SI9010714A

SI9010714A - PLASTIFIED POLYMER COMPOSITIONS

Info

Publication number: SI9010714A
Application number: SI9010714A
Authority: SI
Inventors: Pietro M Boselli; Paul Geoffrey Clutterbuck
Original assignee: Bp Chemical Ltd
Priority date: 1989-04-11
Filing date: 1990-04-11
Publication date: 1997-08-31
Also published as: HRP921367A2

Abstract

Predloženi izum se nanaša na uporabo tetraalkilpiromelitata kot plastifikatorja za PVC za uporabo v predmetih za biomedicino. Piromelitati so manj toksični od konvencionalno uporabljenih ftalatov in trimelitatov in se teže ekstrahirajo z biološkimi tekočinami, s katerimi so v stiku. Predmeti, ki jih lahko izdelamo iz PVC-ja, ki je plastificiran na ta način, obsegajo cevi za dializo, katetre in vrečke za kriThe present invention relates to the use of tetraalkylpyromellitate as a plasticizer for PVC for use in biomedical articles. Pyromellitates are less toxic than conventionally used phthalates and trimellitates and are less easily extracted by biological fluids with which they come into contact. Articles that can be made from PVC plasticized in this way include dialysis tubing, catheters and blood bags.

Description

PIASTIFIKPVflNI POLIMERNI PREPARATIPIASTIFIC PVfl POLYMER PREPARATIONS

Sadašnji pronalazak odnosi se na plastifikovane polimerne preparate, naročite na preparate na bazi polivinilhlorida (ovde kasni je PVC), koji obuhvataju specifične pircmelitatne estre kao plastifikatore za proizvodnju artikala za biomedicinsko koriščenje i na artikle koji su iz njih napravljeni.The present invention relates to plasticized polymer preparations, particularly to preparations based on polyvinyl chloride (here PVC), which include specific pyrmellite esters as plasticizers for the production of articles for biomedical use and to articles made from them.

Koriščenje polimernih materijala nesumnjivo je doprinelo do značajnog progresa u medicini i hirurgiji. Na primer, polimerni materijali se koriste u hemodijalizi, u uredjajima za enteralnu i parenteralnu ishranu, kesama za krv i slično.The use of polymer materials undoubtedly contributed to significant progress in medicine and surgery. For example, polymeric materials are used in hemodialysis, enteral and parenteral nutrition devices, blood bags, and the like.

Medju polimernim materijalima koji se najobičnije koriste su PVC, poliuretani, silikoni i slično. U slučaju PVC, dosada koriščeni plastifikator bio je gotovo isključivo dietilheksilftalat (takodje poznat kao dioktilftalat i ovde kasni je DOP”). U novi je vreme, za neke primene, preporučivan je trioktiltrimelitat (ovde kasni je TOIM) umesto DOP.Among the polymer materials that are most commonly used are PVC, polyurethanes, silicones and the like. In the case of PVC, the plasticizer used until now was almost exclusively diethylhexyl phthalate (also known as dioctyl phthalate and DOP is late).

Medjutim, dosada je uglavnan koriščenje polimera koji sadrže estarske plastifikatore za biomedicinske primene bilo nezadovoljavajuče zbog podložnosti estara ekstrakciji iz. polimera koji su sa njima plastifikovani kada su u kcnrakfcu sa biološkim fluicima. čak i ako TOIM smanjuje takav rizik da se ekstremu je iz poli mera, pošto ji svejedno rizik transfera TOIM u krvotok kao rezultat ekstrakcije, naročito kada su artikli koji su napravljeni iz polimera plastifikcvarih sa TOIM π.cr., kšsč, cevx za čuvanje, itd·, u Konraxru sa mrv-iju.However, until now, the established use of polymers containing ester plasticizers for biomedical applications has been unsatisfactory due to the susceptibility of the ester to extraction from polymers that are plasticized with them when in contact with biological fluids. even if TOIM reduces the risk of extremity from the polymer, since the risk of transfer of TOIM into the bloodstream as a result of extraction, especially when articles made of polymer plasticizers with TOIM π.cr., kššč, tube for storage, etc., are still a risk in Konraxr.

