Novel polymers for DMSO-based in situ-forming implant systems

Novel polymers for DMSO-based in situ-forming implant systems

solvent exchange-based Besides-forming implant systems include a water-insoluble, biodegradable and/or non-biodegradable polymer as a matrix. Systems based on non-biodegradable polymers require an invasive surgical intervention to remove the implant from the site of injection. Therefore, biodegradable polymers used in implant manufacturing that degrade to form non-toxic by-products have grown in popularity. The most popular biodegradable polymers are poly(lactic acid), poly(lactic-co-glycolic acid), poly(I-caprolactone) and polyK copolymers (D,L-lactide-Associate-Caprolactone). These popular polymers also go by PLA, PLGA and PCL respectively. Dimethyl sulfoxide (DMSO), a biocompatible solvent, is one of the most popular solvents used as a vehicle for these injectable formulations. Thus, the final formulation typically consists of a drug dissolved or suspended in a DMSO solution of a biodegradable polymer.1,

Although the polymers listed above are quite popular, their in vivo Administration may be associated with certain deficiencies; Importantly, the accumulation of acidic degradation products generated during the hydrolysis of PLA and its derivatives2, Furthermore, the control of drug release from these polymers is particularly challenging for hydrophilic macromolecules. Non-linear drug release profiles have been observed with high bursts3, Therefore, there is interest in exploring the potential applications of novel polymers for the formation of DMSO-based implants. The results of three representative studies are summarized in this blog.

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) or PHBV, a biodegradable, biocompatible and water-insoluble polymer, is suitable for Besides-forming implant system. Hedayati et al studied in detail the development of a PHBV/DMSO based continuous delivery system for an antipsychotic drug ariprazole.4, Rheological measurements confirmed that the drug-loaded PHBV-DMSO system immediately forms a highly cross-linked network upon exposure to aqueous buffer. The implants showed a biphasic pattern of drug release, with an initial burst release with sustained drug release for 18 days. Drug release profiles were dependent on the initial polymer concentration in DMSO. Burst release decreased over the first 24 hours before increasing the polymer concentration, for example, 56% and 47% of cumulative drug release was observed with polymer concentrations of 2% and 4% w/v, respectively. Interestingly, there was a decrease in overall cumulative drug release over the 18-day period. Scanning electron microscopy (SEM) images showed that the porosity of the PHBV network increased significantly during the study period. The drug release from the PHBV-DMSO implant was compared to a carrageenan-based hydrogel system, which released a comparatively high burst of drug. , Thus, PHBV/DMSO based In in situ The implant provides a new formulation platform for the delivery of ariprazole.

Poly(ethylene carbonate) or PEC, a carbonic acid derivative, is not known to degrade in vitro By hydrolysis at physiological pH. On the other hand, it degrades by oxidation in vivo through surface erosion. In this case, the molecular weight of the polymer mass remains unchanged. Subcutaneous implants of PEC disappear from the body within weeks to months, with ethylene carbonate being the product of degradation.5, Lin et al evaluated the feasibility of using PEC as a surface-eroding biomaterial for the preparation of biodegradable Besides Creating a parenteral drug delivery system2, Various formulations of bovine serum albumin (BSA), the model drug, were prepared in either PEC/DMSO or PEC/NMP solutions. A DMSO formulation of BSA displayed less burst drug release than the NMP formulation. The results from orthogonal techniques were used to explain the higher initial drug release from NMP-based implants. SEM images of the depots made using the DMSO-based solution showed a less porous structure than the NMP formulation. Solvent release studies showed a rapid release of DMSO from the PEC depot relative to NMP, suggesting a comparatively quick formation of the depot from the DMSO solution. The rapid formation of a semi-solid polymer layer on the surface of a depot can become an effective barrier to restrict mass transfer to the depot interior and slow down the phase separation process. The authors propose that the solution of PEC in DMSO will be preferred over NMP due to the low burst release. In summary, these investigations show that Besides Depot forming system can be obtained from PEC solution.

Figure 1. A schematic approach to reduce burst drug release by using PEC as the polymer matrix. The approach is based on a summary of results from the study by Lin et al.2 and Chu et al6,

In a study released by the same research group, the effect of PEC polymer molecular weight on drug release Besides– The depots built were checked. A decrease in polymer molecular weight from 200 kDa (PEC200) to 41 kDa (PEC41) resulted in a significant reduction in burst drug release. PEC 200 in DMSO (15% w/w) was demonstrated by a release of 63.7% BSA (15% w/w over 2 days), compared to 22.5% release from PEC41 samples. Burst drug release can be further reduced by increasing the PEC41 concentration to 25% w/w; After 6 days, only 16.3% of the drug was released. Compared to the depots made using the PEC200, the PEC41 samples had a slower rate of solvent release, a slower phase inversion, and a denser surface. The authors conclude that the initial blast of the protein from the PEC41 depot was significantly reduced, which makes it a promising candidate polymer carrier. A comprehensive strategy for modulating early burst drug release based on two studies is presented in Figure 1.

Seema Thakral, Ph.D.

References:

1. Thakur, RR; McMillan, HL; Jones, DS: Solvent induced phase reversal-based in situ making controlled release drug delivery implants. J Controlled Release, 2014, 76, 8-23.

2. Liu, Y.; Kemmer, A.; Keim, K.; Curdy, C.; Peterson, H.; Kissel, T. Poly(ethylene carbonate) as a surface-eroding biomaterial for in situ forming parenteral drug delivery systems: a feasibility study. Eur J Pharm Biopharma, 2010, 76(2), 222-229.

3.Korber, M.; Bodmeier R. Development of an in situ forming PLGA drug delivery system, I: characterization of a non-aqueous protein precipitation. J Pharm. SCI, 2008, 35, 283-292.

4. Hedayati, A.; G. Yazdi, S.; Dehghankelishadi, P.; B Javan, N.; Akbari, H.; Dorkosh, F. Preparation, optimization and physicochemical characterization of aripiprazole loaded nano-porous in situ forming implants. Pharm Nanotech, 2017, 5(2), 138-147.

5.A Gunatilke, R. Officer, Biodegradable Synthetic Polymers for Tissue Engineering, EUR. Room. mater, 2003, 5, 1-16.

6.Chu, D.; Curdy, C.; Ribessel, B.; Beck-Broichsitter, M.; Kissel, T. In situ forming parenteral depot systems based on poly(ethylene carbonate): the effect of polymer molecular weight on model protein release. Eur J Pharm Biopharma, 2013, 85(3), 1245-1249.

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