DE3347660A1 - Thermoplastics containing antiphlogistics - Google Patents

Abstract

The present invention relates to thermoplastics or prepolymers containing non-steroidal antiphlogistics, and to the preparation of such thermoplastics and to the use thereof for combating inflammation.

Description

Thermoplastics containing anti-inflammatory drugs

The present invention relates to thermoplastically ve.-workable Plastics or prepolymers containing nonsteroidal anti-inflammatory drugs and the Manufacture of such thermoplastics and their use in combating inflammation.

For many medical applications, e.g. cannulas, catheters, Hoses, artificial blood vessels, implants, heart valves, foils, etc. become plastics which, in addition to their specific mechanical properties, also have good blood and tissue compatibility. Locally limited ones can be of particular advantage here be anti-inflammatory effects.

So far, anti-inflammatory drugs have been used orally, rectally or in humans and animals cutaneously applied.

In infusion therapy using plastic or plastic cannulas Material often thrombotic and / or phlebitic if it is kept there for a longer period of time Reactions of the cannulated vein. After A. Fassolt, Switzerland. Rundschau Med. (PRACTICE), 68, 1682-2686 (1979), the mean frequency is more venous Reactions with a 4-day implantation duration already 50%. According to M.A. Galni, A.W. Tuberville, S.A. Obstbaum and J.M. Goldstein, Trans, Ophthal. Soc. U.K. 101, 84 - 86, 1981, e.g. nylon and polypropylene can have a chemotactic effect in human serum.

Promised good physical properties and blood compatibility one z. B. of segmented polyether urethanes and their copolymers, such as "Biomer" (Ethicon, Inc.) and "Avcothane" (Avco-Everett Corp.). Although their biological Properties compared with those of common materials are relatively good (S.D. Bruck, S. Rabin, R.J. Ferguson, Biomater., Med. Devices, Artif. Organs, 1, 191 (1973)), Many attempts at improvement have been made. Some key words are mentioned here: 1. Surface modified hydrogels (S.D. Bruck, J. Biomed. Mater. Res., 7, 387 (1973) and A.S. Hoffmann, G. Schmer, C. Harris, W.G. Kraft, Trans. Am.

Soc. Artif. Intern. Organs 18, 10 (1972)) 2. Chemically, radiation-chemically or microwave-initiated grafting of polymer surfaces 3. Plasma polymerisation (H. Yasuda, "Plasma Polymerization" in "The Synthesis of New Polymers. Modern Methods" (N.Yoda, Ed.), Dekker, New York, N.Y. 1975) 4. Chemical surface modification, z. B. by heparinization (P. Ferruti et al., DOS 2728781 v.

June 25, 77/9. 11. 78), urokinase addition (Unitika KK, JA 54068097 from November 9th, 77/31. 5. 79) or application of pyrazoline derivatives (Unitika KK, JA 54030172 v. August 10, 77/6. 3. 79) For use in polydimethylsiloxane capsules see Jones and Datko, (Agents Actions, 7, 555 (1977)); in networked For polyethylene oxides, see Embrey, Mostyn, Powell (EP 0016652 of March 21, 80), in cross-linked For polyoxyalkylenes, see ICI Ltd. Brit. Patient

1551620 of December 13, 76 (Appl. 8/30/79).

Furthermore, anti-inflammatory and analgesic plasters are known, the z. B. have an indomethacin-containing copolymerized layer (Nitto Electric Ind. Co., Ltd., Jap. Pat. 126269 of September 29, 79) or the active ingredient in the adhesive contained (Jpn. Kokai Tokkyo Koho 81, 20514, February 26, 1981, Appl. 79/96427 27.7. 79).

The materials or methods described above are for manufacture medical supplies only suitable to a limited extent.

It was an object of the present invention to produce active ingredient-containing thermoplastic Provide materials that are compatible with those commonly used in the plastics industry procedure can be processed and biocompatible and anti-inflammatory without further treatment Have properties.

