Title of Invention	A DEPOT MEDICAMENT AND A METHOD FOR THE PRODUCTION OF A CARRIER FOR DEPOT MEDICAMENTS
Abstract	A depot medicament having a pharmacological active ingredient and a carrier, in particular for parenteral administration, characterized in that the carrier is produced with use of a carrier material which comprises a carrier polymer formed from a polypeptide and a biodegradable polyester covalently linked thereto

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The invention relates to a depot medicament having a pharmacological active ingredient and a carrier, in particular depot medicament for parenteral administra- tion, and carrier materials for depot medicaments and a method for the production of these carrier materials. Depot medicaments, especially those which can be administered parenterally or else orally, are becoming increasingly important because they not only allow controlled release of the active ingredients enclosed in the carrier over a lengthy period, and thus a uniform blood level of the active ingredient in the body, but they additionally permit targeted use of the active ingredients and provide protection for unstable active ingredients. Carrier materials which have already been employed are a large number of different biodegradable polymers, especially polyesters such as, for example, polylactides and polypeptides, although all the systems are associated with considerable disadvantages. Thus, R. Mank et al. describe, in Pharmazie (1991), page 9 to 18, "Parenterale Depotarzneiformen auf der Basis von biologisch abbaubaren Polymeren", various starting materials which are possible in principle for producing carrier materials for depot medicaments, namely polyesters and polypeptides. Subsequently, various studies, e.g. L. Meinel et al. , Journal of Controlled Release 70 (2001), pages 193 to 202, "Stabilizing insuline-like growth factor-I in poly(D,L- lactide-co-glycolide) microspheres", have then described the use of polyesters as carrier material for active pharmaceutical ingredients. The study by Y.S. Nam and T.G. Park, J. Microencapsulation 16 (1999), pages 625 to 637, "Protein loaded biodegradable microspheres based on PLGA-protein bioconjugates" is likewise based on poly(D,L-lactide-co-glycolides) , and in this case a prototype active ingredient (lysozyme) is chemically coupled to the polylactide. J.K. Li et al., Journal of Pharmaceutical Sciences 86 (1997), pages 891 to 895, "A Novel Biodegradable System Based on Gelatin Nanoparticles and Poly(lactide-co- glycolic acid) microspheres for Protein and Peptide Drug Delivery" use gelatin-PLGA mixtures. A further publication, namely WO 94/15587, uses ionic molecular conjugates of biodegradable polyesters and biologically active polypeptides. A further example which may finally be mentioned is also the publication of A. Kosasih et al. in International Journal of Pharmaceutics 204 (2000) , pages 81 to 89, "Characterization and in vitro release of methotrexate from gelatin/methotrexate conjugates formed using different preparation variables", where gelatin/ methotrexate conjugates are used for producing depot medicaments. Polypeptides are per se a suitable material as biodegradable carriers, but their rate of dissolution is usually distinctly too high, so that, after parenteral administration, they do not provide adequate protection from proteolytic degradation or, on oral administration, almost instantaneous release of the active ingredients takes place. Peptide active ingredients in particular cannot be brought safely through the gastrointestinal tract via polypeptide carrier materials, because the acidic environment in the stomach leads both to rapid hydrolytic decomposition of the carrier material and of the active ingredient. Accordingly, insoluble polymers, e.g. polylactides, have been preferred in the literature as polyesters which degrade considerably more slowly in an aqueous medium. However, the biodegradation of polylactides in aqueous solution produces protons which may adversely affect the stability of the pharmacological active ingredients and, in particular, may lead to degradation thereof or to their denaturation. With pure polylactide particles there is an accelerated decomposition of the polymeric material in the first place mainly in the interior (heterogeneous bulk degradation), because an acidic medium forms there and does not exchange with the surroundings, so that the higher hydrogen ion concentration consequently formed in the particle interior leads quasi-autocatalytically to an accelerated further degradation of the polylactide particle interior. However, the largest amounts of the active ingredient are usually present in the particle interior, so that, until exchange of the liquid phase in the interior of the particle with the surroundings takes place, most of the active ingredient present in the particle has been modified or else already denatured by the hydrogen ion concentration. This results in an irregular active ingredient release which cannot be determined beforehand. It is an object of the present invention to propose a depot