Tako je realizovano za plastifikator da treba da hude podestan za biomedicinsku primenu, pri čemu artikli koji ih sadrže treta da trudu biokoftxcatibii:ii. To jeste treba da ima ju sposobnost da se petpuno disperguju u polimeru koji je sa njima plastifikovan; treba da su zadovoljavajuče slebodni od rizika da se ekstrahuju biološkim fi uidita sa kojima su u kontaktu? i tre: kaipartmentalizaciju.Thus, it has been realized for the plasticizer that it must be highly suitable for biomedical application, whereby the articles containing them treat the effort of biocoftxcatibii:ii. It is necessary that they have the ability to disperse completely in the polymer that is plasticized with them; must they be satisfactorily free from the risk of being extracted by biological fluids with which they are in contact? i tre: kaipartmentalization.

3a h-v-n enosobni za Vr»·?—3a h-v-n one-room for Vr»·?—

Sada je otkriveno da se odgovarajučim izborcm specifičnih estara, problemi koji prate estre iz rani je tehnike u biomedicinsko j primeni mogu se suštinski ublažiti.It has now been discovered that by appropriate selection of specific esters, the problems associated with prior art esters in biomedical applications can be substantially alleviated.

Prema teme, sadašnji .pronalazak je plastifikovani polimerni preparat koji je podestan za proizvodnju artikala za bicmedicinsku primenu, koji se karakteriše time što plastifikator u preparatu obuhvata jedan ili više piremelitatnih estara formule : - COOR2 (I)According to the subject, the present invention is a plasticized polymer preparation that is suitable for the production of an article for bi-medical application, which is characterized by the fact that the plasticizer in the preparation includes one or more pyremelitate esters of the formula: - COOR2 (I)

COOR4 u kojoj suRj, R^, Rg i Rj isti ile različite (a) alkil ili alkenil grupe, koje mogu biti linearne ili račvaste, i koje sadrže 1-15 atoma ugljenika, ili, (b) ciklične grupe koje sadrže 5-6 atoma ugljenika u prstenu, pri čemu je pcmanuti prsten cikloalifatičan ili aromatičen sa ili bez dppunskih supstituenata u strukturi prstena.COOR4 in which Rj, R^, Rg and Rj are different (a) alkyl or alkenyl groups, which can be linear or branched, and which contain 1-15 carbon atoms, or, (b) cyclic groups containing 5-6 carbon atoms in the ring, wherein the pcmannu ring is cycloaliphatic or aromatic with or without dppon substituents in the ring structure.

Pircmelitati formule (I) u kojima, n.pr., supstituenti R^-R^ pretstavljaju alkil supstituent koriščeni su rani je kao plastifikatori za polimerne preparate samo u kontektstu električnih pramena ali ne i u kontestu bicmedicinskog koriščenja.The pyrrolizates of formula (I) in which, for example, the substituents R1-R2 represent an alkyl substituent have been used previously as plasticizers for polymer preparations only in the context of electrical wires but not in the context of biomedical use.

Pircmelitatni estarski plastifikatori su poželjno oni u kojima su grupe Rj-R₄ linearne ili račvaste alkil grupe. Medju ovima, one u kojima najmanje jedan od supstituenata pretstavlja etil ili oktil grupu su najpeželjnije.Pircmellite ester plasticizers are preferably those in which the Rj-R ₄ groups are linear or branched alkyl groups. Among these, those in which at least one of the substituents represents an ethyl or octyl group are the most preferred.

Uporedjenje relativnih rizika ekstrakcije konvencionalnih plastifikatora sa piromelitatnim estrama u preparatima iz sadašnjeg pronalaska pokazuje da kada su artikli napravljeni iz PVC koji sadrži ove plastifikatora u kontaktu sa, n.pr., volovskem krvi ju, tetraoktilpircmelitat se od 95-98% manje ekstrahuje nego DEHP ili dioktilftalat, i najmanje 85% manje nego TCC-ί. Tako je jasno da u bicmedicinskoj primeni artikli koji su napravljeni od polimernih preparata koji sadrže piremelitatne estre kao plastifikatore pokazuju sledeče prednosti. Oni pokazuju :A comparison of the relative risks of extraction of conventional plasticizers with pyromellitate ester in the preparations of the present invention shows that when articles made of PVC containing these plasticizers are in contact with, e.g., ox blood, tetraoctylpyrcmellitate is 95-98% less extracted than DEHP or dioctylphthalate, and at least 85% less than TCC-ί. Thus, it is clear that in bimedical applications, articles made from polymer preparations containing pyremellite esters as plasticizers show the following advantages. They show:

