CA2108680A1 - Improved retard systems for the sustained release of medicinal and/or biological valuable materials from a depot carrier material - Google Patents

Abstract

IMPROVED RETARD SYSTEMS FOR THE SUSTAINED RELEASE
OF MEDICINAL AND/OR BIOLOGICAL VALUABLE MATERIALS
FROM A DEPOT CARRIER MATERIAL

Abstract of the Disclosure The invention, in a first embodiment, relates to the use of free radical-reactive cross-linker components based on olefinically unsaturated esters of lower hydroxycarboxylic acids and/or oligomers thereof for modifying depot materials, and especially retard systems, which contain medicinal and/or biological valuable materials in admixture with a carrier material in a sustained release of the active substance(s) in practical application. The cross-linkers are present as polymer compounds in the application form of the retard system and may be provided in the retard system or depot material to be applied in a largely homogeneous as well as in a non-uniform distribution.

The invention further relates to retard systems which contain medicinal and/or biological valuable materials and have been based on oligomer and/or polymer compounds of lower hydroxycarboxylic acids as carrier materials providing a sustained release of the active substance, the invention being characterized in that said retard systems and/or depot materials have been modified with polymer compounds prepared from olefinically unsaturated esters of lower hydroxycarb-oxylic acids and/or oligomers thereof.

Description

2108~8() GF

IMPROVED RETARD SYSTEMS FOR THE SUSTAINED RELEASE
OF MEDICINAL AND/OR BIOLOGICAL VALUABLE MATERIALS
FROM A DEPOT CARRIER MATERIAL

The invention relates to a continuation in the development in the field of sustained release systems of active substances, more particularly in the area of medicinal and/or biological valuable materials from a carrier material. Combination materials of this kind are the subject matters of numerous more recent investigations and printed publications - that is in both the fields of pharmaceutical auxiliary materials and of biological preparations, for exa~ple crop protection chemicals.
They are designated by terms such as retard systems, depot or 810w release materials, respectively, or quite generally as mixtures of active substances providing a sustained release of the valuable materials.

Depot materials of this kind usually consist of a carrier with or without any action by its own, in which the active sub-stance the release of which is to be sustained has been incor-porated. In the literature of the most;recent years particular attention has been given to polymer compounds based on poly-esters of lower hydroxycarboxylic acids as carrier materials, more specifically those having from 2 to 6 carbon atom~ in the hydroxycarboxylic acid molecule. Carrier materials of this klnd on their part are prone to undergo hydrolysi~ and are sub~ect to biological degradation mechanisms. Here the corre-~ponding polyesters derived from glycolic acid, lactic acid and/or hydroxyb~tyric acid and having a comparably restricted molecular weight may be of particular importance.
;

- 21~83 Among the more recent pertinent literature, reference may be made, for example, to U.S. Patent No. 4,011,312, which die-closes solid formulations of copolyesters of glycolic acid and lactic acids having molecular weights of below 2,000 as a carrier material in admixture with antibiotically active sub-stances such as tetracycline, neomycin and further antibiotics for the treatment of bovine mastitis at room temperature or body temperature. The preparation of lower molecular weight poly(~-hydroxybutyrate) and the use thereof as a solid carrier material for the formulation of matrix retard tablets contain-ing a pharmaceutically active substance has been described in ~Die angewandte makromolekulare Chemie" 161 (1988), 1-8 (No.
2604). Upon the investigation of the release kinetics it has been shown in the case presented here that the amount released of the active ingredient is highly dependent on the molecular weight of the PHB fraction, the retardation in the release of the active substance being increased with the decrease in the molecular weight.

Numerous investigations deal with the use of resorbable polyesters based on glycolic acid/lactic acid as a carrier material for the sustained release of the active substance when used in combination with medicinal valuable materials, crop protection agents and the like. Reference may be made, e.g., to D. L. Wiese et al. in: aDrug Carrier~ in Medicinea, Academic Press, London 1979, pp. 237-270, and to the literature quoted therein re retard forms of drugs; R.L. Xronenthal, Polym. Sci.
Technol. 1975, 8 (Polym. Med. Surg.), 119-137.

The manner of the release of the active substance is affected, on the one hand, by the interaction between the active substance and the carrier material while, on the other hand, it highly depends on the ~tructure and the properties of the usually polymeric carrier material. For example, the active ~ubstance may have been micro-encapsulated in the - 210868~

polyesters of the type mentioned, it may have been embedded in the polymer matrix, or it may be bonded to the terminal groups.

Thus, the release of the active ingredient proceeds via different mechanisms depending on the given kind of formula-tion. In the ca~e of encapsulated active substances the dif-fusion of the active substances through micropores in the enve-lope plays an important role. If the active substances are dispersed or dissolved in a solid polymer matrix, the release of the active ingredients is governed by the diffusion through the matrix or by the hydrolytic erosion of the matrix or by a combination of these parameters. Nevertheless, the considera-tions of the usability of such a depot system include delibera-tions on how the concerned substance mixture is to handle. The depot material should be storage-stable under normal conditions of storage, should be sufficier.tly solid and, thus, dispensable in portions, should not undergo clogging during the actual con-ditions of manufacture, transportation and storage, should exhibit a sufficient stability to an inevitable access of moisture and the like.

In consideration of these numerous demands which are difficult to reconcile with each other, it is not amazing that to date a use of retard systems and/or depot materials based on body-resorbable polyesters of lower hydroxycarboxylic acids have not been known in practice.

It is the ob~ect of the invention to advance the develop-ment of retard ey~tems and/or depot materials of the described type in ~uch a way that the final product to be put into use may be optimally adapted to the respective case of application.
The invention provides the elements described in detail herein-below for composing the depot material in a sense of a module sy~tem, which element~ then will provide a degree of freedom 80 far unknown for configuring the combination of properties 2~0868~

concretely required to be manifest in the final product in response to the respective actual profile of demands.

Sub~ect matter of the invention The invention, in a first embodiment, relates to the concomitant use of free radical-reactive components based on olefinically unsaturated esters of lower hydroxycarboxylic acids and/or oligomers thereof for modifying depot systems, and especially retard systems, which contain medicinal and/or biological valuable materials in admixture with a carrier material in a sustained release of the active substance(s) in practical application. Said reactive components are present as polymer compounds in the application form of the retard system and may be provided in the retard system or depot material to be applied in a largely homogeneous as well as in a non-uniform distribution.

Accordingly, the invention further relates to retard systems which contain medicinal and/or biological valuable materials and have been based on oligomer and/or polymer com-pounds of lower hydroxycarboxylic acids as carrier materials providing a sustained release of the active substance, the invention being characterized in that said retard systems and/or depot materials have been modified with polymer com-pounds prepared from olefinically unsaturated esters of lower hydroxycarboxylic acids and/or oligomers thereof. These olefinically unsaturated esters of lower hydroxycarboxylic acids and/or oligomers thereof which do form polymer compounds with~n the scope of the teaching of the invention will be designated, for the sake of simplicity, also as ~cross-linkers"
or ~cross-linker components~ within this description of the invention.

21~80 Details of the invention In the following, the system of the teaching according to the invention will be described by means of carrier/valuables mixtures which are designed to be used with humans and/or animals and contain antibiotically active substances - and more particularly so-called broad-epectrum antibiotics - in a carrier material which has been derived from lower hydroxy-carboxylic acids - especially from lactic and/or glycolic acids - and is resorbable by the body. The combination material which is described in detail by way of example hereinbelow i9 rendered tissue-compatible 80 that its incorporation in a living body will be possible. Said material is of particular importance as a retard system which releases an antibiotic with some retardation and sustains said release for a sufficiently long period upon implantation of the multi-component material described according to the invention into human or animal living tissue. Thus, this retard material within the scope of the invention is suitable for wound disinfection upon surgery as an auxiliary material which is resorbable by the body.
Thus, this material is capable of replacing all of the non-resorbable auxiliary means as conventional to date which, for example, ensure a sustained antibiotics release from solids inserted in the surgery region, but which in turn will have to be removed from the human or animal boay.

The illustration of the invention by way of the concrete example as decribed here does not imply any reetriction of the teaching according to the invention towarde this definite di-rection. ~y way of said example there are rather explained only the combinatory elements of acting according to the inven-t~on wh~ch, to the effect, are applicable to other fields of application in the same manner. Thus, more particularly, within the scope of the invention, there may be given any option with re~pect to the valuablee to be releaeed. For -- 21~80 example, important further valuable materials for implantation in the living organism include cytostatics, hormones, insulin, cortisone and the like. Adjustably high local concentrations of the active ingredient are attainable over an extended period of time with a simultaneou~ reduction in the total stress on the organism by embedding the respective depot material(s) in the region concerned by the disease or in any other freely chosen region.