medicament of the type described at the outset.., with which a defined active ingredient delivery over time is obtained and with which the active ingredient is maintained in its pharmacologically active form. This object is achieved according to the invention with the depot medicament described at the outset by producing the carrier with use of a carrier material which comprises, a carrier polymer formed from a polypeptide and a biodegradable polyester covalently linked thereto. Surprisingly, it is possible through the use of such a novel carrier polymer firstly to achieve defined active ingredient delivery over time, i.e. being distributed over a distinctly longer period compared with active ingredient release of active ingredients incorporated into polypeptides, and in addition substantially to avoid denaturation of the active ingredient itself. With the carrier polymer according to the invention, swelling, degradation and dissolution take place homogeneously. This firstly makes continuous diffusion of the active ingredient out of the carrier polymer particles possible and additionally means that no acidic environment can form in the interior of the particle, because this interior of the particle is connected to the exterior aqueous environment and, at the same time, the polypeptide content acts as buffer substance. The carrier polymer can be used to envelop an active ingredient phase so that the active ingredient is employed quasi-encapsulated or present in a matrix. It is also conceivable for the carrier polymer to take up the pharmacological active ingredient by adsorption and/or contain it included in pores which are present. The content of chemically bound polyester in the carrier polymer is preferably 1 mol% or more. This means that on reaction of polyester with polypeptide at least 1 mol% of the polyester employed is chemically linked to polypeptide. Unbound contents of the polyester and/or polypeptide may remain in the mixture. or, for special requirements, be removed by a workup process. It is possible to influence the despot effect of the medicaments or the intended period for release of the active ingredient via the content of polyester in the carrier polymer. The ratio by weight of polyester to polypeptide in the carrier polymer varies preferably in the range from 1:99 to 99:1, preferably in the range from 30:70 to 99:1. The rate of degradation of the carrier polymer can be varied within wide limits, and corresponding thereto the active ingredient release, by varying this ratio. At each of the limits there is a marked change in the degradation behavior of the carrier polymer compared with the respective starting polymers. In particular, even 1% by weight of polypeptide makes itself notice- able with its buffer effect in the process of degradation of the carrier polymer. Experience has shown that in preferred carrier polymers for depot medicaments even polypeptide contents of 2% by weight, in particular 3% by weight, are sufficient to ensure an optimal effect for the release and also the protection of the pharmacological active ingredient by the carrier. Carrier polymers with 10% by weight polypeptide or else more are most preferred. Suitable polyesters are, in particular, polyglycolides, poly(D,L-lactide-co-glycolides), polyalkylene glycol- polylactide block copolymers, polyalkylene glycol-PLGA block copolymers, POE-POP-PLA block copolymers, POE- PLGA block copolymers, pply-e-caprolactams, stereo- isomeric lactide oligomers, oligolactides (n >3) or polylactides. The polypeptide of the carrier polymer is preferably selected from collagen, gelatin, globular proteins and albumins or other hydrogel-forming proteins, enzymes and protein degradation products. Used as basis for the polypeptides are both mammalian collagen materials and their degradation products, in particular gelatin, such as, for example, beef gelatin, pig gelatin, sheep gelatin, but also poultry and fish gelatin. Also suitable of course are genetically engineered protein materials such as, for example, gelatin, collagen or collagen fragments, especially including those which are produced on the basis of plants and which may become increasingly important in future in the light of the BSE discussion taking place at present. Chemically and/or enzymatically modified polypeptides are likewise suitable. The gelatin can have a Bloom number in the range 30-32 0 or be hydrolyzed and be obtained by the acid process (type A) or the alkaline process (type B) or by pressure/temperature or by enzymatic means. Suitable as further constituent of the carrier polymers are conventional plasticizers, buffer substances, surfactants, lipids and pore formers. In the particularly preferred carrier polymers, the linkage of polypeptide and polyester takes place via a free hydroxyl function of the polyester with a reactive group of the polypeptide. An alternative, but also supplementary, possibility is to link polypeptide and polyester via a free carboxyl function of the polyester or, after oxidation of a hydroxyl function to a carbonyl group, via the latter to a reactive group of the polypeptide. The