CA1142433A - Medicinally useful, shaped mass of collagen resorbable in the body - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A shaped mass resorbable in the body, comprises collagen and a bioresorbable binding agent for collagen, the binding agent being selected, e.g., from polymers of C2-16 .alpha.-hydroxyalkanoic acids, polymers of natural amino acids, hydrolyzed collagen or hydrolyzed elastin.

Description

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The present invention concerns a shaped mass based on collagen resorbable in the body, its preparation and its use in medicine, especially as surgical material and/or as an active material depot.
It is known to introduce into the body bioresorbable materials, such as collagenl in freeze-dried or foamed form and thus to fill up, e.g., bone or tissue defects.
Such implants can be used to stop bleeding and can also be employed for the induction of granulation tissue; however, 0 they have the disadvantage that they are relatively loosely constructed and, therefore, upon moisture take-up, lose their shape relatively quickly. Thus, the body tissues scarcely have time to grow again to a sufficient extent. Therefore, it is desirable to develop similar materials which display , the advantages of~the known collagen~preparations, but simul-taneously have a more stable consistency andj therefore, lose their shape less quickly.
It is also known that active materlals, such as -~ antibiotics, can be embedded in certain synthetic resins, ::
such asl e.g.,~polymethacrylates and/or polyacrylates, and are slowly liberated from these non-resorbable carriers when they are used as implantations in the body. Such active material-containing synthetic resins are commercially available, e.g., a~ spheroids which are implanted near the bone or soft tissue infections to be treated and can provide a sufficiently high active material concentration in situ. This new therapy .~
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has proved to be useful in the case of various infections in the body, but has the disadvantage that, in certain cases, the spheroids cannot be left in the organism; on the contrary, after some time; they must b~ removed, which means a renewed surgical intervention and thus a renewed risk of infection.
Therefore, it is also desirable to have an alternate thera-peutic princi~le so that the mentioned removal of the spheroids can be obviated.
From Federal Republic of Germany Patent Specifica-tion No. 12 ~3 396 is alsu known the use of polyhydroxyaceticacid esters for the production of antibiotic-containing, resorbable surgical stitching materials, tubes and films.
Furthermore, in United States Patent 3,773,919 of November 20, 1973, there are described pharmac~utical compositions which are characterized in that they contain an active material in combination with a polylactide or a copolymer of lactide and glycolide units.

Accordingly, it is an ob~ect of this invention to provide a collayen composition which can be formed into a shapable mass wnich is resorbable.
It is a further object of this invention to provide an agent compatible with the body comprising shapable collagen which is suitable as surgical material or as an implantable active material depot with protracted liberati~n of active material.

3L~ 4Z~3 It is another object of this invention to provide a production process for such an agent which is acceptably economical and uses easily and cheaply available starting materials.

These objects have been attained by providing a shaped mass based on collagen resorbable in the body which comprises collagen and a bioresorbable binding agent for collagen.
Furthermore, the resorbable mass can additionally contain an active material, especially an antibiotic and/or calcium phosphate.
This invention also provides a proc~ess for the shaping of collagen, which comprises working-up together collagen and a bioresorbable binding agent for collagen, under the action of pressure and/or heat, wherein an active material and/or calcium phosphate can additionally be incorporated.
The shaped mass based on collagen of this invention can be worked up at sur~risingly low temperatures.
Further aspects o~ this invention are the use of the resorbable, optionally calcium phosphate-containing mass, as surgical materlal, or of a mass of this invention addi-tionally containing an active material as an active material depot.
Preferred compositions oE this invention are those shaped masses comprising collagen which, as bioresorbable binding agent, contain a copolymer of lactic acid and glycolic acid, especially one in which are contained 10 - 30 mole% of glycoliq acid units. Also preferred are those compositions which, as binding agent, contain a protein produced by hydrolysis of collagen, having an average molecular weight of about 2500 - 4000. Additionally preferred are also those compositions which function as an active material depot and which contain gentamycin as the active material.