1. Nizu toksičnost od TC3M ili dioktilftalata pa tako ne utiču štetno na biološke procese.1. The toxicity of TC3M or dioctyl phthalate does not significantly affect biological processes.

2. suštinski zanemarljiv rizik ekstrakcije kada su u kontaktu sa krvi ju ili sa drugim biološkim, fluidima, i2. essentially negligible risk of extraction when they are in contact with blood or other biological fluids, i

3. poboljšanu efikasnost plastificiranja i trajnost artikala napravljenih od polimera koji sadrže pomenute plastifikatore.3. improved plasticization efficiency and durability of articles made of polymer containing the aforementioned plasticizers.

Plastifikatori se mogu koristiti u polimernim preparatima u količini od najmanje 30-100 delava na sto smole (ovde u kasni jem tekstu phr), poželjno 60-90 phr na bazi polimera u preparatu, zavisno od polimera koji treba da se plastifikuje, tvrdoce ili fleksibilnosti željenog finalnog proizvoda, iliod poželjnih barijemih osobina za specifičnu medicinsku/bicmedicinsku pr imenu.Plasticizers can be used in polymer preparations in an amount of at least 30-100 parts per hundred resin (here in the late text phr), preferably 60-90 phr on the basis of the polymer in the preparation, depending on the polymer to be plasticized, the hardness or flexibility of the desired final product, or on the desired barium properties for a specific medical/bi-medical purpose.

Polimeri u polimernim preparatima su podesno termoplastični polimeri, naročite PVC, mada se mogu takodje koristiti podesno u poliuretanskim i silikonskim polimer ima.Polymers in polymer preparations are conveniently thermoplastic polymers, order PVC, although they can also be conveniently used in polyurethane and silicone polymers.

Pniiingrm preparat se može napraviti n.pr., mešanjem plastifikatora sa polimerom. Mešanj se podesno vrši na povišenoj temperaturi od 60-150°C. Polimerni preparati mogu sadržati dopunska konvencionalna unutrašnja ili spoljašnja maziva, stabilizatere i slične. Primeri stabilizatora uključuju cink-dioktanoat, cink-distearat, kalcijum-distearat i smeše ovih, N,N^J-diaciletilendiaraine koji poželjno imaju palmitoil ili stearoil grupe u acil grupama, epoksidovana ulja, n.pr., sojino ulje, laneno ulje.A polymer preparation can be made, for example, by mixing a plasticizer with a polymer. Mixing is conveniently done at an elevated temperature of 60-150°C. Polymer preparations may contain additional conventional internal or external lubricants, stabilizers and the like. Examples of stabilizers include zinc dioctanoate, zinc distearate, calcium distearate and mixtures thereof, N,N ^J -diacylethylenediaraines preferably having palmitoyl or stearoyl groups in the acyl groups, epoxidized oils, e.g., soybean oil, linseed oil.

Polimerni preparati se mogu oblikovati u artikle za biomedicinsku primenu podesno istiskivanjem, n.pr., u filmove. Kada se takvi filmovi koriste za proizvodnju kesa za krv, filmovi treba da su minimačlne debljine oko 0.35 um. Kada preparati treba da se koriste za proizvodnju epruveta, takve epruvete se takodje mogu proizvesti istiskivanjem i debljina zida epruvete može se podesiti prema potrebi. Tipično za primenu u dijalizi epruveta ima unutrašnji prečnik oko 4.5-5 um i spoljašnji prečnik oko 8-8 um, t.j., debljina zida epruvete je oko 0.5-1.8 um.Polymer preparations can be formed into articles for biomedical application by suitable extrusion, e.g., into films. When such films are used for the production of blood bags, the films must have a minimum thickness of about 0.35 µm. When the preparations are to be used for the production of test tubes, such test tubes can also be produced by extrusion and the wall thickness of the test tube can be adjusted as needed. Typically for use in dialysis, the test tube has an inner diameter of about 4.5-5 µm and an outer diameter of about 8-8 µm, i.e. the thickness of the tube wall is about 0.5-1.8 µm.