preferred reactive group of the polypeptide is the amino function. In view of the preferred mode of linkage, lysine- containing polypeptides are to be preferred, with a content of, for example, 3% of lysine groups, where appropriate also modified lysine groups, giving very good results. The invention further relates to a method for the production of a carrier material for depot medicaments, which is characterized in that a polyester is produced in a first step with activated hydroxyl groups, and in a second step a polypeptide is added and reacted with its reactive groups with the activated hydroxyl groups of the polyester to form a covalent bond. This results in a new block copolymer which is outstandingly suitable as carrier material for depot medicaments. Activation of the hydroxyl group is carried out in such a way that it is converted into a good leaving group. Suitable polyesters are a very wide range of compounds with different molecular weights (for example 2000 to 300 000), especially including a wide variety of poly(D,L-lactides) or poly(D,L-lactide-co-glycolides). With the last-mentioned polyesters it is possible to use a wide variety of ratios of glycolic acid and D- or L-lactic acid. It is likewise possible to use polyesters having modified ester end groups, polyalkylene glycols, polypropylene oxide-polyethylene oxide-polylactide-coglycolide- block copolymers (POP- POE-PLGA block copolymers), and various combinations of these polymers are likewise suitable as starting material. Suitable reagents for activating the hydroxyl group of the polyester are, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-bromobenzene- sulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethanesulfonyl chloride and others which are known to the skilled worker for forming good leaving groups. Since most reagents are sensitive to water, this reaction must be carried out in a dry, organic solvent, most preferably under a nitrogen atmosphere. Suitable solvents are tetrahydrofuran, dichloromethane, chloroform and others. In order to trap the hydrogen ions liberated during the reaction, it is possible to add various bases such as, for example, diethylamine, triethylamine, Hiinig's base, pyridine, 2,6-di(tert-butyl)-4-methylpyridine and others to the reaction mixture. The resulting product is isolated in a conventional way. The polypeptides to be employed are those already mentioned above and especially those which form hydrogels, such as, for example, gelatin. In order to adjust the reactivity of the activated polyester, the activated group can also be converted into a halide compound. Suitable for this is a modified Finckelstein reaction, in which case it is possible to obtain the corresponding iodide or bromide compounds. Halide compounds can additionally be obtained directly from the hydroxyl group using, for example, thionyl chloride, the more sensitive triphenylphosphine dibromide or triphenylphosphine in CCl4. The activated polyester can then be reacted with any nucleophilic group of the polypeptide, such as, for example, amino groups or hydroxyl groups. This reaction is carried out in a polar solvent, (e.g. DMF or DMSO) or in solvent mixtures such as, for example, ethyl acetate/water, acetone/water, THF/water, CHCl3/water and CH2Cl2/water. The temperature of the reaction and the reaction time can be varied depending on the reactivity of the reagents used. After completion of the reaction, the solvent is evaporated off, and the product is dried further, resulting in a white or pale yellowish powder. The presence of a novel compound was demonstrated by means of IR and NIR spectroscopy and differential scanning calorimetry (DSC), in which case it is possible to observe a new glass transition temperature for the product. In addition, the solubility of the product is entirely different from the starting materials. These and further advantages of the invention are explained in more detail with reference to the examples. Examples Example 1: Activation of the hydroxyl groups of the polyester component 3.4 g of Resomer RG503H (poly(D,L-lactide-co-glycolide) with a molecular weight of 34 000, glass transition temperature 49.9°C from Boehringer Ingelheim) are dissolved in 10 ml of dry dichloromethane in a dry reaction flask with a capacity of 50 ml under a nitrogen atmosphere. Other solvents which can be employed similarly well are THF, CHC13 and ethyl acetate. 