Collagen, which is not shape-stable under the influence of moisture, is, due to the bioresorbable binding agent of this invention, brought into a shaped mass, i.e., into a permanent shape, without being chemically attacked or changed by this procedure. "Shaping" herein means that the mixture of collagen and binding agent serving as starting matexial can be worked up into a desired shape under the action of pressure and~or heat manually or by the techniques , . .
conventionally employed in the working up of synthetic resins, such as by an injection molding process~ For the shaping of the binding agents of this invention, surprisingly com-paratively low temperatures are necessary. This temperature can be so adjusted that a comparatively large series of diferent active materials can be incorporated undecomposed into the mass. This applies especially to the composition of this inven~ion in which the binding agent is a polymer or copolymer of lactide and/or glycolide units or especially of protein which has been prepared by the decompositi~n of.
collagen. A gentle working up of the active material is thereby rendered possible.

Contrary to expectations, due to the shaping of the composition according to this invention, there is obtained a fairly hard and mechanically stable material, even when the binding agent content of the mass is relatively small, and, e.g., only amounts to 3 - 10 wt%.
Depending upon the intended purpose of use, the composition according to this invention can be brought into different shapes. Thus, there are suitable comparatively large shaped bodies which can be brought into the desired shape b~ cu-tting or hammering operations. Tubes, strands, foils or tablets in various sizes are, e.g., often expedient as shapes. Especially preEerred are spheroidal shaped bodies of various dimensions, e.~., spheroids with a diameter of 0.5 - 10 mm, preferably 2 - 7 mm. Also preferred are granulates with a diameter of 0.1 - 5, preferably of 0.5 -

2 mm.
The composition according to this invention can also suitably be formed into a powder which can be produced, e.g., by conventional comminution of larger shaped bodies, possibly with admixing of conventional addltives, such as talc or starch.
If an active material is present in the composition o~ this invention, after its implantation into the body, it is, surprisingly, very favorably liberated. Whereas -liberation from conventional (e.g., lyophilized) collagen takes place relatively quickly, the active matexial can be liberated protractedly from the composition of this invention, i.e., over a desired period of time, in the necessary con-centrations. The active material is thereby continuously ~L14Z4~3 and slowly given off without cell-damaging side effects caused by the implant. In vitro experiments with the preferred compositions oE this invention which, as binding : agent, contain a copolymer of lactide and glycolide units and, as active material, gentamycin sulphate, have, e.g., shown that the antibiotic is liberated in initially very high, then slowly decreasing concentrations. The amount of the antibiotic liberated and the period of time of the liberation can be controlled by variation of the proportions of the components and of the working-up conditions employed in the production of the composition. The process conditions to be employed are well known to the expert and the desired properties of the process end products can be tested by standard methods.
An addition of a certain percentage of calcium phosphate, especially of tric~alcium phosphate, permits an especially uniform liberation of the active material, and is also often otherwise advantageous since calcium phosphate additionally stimulates the growth of bone.
Especially suitable as binding agents of this invention for tl~e collagen are polymers of glycolic acid and lactic acid, as well as their copolymers in various weight ratios of the monomer units. Especially sui~able are lactide/glycolide copolymers and a glycolide content of 5 - 40 mole %, preferably of about 10 - 30 mole ~. Suitable are, furthermore, e.g., also copolymers of a-hydroxybutyric acid and glycolic acid of a glycolic acid content of 25 ~ 70 mole % and correspon~ing copolymers of a-hydroxybutyric acid and lactic acid of a ~:L4Z433 -lactic acid content of 40 - 85 mole %. Copolymers having a content of 40 - 70 mole % of glycolic acid, 1 - 15 mole %
of ~-hydroxybutyric acid and a residual proportion of lactic acid are also suitable.
Quite generally, there are suitable all homo- and copolymers of a-hydroxyfatty acids of 2 - 16 C-atoms inso~ar as these are non-toxic and still resorbable in the body, thus, e.g., co- and possibly homopolymers of glycolic acid, lactic acid, a-hydroxybutyric acid, a-hydroxyisobutyric acid, a-hydroxyvaleric acid, ~-hydroxyisovaleric acid, a-hydroxycaproic acid, a-hydroxy-a-ethylbutyric acid, a-hydroxyisocaproic acid, ~-hydroxy-~-methylvaleric acid, a-hydroxyheptanoic acid, a-nydroxyoctanoic acid, a-hydroxy-decanoic acid, a-hydroxymyristic acid, a-h~ydroxystearic acid ~nd a-hydroxylignoceric acid. The ~-hydroxy fatty acids can be present wholly or partially in optically-active forms (e.g., D- or L-forms) or in optically-inactive (DL- or racemic) form, thus lactic acid as D-, L- or DL-lactic acid. The amount ratio between the monomer units in the copolymers is in principle unlimited, but copolymers containing higher weiyht a-hydroxycarboxylic acids are, as a rule, more difficult to resorb than polymers containing lower a-hydroxyfatty acids. Thus, copolymers consisting of a-hydroxyvaleric acid and glycolic acid, e.g., are composed mainly of units of glycolic acid, e.g., of 90 wt %
glycolic acid and 10% a-hydroxyvaleric acid. This also a~plies similarly to copolymers with the other mentioned -a-hydroxyfatty acids.

