CA1282330C

CA1282330C - Drug depot containing cytostatics

Info

Publication number: CA1282330C
Application number: CA000506775A
Authority: CA
Inventors: Helmut Wahlig; Elvira Dingeldein
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1985-04-18
Filing date: 1986-04-16
Publication date: 1991-04-02
Anticipated expiration: 2008-04-02
Also published as: EP0202445A3; HU198383B; US4797282A; DE3513938A1; ES8801988A1; AU5465686A; JPS61243015A; IE861018L; AU587432B2; ATE60904T1; ZA862947B; EP0202445A2; ES554090A0; EP0202445B1; IE57523B1; HUT44170A; DE3677545D1

Abstract

ABSTRACT

The Application relates to a drug depot, which can be implanted in the body, for the controlled, delayed release of cytostatics, characterized in that a synthetic material based on polyacrylates and/or polymethacrylates contains a cytostatic and at least one amino acid. The depot can be used in a particularly advantageous manner for the local control of tumours.

Description

Drug deDot conta;n;ng cytostat;cs The ;nvent;on relates to a drug depot, which can be ;mplanted ;n the body, for the controlled, delayed release of cytostat;cs.
Large numbers of mater;als wh;ch can be implanted ;n the body and contain cytostat;cs are known. The basic mater;als wh;ch have been mentioned are both organic poly-mers such as, for example, polyglycolides, polylactides, s;l;cone rubber, polycarboxylic acids, collagen or gela-t;ne, and inorgan;c mater;als such as, for example, sin-tered or compressed tr;calc;um phosphate.
The mater;als wh;ch have hitherto been proposed are ;ntended for del;very in the preformed shape and for ;mplantation at a su;table s;te by a surgeon. As a rule~
these mater;als have no funct;on other than the task of act;ng as an active compound depot. Ho~ever, 1n many cases, such as, for example, in the management of bone defects, the implant also has to assume supporting or load-bear;ng functions. Thus, for example, when on removal of 2û parts of bone w;th mal;gnant affections the stability of the rema;n;ng bone is no longer guaranteed, or when in the management of a defect a prosthes;s has to be implanted.
In these cases, it is additionally essential to be able to adapt the material optimally to the defect.
Thus, there was a need for a material which can be supplied both in the preformed shape and ;n a form which perm;ts the surgeon to adapt the material optimally to the local circumstances, and which is capable of carry;n~ out supporting and load-bearing functions and wh;ch, further-3û more, also releases the incoroorated cytostatic in effec-tive amounts in a reliably reProducible manner.
T`n;s ohject has been achieved by the ~resent ;nven-t;on. Thus, it has been found that a synthet;c mater;al ' ` ~ "
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~L~8~330 based on polyacrylates and/or polymethacrylates, which is known per se as a bone cement, is also suitable as a base material for an active compound depot containing a cyto-static and, moreover, meets all the requirements in respect of stability and shaping but is also capable of releasing the cytostatic in effective amounts when an amino acid is admixed to the base material, especially when the amino acid is used in a specific particle size.
Thus the invention relates to a drug depot, which can be implanted in the body, for the controlled, delayed release of cytostatics, which is characterized in that a synthetic material based on polyacrylates and/or polymeth-acrylates contains a cytostatic and at least one amino acid.
The invention also relates to a precursor for the preparation of a drug depot of this type, which contains about 50 to 75% by weight of a finely divided polymer of acrylic and/or methacryl;c esters, which can optionally contain further additives such as, for example, X-ray con-trast media, pigments and catalysts, and contains 1 to 15%
by weight of an amino acid, 0.1 to 4% by weight of a cyto-static, and 20 to 45% by weight of an acrylic and/or meth-acrylic ester monomer which optionally contains further additives such as, for example, stabilizers and polymeriza-tion accelerators.
The invention furthermore relates to a process for the preparation of a drug depot of this type, which is characterized in that about 50 to 75 parts by weight of a finely divided polymer of acrylic and/or methacrylic esters, wh;ch can optionally contain further addit;ves such as, for example, X-ray contrast media, pigments and cata-lysts, and 1 to 15 parts by weight of an amino acid, 0.1 to 4 parts by weight of a cytostatic, and 20 to 45 parts by weight of an acrylic and/or methacrylic ester monomer which optionally contains further additives such as, ,or example, stabilizers and polymerization accelerators are mixed to form a semi-solid paste, and the latter is c~n-verted into a des;red shape and allowed to harden b~ aol~-merizati~n and crossl nkin~, .~ ,, , :