The area of application of the retard systems according to the invention in the medical and/or veterinary field, however, is not limited to valuables-containing substance mixtures for a direct implantation into living tissue: The invention like-wise includes valuables-containing admixtures that are suitable for any topical administration to human or animal. ~he term "topical administration" is intended to comprise the applica-tion of valuable materials to mucosa regions as well as the so-called transdermal administration of valuable materials by applying the pertinent preparation to selected areas of the outer skin. In all of these cases the substance mixtures of the kind according to the invention are distinguished by the possibility of that the retarded release of valuable is ad-iustable. This, for example, allows the successful application of valuable materials to the living organism over a pre-deter-minable period of time at delivery concentrations which are also to a large degree freely pre-determinable. In any parti-cular case it will be necessary, of course, to examine and de-termine the interactions between the structural elements of the retard ~ystem within the scope of the teaching according to the invontion and the valuablos to be released therefrom, as well a~ tho interaction between the living body and the retard syetem at the site of application thereof. Nevertheless, the great freedom in the selection of the structural elements in composing the retard sy~tems defined according to the invention in cooperation with the comparably great freedom in combining - 2~ 08~8D

said structural elements provides new possibilite~ for the time-controlled release and application of virtually any optional valuable material.

More particularly, the teaching of the invention is suit-able for improvements in the field of the so-called bioadhesive preparations of active ingredients. These are known to be systems which exhibit an increased adhesive strength due to an interaction of functional groups or functional regions, re-spectively, on the surface of the administered active substanc-ce mixture with mucosa regions of the body with the participa-tion of body liquid and, thus, for example, possess an extended residence time in the gastrointestinal tract. As to the term of "bioadhesive preparations of substances", there i8 referred to, e.g., Herve Tournier et al., "New Bioadhesive Polymers for Topic Mucosal Dosage Forms", Proceed. Intern. Symp. Control.
Rel. Bioact. Mater. 15 (1988), Controlled Release Society, Inc., No. 237, pp. 418/419, and the literature quoted therein.

The teaching of the invention comprises a variety of con-crete substance mixtures, depending on the concrete realization of the retard system and the adjustment thereof to the parente-ral, enteral or other topical application. All of these dif-ferent substance mixtures, however, are governed by the uniform principles of the invention as discusse;d in detail hereinbelow.

The carrier material for the sustained release of the active ~ubstance(s) The preferred carrier materials within the scope of the teaching according to the invention are to be defined as oligomer and/or polymer compounds of hydroxycarboxylic acids having from 2 to 6 carbon atoms, among which the corresponding hydroxycarboxylic acids having from 2 to 4 carbon atoms are of particular importance. The respective compounds of glycolic 2~8680 acid and/or lactic acid are compounds of the kind concerned here, which are not only readily accessible on a commercial scale; the ~election and mutual adjustment of these components play an important role, due to the different stabilities there-of to hydrolytic influence. The term of the lactic acid deri-vatives includes the respective components of any steric con-figuration, i.e. D-, L- and/or DL-forms including the racema-tes. The period of the decomposition of the polymer compound under the hydrolytic action of metabolic sources is determined in a per se known manner by appropriately selecting the poly-ester-forming molecular module(s). Thus, polyglycolic acid i8 known to be decomposed by hydrolytic degradation within a few days, whereas the decomposition time of poly-DL-lactide may be within the range of from weeks up to some months.

In recent pertinent publications, accordingly, for polymer materials of the kind as concerned here crucial importance is attached to an adjustment of pre-determined degrees of poly-merization which, if possible, are uniform. Reference may be made, for example, to EP-A1-0 244 114 and to EP-A2-0 299 730.
Here it is attempted to put up with the multiform requirement profile of the depot material by the choice and adjustment of selected parameters of the polyester-based carrier material.

The teaching according to the i~vention, by way of the concomitant use of the above-defined cross-linker components -which will still be described in detail hereinbelow - as an integral constituent of the depot material, allows a largely freo variation of the carrier concerned here which has been derived from lower hydroxycarboxylic acids, especially lactic and/or glycolic acids. More specifically, when the bulk com-ponent of the carrier substance is to be selected, the teaching according to the invention, allows sa~d bulk component to be determined such as to effect an optimization of the 3ustained release of valuables under the respective conditions of appli-- 2108~8Q

cation. Further elements of the requirement profile of the depot material as demanded altogether are generated or satis-fied, respectively, in a manner still to be described by the cross-linker components as concomitantly used.
.

Thus, suitable carrier materials for the teaching of the invention quite generally are oligomers and/or polymers of lower hydroxycarboxylic acids having a tough-viscous to solid consistency at room temperature. More particularly, oligo-esters having average molecular weights within the range of from about 200 to 5,000 may be suitable, wherein preferred oligoester materials have average molecular weights within the range of from about 300 to 2,000.

In the course of the work which the invention has been based on it has surprisingly been shown that, in combination with antibiotics, release rates convenient in practice of the active substances can be achieved, when the bulk mass of the carrier substance is composed such as to have been based on 80-called bone waxes like those described in the printed publica-tions DE 32 29 540, D~ 37 16 302 and DE 38 25 211, the dis-closures of which printed publications re the nature of the tough-viscous to solid waxy polye~ter oligomers are in-corporated by reference in the present disclosure in the context of developing the carrier ;material providing a sustained release of the active substance.

DE 32 29 540 describes resorbable waxes for mechanically ~topping of the blood on endogenous hard tissue from said lower hydroxycarboxylic acids, more particularly the glycolic acid and/or the lactic acid. These waxes, due to their structures, are degradable by endogenous metabolic mechanisms, where the rate of degradation is controllable in a per se known manner.
Oligomera of glycolic acid are decomposed faster than those of lactic acid by the endogenous metabolism. The preferred waxes - 21~8~

exhibit average molecular weights within the range of from about 200 to 1,500, and more specifically within the range of from about 300 to 1,000.

For controlling the average molecular weight of said poly-ester oligomers it i~ proposed to concomitantly use mono-functional and/or polyfunctional alcohols or carboxylic acids.
Then an average molecular weight can be pre-determined in a per se known manner by choosing suitable mixing ratios of the oxy-carboxylic acid and the additional monofunctional and/or poly-functional component(s). The resulting reaction products still contain some amounts of the starting components employed.

DE 37 16 307 describes the advanced optimization of these waxy polyesters. Here, it has been described, more particular-ly, that quite a definite trifunctional alcohol, viz. glycerol, is employed for adjusting the average molecular weight. The combination of glycerol with oligoesters of lactic acid and/or of glycolic acid results in degradable wax-like components of the type mentioned, which when implanted into tissue of the living body are distinguished by a well pronounced compatibi-lity with the body. In order to exclude any undesirable tissue damage, a purification of the degradable wax may be provided to remove unreacted carboxyl groups.

The body-resorbable tough-viscous to solid waxes of the DE 38 25 211 which have been based on oligomers of glycolic acid and/or lactic acid, eventually, are distinguished by a content of body-compatible salts of organic and/or inorganic acid-, whlch ealts have beon formed by the reaction until completion of the free carboxyl groups possibly present in the oligomer wax and/or have been incorporated in the wax in a homogeneous distribution as added salts. Particularly suitable as admixed components are, more particularly, alkali metal, alkaline earth metal and/or aluminum salts, among which the 2las~

salts of sodium, calcium and/or magnesium are of particular importance.

In a preferred embodiment of the invention, oligomeric waxes of the range of comparably low molecular weights are employed as the carrier materials. Waxes of this kind exclusi-vely based on glycolic acid as the lower hydroxycarboxylic acid undergo a rapid decomposition 80 that only a comparably low period of the sustained release of the valuables can be assured. This may be deliberately utilized within the scope of the module principle according to the invention under some partial aspect: The incorporation in the retard system of such proportions of glycolic acid-based wax results in releases of valuables in controllable amounts in the initial phase of the period of action. Thus, in surgical practice it may be desirable to assure a local availability of a comparably high cocentration of antibiotics. The addition of adequate amounts of some rapidly decomposing glycolic acid wax filled with the pre-determined antibiotic would satisfy this need.

Then, however, a glycolic acid-based wax is no longer suitable for the release of an antibiotically active substance over an extended period of time - for example over the sub-sequent period of from two to four weeks - . Applicants' investigations have shown that quite;especially here lactic acid waxes having comparably low molecular weights are di-stinguished by providing the required profile of valuable-roloase. ~hus, lactic acid oligomers having average degrees of oligomerization of from about 6 to 20 lactic acid units pex molecule, and especially those comprising from about 8 to 15 lactic acid units per molecule, are particularly suitable for assuring a local uniform release of antibiotics for the period of from about 1 to 4 weeks after implantation into living tissue. For this application, appropriate lactic acid waxes can be prepared in a particularly simple manner by the - 210868~

concomitant use of, especially polyfunctional, alcohols within the ~cope of Applicants' cited German protective rights. Thus, the glycerol esters of lactic acid having an average of from 3 to 5 lactic acid units per oligoester moiety, which are especi-ally mild to the body, can be used with particular advantage.
As to a use of ethyleneglycol, the indications relating to the average molecular weights of the oligolactic acid moieties are to the effect applicable.

Investigations on the degradation behavior of oligoesters of the kind described here revealed that the respective lactic acid-based glycerol waxes may possess considerable resistance to the hydrolytic degradation so that the absorption thereof in the living organism may take substantially more time than the sustained release period of the pharmacologic valuable material. This fact is irrelevant to the usability of this carrier material within the objective according to the inven-tion. If in an individual case this retarded degradation of the carrier material based on lactic acid/glycerol is consider-ed to be detrimental, then opposite controls may be used by means of further determinative elements of the invention which are constituted, more specifically, by a binary mixture of glycolic acid-based and lactic acid-based proportions of wax and which will still be described hereinbelow.

