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1.
Int J Pharm ; 648: 123616, 2023 Dec 15.
Article in English | MEDLINE | ID: mdl-37977291

ABSTRACT

High concentration formulations have become an important pre-requisite in the development of biological drugs, particularly in the case of subcutaneous administration where limited injection volume negatively affects the administered dose. In this study, we propose to develop high concentration formulations of biologics using a reversible protein-polyelectrolyte complex (RPC) approach. First, the versatility of RPC was assessed using different complexing agents and formats of therapeutic proteins, to define the optimal conditions for complexation and dissociation of the complex. The stability of the protein was investigated before and after complexation, as well as upon a 4-week storage period at various temperatures. Subsequently, two approaches were selected to develop high concentration RPC formulations: first, using up-concentrated RPC suspensions in aqueous buffers, and second, by generating spray-dried RPC and further resuspension in non-aqueous solvents. Results showed that the RPC concept is applicable to a wide range of therapeutic protein formats and the complexation-dissociation process did not affect the stability of the proteins. High concentration formulations up to 200 mg/mL could be achieved by up-concentrating RPC suspensions in aqueous buffers and RPC suspensions in non-aqueous solvents were concentrated up to 250 mg/mL. Although optimization is needed, our data suggests that RPC may be a promising avenue to achieve high concentration formulations of biologics for subcutaneous administration.


Subject(s)
Biological Products , Drug Compounding , Proteins , Excipients , Solvents
2.
Biomacromolecules ; 23(10): 4388-4400, 2022 Oct 10.
Article in English | MEDLINE | ID: mdl-36170117

ABSTRACT

This work reports on a novel polyester copolymer containing poly(dopamine), a synthetic analogue of natural melanin, evaluated in a sustained-release drug delivery system for ocular intravitreal administration of drugs. More specifically, a graft copolymer of poly(ε-caprolactone)-graft-poly(dopamine) (PCL-g-PDA) has been synthesized and was shown to further extend the drug release benefits of state-of-the-art biodegradable intravitreal implants composed of poly(lactide) and poly(lactide-co-glycolide). The innovative biomaterial combines the documented drug-binding properties of melanin naturally present in the eye, with the established ocular tolerability and biodegradation of polyester implants. The PCL-g-PDA copolymer was obtained by a two-step modification of PCL with a final PDA content of around 2-3 wt % and was fully characterized by size exclusion chromatography, NMR, and diffusion ordered NMR spectroscopy. The thermoplastic nature of PCL-g-PDA allowed its simple processing by hot-melt compression molding to prepare small implants. The properties of unmodified PCL and PCL-g-PDA implants were studied and compared in terms of thermal properties (differential scanning calorimetry), thermal stability (thermogravimetry analysis), degradability, and in vitro cytotoxicity. PCL and PCL-g-PDA implants exhibited similar degradation properties in vitro and were both stable under physiological conditions over 110 days. Likewise, both materials were non-cytotoxic toward L929 and ARPE-19 cells. The drug loading and in vitro release properties of the new materials were investigated with dexamethasone (DEX) and ciprofloxacin hydrochloride (CIP) as representative drugs featuring low and high melanin-binding affinities, respectively. In comparison to unmodified PCL, PCL-g-PDA implants showed a significant extension of drug release, most likely because of specific drug-catechol interaction with the PDA moieties of the copolymer. The present study confirms the advantages of designing PDA-containing polyesters as a class of biodegradable and biocompatible thermoplastics that can modulate and remarkably extend the drug release kinetics thanks to their unique drug-binding properties, especially, but not limited to, for ocular applications.


Subject(s)
Melanins , Polyglactin 910 , Biocompatible Materials , Catechols , Ciprofloxacin , Delayed-Action Preparations/pharmacology , Dexamethasone , Drug Delivery Systems , Drug Liberation , Indoles , Polyesters/chemistry , Polyethylene Glycols/chemistry , Polymers
3.
J Pharm Sci ; 111(9): 2514-2524, 2022 09.
Article in English | MEDLINE | ID: mdl-35429492

