POTENTIAL USE OF ETHYLENE VINYL ACETATE COPOLYMER

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USE OF EVA IN PARENTERAL CONTROLLED RELEASE DRUG DELIVERY SYSTEM EVA has a long and successful history in the pharmaceutical industry It not only has been widely used in parenteral drug delivery systems as an excipient for R amp D purposes but also has numerous successes in commercial products Selected commercial parenteral drug delivery products using EVA are listed in Table 1 2 EVAs have

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USE OF EVA IN PARENTERAL CONTROLLED 3 7 subcutaneous implants 8 12 ocular implants 13 17. RELEASE DRUG DELIVERY SYSTEM dental products 18 22 and biological deliveries 23 27. In these applications EVA serves as an excipient where. EVA has a long and successful history in the pharmaceutical APIs are dissolved and or dispersed and the release rate is. industry It not only has been widely used in parenteral drug controlled by diffusion It is also widely reported that EVA has. delivery systems as an excipient for R D purposes but also been used in transdermal drug delivery as a rate controlling. has numerous successes in commercial products Selected membrane as well as other functional components 28 32. commercial parenteral drug delivery products using EVA These applications of EVA in drug delivery systems have been. are listed in Table 1 2 EVAs have successfully enabled comprehensively reviewed in a previous white paper by. the controlled release of parenteral active pharmaceutical Celanese 2. ingredients APIs in intravaginal rings intrauterine devices. Table 1 Commercial parenteral drug delivery products using EVA 2. HOT MELT EXTRUSION EVA IN ORAL DRUG DELIVERY, Hot melt extrusion HME is one of the most widely The successful applications of EVA in parenteral systems. used processing technologies for the use of EVA in the have triggered studies in other drug delivery areas Oral. pharmaceutical industry 33 36 There are other processing administration is one of the most important drug delivery. technologies such as coacervation and spray drying however routes and EVA has received significant attention in this area. HME has been reported the most in the literature The rapid 33 34 42 45. growth of HME in recent pharmaceutical development has. The use of polymers for oral drug delivery has been long. been seen and well reviewed by the industry 33 37 41 In. adapted by the pharmaceutical industry on both academia. the HME process an extruder is used to process a formulated. level and commercial level 41 46 47 It is well known that. polymer containing mixture including binders excipients APIs. the human gastrointestinal system is extremely complex. processing aids and other components in the molten state of. and presents challenges to oral administration such as. the polymer The extrudates then are obtained after the die by. a harsh chemical environment pH 2 in the stomach to. using a series of downstream processing equipment such as a. close to neutral in the ileum or colon and an enzymatic. conveyor belt a cooling water bath a pelletizer or a calender. burden Many polymers have been successfully introduced. In the absence of solvent HME offers a robust continuous. to oral formulations to help provide different functions with. process that enables high API loading a fast processing. controlled release being one of them The current research. rate great homogeneity and solid in solid dispersion In. of EVA oral drug delivery has been focused on the controlled. the process all the materials will experience heat and shear. release of water soluble APIs with low pharmacological. Low temperature processing in HME is usually preferred in. potency relatively short biological half life and good thermal. pharmaceutical manufacturing due to concern about the. stability Examples are metoprolol tartrate MPT and diltiazem. thermal and shear stability of the formulation ingredients most. hydrochloride DTZ 33 34 42 45,significantly the APIs. STABILITY AND PROCESSABILITY OF EVA, In some early studies using EVA with drugs targeting oral. administration reported by Follonier and coworkers a series. of common controlled release polymers were compared. 2015 Celanese 2, with a 40 wt EVA 42 Formulations were prepared by HME extrusion process The combination of a high decomposition. Because of the potential for high temperature exposure temperature a low processing temperature and ease of. during HME the thermal stability of each polymer was first processing offers EVA a wide processing window great. evaluated by thermogravimetric analysis Table 2 EVA showed processing flexibility and simplified processing A study on the. better thermal stability than the other polymer excipients long term storage stability and treatment stability of the same. as indicated by the decomposition temperatures Further EVA system indicated that the EVA based system is robust. evaluation on the extrusion processibility of the same group during processing and storage Table 4 shows the calculated. of materials is listed in Table 3 It is clear that the EVA sample percentage of VA of the reported EVA after the treatment of. used can be processed at a much lower temperature 80 grinding extrusion and storage The results indicated that. oC than all the other polymeric excipients Plasticizers and after a sequential of grinding extrusion and 2 year storage. a drying step were not needed to process EVA while they there was no evidence of significant thermal stability issues or. were required for all the other polymers for the reported compositional changes on the EVA samples 42. Table 2 Thermogravimetric analysis of the reported controlled release polymeric excipients 42. Table 3 Extrusion parameters of the reported controlled release polymeric excipients 42. Table 4 Percentage of weight loss and VA content of the reported EVA samples after various treatments 42. 2015 Celanese 3, CONTRIBUTING FACTORS OF EVA DRUG In this specific study the processing temperature was.