Surprisingly, anti-inflammatory substances were found to be incorporated into plastics that are used for the manufacture of catheters, cannulas, etc. are suitable. The active ingredients are without decomposition and with good content uniformity incorporable. The active ingredients are derived from the corresponding preparations in vivo released over a period of several days. The verum catheters have Compared to placebo catheters (without anti-phlogistics), better venous tolerance.

The invention therefore relates to thermoplastically processable materials Plastics containing non-steroidal anti-inflammatory drugs and human therapeutic agents therefor and veterinary use.

Thermoplastically processable plastics - thermoplastics for short - are organic polymeric masses that form deformable melts and after solidification of the melt are unchanged. You can use several known methods E.g. by extrusion, injection molding, pressing, deep drawing to any shaped body are processed.

Examples of thermoplastics for the purposes of the invention are: polymers such as polyolefins (e.g. polyethylene, polypropylene, fluorinated ethylene / propylene copolymers, Ethy len / propylene copolymers with thermoelastic properties (EPM polymers), ethylene / acrylic acid copolymers and terpolymers made from ethylene, Propylene and small amounts of non-conjugated dienes with thermoplastic properties (EPDM rubber), styrene polymers (e.g. polymethyl methacrylate); Polyvinyl cyanide (e.g. polyacrylonitrile); Polyvinyl halides (e.g. polyvinyl chloride) and a large one Number of copolymers based on the products given above Monomers e.g. copolymers of styrene and acrylonitrile and optionally saponified Copolymers of ethylene and vinyl acetate. Further examples are polycondensates such as polycarbonates (e.g. bisphenol A polycarbonate; polyesters (e.g. polyethylene terephthalate); Polyamides (e.g. polycaprolactam); Polyphenylene oxide, polyacetals (e.g. polyoxymethylene); Cellulose esters (e.g. cellulose propionate) and polyurethanes as far as they are thermoplastic Have properties. For more details see plastic pocket book 19th edition, Pages 207 - 376, Carl-Hanser-Verlag (1974).

There are of course also thermoplastics geeic; liet that after the deformation to moldings still have to be post-cured, above as prepolymers designated.

Nonsteroidal anti-inflammatory drugs within the meaning of the present invention are one or more anti-inflammatory drugs of the general formulas I and / or II.

Anti-inflammatory drugs of general formula I have the following structure: where R1 - R5 denotes hydrogen, halogen, lower alkyl, substituted alkyl, XN or CH and Y denotes hydrogen, metal ions, alkyl or substituted alkyl.

Halogen means fluorine, chlorine, bromine, preferably chlorine and / or bromine. Lower alkyl is preferably alkyl having 1 to 6 carbon atoms, particularly preferably 1 to 4 C atoms, substituted alkyl for R1-R5 preferably denotes trihaloalkyl, especially preferably trifluoromethyl. Among metal ions are the ions of the alkali metals, alkaline earth metals and of aluminum. Substituted Alkyl for Y means preferably alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxalkyl, trihaloalkyl, the number of carbon atoms being 1 to 6 and the alkyl chain being straight or branched can be.

Preference is given to using anti-inflammatory drugs of the general formula I, in which R3 and R4 hydrogen, X nitrogen or a CH group, Y hydrogen, Metal ions, alkyl or substituted alkyl and R1, R2 and R5 hydrogen, halogen, mean lower alkyl or substituted alkyl.

Antiphlogistics of the general formula I are particularly preferred, in which X stands for a CH group and R1, R2 and R5 are methyl, trifluoromethyl or Mean chlorine.