104 mg of triethylamine (dried over KOH) are added thereto. The mixture is cooled to 0°C for 15 min and then 114 mg of methanesulfonyl chloride are metered in through a syringe. The reaction mixture is stirred at room temperature for one hour and then poured into an ice/water mixture for hydrolysis. The aqueous phase is extracted three times with dichloromethane, and the combined organic phases are washed with a saturated sodium bicarbonate solution. After the extraction, the organic phase is dried over magnesium sulfate. The solvent is evaporated off and any remaining solvent residues are removed under high vacuum. Coupling of the polyester component to a polypeptide The freshly prepared activated polyester component is dissolved in 20 ml of chloroform and added to 20 ml of an aqueous solution of 3.7 g of pig skin gelatin (high- Bloom type A, glass transition temperature 67.9°C). The mixture is stirred at a temperature of 55°C (oil bath temperature) for 6 hours and then stirred at room temperature overnight. The solvent is evaporated as far as is possible in a rotary evaporator. The remaining water is removed in a desiccator containing a desiccant. Unreacted PLGA is removed by extraction with methylene chloride. The insoluble residue is dried in vacuo and then taken up in DMSO. The product according to the invention is thus dissolved. Subsequently, the DMSO solution containing the product according to the invention is spray dried. Spherical particles in the diameter range 1-10 mm are obtained depending on the spraying conditions. The product according to the invention has a polyester:polypeptide ratio of 90:10 and a glass transition temperature of 55.9°C. To determine the glass transition temperatures, all the investigated materials have previously been conditioned at 25°C and 25% relative humidity. The IR and NIR data of the product according to the invention differ significantly both from the starting compounds and from superimposed spectra of the starting substances. In contrast to the starting gelatin, the product according to the invention is completely soluble in DMSO. The product is insoluble in otherwise customary solvents such as alcohols, acetone (ketones), ethers and water. The kinetics of degradation can be varied within wide limits through the selection of the polyester type, its chain length and the ratio of gelatin to polyester content in the product according to the invention, and the nature of the end groups of the polyester. The kinetics of degradation of the product according to the invention can also be influenced within certain limits by appropriate selection of the gelatin. Example 2: Various polyester components, namely PLGA, PLA and POP- POE-PLGA copolymers with various ratios of the two polymer groups, are reacted in the same manner as in example 1. The reaction was successful in each of the cases, irrespective of the manufacturer of the particular polyester component (compounds supplied by Boehringer Ingelheim, Medisorp and Vako were tested). The results in terms of yield of product according to the invention are comparable with those of example 1. Example 3: The hydroxyl function of the polyester component was activated by using p-toluenesulfonyl chloride, resulting in a simplified procedure compared with the procedure in example 1: 3.4 of Resomer RG503H are dissolved in 10 ml of distilled dichloromethane in a reaction vessel with a capacity of 50 ml. 104 mg of triethylamine (analytical grade) are added thereto. The mixture is cooled to 0°C for 15 min, and 190 mg of p-toluenesulfonyl chloride are added. The reaction mixture is stirred at room temperature for one hour and then poured into an ice/water mixture for hydrolysis. The aqueous phase is extracted three times with dichloromethane, and the combined organic phases from the extraction steps are washed with a saturated aqueous sodium bicarbonate solution. After the washing with the sodium bicarbonate solution, the organic phase is dried over magnesium sulfate, the solvent is evaporated off, and remaining solvent residues are removed under high vacuum. The advantage of this procedure is that exclusion of water is unnecessary. The freshly prepared activated polyester component is dissolved in 20 ml of chloroform, and 2 0 ml of an aqueous solution of 3.7 g of pig skin gelatin (type A) are added thereto. The mixture is stirred at a temperature of 55°C (oil bath temperature) for six hours and then stirred at room temperature overnight. The solvent is evaporated as far as is possible with a rotary evaporator. Remaining water is removed in a desiccator with a desiccant. The properties of the resulting product correspond to those of example 1. Example 4: 3.4 g of Resomer RG503H are dissolved in 10 ml of dry dichloromethane in a dry flask with a capacity of 50 ml under a nitrogen atmosphere. 104 mg of triethylamine (dried over KOH) are added. The mixture is cooled at 0°C for 15 min, and 114 mg of methanesulfonyl chloride are added using a syringe. The reaction mixture is stirred at room temperature for one hour and then poured into an ice/water mixture for hydrolysis. The aqueous phase is extracted three times with dichloromethane, and the combined organic phases are washed with saturated sodium dicarbonate solution. After the organic phase has been washed it is dried over magnesium sulfate. The solvent is evaporated, and the remaining solvent residues are removed under high vacuum. A difference from the procedure described in example 1 is in this case conversion of the polyester component with activated hydroxyl groups (which in this case are converted into sulfonate groups) into an iodide or bromide in a modified Finckelstein reaction, in which the compound is simply stirred with an excess of sodium iodide or lithium bromide in dry acetone as solvent. After the mixture