The comparably low molecular weight waxes of the kind de-scribed here, and more particularly those lactic acid-based waxes, however, fail to comply with important further require-ments of the guality of such a depot material in as far as, more specifically, questions of handling, non-tackiness, storage stability and the like are concerned. This drawback inherent to said waxes is insignificant to the teaching accord-ing to the invention in its entirety. It will be compensated by the concomitant use of the previously defined cross-linker components in the way still to be explained hereinbelow.

- 210~

The contemplations set forth with re~pect to the selection and nature of certain preferred carrier materials for the immediate implantation into living tissue may be applicable also to listing retard systems for the enteral and/or other topical application. However, here the respective ranges of possible suitable representatives of the carrier material within the scope of the invention are reasonably enlarged.
This may be illustrated by way of the following example: Upon an oral application, the presence of free carboxyl groups in the carrier material is not only tolerable; for the mechanism of the bioadhesion, the interaction of the mucosal areas with functional carboxyl groups on the surface of the administered multicomponent mixture rather is a known and important mecha-nism leading to a sustained bonding of the applied multicompo-nent mixture to the respective mucosal areas. Thus, carboxy-methyl cellulose and/or poiymer or copolymer compounds of acrylic acid and/or methacrylic acid having free carboxyl groups are important known polymeric carriers for bioadhesive preparations of active substances of the kind as concerned here.

According to the invention, by way of appropriately designing the carrier material, this known mechanism for the mucosal interaction can be complied with by using monovalent and/or preferably polyvalent carboxyli;c acids for the regula-tion of the average degree of oligomerization of the hydroxy-carboxylic acid esters. Then, the resulting oligomer molecule i~ characterized by the presence of terminal carboxyl groups which upon the application in the finished product may enter into the bioadhesive interaction with the mucosal areas. Here, physiologically acceptable representatives are especially suit-able as the molecular weight-controlling carboxylic acid, among which the so-called edible acids are to be mentioned as example which are known to include the range of mono- and polyvalent carboxylic acids.

21~3~80 -Then, as to the question of the stability to hydrolytic degradation, the deliberations set forth above in the context of the selection of the defined hydroxycarboxylic acids for synthesizing the oligomeric carrier materials are to the effect applicable in the same manner.

The cross-linker components emploved accordina to the invention The components of active ingredients described as cros~-li~ker components in the following are free radical-reactive components which preferably are polyfunctional and can be reacted via olefinic double bonds to form polymer compounds.
In the ready-to-use depot material the reactive cross-linkers have been converted into the corresponding polymer compounds by polymerizztion and/or cross-linking and, in these forms, deter-mine important material properties of the depot material. They have particular importance inter alia for the sufficient con-solidation of the total composition which contains the carrier materials based on tough-viscous to waxlike oligomer compounds as the major component. Surprisingly it has been shown that soft waxes may be turned into sufficiently solid, non-tacky or even tack-free materials by already comparably low amounts of such reactive constituents. More specifically, an in situ curing of the reactive cross-linker components in admixture with the respectively selected wax-based carrier material will lead to combination materials which posse~s the whole spectrum of the demanded application-technological propertiee. Also here the modular working principle of the invention includes a plurality of concrete embodiments of the final product which will 8till be di~cussed hereinbelow.

The reactive cross-linkers provided according to the in-vcntion and/or the polymer compounds formed thereof by way of reaction are based on olefinically unsaturated esters of lower hydroxycarboxylic acids and/or oligomers thereof. In this 211~8~0 manner al~o here the degradation of the implanted polymer compounds and the resorption of also this material component can be assured.

Suitable for the use as cross-linker components, more particularly, are polyfunctional components of the reported kind which comprise more than one functional olefinic group in the molecule. Especially suitable are di- to tetrafunctional olefinically reactive hydroxycarboxylic acid derivatives which should be comprised of at least a substantial proportion of the cross-linker components.

Preferred cross-linkers within the teaching according to the invention are esters and/or oligoester6 of lower poly-functional alcohols or carboxylic acids with lactic acid and/or glycolic acid, which in addition have terminal olefinically un-saturated groups. Here again particularly suitable are cross-linker components derived from lower di- to tetrahydric alco-hols, and more specifically from ethyleneglycol and/or gly-cerol, which have been olefinically substituted in the terminal positions with acrylic acid and/or methacrylic acid moieties -designated as (meth)acrylic acid moieties within this descript-ion of the inventicn.

Reactive components of the kind mentioned here have been described in detail, for example, in DE-A1 32 04 504 and DE-Al 32 29 635. In these references, more specifically, there have been provided (meth)acrylate compounds having terminal (meth)acrylic acid moieties on an oligomer chain of hydroxy-carboxylic acids, said compounds being slow-evaporating and liquid to solid at room temperature, wherein the polyester oligomers have an average molecular weight within the range of from 200 to 600. The polyfunctional (meth)acrylic acid ester~
of this kind are intended to be u8ed as surgical binder systems for bonding endogenous hard tissue, if desired together with 2 1 ~

plastics and/or metal. Compounds of this kind are a suitable example for cross-linkers within the scope of activities according to the invention.

However, reactive cross-linker components are not limited to (meth)acrylic acid esters of the described kind. The intro-duction of reactive olefinic groups into an ester molecule con-cerned according to the invention may be effected in any optional per se known manner. Reference may be made here only by way of example to the known introduction of terminal olefin-ic groups into basic structures containing carboxyl groups.
Then, to the effect, the same considerations are applicable as those already set forth in the context of those carrier materials which in one preferred embodiment are oligomers terminated with hydroxyl groups, while they have been formed as corresponding carboxyl group-terminated compounds for certain intended uses - for example for bioadhesive materials - . One class of cross-linker components which are especially important for use in the living human and animal organism is constituted by the reaction products of glycerol esters of lactic acid and/or oligo-lactic acids modified with terminal (meth)acrylic acid moieties. Here, in addition to or in the place of lactic acid, also glycolic acid moieties may have been incorporated in the cross-linker molecule. In a preferred embodiment, these cross-linkers, as a random average,; contain at least two olefinically unsaturated terminal groups, among which cross-linker components which have been completely reacted with (meth)acrylic acid and/or the reactive derivatives thereof are a particularly interesting clas~ of cross-linker components with~n the teaching according to the invention. The3e cross-linkers comprising, a~ a random average, from 2 to 3 olefinic terminal groups per one mole of glycerol, in one important embodiment may contain from 3 to 12 moles of lactic acid moieties, and especially from 3 to 6 moles of lactic acid - - 21~68~

moieties, as a random average per one mole of glycerol. Re-active glycerol derivatives having a molar ratio of glycerol/lactic acid/(meth)acrylic acid of about 1/4/3 are highly effective cross-linker components, which when admixed in an amount of, for example, from 1 to 5~ by weight - relative to the weight of the non-reactive carrier material - are capable of reshaping a tough-viscous or soft waxy carrier in its physical nature 80 that it sati~fies the requirements according to the invention.

The following deliberations, more particularly, are relevant to retard systems to be implanted into the living body: Here the teaching according to the invention intends to provide material mixtures which with respect to all components thereof have been optimized to body compatibility. This de-liberation may be especially important with respect to the cro~s-linker components.

The cross-linkers are systems susceptible to undergo a re-action via free radicals. Such systems, in order to safely exclude an undesirable premature reaction, require the con-comitant use of radical inhibitors. More particularly, such radical inhibitors are also needed already in the preparation of the free radical-reactive systems - i.e., e.g., the poly-functional (meth)acrylate esters. It is just the high gelling tendency of the polyfunctional (meth)acrylic acid esters of the kind involved here that demands the use of highly efficient in-hibitors already in the production process. In accordance with one es8ential feature of the invention the concomitantly used cros8-linker components are free from inhibitors which as to kind and/or amount are undesirable and would be left from the production, storage and/or processing of the polyfunctional component8.

210~8i~

One particularly important example for a suitable in-hibitor within the activities according to the invention is constituted by tocopherol compounds and, among these, more specifically, a-tocopherol and, thus, vitamin E.

The use of physiologically compatible tocopherol com-pounds, and more specifically of vitamin E, as application inhibitor, but optionally also already as a preparation inhi-bitor, in connection with polyfunctional (meth)acrylic acid compounds is in detail the subject matter of Applicants~ older application DE 39 39 161, the disclosure of which older pro-tective right is hereby incorporated by reference in the dis-closure of this invention.

Within the scope of the teaching according to the invention, relevant to the cross-linker components may be also that part of the disclosure of the quoted older application DE 39 39 161 which describes the use of olefinically reactive (meth)acrylic acid esters which are free from solvents, and more epecifically of residual amounts of solvents left from the production. Accordingly, also according to the invention in the preferred embodiment, in the preparation of the cross-linker components there is a priori used no solvent, more specifically no physiologically questionable solvent. In this context reference is made at the same time to the disclosures of Applicants' printed publications DE-Al 38 43 854, 38 43 938, 38 43 930 and 38 43 843.