ABSTRACT

PURPOSE: For injectable biopharmaceuticals, the subcutaneous route of administration is increasingly preferred over intravenous administration. However, one of the challenges in the development of subcutaneously administered biopharmaceuticals is a reduced bioavailability, which is difficult to predict. Since animal models do not reliably reflect bioavailability in patients, in vitro models could help to develop drug candidates. The purpose of this study was to evaluate a versatile set of in vitro tools for their suitability to predict bioavailability of biopharmaceuticals after subcutaneous administration. METHODS: We examined seven commercially available biopharmaceuticals using three instruments, i.e., the Subcutaneous Injection Site Simulator (Scissor), the Osmomat 050, and a dialysis system using three artificial extracellular matrices, two dissolution apparatuses, i.e., the USP4 and the USP7, and two evaluation tools, i.e., the affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) and the Developability Index (DI). Results were evaluated for their usefulness to predict the bioavailability and other pharmacokinetic parameters in humans using the Pearson correlation. RESULTS: None of the tested instruments and methods could reliably approximate bioavailability. Only pressure values derived with the Osmomat 050 instrument correlated with Cmax with a Pearson correlation coefficient greater than 0.8. CONCLUSION: No single in vitro method confidently predicted the bioavailability in humans. We only found a correlation to maximum plasma concentration values for one of the tested approaches. However, a more focused evaluation would be necessary to confirm our findings and test combinations of orthogonal methods that may improve the confidence of such a prediction.


Subject(s)
Biological Products , Animals , Biological Availability , Humans , Injections, Subcutaneous , Pharmaceutical Preparations/chemistry , Renal Dialysis , Subcutaneous Tissue , Ubiquitin-Specific Peptidase 7 , Ubiquitin-Specific Proteases
4.
Annu Rev Pharmacol Toxicol ; 62: 341-363, 2022 01 06.
Article in English | MEDLINE | ID: mdl-34990203

ABSTRACT

Innovative formulation technologies can play a crucial role in transforming a novel molecule to a medicine that significantly enhances patients' lives. Improved mechanistic understanding of diseases has inspired researchers to expand the druggable space using new therapeutic modalities such as interfering RNA, protein degraders, and novel formats of monoclonal antibodies. Sophisticated formulation strategies are needed to deliver the drugs to their sites of action and to achieve patient centricity, exemplified by messenger RNA vaccines and oral peptides. Moreover, access to medical information via digital platforms has resulted in better-informed patient groups that are requesting consideration of their needs during drug development. This request is consistent with health authority efforts to upgrade their regulations to advance age-appropriate product development for patients. This review describes formulation innovations contributingto improvements in patient care: convenience of administration, preferred route of administration, reducing dosing burden, and achieving targeted delivery of new modalities.


Subject(s)
Drug Delivery Systems , Peptides , Drug Delivery Systems/methods , Humans , Patient Care , Pharmaceutical Preparations , Proteins
5.
Adv Drug Deliv Rev ; 178: 113990, 2021 11.
Article in English | MEDLINE | ID: mdl-34600963

ABSTRACT

Additive manufacturing (AM) or 3D printing is enabling new directions in product design. The adoption of AM in various industrial sectors has led to major transformations. Similarly, AM presents new opportunities in the field of drug delivery, opening new avenues for improved patient care. In this review, we discuss AM as an innovative tool for drug product design. We provide a brief overview of the different AM processes and their respective impact on the design of drug delivery systems. We highlight several enabling features of AM, including unconventional release, customization, and miniaturization, and discuss several applications of AM for the fabrication of drug products. This includes products that have been approved or are in development. As the field matures, there are also several new challenges to broad implementation in the pharmaceutical landscape. We discuss several of these from the regulatory and industrial perspectives and provide an outlook for how these issues may be addressed. The introduction of AM into the field of drug delivery is an enabling technology and many new drug products can be created through productive collaboration of engineers, materials scientists, pharmaceutical scientists, and industrial partners.


Subject(s)
Drug Design , Pharmaceutical Preparations/chemical synthesis , Drug Industry , Humans , Pharmaceutical Preparations/chemistry
6.
Eur J Pharm Sci ; 104: 65-71, 2017 Jun 15.
Article in English | MEDLINE | ID: mdl-28347774