has been stirred for one day (at room temperature) , it is filtered off and the acetone is removed from the resulting product. The reactivity and thus the degree of conversion of a coupling reaction can be influenced by the subsequent Finckelstein reaction. Coupling reaction of the polyester component with the polypeptide component The freshly prepared polyester component (see above) is dissolved in 20 ml of chloroform, 20 ml of an aqueous solution of 3.7 g of pig skin gelatin (type A) are added thereto. Alternative solvents are in this case 1:1 water/dichloromethane, 1:1 water/ethyl acetate, DMF and DMSO. The mixture is stirred at 55°C (oil bath temperature) for six hours and then stirred at room temperature overnight. The solvent is evaporated as far as is possible with a rotary evaporator. Remaining water is removed in a desiccator containing a desiccant. Example 5: The same procedure as in example 1 is used, but in this case a type B gelatin which is produced from bone or ox skin is used in place of the pig skin gelatin of type A. It was possible to carry out the coupling reaction of polypeptide component and polyester component in the same way as described previously. Example 6: The same production method as in example 1 is used, but enzymatically hydrolyzed gelatin (Gelita-Collagel® A) is used in the coupling reaction of the polypeptide component with the activated polyester component. Example 7: The same preparation method as in example 1 is used, but gelatin hydrolyzate (enzymatically hydrolyzed gelatin such as, for example Gelita-Sol® D/Sol DA and others) is used for the coupling reaction of the polypeptide with the activated polyester. Example 8: The same production method as in example 1 is used, but ovalbumin is used as polypeptide component for the coupling reaction with the activated polyester. Example 9: The same preparation method as in example 1 is used, but the coupling reaction of the activated polyester component with the polypeptide is carried out in basic solution. The basicity of the reaction medium enhances the reactivity and thus shortens the reaction time. The same preparation method as in example 1 can be used although the coupling reaction of the activated polyester component with the polypeptide component is carried out in an acidic solution. The reaction time is reduced by the acidic environment of the reaction medium. Example 10: The same production method as in example 1 is used, but the coupling reaction of the activated polyester component with the polypeptide component is carried out at room temperature with a prolonged reaction time compared with example 4. The same preparation method as in example 1 can be used, although the reaction of the activated polyester component with the polypeptide component is carried out by refluxing the reaction mixture with a corres- pondingly reduced reaction time. Example 11; This example is intended to describe the introduction of an active ingredient into a carrier material and thus the production of a depot medicament, using the enzyme lysozyme as model active ingredient. Both the kinetics of release and the activity of the released model active ingredient is determined. The model active ingredient lysozyme is introduced in an amount of 10% by weight based on the total solids content, of the DMSO solution contained in the workup of the reaction product of the coupling reaction of example 1, into the latter, and the solution is then spray dried in the same manner as described in example 1. The particles obtained in this way correspondingly have a lysozyme content of 10% by weight. The degradation behavior of the carrier polymer according to the invention, and the release, corresponding thereto, of the model active ingredient lysozyme, was measured in an isotonic PBS solution with serum hydrolases at a temperature of 37°C and at a pH value of 7.4. Figure 1 shows three release curves of the model active ingredient lysozyme from microparticles consisting of polypeptide (¦) (high-Bloom gelatin of type A, glass transition temperature 67.9°C), polyester ( ) (Resomer RG503A) and the carrier polymer according to the invention (?) over the course of 28 days. 10% by weight lysozyme had been added as model active ingredient to the three types of polymer, as described at the outset of this example. The polypeptide (gelatin) shows virtually immediate 100% release of the model active ingredient lysozyme within the chosen timescale. The release of lysozyme from the polyester is not complete even after 28 days. As the incubation time increases there seems to be a progressive inactivation of the active ingredient and a gradual stagnation of release. Release from the carrier polymer of example 1 according to the invention takes place very uniformly over five days without an adverse effect on the activity of the active ingredient. Comparable release profiles are obtained with the carrier materials according to the invention produced as per examples 2 to 10. WE CLAIM: 1. A depot medicament having a pharmacological active ingredient and a carrier, in particular for parenteral administration, characterized in that the carrier is produced with use of a carrier material which comprises a carrier polymer formed from a polypeptide and a biodegradable polyester covalently linked thereto. 