The mixing ratioe between the carrier material, on the one hand, and the cro~-linker components and/or the polymer compo-nente formed by the reaction thereof, on the other hand, may vary within wide limits. They are in detail governed by a plurality of parameters, among which t;he following may be men-tioned in particular: Nature of the carrier material, eepecially ite phy~ical nature at room temperature and at the 2108~80 application temperature, profile of requirements set for the quality and nature of the depot material upon storage and application, reactivity and individual nature of the cross-linker componentg and/or of the polymer components formed by the reaction thereof, as well as the profile of requirements set for the final material in view of the intended use. More particularly, as to the last item it will be readily conspi-cuous that materials to be implanted into a living organism to release pharmaceutical compositions will have to meet re-quirements different from those set for a depot material to be used for the sustained release of biologically active substan-ces, for example, in the agricultural sector. As far as the mixing ratios are concerned of the non-reactive carrier material, on the one hand, and the reactive carrier components, on the other hand, in general there will be applicable that the cross-linker components will comprise not more than half of the entire system. In a preferred embodiment distinctly lower amounts of cross-linker components will be used. More specifically, the modifying and at least partially reacted cross-linker components may be present in the mixture in pro-portions of from about 0.5 to 40% by weight, and preferably in proportions of from about 1 to 10% by weight - ~ by weight here relative to the sum of carrier material and cross-linker compo-nents. For a use of the retard systems according to the in-vention in the medicinal sector, and especially for the implan-tation into the living tissue, proportions of the cross-linker components of at most about 10% by weight may be preferred. As ha8 already been mentioned, here good results are obtained with mixing ratios of up to 5% by weight, and especially by using mixtures containing from about 2 to 5% by weight of cross-linker components. This is more particularly applicable to the uso of compounds exhibiting a comparably high cross-linking activity, for example those of the kind of the three-functional (meth)acrylic acid esters of the hydroxyl-terminated glyce-rol/lactic acid esters or oligoesters.

- 21~868~

The various embodiments of the ~etard svstems It is difficult to safely predict the release behavior of retard systems - which fact has already been adverted to in the introduction - because a variety interaction parameters will affect the ultimate activity of the system. It is a particular advantage of the teaching according to the invention that it provides the chance to effect an optimization towards the profile of requirements set for the individual case by means of varying the concrete embodiment of the system. This will be understood from the following contemplations:

The major portion or at least an essential portion of the depot material is usually comprised of the carrier material as described hereinbefore. The time-control of the release mecha-nism can be influenced by means of the selection of the com-ponents forming the oligomer and/or polymer components and the release characteristics dependent thereon. This is applicable already to uniform types of compounds definitely selected and composed with respect to the constitution thereof. A further modification ensues from the use of carrier materials having an at least binary composition combining different wax or resin types. For example, here oligomer and/or polymer compounds adapted to undergo a comparably fast degradation, on the one hand, are used in combination with compounds, on the other hand, that are subject to a slower degradation. A further option of exerting influence is provided by the definite manner of how to mix such different components of the carrier ma-terial. It cover~ the whole range from homogeneous mixtures through types of mixtures which combine delimited sectors of a matorial having a pre-solected definite composition with cor-responding sectors of a material having a different composition and, hence, a different degradation ~ehavior. The form pre-sented here, for example, may control a porosity being formed in practical uee, i.e. the permeability of a block compri~ing - 21~80 carrier material composition to a permeation of body liquid and/or permeation of cell growth. Eventually, also a layer-like arrangement of the various components of the carrier material may be taken into consideration to form a primarily continuous material block which in practical u~e would comply with definite characteristic requirements, due to the different degradation rates of the individual layered blocks.

The modifications outlined here which are due to the re-spective modification of the carrier material are substantially extended by the concomitant use according to the invention of the cross-linker components. Applicable are, to the effect, the indications given above also to the substance mixtures com-posed of carrier material and cross-linker components. Thus, in one embodiment carrier material and cross-linker components - together with the valuable materials - may be present as a largely homogeneous mixture. Nevertheless it is also possible that the cross-linker components and/or the polymer compounds resulting therefrom are present, for example, in a layerwise arrangement in the retard system so that, at least to a large extent, regions free from cross-linkers of the valuable-carrier mixture are interspersed and/or enclosed by regions occupied by material comprising reacted cross-linker components. Cross-linker components need not be combined with all of the carrier material0. Thus, for example, as rel;ease-retarding carriers there may be especially suitable those types of lactic acid oligomers which are in a tough-viscous state at room and/or application temperature and are interspersed with cross-linker component~ within the scope of the invention and are fixed such ae to be dimensionally stable, for example for the reason of ~mproved handling. Combination materials of this kind may then be mixed with further carrier materials - for example tho0e based on type0 of polymers having higher molecular weight0 or the glycolic acid oligomers and/or polymer~ which anyway are obtained in the solid 0tate.

- 2103~81~

The pos~ibilities as enumerated here elucidate the follow-ing: Due to the cross-linker components and the possibility provided thereby of influencing the nature of the material of those regions of the depot material which are determined by the cross-linker components and/or the polymer compound~ produced thereby, it is possible for the first time, more particularly, to put into the intended use that region of comparably low molecular weight carrier materials of the type here concerned of hydroxycarboxylic acid oligomers; in many cases it is just these carrier materials having comparably low molecular weights which in many cases exhibit the desirable retarded release characteristics. ~indrances to the regenerative cell growth can be reliably excluded by that the individual regions of the respective carrier materials - for example those based on lactic acid - are kept small. The depot material etabilized according to the invention may be introduced as a finely granular matter or even as a powder into the tissue regions concerned, or it may be employed in topical application forms;
however, it is as well possible to fix larger three-dimensional forms, for example in the shape of plates, rod~, spheres or in any other optional three-dimensional form in the living tissue and, due to the concrete decay characteristics of such an enlarged volume unit in the living organism, with certainty to exclude undesirable delays of the regenerating cell growth.

Curing of ~he ç~Qss-linker components In conjunction with just the contemplations as discussed last re the po~ible variety of the depot materials to be de~igned according to the invention, it will be intelligible that there is also a multiplicity of possible approaches for converting the cro~s-linker components defined accord~ng to the invention into their polymer compound~-. Thereby it ie pos~ible to realize an adaption to the particular circumstance~ and to reliably attain the main object of providing a depot material - 21 ~3~80 which in practical use makes the valuable materials available in intact conditions.

Investigations conducted by Applicants have shown that in an obviously broad range of concrete carrier/valuables mixtures it is possible to admix cross-linker components to form a homo-geneous mixture and to allow an in situ reaction without there-by inducing a substantial damage or deterioration to the va-luable material. In this simplest embodiment of the materials according to the invention the modifying polymer compounds have then been prepared in situ from the radical-reactive cross-linker components in admixture with at least one portion of the depot material based on carrier/valuable material. Thus, mixtures of active materials of glycerol/lactic acid-based oligomers as carrier material and aminoglycoside antibiotics may be prepared by melting the carrier material at comparably low temperatures and suitably introducing the valuables to form a homogeneous mixture. For example, temperatures of below or at least within the range of about 70 C are in fact sufficient for melting said carrier materials. Within the same temperatu-re range, low amounts, for example from 1 to 5%, and especially from 2 to 4% by weight, of cross-linker components based on glycerol/lactic acid/(meth)acrylic acid can be admixed to form a homogeneous mixture. The in situ cross-linking of the cross-linker components is successfully accomplished by means of a free radical-initiated reaction, whereby the corresponding polymer compounds are formed which then are crucially involved in determining the ultimate phenotype of the depot material de~igned to relea~e pharmaceutical compositions. For example, ~haped articles may be produced which are largely tack-free in the dry state and may be ~ubjected to further comminution, if ~o desired.

If it appear~ that there may be some danger of inter-action~ to take place between the particular valuable material .`- 2103~

and the cros~-linker component~ employed according to the invention that would cause the characteristic of the valuable material to be impaired, then the principle accordin~ to the invention nevertheless may be applied without efforts: In euch a case, the carrier/valuables mixtures are converted into some predetermined particulate form and then provided with an envelope containing cross-linker components within the scope of definition according to the invention. Here again mixtures of carrier material and cross-linker components can be employed which, however, now are free from valuables within the envelope region. The carrier material used in thi~ case may be the same as or different from the carrier material used in the interior region for the valuable to be released. In the subsequent curing step there cannot take place any substantial interaction of the cross-linker components with the valuable material em-bedded in the core. The two embodiments presented here are just to be understood as examples. They may be employed separately from each other or also in combination with each other, with further concrete embodiments being derivable for the concrete design of a particular depot material, to the effect, from the numerous possible combinations as described hereinabove.

In one preferred embodiment for the teaching according to the invention the initiation of the reaction can be performed under conditions which exclude any physiologically undesirable components from being introduced into the ultimate product.
Hereto, reference i8 made to the indications set forth in the Applicant~' older German Patent Application P 40 37 516, the pertinent disclosure ie hereby incorporated by reference in the disclosure of the present invention.