The following anti-inflammatory drugs are very particularly preferred: 1. N- (α, α, α-trifluoro-m-tolyl) anthranilic acid = flufenamic acid 2. N- (2,3-xylyl) anthranilic acid 3. N- (2,6-dichloro-m-tolyl) anthranilic acid 4. N- (3-chloro-o-tolyl) -anthranilic acid 5. N- (2,3-dichlorophenyl) anthranilic acid 6. N- (α, α, α-trifluoro-m-tolyl) nicotinic acid = nifluminic acid 7. N- (2,3-xylidino) nicotinic acid 8. 2- (2-Methyl-3-trifluoromethylanilino) nicotinic acid 9. N- (3-chloro-o-tolyl) nicotinic acid 10. 2- (2,6-xylidino) nicotinic acid and their esters, especially 11. 2- (2-Hydroxyethoxy) ethyl-N- (α, α, α-trifluoro-m-tolyl) anthranilate = etofenamate 12. Ethoxymethyl N- (2,6-diclorom-tolyl) -anthranilate 13. Methyl-, ethyl-, i./n- propyl-, butyl-N- (α, α, α-trifluoromolyl) -anthranilate, e.g.

Nonsteroidal anti-inflammatory drugs within the meaning of the present invention are also anti-inflammatory drugs of the general formula II with the structure: in which R is hydrogen, lower alkyl, substituted alkyl, Ar aryl, heteroaryl, substituted aryl, substituted heteroaryl and n + m is an integer and is zero, 1 or 2, p is zero or 1, with the proviso that Ar is not aryl or heteroaryl when n and m and p have the value zero, as well as their esters or amides.

Lower alkyl R are preferably radicals having 1 to 6 carbon atoms, preferred 1-4 carbon atoms, substituted alkyl, alkoxyalkyl or trihaloalkyl; Aryl resp. Heteroaryl phenyl, naphthyl, thiophenyl, pyrolyl, indenyl, indolyl, benzthiazinyl, Phenothiazinyl.

Substituents for aryl or heteroaryl are alkyl, preferably straight and branched-chain alkyl with up to 6 carbon atoms, alkoxy, oxalkyl, acyl, hydroxyl, Acetoxy, benzoyl, substituted benzoyl, phenyl, substituted phenyl, phenoxy, Halogen, phenylalkenyl, phenylalkyl.

The esters are alkyl esters with 1 - 6 carbon atoms, preferably 1 - 4 carbon atoms, particularly preferably methyl, ethyl, i- and n-propyl, substituted alkyl, e.g. ß-hydroxyethyl, Ester with glycolic acid. The amides can be in the group -CO-NH2 instead of a or both amide hydrogens also contain lower alkyls or substituted alkyls.

The following anti-inflammatory drugs of the general formula II are particularly preferred: 14. 2-Hydroxybenzoic acid 15. 2-acetoxybenzoic acid 16. 2 ', 4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid 17. 2-hydroxybenzamide 18. [2- (aminocarbonyl) phenoxy] acetic acid 19. 4-Allyloxy-3-chlorophenylacetic acid = Alclofenac 2 - [(2,6-dichlorophenyl) amino] -20.

phenylacetic acid = diclofenac 21. 10-methyl-phenothiazin-2-ylacetic acid = metiazinic acid 22. 1-methyl-5- (p -toluoyl) pyrrole. 2-yl acetic acid 23. propionic acid = naproxen 2- (p-isobutylphenyl) propionic acid 2- (3-phenoxyphenyl) propionic acid 26. 2- (m-Benzolyphenyl) propionic acid = ketoprofen 27. 2- [4- (1-Oxo-2-isoindolinyl) phenyl propionic acid = indoprofen 28. 2- (2-Fluorobiphenyl-4-yl) propionic acid 29. 3- (4-Biphenylylcarbohyl) propionic acid 30. 2- (5-Benzoyl-2-thienyl) propionic acid 31. l- (p-Chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid = indomethacin 32. [1- (p-Chlorobenzoyl) -5-methoxy-2-methylindole-3-acetoxy] acetic acid = acemetacin 33. (Z) -5-Fluoro-2-methyl-1 - {[(4-methyl = sulfinyl) phenyl] methylene) -1H-indene-3-acetic acid 34. 4-Butyl-1,2-diphenyi-3,5-pyrazolidinedione = phenylbutazone 35. 4-prenyl-1,2-diphenyl-pyrazolidine-3,5-dione = feprazone as well as their alkyl esters and substituted alkyl esters.