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Other resorhable binding agents include those which are derived from polyamino acids having a molecular weight of ~ 2000 - 8000, whereby the molecular weight can, however, exceed these limits upwardly or downwardly.
Among these are preferred hydrolytically produced decom-position products of collagen or alqo of elastin and similar proteins, which products possess a molecular weight of 2500 - 4000, preferably of about 3000. Conditions employed for such hydrolyses are conventional and are disclosed, for example, in Treatise on Collagen/ G.N. Rama-chandran, Gen. Ed (Academic Press, New ~ork, 1967).

i Also usable are resorbable, synthetically produced polyamino acids of about the same molecular weight, e.g., of proline, hydroxyproline and/or glycine units. However, it is also possible to employ other polymers and copolymers of, e.g., natural amino acids, e.g., of alanine, lysine, glycine, valine, leucine, isoleucine, phenylalanine, serine, threonine, cysteine, methionine, asparagine, glutamine, arginine, histidine, proline, hydroxyproline and/or other amino acid units.
Equivalent suitable agents for the collagen include, in principle, all polymers which are bioresorbable, i.e., which are broken down or resorbed in the body.
In the resorbable mass of this invention, the rati~
25 between collagen and the binding agent can be varied within : wide ranges. However, those compositions are preferred in which the pro~ortion of the bindinq agent is 1 - 25, preferably 3 - 10, and especially 5 wt % of the total amount of collagen and binding agent. Especially preferred are those compositions in which the least possible amount S of binding agent i5 contained but which, nevertheless, are still shapable, i.e., those which contain the minimum amount effective for rendering the composition shapable.
Those compositions are also preferred which can be shaped at the lowest possible tempèrature, e.g., at tempera-tures of from room temperature to 200C, preferably of70 ~ 110C.
Especially preferred are compositions of 90 -96 wt % of collagen and 10 - 4 wt % of hydrolyzed collagen (protein powder with a molecular~weight of about 3000) which, under certain conditions, can already be shaped at temperatures of 80 - 100C.
Quite generally, amony the compositions of this invention, those-are also preferred in which the bindiny agent possesses a reduced specific viscosity (i.e., the ratio between specific viscosity and concentration) of 10 -- 450, preferably of over 30 cm3/g.
The expression "active material" is used herein in a very wide sense and includes all articles which are intended, by parenteral routes, fox the healing, amelioration, treat-ment and/or prevention of health disturbances in patients,e.g., humans, and anima~s, e.g., mammals, or are able to influence a function of the body of humans or animals.
In particular, there are to be mentioned antibacterially active mat~rials of various kinds, especially antibiotics.