In ~aid older Application P 40 37 516 there have been de8cribed degradable high-strength materials and shaped articles for the implantation into human and animal organisms, 21~3~8~

which material~ have been composed of cured (meth)acrylic acid esters of polyfunctionally hydroxy-terminated oligomers of lower hydroxycarboxylic acids. They are characterized in that, inter alia, they are substantially free from reaction aids and/or other additives resulting from the production (con-taminants of the active sub~tances) which are undesirable with respect to kind and/or amount, since here, more particularly within the production procedure, there has been effected an adjustment - with respect to kind and amount - between the inhibitors of the polyfunctional (meth)acrylic acid esters and the initiators and/or starter systems, respectively, as option-ally used for cross-linking same. Curing is to be effected either by radiation curing - especially using W radiation - or by using starter systems which have substantially been based on body-compatible components or have at least been restricted as to kind and amount so that the residual matter released upon the degradation does not give rise to any physiological problems.

Within the scope of radiation curing there may also be taken into consideration, in addition to curing by W light as already mentioned, the use of any other reaction-inducing types of radiation, among which, for example, laser beams, X-ray or y-rays may be mentioned. Any concomitant use of per se known initiators is possible; in this context;, reference is made, for example, to the printed published indications in Encyl. Polym.
Sci. and Eng. (2nd edition~, Volume 11, 187-207, and pertinent commercial products, available, e.g., from the companies Merck, Darmstadt (DE), and Ciba-Geigy (Switzerland).

According to the invention, what is especially possible is also curing the reactive material in a per Be known manner by a chemically induced free radical-initiated polymerization. If here known auxiliary agents are intended to be employed, the following may serve to facilitate the selection of reaction - 21~3~80 aids: In prior art there is known a multiplicity of redox systems based on peroxidic compounds which are used in combina-tion with reducing agents and/or metal compounds of such metals that may occur in several valency states. In thi~ context reference is made, for example, to the survey presented in PROGRESS IN POLYMER SCIENCE, Vol. 8, Pergamon Press, Oxford-New York, 1982, pp. 61-131, and the voluminous primary literature referred to therein.

In the selection of suitable redox systems which do not give rise to any substantial physiological doubts with respect to kind and amount of the residual materials remaining in the reacted material, the following state of facts is particularly beneficial for the activities within the scope of the inven-tion. Reactant systems which physiologically are comparably safe, have been described in prior art especially in connection with aqueous polymerization systems. The material to be cross-linked according to the invention is per se an anhydrous system. However, due to its oligomeric structure derived from lower hydroxycarboxylic acids, the solubility ratio i9 fre-quently assured within the scope of the invention also for those compounds which are otherwise employed in the aqueous systems. Thus, it will be possible to accomplish a really homogeneous distribution of physiologically largely acceptable activator systems also in the anhydro~s reaction phase of the polyfunctional (meth)acrylic acid esters or of the admixtures thereof with the carrier materials, 80 that then cross-linking can be effected at the pre-determined temperatures.

It i~ only by way of example that from the broad class of suitable components for such redox systems the following may ne mentioned here: Peroxide compounds such as peracids, diacyl peroxides, hydroperoxides and the like; among which physiologi-cally compatible acids, for example so-called edible acids, may be of particular importance as the peroxide-forming constitu-- 21~68~

ent. From the broad class of the activators or reducing agents, compounds offering themselves are compounds such as ascorbic acids, sorbose, fructo~e, dextrose or other sugars, all of which throughout are physiologically acceptable com-ponents.

Metal compounds which are suitable for stimulating and/or activating the redox system are derived, more ~pecifically, from iron which in a per se known manner may be added to the redox systems in the form of di- and/or trivalent iron. The successful formation of a homogeneous iron-containing mixture is especially safely effected, for example, by using the corre-sponding salts of glycolic acid and/or of lactic acid.

As has already been reported and will also be conspicuous, the variety of possible embodiments for the retard systems within the scope of the invention ensures an almost unlimited applicabilty of the carrier/cross-linker system to the broad range of interesting valuable materials of medicinal and generally biological activity. Not only the active substances themselves, but also the application forms thereof can be varied within wide limits. It is only by way of an example that this again may be illustrated by mixtures containing valuable materials which exhibit antibiotic action: The depot material designed to release pharmace~tical compositions, for example, may be placed into the tissue regions susceptible to become infected - for example laid thereinto - and then en-cloeed. However, on the other hand it i8 also possible to apply the depot material onto open wound areas, for example wounds caused by burns or the like, and then to leave it there-on and/or to remove it at least partially and to replace it by new pharmaceutical depot material in the course of a dreeeing change.

210~

The concentrations of the valuable materials in the pharmacological depot material may vary within wide limits.
The dominant idea for the substance mixtures important in practice is the adjustment of the desired time-retarded release of the active substance. The valuable material will in general not amount to more than 40 to 45~ by weight of the retard system in its entirety. For the important sector of medicinal valuables to be applied to the human and to the animal body, valuables concentrations of from about 20 to 25% by weight and preferably of from about 10 to 15% by weight will rarely be exceeded. Highly active valuables, such as the antibiotically active substance~, cytostatics, hormones and the like will generally be used in amounts of from about 0.1 to 10~ by weight, and especially in amounts of from about 1 to 8% by weight, in the pharmaceutic release materials.

The valuable materials in general will be charged in an intimate admixture with at least a portion of the carrier material employed, in order to achieve an optimum control of the release of the valuable material. Moreover, the consider-ations set forth above are applicable as relating to the possible inhomogeneous distribution of the active material in the particular unit of the retard system. The application forms of these retard systems within the teaching according to the invention range from a powdery nature to three-dimensional bodies shaped ad libi tum. The amount of the retard systems applied which quantitatively is readily detectable and the predetermined amount of the valuable, relative to unit volume or weight of said retard system, allow the quantified admini-~tration of the valuable materials present in the depot material.

The utilization of the teaching according to the invention in connection with adminietration forms lese critical than that of a direct implantation into the living tis~ue allows the con-21~68~

comitant use of conventional galenic auxiliary materials and/orthe formulation of the retard ~ystems according to the inven-tion into administration forms as common in practice. This may be illustrated again by way of an example as follows: Pharma-ceutic depot materials produced according to the invention as finely divided particulates may have been formulated into tablets, suppositories, ointments and the like and, when in such form, may be introduced into the body or applied onto the body ~urface. Said galenic auxiliary materials in turn may contain non-retarded portions of pharmaceutics which will display immediate activity upon the introduction or applica-tion, which will subsequently be followed by the time-retarded period of action of the retarded release of the active substan-ce.

In other cases, per se known auxiliary materials can be included in the use, thereby in a controlled manner to provide or enhance effects which are also characteristic of the sub-stance properties concretely adjusted within the scope of the invention. This may be exemplified by way of preparations of bioadhesive valuable materials: The covalent bond from the surface of the multi-substance mixture within the scope of the teaching according to the invention to the surface of the mucosa and, hence, the effect of the bioadhesion, is directly caused by functional groups (carboxyl; groups and/or hydroxyl groups) within the carrier material accordins to the invention.
This effect may be further enhanced by concomitantly using known mucosa-adhesive materials as fillers in the multi-~ub~tance mixturo. Suitable materials that have been well-proven in practice are, for example, in addition to carboxy-methyl celluloses and (meth)acrylic acid polymers and/or co-polymer~, respectively, alginates, hydroxyalkylcelluloses, gelatin, pectins, polyvinylpyrrolidone, solid polyethylene-glycols and the like. In this respect, there may be referred, for example, to the following additional references from the ~8680 literature: J.D. Smart et al., ~An in-vitro investigation of mucosa-adhegive materials for use in controlled drug delivery", J. Pharm. Pharmacol. 1984, 36, 295-299; as well as Kinam Park et al., "Bioadhesive polymers a~ platforms for oral-controlled drug delivery: method to study bioadhesion", International Journal of Pharmaceutics 19 (1984), 102-127.

The proportions of amounts of such concomitantly used auxiliary materials may vary within wide ranges and, in the concrete galenic embodiment, may also comprise a multiple of the substance mixture~ within the scope of the definition according to the invention. Then, however, what always is essential for such preparations is that a non-insignificant section of the activity in practical use is governed by the substance combination defined according to the invention.

2~Qs6sa E X A M P L E S

Example 1 1. Preparation and description of the resorbable waxes a. Waxes, produced from glycolic acid/glycerol General procedure for preparinq the reaction ~roducts of alYcolic acid with glycerol A three-neck flask equipped with stirrer, Claisen head and condenser (ndistillation bridgen) is charged with glycolic acid and glycerol. The mixture is completely put under an inert nitrogen gas atmosphere and heated at 150 C, and the reaction is continued for 3 to 5 hours until no further water of reaction is eliminated. Then the flask is cautiously evacuated at 150 C to 10 torr.
After two more hours at these reaction conditions, the mixture is cooled to 100 C and brought to atmospheric pressure, is neutralized as described above, and the product is dispensed while hot.

The compositions of the batches and the properties of the oligomers are shown in Table ~.