Istiskivanje preparata se podesno vrši na temperaturi 120-190°C.Extrusion of the preparation is conveniently carried out at a temperature of 120-190°C.

Polimerni preparati iz sadašnjeg pronalaska koji sadrže piranelitatne estre kao plastifikatore mogu se koristiti za proizvodnju mnogih artikala za biomedicinske primenu kao što su epruvete, fleksibilne epruvete, kese, kat eter i, ploče, retametrs i druge takve komponente koje su potrebne za direktno koriščenje i/ili pribori za funkcionisanje makojeg aparata za biomedicinske primene uključujuči dijalizu, enteralnu ili parenteralnu ishranu, vantelesni krvotok, veštačke organe i slično.The polymer preparations of the present invention containing pyranellite esters as plasticizers can be used for the production of many articles for biomedical applications, such as test tubes, flexible test tubes, bags, catheters, plates, retameters and other such components that are necessary for direct use and/or accessories for the functioning of the poppy apparatus for biomedical applications including dialysis, enteral or parenteral nutrition, extracorporeal blood flow, artificial organs and the like.

U drugoj realizaciji, sadašnji pronalazak se odnosi na makoji oblikovan artikl koji je proizveden iz polimernih preparata koji su gore zaštičeni i opisani.In another embodiment, the present invention relates to a molded article manufactured from the polymeric compositions described above.

Sadašnji pronalazak je dalje ilustrovan sledečim Primer ima.The present invention is further illustrated by the following Example.

Primer :Example:

Proizvedena su dva tipa epruveta za dijalizu porodu konvencionalnih tehnika isti skivanja koriščenjem različitih formulacija. Korišdene formulacije prikazane su niže :Two types of delivery dialysis tubes of conventional techniques have been produced using different formulations. The formulations used are shown below:

Jedinjenje Unification Trgovačko ime/izvor Trade name/origin Korišdene količine (Kg) Quantities used (Kg) Epruveta 1 Test tube 1 Epruveta 2 Test tube 2 PVC PVC PAVINTL* S70M (Ex Enichem) PAVINTL* S70M (Ex Enichem) 50.000 50,000 52.000 52,000 TOPM TOPM BP Chemicals BP Chemicals 35.526 35,526 45.000 45,000 Epoksidovano sojino ulje Epoxidized soybean oil EDENCL-D82* (Ex Henkel Chimica) EDENCL-D82* (Ex Henkel Chimica) 1.885 1,885 2.150 2,150 Stearatne soli Stearate salts S.T. 88 iz Zn/Ca stearata S.T. 88 from Zn/Ca stearate 0.153 0.153 0.174 0.174 Ca/Zn Kotpleks Ca/Zn Coupling PPDSPER 128* (Ex Čemer spa Lodi, Milan) PPDSPER 128* (Ex Čemer spa Lodi, Milan) 0.048 0.048 0.054 0.054 Gliserolni estar Glycerol ester IPGAWAX 361* (Ex Ciba Geigy) IPGAWAX 361* (Ex Ciba Geigy) 0.048 0.048 0.054 0.054 Mazivo Lubricant VASET.INE P.F. (Ex Witco - Snowwhite EC USP) VASET.INE P.F. (Ex Witco - Snowwhite EC USP) 0.026 0.026 0.030 0.030

Beležke : PVC - PolivinilhloridNotes: PVC - Polyvinyl chloride

TOPM - Tetraoktilpircmelitat * - Pegistrovano trgovačko imeTOPM - Tetraoctylpircmelitate * - Registered trade name

S.T.88 - Napravljen honogenim mešanjem kalcijum-stearata (66% w/w) i cink-stearata (34% w/w) u obliku prahova.S.T.88 - Made by homogenous mixing of calcium stearate (66% w/w) and zinc stearate (34% w/w) in the form of powders.