RELEASE PROFILE also identified as an important factor A low processing. temperature had shown negative impact on the release. The in vitro drug release profile of the EVA based system in properties Figure 4 The total drug release increased from. comparison with selected polymeric excipients is shown in about 25 to about 40 as the processing temperature. Figure 1 42 Diltiazem hydrochloride was the studied API increased from 60 oC to 80 oC This reported processing. Under the same API to polymer ratio the EVA based system temperature dependency may be due to the influence of. exhibited a significantly lower cumulative drug release than processing temperature on the drug crystallinity in the EVA. the ethyl cellulose EC and the poly ethyl acrylate derivative matrix The percentages of crystallinity of MPT in the EVA. systems In the time span of the first 8 h the total percentage MPT extrudates were found to decrease with the increase of. of released drug from the EVA system was about 20 wt processing temperature based on the reported DSC data 34. in a pH 7 0 phosphate buffer at 37 oC This slow release Other contributing factors such as pellet size and porosity have. characteristic with low total drug released illustrates the also been reported. potential of a controlled release system with very high drug. loading 42 Further studies have suggested that the EVA drug. release profile can be influenced by many other EVA properties. and can be tuned by modifications, Figure 2 Cumulative drug release of MPT from EVA40 EVA28. EVA15 and EVA9 matrices EVA MPT w w 50 50 34, Figure 1 Release profiles of diltiazem hydrochloride from. extruded pellets based on various polymers polymer drug ratio. 1 1 size 2x2 mm 42, There are many other factors affecting the drug release properties. for EVA based oral controlled release system In a separate study. by Almeida and coworkers 34 it was found that the VA content. of the polymer the drug loading and the processing temperature. can significantly affect the in vitro drug release behavior Figures 2. 3 and 4 showed the results of cumulative drug release properties. of the reported EVA metoprolol tartrate MPT system with the. stated variables in demineralized water at 37 oC 34 When an Figure 3 Cumulative drug release of MPT from EVA40 MPT. EVA sample with 15 wt VA EVA15 was used a cumulative drug matrices containing different drug loadings 10 wt 20 wt. release 80 was obtained within the first 12 h This was more 30 wt 40 wt x and 50 wt 34. than double the total drug release obtained from EVA 40. As shown in Figure 3 increasing the drug loading increased. the cumulative drug release In the EVA40 MPT system a. significant total drug release increase was observed at a drug. loading of 50 wt over lower drug loadings 34 With an extra. 10 drug loading from 40 wt x to 50 wt in Figure 3, the cumulative dry release increased from 20 to 40 in the. first 12h Similar results on the drug loading also have been. reported on an EVA DTZ system 43,2015 Celanese 4, Figure 4 Cumulative drug release of MPT from EVA40 MPT.
matrices 50 50 w w processed at 60 oC 80 oC 90 oC,and 100 oC 34. Figure 5 Release profiles of diltiazem hydrochloride from EVA. MODIFICATIONS OF EVA FOR DRUG RELEASE based pellets with non ionic hydrophilic polymer additives at pH. PROFILE TUNING 7 0 43, An important way to tune the drug release profile is to modify When ionic hydrophilic polymers were added to the EVA. the EVA drug systems with additional components The results based drug release system both a significant increase in. here are based on the work of several research groups and total drug release and a pH response occurred 43 Figure 6. illustrate the manipulation of the EVA drug release profile of illustrates use of chitosan lactate and methoxyl pectin at a 20. water soluble APIs by using additives 42 45 wt loading on the EVA MPT system The total drug release. was clearly enhanced by the additives Within the first 12 h. It was reported in a later publication by Follonier and. the cumulative drug release was about 90 for the chitosan. coworkers that the addition of non ionic hydrophilic. modified systems and 80 for the pectin modified systems. polymers can significantly accelerate the drug release 43. For both additives the release rate at pH 7 0 showed a smaller. Polyvinylpyrrolidone PVP and polyvinyl alcohol PVOH are. increase when compared with the increase at pH 1 0 This is. shown as two examples in the non ionic hydrophilic polymer. due to the proposed mechanism that at pH 7 0 both additives. category In Figure 5 PVP and PVOH were used at a loading. presented a water insoluble barrier layer on the surface and in. of 20 wt From a baseline 20 EVA with no additives,the