- 2~Q~68~

Table 1 Oligohydroxycarboxylic acids from glycolic acid and glycerol Example I A I B
Startina materials:
Glycolic acid (moles) 8 9 Glycerol (moles) 1 1 Yield: Water of reaction (%) 100 99,1 Consistency at room temperature turbid, turbid, highly highly viscous viscous after neutralizationturbid, turbid, highly highly viscous viscous Viscosity at 100 C
MK-D at 20 rpm (mPa-s) 5,000 10,000 after neutralization 5,000 10,000 Degree of stringyness (cm to the break) 2 2 after neutralization 7 7 b. Waxes, produced from lactide and 'glycerol General procedure for preparina the reaction products of lacitd with glycerol Lactide {L(-)-lactide N from the company Bohringer, Ingelheim} and glycerol were heated with stirring at 195 C in a conventional laboratory apparatus. The reaction was allowed to proceed at 195 C for 3 hours, and after neutralization the product was dispensed while hot.

6 ~ ~

A solution of Sn(II) chloride in ether had been added as a catalyst (7 ml of a solution of 2.5 g of SnCl2 in l,ooo ml of ether in the reaction of 3 mole~ of lactide with 1 mole of glycerol).

The compositions and the properties of the oligomers are shown in Table 2.

Table 2 Oligohydroxycarboxylic acids from glycerol and lactide Example ¦ C ¦ D
.
Starting materials:
Glycerol (moles) 1 Lactide (moles) 5 6 : Consistency at room temperature clear, clear, viscous viscous after neutralization turbid, turbid, highly highly viscous viscous Viscosity at 100 C
MR-D at 20 rpm (mPa-s) 8,000 10,000 after neutralization 10,000 10,000 Degree of stringyness (cm to the break) about 60 about 50 after neutralization 30 30 2~98~80 2. Preparation of the reactive cross-linker component 2.1 Pre~aration of the glycolic acid/ethylene glycol 4:1 oligomer A 25 1 test reactor was charged with 16.72 kg of glycolic acid and 3.41 kg of ethylene glycol. The cryetal pulp was melted in an inert atmosphere under a nitrogen stream and then further heated to a maximum temperature of 145 C to 150 C (bottoms temperature). After the re-action had started with distillation of water, it was continued for 11 hours until no more reaction water was formed (drop in the vapor temperature to 70 C to 73 C at a conversion of 70~). The aqueous solution obtained upon distillation was analyzed for the quantity of distillate, the acid value (glycolic acid contents) and the water contents by the Rarl Fischer method. In order to lead the reaction to completion, the mixture was carefully evacua-ted to 400 Torr, and the pressure was further reduced to 10 Torr within 2 hours and maintained at this level for 1 hour, in order to remove the residual water of reaction for accomplishing a quantitative conversion.

The additional amount of condensate was collected for quantification in a cold trap (~ooled with dry ice and ethanol). After the total period of reaction, the mixture was cooled to 100 C and re-pressurized to atmospheric pres~ure with nitrogen, and the product was dispen~ed while still hot. The product was directly used for the preparation of oligo-glycolic acid bis-methacrylate without further purification.

2~Q~sa 2.2 Yield and mass balance Amount of Di~tillate 4 222.8 g Glycolic acid (from acid value = 46): 263.58 g - 263.6 g Ethylene glycol determined by HPLC
Amount of water (by the Karl Fischer method) 91.6% in the di~tillate = 3 868.1 g - 97.7% conver~ion.

Analytical result~ of the oliqomer Designation Immediately 1 Month old 1 Year old after the preparation _ Batch size kg 20 4.5 2 Con~istency pastou~ pastous pastous Viscosity at room temperature mPa-s 12,500 13,000 12,800 (Epprecht Vl~cosimeter MK4) Molecular weight M ~ 438 455 454 Free glycolic acid t 2.1 1.4 1.9 Free ethylene glycol t 0.2 0.2 0.2 Saponification value 765.4 754.4 754.0 Behavior in water pH after 2 minutes 3.8 ; 3.8 3.8 i~ pH after 60 nlDutes 3.4 3.4 3.4 Porox~de contentnegatl~e Analytlcal composltloD
of the product glycollc acld/ethyl~ne glycol 3.975:13.972:1 3.972:1 Detormlnatlon of the molecular weight a~ GPC analysi~. Slnce the c l~bsatloD ~a~ effectod with polyethylene glycol as standard, the d~ffereDce betweeD Mn:iD theory and MD a~ found 1~ due to the callbr~tloD method.

21Q~80 2.3 Oliaoalvcolic acid bis-methacr~late Commercially available methacrylic acid tcompany Roehm) i9 newly inhibited with vitamin E according to the following procedure:

In a vacuum distillation apparatus, 15 moles ~-1,291.35 g) of methacrylic acid (b.p. 163 C) are admix-ed with ~.87 g ~= 3,000 ppm) of phenothiazine (as stabi-lizer); the methacrylic acid was distilled off under a strong stream of air in a water-jet vacuum. 100 ppm of vitamin E (Covitol F-1000-2, 67%, Henkel KGaA) ~= 139 mg/l) are placed in the receiver, and the meth-acrylic acid i8 distilled with stirring. The distilla-tion is stopped, once 932 g of the methacrylic acid have been collected after distillation.

2.4 Course of the reaction A three-neck flask equipped with stirrer, Claisen head and condenser (ndistillation bridgen) was charged with 294 g of oligoglycolic acid, 206.4 g methacrylic acid and 17.5 g of p-toluenesulfonic acid; the mixture was inhibited with 0.86 g of vitamin E (a-tocopherol).
Throughout the reaction, air was pas~ed through the mixture at a rate of at least 40 l/h.

The esterification was effected at a maximum tem-perature of 105 C by removal of the water formed, until the quantity of water removed was more than 35.78 g (more than 97% conversion).

The distillation receiver was cooled with a dry - ice/ethanol mixture throughout the reaction. At a maximum bottoms temporature of 105 C and a pressure of :`

2108~8 ~

500 mbar the esterification time was between 12 and 14.5 hours at a total conversion of from 97 to 98.5~.
The aqueous solution (as recovered from the receiver and cold trap) was sampled every 1.5 hours and was analyzed for the quantity of distillate, the acid value (meth-acrylic acid contents) and the water contents by the Karl Fischer method.

The water content and the amount of methacrylic acid as entrained in the distillation were calculated from the differences; after each determination, it was checked whether enough methacrylic acid was still avail-able for the reaction. In most cases, additional 0.1 moles of methacrylic acid had to be replenished after about 7.5 or 8 hours.

Upon completion of the reaction (conversion in ex-cess of 97%) the product was dispensed for purification.

2.S Work-up of the reaction product In the end of the reaction period, the product is not quite free from acid. Therefore, it was neutralized with Ca(OH)2. Since in the determination of the acid value, due to the water required;for the determination, the product underwent hydrolysis and a continuously increasing amount of acid was released by this reaction, it wa~ not po~ible to determine the acid content by titration.

Therefore, the acid value had to be theoretically calculated.

The amount of Ca(OH)2 calculated to be required for neutralization was introduced into the warm reaction 210~6~

product and the mixture was treated with stirring at 105 C for 30 minutes, while 40 l/h of air under 500 mbar (gauge) were passed therethrough.

The neutralized product (highly viscous at 100 C
to 105 C) i8 filtered by means of a pressurized nutsch filter and a Loeffler filter (80 NM012) at from 100 C
to 105 C under 3 bar.

Then, the product - while still hot - was once more filtered under otherwise the same conditions through a round filter (NNG 16, medium filtering speed).

~xample 2 Preparation of mixturec com~risinq resorbable waxes and reactive cross-linkers and the reaction thereof The reactive cross-linker (monomer in accordance with Example 1.2) is mixed with alternatively either of the two waxes according to Example l.la based on glycolic acid or according to Example l.lb based on lactic acid. The proper-ties of the mixtures are set forth in the Tables 3 through 6.
For the preparation of the polymerizates, the mixtures were exposed to the radiation from a W ~ight source (Dr. Honle GmbH; W ASpot 400/T; 400 W, 200/230 V) for 5 hours.

In tho following Tables, "GS~ refers to glycolic acid, ~nd ~EG~ refers to ethyleneglycol. The substance mixtures ~et forth in Tables 3 and 4 were reacted under W light with-out addition of a stabilizer. In contrast thereto, the sub-etance mixtures set forth in Tables 5 and 6 were reacted with the addition of a W sensitizer (cf. the indications in the headline of Table 5).

21~3~ ~

Table 3 Properties of mixtures comprising wax (glycolic acid/glycerol 9:1) and cross-linker {oligoester (GS/EG 4:1) bis-methacryla-te} before and after reaction. Curing under W light without sensitizer.

No. Mlxlng ratio Propertles of tho Properties of the mixture uncured mixture after the reaction Wax Cross-~ linker 2.1 982 white waxy mass, waxy deformable white slightly tacky elastic material, _ slightly tacky 2.2 973 white waxy mass, waxy deformable white slightly tacky elastic material, _ slightly tacky _.
2.3 95s white waxy mass, waxy deformable white almost tack-free elastic material, _ almost tack-free 2.4 90 10 light-beige waxy mass, waxy deformable light beige almost tack-free elastlc material, almost tack-free 2.s 8020 miscible white waxy material, _ tack-free : 2.6 6040 miscible white hard brittle material, tack-free 2.7 4060 miscible glassy hard material, slightly turbid 2.8 2080 n~Jclblo glassy hard matorial, . slightly turbid 24lO~680 Table 4 Properties of mixtures comprising wax (lactide/glycerol 6:1) and cross-linker (oligoester (GS/EG 4:1) bis-methacrylate}
before and after reaction. Curing under W light without sensitizer.