These are to be stable, especially chemically stable, towards the resorbable mass of the invention and especially its individual components and otherwise system compatible.
Their activity spectrum includes gram-positive or gram-negative pathogens or preferably both groups. The activematerials are, as far as possible, to bring about no or only a delayed resistance in the pathogens. Among the antibacterially active materials, the following antibiotics are mentioned by way of example: aminoglycoside antibiotics, such as amikacine, butirosin, didesoxykanamycin B (DKB), fortimycin, gentamycin, kanamycin, lividomycin, neomycin, Netilmycin, ribostamycin, sagamycines, seldomycins and their epimers, sisomycin, sorbistin, tobramycin; chloroamphenicol and derivatives, such as thiamphenicol; erythromycins;
lactone antibiotics, such as novoblocin; leucomycins, such as josamycin, maridomycln, midecamycin, spiramycin;
lincomycins, such as clindamycin, lincomycin, macrolides, such as rosamycin; penicillins, such as amoxicillin, ampi-cillin, azlocillin sodium, dicloxacillin sodium, furoxa-cillin, mecillinam, piperacillin; peptide antibiotics,such as bacitracin, colistimethate sodium, gramicidin, polymyxins; rifamycins, suGh as rifampicin, rifamycin;
steroid antibiotics, such as fusidic acid; trimethoprim;
streptomycins; tetracyclones, such as doxycyclin, minocyclin, tetracyclin; cephalosporins, such as cefalothin, cefamandol, cefazedone, cefazolin, cefoxitin, cefuroxime; as well as other antibiotics, e.g., cycloserine, fosfomycin, vancomycin, etc. The aminoglycoside antibiotics, especially gentamycin, ~243~

are thereby especially suitable because of their wide antibacterial spectrum and their heat stability.
It is also possible to combine two or more of these antibiotics with one another, e.g., gentamycin with clindamycin; combi'nations of these antibiotics with other active materials, e.g., with antiseptics, are also suitable.
Further suitable antibacterially active materials are, e.g., sulphonamides (such as'sulphadiazine), as well as tuberculosis and leprosy agents (such as aminosalicylic acid of sulphones).
Also preferred are active materials for other indi-cations, e.g., antiseptic~s (such as bromochlorophen, hexe-tidine, buclosamide, salicyclic acid, cerium nitrate, chlor-hexidine, 5 chloro-8-hydroxyquinoline, copper 8-hydroxyquinolate', acridine orange, undecenoic acid, undecoylium chloride, silver salts, such as silver sulphadiazine, mafenide, nitrofurazone, cloflucarban, tribromsalan, tauroline, noxythioline, etc., furthermore inflammation inhibitors (such as salicylates, phenylbutazone, indomethacin, ibuprofen, p-aminophenol~derivatives le-g-, acetaminophen~, pyrazolones, hydrocortisone palmitate, etc.), as well as cytostatics (such as fluorouracil, vinblastin, doxor~icin, prednisone, etc.). '' The amount of the active material to be added can be varied over wide ranges and depends essentially upon its activity. In generaly, the amount of the active material is about 0.2 - 20 wt %, preferably at about 2 - lO
wt ~, referred to the bioresorbable mass.

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For gentamycin, e.g., additions of 1 - ~ wt. ~
have proved to be especially favorable (calculated on the basis of gentamycin base). The other active materials are ~referably admixed in amounts which are adequat~ for their activ.ity. Active material mixtures can thereby also be chosen.
According to the inven-tion, the resorbable composi-tions can also contain calcium phosphate, especially tri-calcium phosphate. This additive can be present in an amount of 0.1 - 40 wt~ based on the weight of resorbable mass. Preferred are calcium phosphate contents of about 1 - 25, and especially of 5 - about 20 wt %. Especially suitable is, e.g., a preçipitated crystalline calcium phosphate material, the particles of which can be up to ~15 about 1 mm in dimension. Preferred are particle diameters of between 0.02 and 0.25 mm. Amorphous, molten, vitreous and/or sintered calcium phosphate of about the same particle size is also usable. The calcium phosphate, especially tricalcium phosphate, is employed as a bioactivatlng additive. As is known, it stimulates the growth of bone and has, astonishingly, a favorable action on the protracted liberation of the active materiaL. Calcium phosphate addi-tions are, in particular, expedient in the case o~ those compositions of the invention which are to serve as surgi-25- cal material in the healing and supplementing of bone.
For the production of the composition of this invention, collagen and the bioresorbable binding agent for collagen can be worked up with one another in various ~4~4;3 ;~
.