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, .. ': , ' ' , : . , ~a'2330 Finally, the invention also relates to the use of a drug depot of this type for controlling tumours.
The synthetic materials based on polyacrylates and/
or polymethacrylates, which are used as starting materials for the preparation of the drug depot according to the invention, are known per se. An example of one which is very useful is a bone cement which contains in a standard pack 2 bags each containing about 40 9 of powder and 2 ampoules each containing 20 ml of liquid. The powder is a fine bead polymer of methyl methacrylate with a methyl acry-late contribution to copolymerise.
About 0.5% dibenzoyl peroxide is added to the powder as catalyst. During the preparation, traces of chlorophyll are polymerized in to identify the material. The powder can optionally also contain, for example, zirconium dioxide as X-ray contrast medium. The relevant liquid consists of monomeric methyl methacrylate, to whirh have been added about 0.7~ dimethyl-p-toluidine as polymerization accelera-tor, and traces of hydroquinone as stabilizer. This liquid is also, as a rule, coloured with traces of chlorophyll for identification. The powder packed in the polyethylene bag is sterilized with ethylene oxide. The liquid is steri-lized by filtration and dispensed into glass ampoules.
When two parts by weight of powder are mixed with one part by weight of liquid, the dibenzoyl peroxide reacts with the dimethyl-p-toluidine in the liquid, by which means the radical polymer;zation is initiated. The mixture is balanced so that it can be used as a doughy paste after only about one minute. This paste remains kneadable for several minutes ancl then starts to harden, with evolution of heat. The polymerization is essentially complete after about 5 to 10 minutes. During the polymerization, as long as the paste can still be moulded it can be converted into any desired shape, that is to say, for example, introduced directly into the body for filling bone cavities or for cementing in prostheses, or used for the preparation of moulded articles which harden outside the body and then c3n be inserted at any desired point in the body.

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a According to the invention, a cytostatic is added to this base material. This cytostatic can be admixed as a finely divided powder to the other constituents, that is to say to the prepolymer and the monomer, and thus be homo-S geneously distributed in the resulting polymer. However,it is also possible for it to be incorporated in the pre-polymer even during its preparation.
Large numbers of cytostatics are known and, in principle, all can be used for the purpose according to the 1û invention, as long as they are compatible with the other constituents of the depot and are not decomposecl by the heat being produced during the polymerization of the material. However, it is preferable to use adriamycin, 5-fluorouracil and methotrexate, very good results being ach;eved with methotrexate in particular.
The cytostatic is used in effective amounts, which may differ depending on the active compound used. As a rule, the amount incorporated is such that the concentra-tion resulting in the drug depot is about 0.1 to 4% by weight. Especially with methotrexate, preferred concen-trations are 0.2 to 2% by weight and, in particular, 0.4 to 1% by weight.
It is essential for reliable release of the active compound that additionally an amino acid is homogenrously incorporated, relatively large amounts of about 1 to 15%
by weight being necrssary to promote the desired release of the active compound. Preferably about 2 to 10% by weight are used, and in particular about 3 to 8% by weight are used. In principle, all natural amino acids which are compatible with the base material and physiologically tolerated are suitable, particularly suitable being mono-basic amino acids with molecular weights of about 75 to 200, such as, for example, glycine, alanine, histidine, leucine, threonine and arginine.
Arginine is particularly preferably used.
It is especially surprising that it has emerged that not only the amount of the amino acid but 3lso i ~5 par-~icle si7e exerts an effect on the rele3s? o; t~e cytostatic.