The following anti-inflammatory drugs of the general formula III are also preferred: in which R1 and R2 together form an aryl or heteroaryl ring with one nitrogen atom, R3 is a lower alkyl group with 1-4 C atoms, R4 is a heteroaryl radical with at least one heteroatom.

The following anti-inflammatory drugs of the general formula III are particularly preferred: 36. 4-Hydroxy-2-methyl-N-2-thiazolyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 37. 4-Hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide The above-mentioned anti-inflammatory drugs of the general formulas I and II can be incorporated into the thermoplastics either individually or in groups.

The anti-inflammatory drugs can be used in an amount of 1 to 30% by weight, preferably 2-20% by weight can be incorporated into the thermoplastics.

This can be done using conventional plastic compounding methods serve. For example, one can use the anti-inflammatory drug in solid or in liquid Mix the form with the thermoplastics available as powder or granules and the Melt the mixture in an extruder, homogenize and the extrudate again granulate. You can also use the anti-inflammatory, also solid or liquid work into the polymer using the roller mill. The resulting rolled head can are then granulated. It is also possible to do the anti-inflammatory course Incorporate kneading in a conventional kneading device. The working temperatures must be chosen for each individual case so that the thermoplastic can be plasticized, but the decomposition temperature of the active ingredient to be incorporated is not achieved. It has been found to be preferred for good homogeneity of the product, the active ingredient should be in liquid form, i.e. melted or optionally dissolved in a suitable solvent.

Preference is given to working with compounds having a low melting point and good thermal stability, e.g.

Alclofenac at 91-170 ° C, ketoprofen at 94-1800C, phenylbutazone at 105 - 180 ° C, etofenamate up to 180 ° C, didofenac (acid) at 156 - 176 ° C.

Compounds with melting points of up to are also particularly suitable 1600 and good thermal stability, e.g. Acemetazine (incorporation 150-1900C, flufenamic acid 133-18O0C, Indometacii! 155-1800C, naproxen 154-1800C, feprazone 153-1800C, and metiazinic acid 146-1600C).

Compounds with a high melting point are also particularly suitable, which do not decompose, e.g. nifluminic acid (incorporated at 204-2200C), Sulindac (189-2100C) and indoprofen (213-2200C).

The in vivo liberation of anti-inflammatory drugs from plastic catheters could be proven by animal experiments.

The experiments were carried out with male rats / strain: Boron: WISW (SPF-Cpb), Weight carried out by 200 7. Polyethylene catheters with compound 11 became rats advanced into a femoral vein at the level of the groin, the catheter through an external suture around the vessel that did not result in a ligature was fixed. That The end of the catheter was welded. The duration of application was 1, 7 or 10 days. Thereafter, the content of compound 11, compared to non-implanted 11-containing Catheters determined. The amount of active ingredient paid in results from the difference the salary before incorporation and after different lengths of stay. at Rats were liberated up to 59.2 + 4.9% of compound 11 in vivo.

It was also used in rabbits (instillation of the catheter into the ear vein) a liberation increasing with the length of stay up to approx. 75% (10th day) was found.

The tissue tolerance was determined by comparing verum and placebo catheters (with and without anti-inflammatory drugs) each tested on the same animal.

Annex to the input The protective effect of the connection 11, which in PE catheter was incorporated into rabbits (male while New Zealanders; Weight 2.3 - 4.1 kg) can be demonstrated.

Verum and placebo catheters (with resp.

without 11j incorporated in ear veins, fixed and 7 days in the veins left. The images show different vein cross-sections.

In Fig. 1 there is a cross-section of a vein after 7 days of implantation Placebo catheter, shown in Fig. 2 after 7 days of implantation of a verum catheter.

Fig. 1 shows an extensive inflammatory response in the ear vein of the rabbit on the 7th day after implantation of a PE catheter.

According to Fig. 2, the implantation of an 11-part PE catheter calls in the ear vein of the rabbit almost no inflammatory reaction on the 7th day after implantation emerged.