ways. In the simplest case, these materials are directly mixed with one another and then worked up. If calcium phosphate is to be present, then, here, too, it can be worked hy this same simple process wllich, for economic reasons, is itself preferred. However, for the better embedding of the calcium phosphate, it can first be worked up with the binding agent and then this premixture can be pressed and/or sintered together with the collagen.
For the production of an active material-containing composition of this invention, numerous possibilities are also available. The working up of a previously prepared mixture of all components is itself preferred. For effecting this process, e.g., collagen, the binding agent, the active material, and optionally calcium phosphate, are carefully mixed with one another and homogenized. The powder obtained is then melted and/or sintered under pressure and/or heat.
The temperatures - depending upon the heat stability of the active material and/or of the binding agent - can thereby be varied over a wide range, e.g., from room tem-perature to 200C. If the binding agent consists, e.g., of copolymers of glycolic acid and lactic acid units, tem-peratures of about 130 to 170C are preferred. If, on the other hand, a proteinaceous material, e.g., of hydrolyzed collagen, is employed as binding agent, then lower tempera-25 tures, e.g., ~0-90C, preferably 60-85C, are advantageous but, of course, higher temperatures can be employed if neces-sary for technical reasons.

42~33 The work-up of the components can also be carried out in such a manner that the active material - with or without calcium phosphate - is first melted, sintered or pressed with the binding agent (e.g., the copolymers of glycolic S acid and lactic acid units), whereupon the resulting, rela-tively active material-rich premixture is cooled and com-minuted, e.g., by grinding. Thereafter occurs the admixing with collagen and, optionally, additional active material, and the final work-up under the influence of pressure and/or heat.
Compositions of this invention which are prepared according to this process frequently display a better and more uniform liberation of active material and are, therefore, sometimes preferred in comp~rison wit~h those produced according to the simple mixing process.
For the preparation of the premixtures, possibly lower temperatures can be used than for the final shaping under the;above-stated conditions.
When calcium phospha-te is used, lt can be worked up, ~;~ together with the active material, with the premixture or can be first admixed at the final shaping. The first-mentioned ~ ~ process has the advantage that the~mixing of the active material ; with calcium phosphate is especallly intimate, from which results a favorably protracted liberation of the active mater-- ial in implantations, e.g., in bones.
~ The final shaping of the process components of this invention can be carried out according to all conventional processes o synthetic resin technology which permit the production of solid shaped parts under the action of pressure and/or heat. Very favorable is, e.g., the pressure technique in which pressures of 300-1200, preferably of about 600-750 --1'1--24~;~

bar are employed. In this method, the compositions are brought into the desired shape using negative molds of, e.g., metal.
Work-up is also possible according to the technically very advantageous injection molding process, with which numerous dlfferent shapes can be formed. Very suitable is also the extrusion process which, in contradisti~ction to the pre-viously mentioned processes, operates continuously~ Thereby can be obtained, e.g., strands, fibers, tubes, pipes and foils which can subsequently be divided up or comminuted in any desired manner. Another suitable process for shaping is the impact sinter process according to which the material to be shaped is briefly heated up and is sintered together by sudden application of pressure. The sintering frequently only takes place on the surface of the substance grains.
In this manner, the working up temperature~ are comparatively low and permit a substantial protection of the active material to be embedded. Other work-up techniques are also applicable, e.g., the "cold sintering together" by ultrasonics.
The compositions of this invention can be employed as active material depot or as surgical materlals, e.g., as bond material (alone or in conjunctlon with spongiosa) for bone breakages or shatterings. A content of calcium phosphate and especially of tricalcium phosphate can stimulate the bone growth and is, therefore, expedient even though not absolutely essential. A certain content of antibiotic is also ~avorable for the prevention of infections,e.g., of l-S wt.%. As shaped parts, small plates, spheres of various size and gran-ulates are preferred.