~LZB2~313 Thus, it has been found that particle sizes of, in particu-lar, < 125 ~m bring about an advantageous~y uniform and reproducible release. It is possible to use for this pur-pose the cbmmercially available materials from which particles with diameters above 125 ~m have been removed.
Attention should be drawn at this point to the fact that the characterization of a particle by the particle size or the diameter is, strictly speaking, only possible with isometric particles, that is to say which have the same measurements in all three dimensions (spherical in the ideal case). And this is the case with the commercially available material, for example the arginine obtained from E. Merck under Catalogue No. 1542~ However, it has been found, surprisingly, that the good results achieved with a material of this type can be improved further by a modifi-cation of the shape of the amino acid particles. Thus, a further marked improvement in the release can be achieved by micronization of the particles, the material obtained being in the form of rods and consisting, according to particle analysis by air-jet screening, of at least 95% by weight of particles < S0 ~m.
The release of the active compound is improved to an even greater extent by freeze-drying of the amino acid.
This results, in the case of arginine, in needle-shaped particles which have a ratio of the smallest to the largest dimension of about 1 to 2 to 1 to 20. The length of these particles can be a multiple of 100 lum, but the thickness is markedly less than 50 lum as a rule.
It is clear from the examples that an additional improvement in the release of active compound can be achieved by the amino acid particles being reduced in size and/or converted into a shape which substantially differs from the spherical shape. The notional "diameter" of a particle of this type, for example in the form of a needle or rod, is to be understood to be that of a spherical particle of the same volume. Thus, within the meaning of this definition, a particle in the shaPe of a rod having a length of about 533 lum and a thickness of about 50 ~m like-, ~ z~33~
--6wise has a "diameter" of about 125 ~um. Particularly pre-ferred particles have a "diameter" below 50 lum and the shape of a rod or needle.
The admixture of the amino acid to the base mater-ial is carried out in analogy to that of the cytostatic, it also being possible, where appropriate, previously to mix the amino acid and cytostatic or to incorporate the amino acid in the prepolymer.
Although the drug depot according to the invention is primarily used for controlling tumours, it may neverthe-less be advantageous to include in the drug depo~ other additional active compounds acting in other directions, in particular antibiotics and/or antiseptics to control or prevent infections at the site of implantation. Anti-biotics should, where possible, be active against bothGram-positive and Gram-negative pathogens and should induce in the pathogens either no or only delayed resistance.
Examples which may be mentioned as suitable are aminoglyco-side antibiotics such as amikacin, butirosin, dideoxykana-mycin B (DKP), fortimycin, gentamycin, kanamycin, livido-mycin, neomycin, netilmicin, ribostamycin, sagamycins, seldomycins and their epimers, sisomicin, sorbistin, tobra-mycin, streptomycins, linkomycins such as clindamycin, lincomycin and rifamycins such as rifampicin and rifamycin.
ZS Examples of suitable antiseptics are bromchlorophen, hexetidine, buclosamide, salicylic acid, cerium nitrate, chlorhexidine, 5-chlorc,-8-hydroxyquinoline, copper 8-hydroxyquinolate, acridine orange, undecenoic acid, un-decoylium chloride, silver salts such as silver sulfadi-azine, mafenide, nitrofurazole, cloflucarban, tribromsalan,taurolin and noxythiolin. It is also possible to admix these additional active compounds, whose nature and amount depend on the desired additional action, to the other materials in a manner customary per se, preferably in the form of a finely divided powder, it again being possible, where appropriate, previously to mix them with other indi-vidual constituents or to incorporate them in the pre POlymer.