It can be clearly seen that under the influence of the in vivo liberated Active ingredient largely prevents an inflammatory reaction compared to the placebo will.

In the figures: 1 / Tunica intima, 2 / Tunica media and 3 / Tunica externa.

The in vivo liberation of compounds 1 and 11, which in amounts of 10% were incorporated in polyethylene catheters, male rats were given Animals, strain: BOR; WISW (SpF-Cpb), weight around 200 mg? To which the catheter has a '7Braun's cannula were placed in the intraperitoneal space and which there 3 and remained for 7 days, respectively. Liberation was made through investigation of the residual content of 1 or 11 in the catheter after application over several days, in comparison intended for non-implanted verum catheters.

Active ingredient application% in vivo Liberation (d) 1 3 57.7 # 3.7 7 78.9 # 3.4 11 3 75.0 # 1.7 7 86.3 # 4.8 34 3 51.4 + 6.0 7 79.8 + 2.2 In vitro, etofenamate incorporated in ethylene-propylene copolymer can be isolated quantitatively with acetone, while etofenamate is extracted from polyurethane preferably with ethanol (boiling point, with stirring and reflux). In vitro liberation occurs more quickly from polyurethane than from the ethylene-propylene copolymer. There are no by-products or decomposition products, the content uniformity is good.

Example 1 1000 g of polyethylene (Baylon 22H764) were placed on a troester Laboratory roller mill for 40 minutes at 1300C with the addition of a total of portions in portions 100 g of etofenamate rolled, then granulated. It resulted in an evenly opaque granulate that can be further processed into homogeneous press plates 0.3 to 2 mm thick let. The active ingredient was chemically unchanged and distributed homogeneously in the plastic.

Example 2 1000 g polyethylene (Baylon 22H764) and 100 g etofenamate were processed into an opaque rolled sheet at 1600C and then granulated. The granulate was then on a laboratory extruder at melt temperatures of 160 - 1700C processed into hoses with a diameter of 1 - 3 mm. These hoses contained 10% unchanged etofenamate in even distribution and showed an opaque Appearance and a "greasy" appearing surface. Laboratory and animal tests proven a significant release of active ingredients and significantly positive physiological effects (see above).

Example 3 1000 g of polyethylene (Baylon 19N430) and 100 g of etofenamate (Compound 11) were processed into a rolled sheet at 90 ° -950 ° C., then granulated and pressed into homogeneous sheets.

Example 4 400 g of ethylene / propylene copolymer (Levaflex EP 281) and 83.6 g of etofenamate were processed into a rolled sheet at 1700C, then granulated and pressed into homogeneous, very flexible, conformable, 0.5 mm thick plates.

Example 5 1000 g of ethylene / vinyl alcohol copolymer (Levasint s 31 natural) and 100 g etofenamate were at 900C to a rolling fur processed, then granulated and pressed into homogeneous sheets.

Example 6 500 g of polyethylene (Baylon 19N430) and 52.5 g of indomethacin became one on a "Schwabenthan 200" mixing mill at 1550C in 10 minutes processed white rolled skin, then granulated and at 1500C into tubes 1 - 3 mm in diameter extruded. The material showed good content uniformity, clear release of active ingredients in vivo and positive physiological effect (see above).

Example 7 500 g of polyethylene (Baylon 19N430) and 53.1 g of flufenamic acid was processed into an amber-colored rolled skin at 1550C, then granulated and extruded into thin tubes at 1500C. The material showed good content uniformity, significant drug liberation in vivo and positive physiological effect (see above).

Example 8 500 grams of polyethylene (Baylon 19N430) and 51.9 grams of acemetacin were processed into a yellow rolled sheet at 1550C, then granulated and pressed into 0.3 mm thick plates. The active ingredient was chemically unchanged and homogeneous distributed in the plastic. Drug liberation and pos. physiological effect was proven (see above).

Example 9 500 grams of polyethylene (Baylon 19N430) and 50 grams of phenylbutazone were processed into a rolled sheet at 1400C, then granulated and at 1500C extruded into thin tubes. The material showed good content uniformity, significant drug liberation in vivo and positive physiological effect (see above).