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The active material-containing compositions of this invention are also preferred as active material depot. If the active material is an antibiotic, then the composition is suitable, e.g., for the prophylaxis of infection in the case of contaminated, comparatively extensive soft tissue wounds or in the case of smashed zones of open bone breakages, such .
as frequently occur in the case of accidents. Infected wound cavities can be well closed off and filled up with these agents. It is thereby possible to apply active materials and especially antibiotics locally in depot form, i.e., directly at the infected or endangered places.
Advantageously, in the case of this embodiment, the composition of this invention generally needs only to be applied a single time since it is fully resorbed in the course of time. Therefore, it is no longer necessary to remove the implant after the healing of the woundO
A further field of use for the antibiotic-containing compositions of this invention is in bone surgery, especially the treatment of post-traumatic osteomyelitis. The new agent is very well suited - especially when contalning calcium phosphate and particularl~ tricalcium phosphate - for the filling up of osteomyelitic holes. Simultaneously with the gradual resorption of the implant of this invention, the newly forming tissue will be grown into it, whereby there results a healing process as in an aseptic medium.
The antibiotic-containing new agent is also suitable as an aseptic carrier for the transplantation of a patient's own spongiosa~ For this purpose, e.g., an antibiotic-con-taining granulate of this invention is introduced with the ,o patient's own spongiosa into the infected bone cavity. In ~Z~3 comparison with the conventional methods, this has the advantage that, because of the local presence of the anti-biotic, an infection will result less easily or to a lesser extent. Therefore, unlike the conventional mode, the implanta-tion need not be repeated one or more times. The loss of thespongiosa, which is only available to a limited extent, is thereby reduced.
In the case of an implantation, the wound cavity in the bone or in the tissue is carefully filled up with the composition of this invention and, in this way, closed off. A comparatively large piece of the composition of this invention can thereby be exactly adapted to the wound or, the cavity can be filled with smaller dimensioned particles or spheres. By suitable dimensionsing of the particles, an optimum filling can thereby be achieved. After application~of the antibiotic-containing agent of this invention, the purulent secretion in the treatment of osteomyelitis is overcome comparatively quickly.
With the composition of this invention, filled wound cavities no longer display any indications of inflammation after some time. Insofar as calcium phosphate is present, the resorption can thereby be easily controlled and monitored since the cal-cium phosphate particles can be easily recognized in an X-ray.
Apart from the antibiotic-containing compositions of this invention, those compositions are preferred in which anti-septics or inflammation inhibitors are present. In all of thesecases, for the use at specific locations of the body, relatively high active material concentrations can be achieved. This local action is, in many cases, desired and represents an especial advantage of this invention. Finally, the use of the active material-containing compositions of this invention takes place in about the same way as the use of the previously known products employed for the same purpose.

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. Without further elaboration, it is believed thatone skilled in the art can, using the preceding description, utiliæe the present invention to its fullest extent.
The following preferred specific embodiments are, therefore, to be construed as merely illustrativeO

In the following examples, all temperatures are set forth uncorrected in degrees Celsius; unless otherwise indicated, all parts and percentages are by weight.

EXAM2LE 1 (Tablets) A mixture of 475 g of finely ground collagen, 25 g of a copolymer of 80 mole % L-lactide and 20 mole % glycollde, with a reduced specific viscosity of 42 cm3/g and 10 g of gentamycin sulphate is well homogenized. The mixture is subsequently pressed in a heated press at 135C under a pressure of about 630 bar for one minute in a metal negative mold to produce tablets with a diameter of 1 cm and a height of 2 mm; each tablet contains 93 wt % of collagen, 5 wt %
of copolymer and about 2 wt % of gentamycin sulphate.
A sterilization, e.g., by gassing with ethylene oxide or irradiation, can optionally follow. The tablets ; can be employed for the prophylaxis of infection inthe case of soft tissue wounds or zones of destruction in the case of open bone breakages or also for the filling of osteomyelitic cavities.

EXAMPLE 2 (Tablets?

Analogously to Example 1, 425 g of collagen and 25 g of a copolymer of 80 mole % L-lactide and 20 mole %
glycolide, with a reduced specific viscosity of 42 cm3/g are worked up to a platelet (l x 3 x 0.5 cm). The platelet contains 95 wt % of collagen and 5 wt % of copolymer.