No. Mixing ratio Properties of the Properties of the mixture _ uncured mixture after the reaction Wax Cro~-~ linker 2.9 98 2 tacky tough elastic, ~omewhat tacky highly stringy glass-clear product glass-clear mass 2.10 97 3 tacky tough ela~tic, virtually tack-highly stringy free glass-clear product glass-clear mass 2.11 95 S tacky tough highly slightly brittle elastic stringy light- ~lightly turbid colorless beige clear mass material 2.12 94 6 _ ~uyb ~Lghl~ somewhat brittle elastic stringy light- slightly turbid colorless beige clear mass material 2.13 90 10 tacky tough highly hard brittle tack-free stringy light- light-beige turbid material yellow clear mass 2.14 80 20 tacky highly stringy hard brittle tack-free light-yellow slightly beige turbld raterial 2.15 60 40 slightly tacky readily hard brittle tack-free fluid slightly stringy beige turbid material gold-colored turbid 2.16 40 60 mlscible, llguid hard brlttle tack-free light-brown turbld material 2.17 20 80 mi~clble, llquld hard brlttle tack-free l l llght-brown turbld material 210~80 Table 5 Properties of mixtures comprising wax (lactide/glycerol 6:1) and cross-linker {oligoester (GS/EG 4:1) bis-methacrylate) before and after reaction. Curing under W light with sensitizer - 4-(2-acryloyloxyethoxy)phenyl-(2-hydroxy-2-propyl)ketone (Company Merck) (4%, relative to the total composition).

No. Nixing ratio Properties of the Irradiation time, uncured mixture properties of the mixture Wax Cross- after the reaction (W
% linker curing) 2.18 98 2 tacky tough highly 5 minutes; somewhat tacky stringy glass-clear light-yellow clear material mass -n n tacky tough highly 15 minutes; deformable stringy glass-clear somewhat tacky light-yellow mans lear material n ~ tacky tough highly 1 hour; readily deformable stringy glass-elear lmost tackfree yellow mass clear material n tacky tough highly 5 hours; elastic somewhat stringy glass-clear rittle tackfree golden-mass yellow elear material 2.19 97 3 tacky tough highly 5 minute~; deformable some-stringy glass-clear what tacky light-yellow mass clear matorial .. ,. taeky tough highly is minute~; deformable stringy glass-elear somewhat tacky llght-yellow mass clear materlal taeky tough highly 1 hour; roadlly deformable ~trlngy glass-elear almo~t taekfree yellow ma~ elear material taeky tough hlghly S hours; somewhat elastie striDgy glass-clear brittle tackfree golden-ma~ yellow elear materlal _ _ ~

210~680 Table 6 Properties of mixtures comprising wax (lactide/glycerol 6:1) and cross-linker {oligoester (GS/EG 4:1) bis-methacrylate~
before and after reaction. Curing under W light with sensitizer - (~ame as in Table 5).

No. Mixing ratio Properties of the Irradiation time, _ uncured mixture properties of the mixture Wax cross- after the reaction ~W
t linker curing) 2.20 96 4 tacky tough highly 5 minutes; deformable some-stringy glass-clear what tacky light-yellow mass clear material n ~ tacky tough highly 15 minutes; deformable stringy glass-51ear somewhat tacky light-yellow mass clear material tacky tough highly 1 hour; readily deformable stringy glass-clear almo~t tackfree yellow ; mass clear material n ~ tacky tough highly 5 hours; slightly elastic stringy glass-clear brittle tackfree golden-mas8 yellow clear material 2.21 95 5 tacky tough highly 5 minutes; deformable some-stringy glass-clear what tacky light-yellow mass clear material tacky tough highly 15 minutes; deformable stringy glass-clear somewhat tacky light-yellow mass clear material tacky tough highly 1 hour; slightly deformable stringy glass-clear almost tackfree yellow mass clear material taeky tough highly 5 hour~; ~lightly elastie tringy gla-s-clear brittlo taekfree golde~-_ ma~- yellow elear material - 21~80 Example 3 -Samples of depot material according to the invention loaded with valuable material(s) according to the indications set forth hereinbelow are prepared, which samples are used for the determination of the release of the valuable material in an experimental model in series experiments.

As the valuable materials there are employed various commercially available antibiotics which are first incorpor-ated in the carrier to form a homogeneous mixture. Then the cross-linker is added into the mixture, and the multi-component mixture as a material layer of about 1 to 2 mm in thickness applied onto a Teflon film is exposed to W light for several hours.

Under the working conditions employed (no sensitizer added; cooled W lamp 500 W, irradiation time 10 hours, temperature of the multi-component mixture 28 C) there is obtained a material the surface of which is not yet tack-free. If so desired, the mass is after-cured with an un-cooled W lamp until tack-free (15 hours; temperature 80 C).

The following details are applicable:

Carrier material: Condensation product of lactide/glycerol in a molar ratio of 6/1 Cro88-linker: Oligo(glycolic acid/ethyleneglycol 4:1) bis-methacrylate Valuable materials: The antibiotic active substances avail-able under the following tradonames Gentamycinsulfat~, Chloramphenicol~ and Tetracyclin~.

- 2108~3 Mixing ratios of valuables/carrier:
5% by weight and 0.1~ by weight Amount of cross-linker, relative to the valuables/carrier mixture: 3~ by weight The depot materials containing the valuable materials are prepared as follows: The oligolactic acid-based carrier material i8 intimately mixed with the finely divided antibio-tic in the re~pective predetermined amounts, optionally with 81ightly warming the carrier material. At a temperature of S0 C, the cross-linker component is introduced 80 that a homogeneous mixture is formed. The composition i8 spread over a Teflon film to form a layer of from 1 to 2 mm in thickness and then subjected to W curing.

Determination of the retard effect Glass plates coated with nutrient agar were inoculated over a large area and uniformly with the test bacteria em-ployed. The material samples to be tested were brought into contact with the substrate. After two days of incubation, the inhibitory zones formed around the respective material sample to be tested were measured by determining the distance between the sample substance contain;ing the antibiotic and the outer borderline of the inhibitory zone. Then the anti-biotic-containing material samples are subjected to stepwise leaching in running tap water. After completion of each washing stage the inhibitory zones still to be formed are determined on freshly inoculated nutrient agar plates. This operation i8 repeated in a number of steps until no inhibi-tory zone~ are detectable any more around the tested material samples.

Staphylococcus aureus (ATCC 6538) and Escherichia coli (AT~C 11229) were used as the test bacteria.

The operation of leaching with water is carried out as follow~: The material to be leached is placed between to synthetic sponges. Then, using a hand shower, a uniform water flow is formed through the sponge. If required, the material samples are wrapped in a permeable thin fabric in order to exclude any material losses due to possible breakage in the course of the leaching operation.

For a better evaluation of the retard effect of the depot materials providing a sustained release of the active substance according to the invention the leaching behavior of a commercially available retard antibiotic preparation used in clinical practice is tested, in a parallel procedure under identical working conditions. The material employed here i9 sold by the Company Merck, Darmstadt, under the tradename of "Septopal~-lOer-Minikette. Said material of prior art is a methyl methacrylate-methyl acrylate copolymer which has been admixed with 5~ by weight of gentamycin sulfate. This poly-mer carrier is not body-resorbable. After a surgical im-plantation, said material will have to be completely removed - usually after 5 to 7 days - or even after a period of from about 1 to 3 month(s), if necessary by;surgery.

3.1 Test aerm emDloyed: Staphylococcus aureus In a test series including 6 ~teps a retard material having the composition a~ ~et forth in the beginning of Example 3 and containing 5~ by weight of gentamycin is sub-~ected to leaching for altogether 19 days. The inhibitory zones to be formed around the re~pective tested mater~al 8ample are determined in the beginning of the test and 21~80 between the individual leaching steps in the above-described manner.

The long-term behavior of the "Septopal2" element is te~ted in parallel and under absolutely identical conditions.

Leaching is carried out in the following sequential steps interrupted by the determination of the inhibitory zones:
1st step 4 days 2nd step 4 days 3rd step 3 days 4th step 2 days 5th step 3 days 6th step 3 days The size of the observed inhibitory zones (in mm) i~
summarized in the following Table 7:

Table 7 .
Depot material of n septopal~ n Example 3 Inhibitory zone (mm)12 - 15 12 - 15 1st step 8 ' 8 - 10 2nd step 5 - 7 5 - 10 3rd step 6 - 8 7 - 9 4th ~tep 5 7 5th step 6 - 8 6 - 8 6th ~tep _ 2 - 3 In a comparable inve~tigation the depot material of the above-do~cribed compo~ition according to the invention i~

21~8~
-^47 -admixed with gentamycin sulfate in a concentration of 1% by weight and i9 then subjected to stepwise leaching in the same manner. The inhibitory zones determined with the fresh material and after the re~pective steps are as follows:

Fresh material 7 - lO mm Days of water leaching let step 4 5 mm 2nd step 4 1 - 2 mm 3rd step 3 3 - 5 mm 4th step 2 O mm 3.2 Comparable investigations are carried out with depot materials according to the invention which contained the following valuable materials, each in a concentration of 0.1%
by weight of the antibiotic: Gentamycin sulfate, erythro- V
mycin, tetracyclin and chloramphenicol.