2. The depot medicament as claimed in claim 1, wherein the ratio by weight of polyester content to polypeptide content is from 1:99 to 99:1. 3. The depot medicament as claimed in claim 1 or 2, wherein the ratio by weight of polyester content to polypeptide content is from 30:70 to 99:1. 4. The depot medicament as claimed in any of claims 1 to 3, wherein the polyester is selected from polyglycolides, poly(D,L-lactide-co-glycolides), polyalkylene glycol-polylactide block copolymers, polyalkylene glycol- PLGA block copolymers, POP-POE-PLA block copolymers, POP-PLA block copolymers, POP-PLGA block copolymers, POE-PLGA block copolymers, poly-£-caprolactams, stereoisomeric lactide oligomers, oligolactides (n > 3) or polylactides. 5. The depot medicament as claimed in any of claims 1 to 4, wherein the polypeptide is selected from collagen, gelatin, globular proteins or other hydrogel-forming proteins, enzymes and protein degradation products, which may be chemically and/or enzymatically modified. 6. The depot medicament as claimed in any of claims 1 to 5, wherein the linkage of polypeptide and polyester takes place via a free hydroxy function of the polyester with a reactive group of the polypeptide. 7. The depot medicament as claimed in any of claims 1 to 6, wherein the linkage of polypeptide and polyester takes place via a free carboxyl function of the polyester, or a carbonyl function obtained by oxidation of the hydroxyl function, with a reactive group of the polypeptide. 8. The depot medicament as claimed in claim 6 or 7, wherein the reactive group of the polypeptide is an amino function. 9. A method for the production of a carrier material for depot medicaments, wherein the steps of: reaction of a polyester component with an activating agent in order to convert hydroxyl groups of the polyester component into an activated form, addition of a polypeptide component and reaction of reactive groups of the polypeptide with the activated hydroxyl groups of the polyester to form covalent bonds. 10. The method as claimed in claim 9, wherein the hydroxyl groups are converted with the activating agent into good leaving groups. 11. The method as claimed in claim 9 or 10, wherein the polyester component is selected from polyglycolides, poly(D,L-lactide-co-glycolides), polyalkylene glycol-polylactide block copolymers, polyalkylene glycol- PLGA block copolymers, POP-POE-PLA block copolymers, POP-PLA block copolymers, POP-PLGA block copolymers, POE-PLGA block copolymers, poly-e-caprolactams, stereoisomeric lactide oligomers, oligolactides (n £ 3) or polylactides. 12.The method as claimed in any of claims 9 to 11, wherein the polypeptide component is selected from collagen, gelatin, globular proteins or other hydrogel-forming proteins, enzymes and protein degradation products. 13.The method as claimed in any of claims 9 to 12, wherein the activating agent is selected from p-toluenesulfonyl chloride, methanesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride and trifluoromethanesulfonyl chloride. 14. The method as claimed in any of claims 9 to 13, wherein the step of activation of the hydroxyl groups of the polyester component is carried out in a solvent which is selected from tetrahydrofuran, dichloromethane, chloroform and any mixtures of the aforementioned solvents. 15. The method as claimed in claim 14, wherein the solvents are employed dry, and the step of activation of the hydroxyl groups is carried out under a protective gas atmosphere, in particular nitrogen atmosphere. 16. The method as claimed in claim 15, wherein a basic agent is added to the reaction mixture in the step of activation of the hydroxyl groups in order to trap liberated hydrogen ions. 17. The method as claimed in claim 16, wherein the basic agent is selected from diethylamine, triethylamine and Hunig's base. 18.The method as claimed in any of claims 9 to 17, wherein the polyester component with the activated hydroxyl groups is reacted in a modified Finckelstein reaction in order to convert the activated hydroxyl groups into halide groups, before the polyester component is reacted with the polypeptide component. 19.The method as claimed in any of claims 9 to 18, wherein the reaction of the polyester component with the polypeptide component is carried out in a polar solvent which is selected from DMF, DMSO and solvent mixtures such as, for example, ethyl acetate/water, acetone/water, THF/water, CHCI3/water and CH2CI2/water. 20. A polyester-polypeptide block copolymer obtainable by a method as claimed in any of the preceding claims. A depot medicament having a pharmacological active ingredient and a carrier, in particular for parenteral administration, characterized in that the carrier is produced with use of a carrier material which comprises a carrier polymer formed from a polypeptide and a biodegradable polyester covalently linked thereto

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