pores of the EVA matrix 43. both PVP and PVOH enhanced the drug release of the EVA. based system to about 60 and 90 respectively in 12h Some swelling agents were also studied as additives in. at a pH of 7 0 for the EVA MPT system The difference in the EVA based controlled release systems In studies showed. enhancement was attributed to the difference in the hydration in Figure 7 43 croscarmellose sodium low substituted. power of the additives Similarly other non ionic hydrophilic hydroxylpropylcellulose L HPC crospovidone and sodium. polymers have also been reported to have the same starch glycolate were evaluated Without the initial burst effect. acceleration effect These polymers include polyethylene oxide pronounced increase in drug release rate was observed from. cellulose acetate phthalate and hydroxylpropylmethylcellulose all the swelling agent modified EVA MPT systems Among. phthalate 43 44 all the systems in Figure 7 the sodium starch glycolate. modified system showed the highest total release of about. 95 within the first 12 h at a loading of 20 wt It was later. reported that the swelling agent effect was still valid at a. much lower concentration in an EVA based microparticle. system synthesized by a coacervation method 45 Figure 8. shows the cumulative drug release of the EVA microparticle. system modified by 2 00 wt of sodium starch glycolate in the. simulated gastric fluid and the intestinal fluids at different pH. 2015 Celanese 5, Figure 8 Cumulative amount of diltiazem HCl released mean. Figure 6 Release profiles of diltiazem hydrochloride from EVA SD from treated microparticles containing 2 00 w w sodium. based pellets with cationic polymer additives at pH 1 0 and 7 0 starch glycolate into 900 mL simulated gastric fluid pH 1 2. 43 0 120 min simulated intestinal fluid pH 5 0 120 360 min and. simulated intestinal fluid pH 6 8 360 720 min at 37 oC and 100. Independent of the pH of the medium the modified EVA. rpm n 2 45, system provided a very constant release rate and a total drug.
release of about 75 in the span of 12 h The drug release rate. of this modified system was then compared with a commercial. formulation Cardizem CD The sodium starch glycolate. containing EVA system exhibited a controlled release rate with. better consistency than the Cardizem CD system in the in. vitro study as demonstrated in Figure 9 45 The in vivo study. of the two systems in rabbits suggested that the modified. EVA system showed equivalent drug plasma concentration. to Cardizem CD but with less subject variability indicated by. smaller coefficient of variation Similar equivalency in drug. plasma concentration was reported in a PEO modified EVA. MPT drug delivery system when compared to the Slow. Lopressor 200 Dvitabs in the in vivo study in dogs 44. Figure 9 Diltiazem HCl release rates from the new controlled. release formulation and Cardizem CD into 900 mL water at 37. C and 100 rpm 45,ORAL TOXICITY OF EVA, As the parenteral pharmaceutical usage of EVA is well. established the toxicology study in the area has been well. investigated Biocompatibility data including cytotoxicity. sensitization irritation intracutaneous toxicity acute systemic. toxicity implantation and genotoxicity are readily available. EVA is also approved for FDA indirect contact and is on the. FDA inactive ingredient list for approved non oral drug. products in many categories 48 49, Figure 7 Release profiles of diltiazem hydrochloride from EVA. based pellets with swelling agents at pH 7 0 43 The oral toxicity of EVA was evaluated by Simulator of the. Human Intestinal Microbial Ecosystem SHIME by a group of. 2015 Celanese 6, researchers 34 Table 5 summarizes the results of the control significant evidence was observed that EVA was enzymatically. group where no EVA was used and the treatment group or chemically altered by the simulated GI tract fluids Data in. which was treated with 40 wt VA EVA at the concentration of Table 5 also suggests that the simulated intestinal fluid was not. 2 g L The EVA samples after the treatment were characterized significantly changed in composition by the EVA treatment. by DSC X ray diffraction SEM and Raman spectroscopy No. Table 5 Results pH bacterial group ammonium and fatty acid concentration of the SHIME experiments after exposure of EVA40 to. simulated intestinal fluid 34, The EVA concentration was 2 g L in the treatment group no EVA was used in the control group. Indicated a significant difference between the control and the treatment group p 0 01 a 5 with a mean difference of 9 46. CFU ml 1 for total aerobes, The oral toxicity of some EVA structural or compositional analogs such as polyvinyl acetate and vinyl acetate is also available.