Hcsnogenizacija formulacije postiže Hcsnogenization of the formulation achieves se pri mešanju, dok su granulacija i during mixing, while granulation i tura istiskivanja prikazani niže : ture of extrusion shown below: Faza/Tehnike Phase/Techniques Temperatura °C Temperature °C Mešanje : Mixing : Epruveta 1 Test tube 1 Epruveta 2 Test tube 2 Početna plastifikacija Initial lamination 65 65 60 60 Finalna Final 110 110 105 105 Granulacija (Mešanje pri 20 rpn) : Granulation (Mixing at 20 rpm) : 20-170 20-170 23-170 23-170 Istiskivanje (čeona temperatura) : Extrusion (head temperature): 170-90 170-90 170-90 170-90 Dobivene epruvete imale su sledeče karakteristike : The test tubes obtained had the following characteristics: ♦ ♦ Karakteristike proizvoda : Product Features: Epruveta 1 Test tube 1 Epruveta 2 Test tube 2 Unutrašnji prečnik (mn) Inner diameter (mn) 4.7 4.7 4.7 4.7 Spoljašnji prečnik (mm) Outer diameter (mm) 7.2 7.2 7.2 7.2 Debljina zida (mn) Wall thickness (mm) 1.25 1.25 1.25 1.25 Tvrdoča Hardness A 70 D35 A 70 D35 A 60 D35 A 60 D35 VUčna jačina (MPa) Tensile strength (MPa) 16.6 16.6 13.8 13.8 Izduživanje pri kidanju (%) Elongation at break (%) 413 413 394 394

Proizvedene su dalje epruvete za dijalizu sličnih dimenzija koriščenjem PVC formulacija koje sadrže plastifikatore dioktilftalat (DOP) i trioktiltrielitat (TOTM) tako da se uporede njihove performanse sa epruvetama koje sadrže tetraoktilpiromelitat (TOPM). Korišdene su slične formulacije sa onima za gomju Epruvetu 1 ali su u svakom slučaju količine PVC i plastifikatora bile :Further dialysis tubes of similar dimensions were produced using PVC formulations containing the plasticizers dioctylphthalate (DOP) and trioctyltriellite (TOTM) so that their performance was compared with tubes containing tetraoctylpyromellitate (TOPM). Similar formulations were used to those for rubber Tube 1, or in any case the amounts of PVC and plasticizer were:

DOP - 45 kg PVC - 75 kgDOP - 45 kg PVC - 75 kg

TOTM - 54 g PVC - 75 kgTOTM - 54 g PVC - 75 kg

TOPM - 35.526 kg PVC - 50 kgTOPM - 35,526 kg PVC - 50 kg

Dobivene epruvete testirane su na njihovo gubi jen je plastifikatora ekstrakcijan kada su u kontaktu sa volovskem krvi ju koja kruži kroz svaku od ovih epruveta termostatiranih na 37°C tokom 4 časa brzinom od 15 minuta po ciklusu. Rezultati su pokazali da je brzina ekstrakcije plastifikatora kako sledi :The obtained test tubes were tested for their wrinkles, the plasticizer was extracted when they were in contact with ox blood circulating through each of these test tubes thermostated at 37°C for 4 hours at a rate of 15 minutes per cycle. The results showed that the rate of extraction of the plasticizer is as follows:

TOPM se ekstrahuje u količini koja je od 90-98% manja od DOP dok se TOPM ekstrahuje u količini koja je od 70-80% manja od TOTM.TOPM is extracted in an amount that is 90-98% less than DOP, while TOPM is extracted in an amount that is 70-80% less than TOTM.