The leaching steps were carried out in periods of one day each, between which the size of the inhibitory zone as still observable is determined.

The blank value for the inhibitory zone (test germ:
Staph. aureus) is about 5 to 6 mm for all of the material 8ample8 employed. The activity of the gentamycin sulfate depot material remains virtually unchanged until the third day of water leaching; then an approximately linear decrease of the size of the inhibitory zone is observed, reaching zero in the end of the 7th day of leaching. Approximately com-parable is the course of the plot of the inhibitory zone size over the time for the retard material containing erythro-2108~0 mycin. Here, however, the zero value is reached only after the end of the 8th day of leaching. Within the periods of leaching steps 5 to 7 the inhibitory zone values are improved over those of the preparation containing gentamycin ~ulfate.

The retard preparation containing tetracyclin shows hardly any reduction in activity after the first leaching step; then, however, a rapid activity 1089 occurs. The pre-paration containing chloramphenicol shows an activity 1088 to less than 50% of the initial value already in the end of the 1st day of water leaching.

If, however, now the concentration of the active ingredient is increased to 5~ by weight and an oligomer based on glycerol/glycolic acid/lactic acid in a molar ratio of 1/2/10 is employed, then the blank value of the inhibitory zone produced by the tetracyclin-containing preparation (42 mm) is just comparably insignificantly decreased by about 10 units (31 mm) within a period of 8 days of water leaching.
Somewhat higher within said period is the activity 1088 of the material samples containing, on the one hand, gentamycin sulfate and, on the other hand, erythromycin as the antibio-tic. Nevertheless, also here an antibiotic activity of more than 50~ of the blank value is retained.

Corresponding investigations carried out on nutrient substrates with E. co~i as the test germ confirm the retard effect in the release of the antibiotic substances within the meaning of the teaching according to the invention.

Claims (21)

C L A I M S :

1. Retard systems which contain medicinal and/or biological valuable materials and have been based on oligomer and/or polymer compounds of lower hydroxy-carboxylic acids as carrier materials providing a sustained release of the active substance, characterized in that said retard systems and/or depot materials have been modified with polymer compounds prepared from olefinically unsaturated esters of lower hydroxy-carboxylic acids and/or oligomers thereof (cross-linker components).

2. The retard systems according to claim 1, characterized in that they at least portionwise contain polymers of olefinically polyfunctional cross-linker components of the type indicated as modifying agents, wherein di- to tetrafunctional olefinically reactive hydroxycarboxylic acid derivatives may be preferred.

3. The retard system according to claims 1 and 2, characterized in that they contain oligomer and/or polymer compounds of hydroxycarboxylic acids having from 2 to 6 carbon atoms, and preferably from 2 to 4 carbon atoms, and especially such compounds of lactic acid and/or glycolic acid as carrier materials providing a sustained release of the active substance, wherein the preferred cross-linker components are reactive deriva-tives of hydroxycarboxylic acids of the ranges of numbers of carbon atoms as indicated and especially those derived from lactic acid and/or glycolic acid.

4. The retard systems according to claims 1 to 3, characterized in that they are suitable for use in and/or on the human and/or animal organism and, more specifically have been provided for implantation into the living organism and/or for topical administration.

5. The retard systems according to claims 1 to 4, characterized in that the cross-linker components at least portionwise are esters and/or oligoesters of lower polyfunctional alcohols or carboxylic acids with lactic acid and/or glycolic acid and have terminal olefinically unsaturated groups, wherein preferred cross-linker components are derived from lower di- to tetrahydric alcohols, and more specifically from ethyleneglycol and/or glycerol, and have been olefinically substituted with (meth)acrylic acid moieties.

6. The retard systems according to claims 1 to 5, characterized in that the cross-linker components thereof are reaction products of glycerol esters of lactic acid and/or its oligomers and (meth)acrylic acid and/or reactive derivatives thereof which, as a random average, comprise from 2 to 3 olefinic terminal groups per one mole of glycerol.

7. The retard systems according to claims 1 to 6, characterized in that they contain oligomers and/or polymers of the lower hydroxycarboxylic acids having a tough-viscous to solid nature at room temperature as carrier materials providing a sustained release of the active substance, wherein for the range of use for implantation into the living organism it is preferred also here that esters of lower functional alcohols, and especially of ethyleneglycol and/or glycerol, are present as the oligomer compounds, whereas for the range of use of a topical application also oligomer compounds having terminal carboxyl groups can be employed at least portionwise in the carrier material.

8. The retard systems according to claims 1 to 7, characterized in that oligoesters having average molecu-lar weights within the range of from about 200 to 5,000, and preferably of from about 300 to 2,000, are present as carrier materials providing a sustained release of the active substance, wherein glycerol/oligo-lactic acid esters having average molecular weights within the range of from about 200 to 1,500, and more specifically within the range of from about 300 to 1,000, can be especially preferred.

9. The retard systems according to claims 1 to 8, characterized in that they contain the modifying and at least partially reacted cross-linker components in minor amounts - relative to the weight of the carrier materials providing a sustained release of the active substance - , wherein mixing ratios of from about 0.5 to 40% by weight, and preferably of from about 1 to 20% by weight of cross-linker - % by weight here relative to the sum of carrier material and cross-linker compo-nents - may be preferred and, more particularly, the content of cross-linker components is less than about 10% by weight.

10. The retard systems according to claims 1 to 9, characterized in that the carrier material and the poly-meric cross-linker components are present in the retard system in combination with the valuable materials either in a largely homogeneous admixture and/or, for example, in a layered arrangement such that regions which are at least largely free from cross-linker of the valuab-les/carrier mixtures are enclosed by material regions having a content of reacted cross-linker components.

11. The retard systems according to claims 1 to 10, characterized in that the carrier material has an at least bimodal structural nature and thereby combines oligo- and/or polyesters having a comparably high decay rate under the conditions of use, especially in the living organism, with oligo- and/or polyesters having a slower decay rate, wherein the material portions of high decay rate are preferably derived from glycolic acid, and the material portions of slower decay rate are pre-ferably derived from lactic acid.

12. The retard systems according to claims 1 to 11, characterized in that they contain at least largely homogeneous admixtures of oligomers and/or polymers derived from lactic acid and those derived from glycolic acid as the carrier material, wherein also multiphase admixtures of discrete material regions of the indi-vidual components of the carrier material may be present.

13. The retard systems according to claims 1 to 12, characterized in that - especially in the case of multi-phase mixtures of the carrier material- also the poly-meric cross-linker components may be present in the retard system in the multiphase state according to con-figuration, kind and/or amount.

14. The retard systems according to claims 1 to 13, characterized in that they contain components having medicament activity as valuable materials, and especial-ly antibiotics, cytostatics, cortisone and/or hormones and thereby, more particularly, have been designed for implantation into the living organism, or contain active substances from the area of crop protection and/or plant growth promotion as valuable material.

15. Use of cross-linker components which are reactive via free radicals, said components having been based on olefinically unsaturated esters of lower hydroxycarb-oxylic acids and/or oligomers thereof, for modifying depot materials, and especially retard systems, which contain medicinal and/or biological valuable materials in admixture with a carrier material in a sustained release of the active substance(s) in practical appli-cation.

16. The embodiment according to claim 15, characterized in that in the application form of the retard system the cross-linkers are present as polymer compounds and therein have been arranged in a largely homogeneous or also non-uniform distribution in the retard system to be applied.

17. The embodiment according to claims 15 and 16, characterized in that the modifying polymer compounds have been prepared in situ from the free radical-reactive cross-linker components in admixture with at least a proportion of the depot material.

18. The embodiment according to claims 15 to 17, characterized in that polyfunctional cross-linker com-ponents are employed which have been derived from lactic acid and/or glycolic acid esters, said components con-taining at least portionwise from 2 to 4, and preferably at least 2 and/or 3, olefinic groups in the molecule.

19. The embodiment according to claims 15 to 18, characterized in that polyfunctional (meth)acrylic acid esters of hydroxy-terminated reaction products from the reaction of lower polyfunctional alcohols, and especial-ly ethyleneglycol and/or glycerol, with lactic acid and/or acid or glycolic acid are used as the cross-linker components.

20. The embodiment according to claims 15 to 19, characterized in that either the cross-linker components are admixed into the carrier/valuables mixture and are allowed to react therein, and/or that a carrier/valuab-les mixture is enclosed by a material layer containing reacted curing components.

21. The embodiment according to claims 15 to 20, characterized in that body-compatible oligomers and/or polymers of lower hydroxycarboxylic acids, especially those based on lactic acid and/or glycolic acid, are present as carrier material, which components preferably have average molecular weights within the range of from about 200 to 5,000, and especially of from about 300 to 2,000.