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As already mentioned, the drug depot according to the invention can be made available completely polymerized and thus in a predetermined shape. This will be the case in particular when, for example, the only function to be carried out is as a local source of active compound when used in soft tissues. For this purpose, the depot can be prepared in any desired form such as, for example, as granules, as cube, sphere or ellipsoid, as film, sheet, pin, tube or another form adapted to the particular use.
However, as a rule the surgeon will be provided with the material according to the invention as the pre-cursor so that moulding does not take place until implan-tation, and thus the drug depot can be adapted optimally to the local circumstances and the material can also be used like a conventional bone cement for the implantation of prostheses.
For this purpose, the constituents are packed ready for use, in analogy to the known bone cements described above, in such a manner that the amounts of the solids and the liquid (of the monomer) present ;n a pack are balanced with respect to one another. It is then possible, in a straightforward manner, to prepare the drug depot from this precursor by mixing the components, the polymerization of the monomer being initiated by the catalyst which is included ;n the solid component, and the hardened final product being obtained after a reaction time of a few minutes. In the intervening time, during which the mater-ial ;s plastically deformable, it can be introduced into the body and, at the same time, moulded.

Example 1 39.2 9 of a sterile, fine bead polymer, consisting of a copolymer of methyl acrylate and methyl methacrylate which additionally contains 0.5% dibenzoyl peroxide and traces of chlorophyll, are mixed with 0.8 9 of L-arginine (substantially isometric particles of a size < 125 umj 3nd 0.5 9 of methotrexate, and are packed sterile, toget~er with an ampoule containing Z0 ml of methyl methacryi3te with the addition of aoout 0.7" dimetiryi-p-tolui~ine 3ri -: , , ' ' ': ~ ` ~ ,,, ', ~ .' .

33~3 about 0.006% hydroquinone (monomer liquid), to form a unit ready for use.
The process in the following examples is analogous, the following amounts of the starting materials being used:

Example 2 38.0 9 of bead polymer, 2.0 9 of L-arginine, 0.5 g of methotrexate and 20.0 ml of monomer liquid Example 3 37.0 9 of bead polymer, 3.0 9 of L-arginine, 0.5 9 of methotrexate and 20.0 ml of monomer liquid Example 4 36.0 9 of bead polymer, 4.0 9 of L-arginine, 0.5 9 of methotrexate and 20.0 ml of monomer liquid Example S
34.0 g of bead polymer, 6.0 9 of L-arginine, 0.5 9 of methotrexate and 20.0 ml of monomer liquid Example 6 37.0 9 of bead polymer, 3.0 9 of L-arginine, 0.1 9 of methotrexate and 20.0 ml of monomer liquid Example 7 37.0 g of bead polymer, 3.0 9 of L-arginine, 0.25 9 of methotrexate and 20.0 ml of monomer liquid Examples 8 to 14 The process is analogous to that of Examples 1 to 7, the arginine being used in a micronized form~ with a particle dlameter below 50 ~m.

Examples 15 to 21 The process ;s analogous to that of Examples l to 7, the arginine being used in the freeze-dried form (needles) with a partlcle diametar be~w 125 Im.

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Examples 22 to 42 The process is analogous to that of Examples 1 to 7, in each case L-hist;d;ne, L-leuc;ne or L-threon;ne be;ng used ;n place of arg;nine.

Examples ~3 to 49 The process ;s analogous to that of Examples 1 to 7, 0.5 9 of gentamycin add;t;onally be;ng adm;xed to the sol;ds.

Examples 50 ~o 56 The process is analogous to that of Examples 1 to 7, û.25 9 of gentamyc;n addit;onally being adm;xed to the sol;ds.

Example 57 A paste ;s prepared from a precursor according to Examole 4, by mixing the solid component with the monomer l;quid, and is ;ntroduced or ;njected, manually or w;th the a;d of a gun, into a bone cavity and is allowed to harden there.
The precursors according to the rema;n;ng Examples 1 to 56 can be used ;n the same way.
It is possible to push a prosthesis, such as, for example, an endoprosthes;s, into the paste wh;ch has heen ;ntroduced ;nto the body but has not yet hardened. The prosthesis ;s sol;dly anchored ;n the body after the syn-thet;c matcr;al has hardened.