.
EXAMPLE 3 (Granulate) A mixture of 375 g of finely powdered collagen, 25 g of a copolymer of 70 mole % L-lactide and 30 mole %
glycolide, with a reduced specific viscosity of 53 cm3/g, lO0 g of finely powdered tricalcium phosphate and 10 g of gentamycin sulphate is well homogenized and subsequently shaped in a heated extrudex at a mass temperature of about 145C to give a strand of 1.5 mm diameter which is subse-quently chopped up into 1 mm lengths to give a granulate.
This contains 74 wt % of collagen, 5 wt % of the copolymer, 19 wt ~ of tricalcium phosphate and about l.9 wt % of gentamycin sulphate. The cylinder-shaped particles have a diameter of about 1 mm and a length of about 1.5 mm.
Sterilization is optional, analogously to Example 1.

E~AMPLE 4 (Platelets) . ~

25 g of a copolymer of 80 mole % L-lactide and 20 mole ~ glycolide, with a reduced specific viscosity of -1'3 42~

60 cm3/g is heated together with 10 g o gentamycin sulphate to 135 - 1~5C until an outwardly homogeneously appearing metal results. After cooling, the solidified melt is finely powdered and mixed with 475 g of collagen. This mixture is shaped into platelets with a size of 1 x 2.5 x 0.4 cm at a mass temperature of about 165C with an injection molding machine. The platelets contain 93 wt % of collagen, 5 wt ~ of the copolymer and about 1.9 wt % of gentamycin sulphate.
Sterilization can be performed analogously to Example 1.

EXAMPLE 5 (Spheroids) A mixture of 475 g of collagen, 25 g of a hydrolyzed water-soluble collagen (protein powder) with an average molecular weight of about 3000 and 10 g of gentamycin sul-phate is pressed analogously to Example 1, but at 86Cto give spheroids with a diameter of about 7 mm. The spheroids contain 93 wt % of collagen, 5 wt % of hydrolyzed collagen (protein powder) and 2 wt % of gentamycin sulphate.
Sterilization can be performed analogously to Example 1.

EXAMPLE 6 (Spheroids) A mixture of 25 g of a hydrolyzed water-soluble collagen (protein powder) with an average molecular weight - of about 3000, 10 g of gentamycin sulphate and 100 g of finely powdered tricalcium phosphate is pressed at about `

650 bar and ~0C for two minutes. The pressed material is subsequently ground and the resultant powder mixed up with 375 g of finely powdered collagen. The mixture is subse-quently pressed for 1 minute at about 650 bar and 85C
to give spheroids with a diameter of about 6 mm. The spheroids contain 74 wt % of collagen, 5 wt % of protein powder, about 19 wt ~ of tricalcium phosphate and about 1.9 wt % of gentamycin sulphate.
Sterilization can be performed analogously to Example 1.

EXAMPLE 7 tSpheroids) . . _ . .

A mixture of 475 g of finely ground collagen, 25 g of a copolymer of 90 mole % L-lactide and 10 mole % of glycolide with a reduced specific viscosity of 48 cm3/g, and 15 g of gentamycin sulphate is well homogenized. The powder obtained is sintered at 150C under a pr~ssure of about 600 bar for 2 minutes into the desired shape, pre-ferably spheroids o~ 7 - 10 mm diameter or rodlets of 1.5 cm length and 0.5 mm diameter. The shaped particles contain 20 92 wt % of collagen, about 5% of copolymer and 2.9%
of gentamycin sulphate.

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EXAMPLE 8 (Granulate) A mixture of 450 g of collagen, 50 g of a water-soluble protein powder with an average molecular weight of Z5 about 4000 (prepared by hydrolysis of collagen) and 80 mg of 9~-fluoro-16-methyleneprednisolone 21-acetate is shaped in a heated extruder at a mass temperature of about 80C
to a strand of 1 mm diameter which is subsequently chopped up in len~ths of 0.9 mm to give a granulate. This contains 89 wt~ of collagen, about 9.4 wt ~ of protein as binding agent and about 1.6 wt % of 9~-fluoro-16-methyleneprednisolone 21-acetate and can optionally be sterilized analogously to Example 1. The particle size is about 1 x 1 ~ 0.9 mm.