Za svrhe testiranja moguenosti e+strahovanja ili raspodele plastifikatora porodu bioloških fluida, naročite krvi, može se pretpostaviti da je krv suštinski sestavljena od dve komponente : hidrofilne komponente i lipofilne komponente u odnosima 90 : 10. Testovi se zato vrše korišdenjsn čistih plastifikatora za odredjivanje sposobnosti ekstrahovanja ili raspodele mudkanjem plastifikatora sa 5o:50 w/w smeše homogena hidrofilna (voda)/lipofilna (maslinovo ulje) disperzija. U ovim eksperimentira, koji su radjeni po najgorem soenatiu (zbog njihovog relativno visokog lipofilnog sadržaja), rezultati su pokazali da je ekstrakcija/raspodela odgovarajudih plasti f ikatora porodu homogene disperzij e bila kako sledi :For the purposes of testing the possibility of e+scaring or distributing the plasticizer to the delivery of biological fluids, such as blood, it can be assumed that blood essentially consists of two components: a hydrophilic component and a lipophilic component in the ratio of 90:10. Tests are therefore carried out using pure plasticizers to determine the ability to extract or distribute the plasticizer by mixing with a 5o:50 w/w mixture of homogeneous hydrophilic (water)/lipophilic (olive oil) dispersion. In these experiments, which were produced after the worst combination (due to their relatively high lipophilic content), the results showed that the extraction/distribution of the appropriate layers of the homogenous dispersion was as follows:

TOPM se ekstrahuje/raspodeljuje u lipofilnoj fazi u količini koja je od 75-85% niža od DOP dok se TOPM ekstrahuje u istoj fazi u količini koja je od 55-65% niža od TOTM.TOPM is extracted/distributed in the lipophilic phase in an amount 75-85% lower than DOP while TOPM is extracted in the same phase in an amount 55-65% lower than TOTM.

Ekstrakcija/raspodela plastifikatora u hidrofilnoj fazi je relativno zanemarljiva.Extraction/distribution of the plasticizer in the hydrophilic phase is relatively negligible.

Poznate jo da jo akutna toksičnost ovih plastifikatora za miševe reda DQP.’TOTM> TOPM. Tako, pored toga što su man je toksični za biološke procese nego druga dva dobro poznata PVC plastifikatora, ovi rezultati pokazuju da se TOPM takodje ekstra huje u značajno manjoj količini porodu bioloških fluida. Nastaje sinergizam ekstrakcija toksičnost i zato su rezultati čak povoljniji kada se koristi TOPM.You know it as the acute toxicity of these plasticizers for mice of the order DQP.'TOTM> TOPM. Thus, in addition to being more toxic to biological processes than the other two well-known PVC plasticizers, these results show that TOPM is also extracted in a significantly smaller amount of biological fluids. Synergism and toxicity occur, and therefore the results are even more favorable when TOPM is used.

-L·-L·

Claims

PATENT APPLICATIONS

A plasticized polymer composition for the production of molded objects for biomedical use, characterized in that the plasticizer in the composition comprises one or more pyromellate esters of formula (I):

in which R _p R ₂ , R ₃ and R ₄ are the same or different and mean:

(a) alkyl ab alkenyl groups, which may be linear or branched and contain 1-15 carbon atoms ab (b) cyclic groups containing 5-6 carbon atoms in the ring, said ring being cycloaliphatic ab aromatic with additional substituents in ring structure ab without them.

Polymer composition according to claim 1, characterized in that at least one of the substituent groups RfR ₄ represents an ethyl ab octyl group.

Polymer composition according to claim 1 or 2, characterized in that the plasticizer is present in a cube of 30-100 parts per hundred parts of polymer based resin in the composition.

Polymer composition according to any one of the preceding claims, characterized in that the plasticizer is present in a cube of 60-90 parts per hundred parts of polymer based resin in the composition.

Polymer composition according to any one of the preceding claims, characterized in that the polymer in said composition is thermoplastic.

Polymer composition according to any one of the preceding claims, characterized in that the polymer is in the PVC composition.

Polymer composition according to any one of the preceding claims, characterized in that

-7 that said composition is useful for the manufacture of articles for biomedical use, said articles being selected from films, tubes, whether flexible or rigid, bags, catheters, plates, sheets, rotameters and artificial organs.

Polymer composition according to claim 7, characterized in that it is a thermoplastic PVC composition useful for making films and / or blood bags.

Polymer composition according to claim 7 or 8, characterized in that the film produced has a thickness of about 0.35 mm.

10. Articles for biomedical use, characterized in that they are produced from a plasticized polymer composition comprising one or more pyromellate esters of formula (I) as a plasticizer.