Example 10 500 g thermoplastic polyurethane (for medical Requisite suitable PU 786 from Bayer AG) and 50 g etofenamate were at 1700C processed into a rolled skin, then granulated and 0.3 mm thick sheets pressed. The result was an almost transparent, highly flexible material with high elongation at break (> 600%). The active ingredient was homogeneously distributed in the plastic and became chemical released unchanged.

Example 11 500 g of thermoplastic polyurethane based on MDI / polyether / polyester (Desmopan 786 from Bayer AG) and 50 g piroxicam became a rolled head at 210 ° C processed, then granulated and made into highly flexible, 0.3 mm thick panels pressed. The active ingredient was homogeneously distributed in the plastic and was chemically unchanged released.

Example 12 500 g of polyethylene (PE 22H768 from Bayer AG) and 50 g of diclofenac (Acid) were processed into a rolled sheet at 170 - 1750C, then granulated and pressed into 0.3 mm thick plates. The active ingredient was homogeneously distributed in the plastic and was released again chemically unchanged.

- blank page -

Claims (11)

Claims 1. Containing thermoplastically processable plastics nonsteroidal anti-inflammatory drugs. 2. Thermoplv table processable plastics according to claim 1 containing as thermoplastic one or more from the group of polyethylene, fluorinated polyolefins, Polypropylene, ethylene / propylene copolymers, ethylene / acrylic acid copolymers (EAA), saponified or unsaponified ethyl vinyl ester copolymers, thermoplastic polyurethanes or mixtures thereof. 3. Plastics according to claim 1 or 2 containing one or more non-steroidal anti-inflammatory drugs of the formula I: where R -R stands for hydrogen, halogen, lower alkyl, substituted alkyl, x for N or CH and Y for hydrogen, metal ions, alkyl and substituted alkyl, and / or of the formula II: where R is hydrogen, lower alkyl, substituted alkyl, Ar is aryl, heteroaryl, substituted aryl, substituted heteroaryl, and n + m is an integer and is zero, 1 or 2 and p is zero or 1, with the Condition that Ar is not aryl or heteroaryl when m + n and p have the value zero, as well as their esters or amides, and / or of the formula III: where Rl, R2 together form an aryl or heteroaryl ring with one N atom, R3 a lower alkyl group with 1-4 C atoms, R4 a heteroaryl radical with at least one heteroatom. 4. Process for the production of thermoplastics according to one or more of claims 1 to 3, characterized in that non-steroidal anti-inflammatory drugs incorporated into the thermoplastic in a manner known per se. 5. Use of thermoplastics according to one or more of the claims 1 to 3 to fight inflammation. 6. Cannulas and catheters consisting of thermoplastics according to one or several of claims 1 to 3, in particular made of polyethylene, its copolymers EPM, EPDM and EAA or thermoplastic polyurethane containing etofenamate. 7. Cannulas and catheters consisting of thermoplastics according to one or several of claims 1 to 3, in particular made of polyethylene, its copolymers EPM, EPDM and EAA or thermoplastic polyurethane containing indomethacin. 8. Cannulas and catheters consisting of thermoplastics according to one or several of claims 1 to 3, in particular made of polyethylene, its copolymers EPM, EPDM and EAA or thermoplastic polyurethane containing acemetacin. 9. Cannulas and catheters consisting of thermoplastics according to one or several of claims 1 to 3, in particular made of polyethylene, its copolymers EPM, EPDPI and EAA or thermoplastic polyurethane containing diclofenac. 10. Cannulas and catheters consisting of thermoplastics according to one or several of claims 1 to 3, in particular made of polyethylene, its copolymers EPM, EPDM and EAA or thermoplastic polyurethane containing piroxicam. 11. Cannulas and catheters consisting of thermoplastics according to one or several of claims 1 to 3, in particular made of polyethylene, its copolymers EPM, EPDM and EAA or thermoplastic polyurethane containing ketoprofen.