Example 58 36 9 of a f;nely d;v;ded copolymer of metnyl acryl-ate and methyl methacrylate, wh;ch add;t;onally conta;ns 0.5% d;benzoyl perox;de and traces of chlorophyll, and 4 9 3û of m;cron;zed L-arg;n;ne, ~.5 9 of methotrexate, n.s 9 of gentamyc;n and zn ml of methyl methacrylate, wh;ch contains about 0.7~ d;methyi-p-tolu;d;ne and ahout 0.006% hydroqu;n-- one, are thoroughly m;xed. The resulting paste is used to shape spheres, p;ns and ovoids as ~ell as larqer ;mplants, :

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such as cylinders, tubes, sheets, films and other articles of any desired shape and size, which have hardened after a fe~ minutes. The articles are packed sterile and can be used as local active compound depots.
S - Precursors according to Examples 1 to 56 can be processed to moulded articles in an analogous manner.

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A drug depot, which can be implanted in the body, for the controlled, delayed release of a cytostatic, which depot comprises a synthetic material based on a polyacrylate or polymethacrylate that contains a cytostatic and at least one amino acid, wherein the amino acid is present in a particle size essentially smaller than 125 µm.

2. A drug depot according to claim 1, wherein the cytostatic is present in an amount of 0.1 to 4% by weight.

3. A drug depot according to claim 1, wherein the amino acid is present in an amount of 1 to 15% by weight.

4. A drug depot according to claim 1, 2 or 3, wherein the amino acid is in the form of micronized particles in the shape of rods that consist according to particle analysis by air-jet screening, of at least 95% by weight of particles smaller than 50 µm.

5. A drug depot according to claim 1, 2 or 3, wherein the amino acid is glycine, alanine, histidine, leucine, threonine or arqinine.

6. A drug depot according to claim 1, 2 or 3, wherein the amino acid is arginine.

7. A drug depot according to claim 1, 2 or 3, wherein the cytostatic is adriamycin, 5-fluorouracil or methotrexate.

B. A drug depot according to claim 1, 2 or 3, wherein the cytostatic present is methotrexate.

9. A drug depot according to claim 1, 2 or 3, which also contains an antibiotic or an antiseptic.

10. A precursor for the preparation of a drug depot according to claim 1, which precursor contains about 50 to 75% by weight of a finely divided polymer of an ester of acrylic or methacrylic ester, 1 to 15% by weight of an amino acid having a particle size essentially smaller than 125 µm, 1 to 4% by weight of a cytostatic, and 20 to 45% by weight of an ester monomer of acrylic or methacrylic acid.

11. A precursor according to claim 10, which further contains one or more members selected from the group consisting of X-ray contrast media, pigmants, catalysts, stabilizers and polymerization accelerators.

12. A precursor according to claim 10, which also contains an antibiotic or an antiseptic.

13. A process for the preparation of a drug depot according to claim 1, wherein about 50 to 75 parts by weight of a finely divided polymer of an ester of acrylic or methacrylic ester, 1 to 15 parts by weight of an amino acid having a particle size essentially smaller than 125 µm, 0.1 to 4 parts by weight of a cytostatic, and 20 to 45 parts by weight of an ester monomer of acrylic or methacrylic ester monomer are mixed to form a semi-solid paste, and the latter is converted into a desired shape and allowed to harden by polymerization and crosslinking.

14. A process according to claim 13, wherein there is admixed with the finely divided polymer of an ester of acrylic or methacrylic acid one or more members from the group consisting of X-ray contrast media, pigments and catalysts.

15. A process according to claim 14, wherein there is admixed with the ester monomer of acrylic or methacrylic acid one or more members selected from the group consisting of stabilizers and polymerization accelerators.

16. A process according to claim 13, wherein an antibiotic or an antiseptic are additionally incorporated into the paste.

17. Use of a drug depot according to claim 1, 2 or 3 for controlling tumours.