, EXAMPLE 9 (Powder) A mixture of 450 g of collagen, 50 g of a water-soluble protein powder (molecular weight about 3000, pre-pared by hydrolysis of collagen or elastin) and 120 mg of 9a~fluoro-16-methyleneprednisolone 21~acetate is shaped in a heated extruder at a mass temperature of about 80C
to give a strip of 1 cm breadth and 1 mm height and sub~
sequently comminuted by cutting and grinding. The product is ground, together with 50 g of maize starch and 50 g of talc, to a fine powder which, in to-tal, contains 72 wt %
of collagen, 8.2 wt % of protein binder, 2 wt % of 9a-fluoro-16-methyleneprednisolone 21-acetate, 8.2 wt % of maize starch and 9.2 wt % of talc.
Sterilization can be performed analogously -to . Example 1.

EXAMPLE 10 (Sterolds?

, A mixture of 450 g of collagen, 25 g of copolymer of glycine and alanine with a molecular weight of about -2~-~Z~33 3000 (50 mole % each of the monomers) and 100 mg of gentamycin sulphate is homogenized and pressed in a heated press at 195C under a pressure of about 700 bar ~or 1 minute in a negative mold of metal to give spheroids with a diameter of 3 mm. Each spheroid contains 93 wt % of collagen, 5 wt % of polyalanineglycine and about 2 wt % gentamycin sulphate.
Sterilization can be performed analogously to Example 1.

EXAMPLE 11 (Tablets, Impact Sintered) A mixture of 475 g of finely ground collagen, 25 g of a copolymer of 70 mole % L-lactide and 30 mole % glycolide, with a reduced specific viscosity of 80 cm3/g and 10 g of gentamycin sulphate is well homogenized. The mixture is subsequently briefly heated up in an impact sintereing device to 150C and sintered together by sudden pressing togehter. In the case of this procedure, the average temperature in the particles lies at about 50 - 60C.
It is cooled for about 10 seconds and possibly sterilized analogously to Example 1. Each tablet has a diameter of ; 6 mm and a height of 2.5 mm; it contains 93 wt % of collagen, 5 wt % of copolymer and about 2 wt % of gentamycin sulphate.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Claims (7)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A shaped mass resorbable in the body, comprising 75 - 99% by weight collagen and 1 - 25% by weight of a bioresorbable binding agent for collagen, the binding agent being selected from co- and homopolymers of lactide, glycolide, C2-16-.alpha.-hydroxyalkanoic acids, and of natural amino acids, hydrolyzed collagen or hydrolyzed elastin.

2. The resorbable mass of claim 1, further comprising a pharmacologically active material.

3. The resorbable mass of claim 1, further comprising calcium phosphate.

4. The resorbable mass of claim 1, comprising 1-25 wt.% of the binding agent based on the total amount of collagen and binding agent;
0.2-20 % by weight of the resorbable mass of the pharmacolo gically active material; and 0.1-40 % by weight of the resorbable mass of calcium phosphate.

5. The resorbable mass of claim 1, wherein the binding agent is a copolymer of lactide and glycolide containing 10-30 mole % of glycolic acid units or hydrolyzed collagen of a molecular weight of 2500-4000.

6. A process for shaping the resorbable mass of claim 1, which comprises working up collagen and a bioresorbable binding agent for collagen, selected from co- and homopolymers of lactide, glycolide, C2-16 -hydroxyalkanoic acids, and of natural amino acids, hydrolyzed collagen or hydrolyzed elastin, under the influence of pressure of 300-1200 bar and/or heat from a temperature of room temperature to 200° C.

7. A process for shaping the resorbable mass of claim 2, which comprises first melting, sintering or pressing the active material with the binding agent; comminuting the resultant product; subsequently. mixing it with collagen;
and shaping the resultant mixture under pressure of 300-1200 bar or heat from a temperature of room temperature to 200° C.