from many sources 49 50 Table 6 shows the animal rat and mouse oral toxicity data of polyvinyl acetate which is a polymeric. structural analog of EVA 49 The data suggest that polyvinyl acetate presents a very low oral toxicity with LD50 25 mg Kg. Table 6 Oral toxicity of polyvinyl acetate 49,2015 Celanese 7. CONCLUSION subcutaneous hydromorphone implants, Ethylene vinyl acetate EVA copolymers have shown excellent designed for the treatment of cancer pain Pain. stability processability and versatility in the controlled release 1996 65 2 3 265 272. of selected oral administrated drugs via hot melt extrusion. HME For the drug systems discussed in this paper desired 10 Costantini LC Kleppner SR McDonough J. release profiles can be achieved with proper modifications Azar MR and Patel R Implantable technology for. Promising results have been reported in both in vitro drug long term delivery of nalmefene for treatment of. release studies as well as through in vivo studies in comparison. with commercial drug products EVA based systems have alcoholism Int J Pharm 2004 283 1 2 35 44. shown great potential in controlled release of drugs for oral 11 Sabel BA Dominiak P Haeuser W During MJ. administration,and Freese A Extended levodopa release from a. subcutaneously implanted polymer matrix in rats,REFERENCES Ann Neurol 1990 28 5 714 717. 1 Malpass DB Introduction to Industrial 12 Ling W Casadonte P Bigelow G Kampman KM. Polyethylene Properties Catalysts and Processes Patkar A Bailey GL Rosenthal RN and Beebe KL. John Wiley Sons Dec 17 2010 Buprenorphine implants for treatment of opioid. dependence A randomized controlled trial,2 Applications of Ethylene Vinyl Acetate.
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M Zhang F Martin C and McGinity James 46 Siegel RA Kost J and Langer R Mechanistic. W Pharmaceutical applications of hot studies of macromolecular drug release from. melt extrusion Part II Drug Dev Ind Pharm macroporous polymers I Experiments and. 2007 33 10 1043 1057 preliminary theory concerning completeness of. drug release J Controlled Release 1989 8 3 223,39 Kolhe SR Chaudhari PD and More DM Recent. advances in hot melt extrusion technology Int J, Pharm Sci Res 2012 3 12 4658 4669 47 Siegel RA and Langer R Mechanistic studies of. macromolecular drug release from macroporous,40 Maniruzzaman M Boateng JS Snowden. polymers II Models for the slow kinetics of drug,MJ and Douroumis D A review of hot melt. release J Controlled Release 1990 14 2 153 167,extrusion process technology to pharmaceutical.
products ISRN Pharm 2012 436763 436769 pp 48 21 CFR 2013 Code of Federal Regulations. Reg Nos 175 105 175 300 176 180 177 1200,41 Lee Thomas WY Boersen Nathan A Hui HW. 177 1210 177 1350 177 1390 178 1005 179 45,Chow SF Wan KY and Chow Albert HL Delivery. of poorly soluble compounds by amorphous 49 RTECS 2013 Polyvinyl acetate CAS No. solid dispersions Curr Pharm Des 2014 20 3 303 9003 20 7 Registry of Toxic Effects of Chemical. 324 Substances, 42 Follonier N Doelker E and Cole ET Evaluation 50 Journal of the American College of Toxicology. of hot melt extrusion as a new technique for 1982 1993 1 12 11 465. the production of polymer based pellets for,sustained release capsules containing high. loadings of freely soluble drugs Drug Dev Ind,Pharm 1994 20 8 1323 1339.
43 Follonier N Doelker E and Cole ET Various,ways of modulating the release of diltiazem. hydrochloride from hot melt extruded sustained,release pellets prepared using polymeric. materials J Controlled Release 1995 36 3 243,2015 Celanese 10. Celanese EVA Polymers,celanese com eva polymers,vitaldose com. CELANESE EVA POLYMERS,222 W Las Colinas Blvd,Suite 900N.
Irving TX 75039,CUSTOMER SERVICE,t 1 800 661 3663,e orderseva celanese com. MANUFACTURING,Edmonton Alberta Canada,TECHNOLOGY AND. PRODUCT STEWARDSHIP,8040 Dixie Highway,Florence KY 41042. t 1 859 525 4740,e eva techservice celanese com, 2015 Celanese or its affiliates All rights reserved. This publication was printed based on Celanese s present state of knowledge and Celanese undertakes no obligation to update. it Because conditions of product use are outside Celanese s control Celanese makes no warranties express or implied and. assumes no liability in connection with any use of this information Nothing herein is intended as a license to operate under or a. recommendation to infringe any patents, 2015 Celanese the C ball design and VitalDose are registered trademarks of Celanese or its affiliates.
EVA 004 EVAinOralControlledRelease WP Global EN 1214.

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