human or veterinary medical purposes.

19. The use of a composition as claimed in one of claims 1 to 14, or of a suspension comprising this composition, for injection. 10

20. The use of spherical microparticles as claimed in one of claims 1 to 14 for parenteral administration. 15

21. The use of spherical microparticles as claimed in claim 20, wherein the microparticles are employed as a contrast agent.