ABSTRACT

The aim of this study was to investigate the interaction between the positively charged gonadotropin releasing hormone receptor antagonist degarelix and the two polyanions alginate and carboxymethyl cellulose (CMC). Light as well as transmission electron microscopy revealed that complexes formed by simple mixing of the peptide with one of the polymers had a nano-structure consisting of twisted fibers. The remarkable unique process of complex formation could be followed by isothermal titration calorimetry: We found that peptide self-aggregates dissolved upon the addition of polyanion and peptide-polymer-complexes formed thereafter with the anionic polymer as a template. Peptide release from the complexes was tested in vitro and in vivo and compared to the dissolution of drug from self-aggregates. In vitro the release was monitored over a period of three months. We could find only slight differences in the release kinetics for the alginate and the CMC complexes compared to the pure drug. An in vivo study in Sprague Dawley rats showed similar degarelix plasma concentration levels for the complex formulations and an aqueous degarelix solution following subcutaneous injection. Overall, our findings suggest a competition between complex formation and peptide aggregation, which did not increase the availability of free drug.


Subject(s)
Oligopeptides/administration & dosage , Polymers , Animals , Circular Dichroism , Delayed-Action Preparations , Male , Microscopy, Electron, Transmission , Polyelectrolytes , Rats , Rats, Sprague-Dawley
7.
Eur J Pharm Sci ; 93: 21-8, 2016 Oct 10.
Article in English | MEDLINE | ID: mdl-27460846

ABSTRACT

Protein-protein and peptide-peptide (self-)interactions are of key importance in understanding the physiochemical behavior of proteins and peptides in solution. However, due to the small size of peptide molecules, characterization of these interactions is more challenging than for proteins. In this work, we show that protein-protein and peptide-peptide interactions can advantageously be investigated by measurement of the diffusion coefficient using Taylor Dispersion Analysis. Through comparison to Dynamic Light Scattering it was shown that Taylor Dispersion Analysis is well suited for the characterization of protein-protein interactions of solutions of α-lactalbumin and human serum albumin. The peptide-peptide interactions of three selected peptides were then investigated in a concentration range spanning from 0.5mg/ml up to 80mg/ml using Taylor Dispersion Analysis. The peptide-peptide interactions determination indicated that multibody interactions significantly affect the PPIs at concentration levels above 25mg/ml for the two charged peptides. Relative viscosity measurements, performed using the capillary based setup applied for Taylor Dispersion Analysis, showed that the viscosity of the peptide solutions increased with concentration. Our results indicate that a viscosity difference between run buffer and sample in Taylor Dispersion Analysis may result in overestimation of the measured diffusion coefficient. Thus, Taylor Dispersion Analysis provides a practical, but as yet primarily qualitative, approach to assessment of the colloidal stability of both peptide and protein formulations.


Subject(s)
Models, Chemical , Peptides/chemistry , Protein Binding , Viscosity
8.
J Control Release ; 165(3): 199-206, 2013 Feb 10.
Article in English | MEDLINE | ID: mdl-23220105

ABSTRACT

Hexylsubstituted poly(lactic acid) (hexPLA) is a viscous polymer, which degrades in the presence of water similar to the structure related poly(lactic acid). With hydrophilic active compounds, like Triptorelin acetate, the lipophilic polymer was formulated in form of parenterally injectable suspensions. This first in vivo study toward the biocompatibility of hexPLA implants in rats over 3 months in comparison to in situ forming poly(lactic-co-glycolic acid) (PLGA) formulations is presented here. The hexPLA implants showed only a mild acute inflammation at the injection site after application, which continuously regressed. In contrast to the PLGA formulations, hexPLA did not provoke an encapsulation of the implant with extracellular matrix. Prior to the formulation application, the stability of Triptorelin inside the hexPLA matrix was assessed under different storage conditions and in the presence of buffer to simulate a peptide degrading environment. At 5°C Triptorelin showed a stability of 98% inside the polymer for at least 6 months. The stability was still 78% at an elevated temperature of 40°C. HexPLA protected the incorporated peptide from the surrounding aqueous environment, which resulted in 20% less degradation inside the polymer compared to the solution. This protection effect supports the use of Triptorelin-hexPLA formulations for parenteral sustained-release formulations. In a second in vivo evaluation in Wistar Hannover rats, formulations containing 5% and 10% Triptorelin in the polymeric matrix released the active compound continuously for 6 months. The formulations showed a higher release during the initial 7 days, which is necessary for the clinical use to down-regulate all GnRH-receptors. Afterwards, a zero order drug release was observed over the first 3 months. After 3 months, the plasma levels decreased slowly but remained at effective concentrations for the total of 6 months. Furthermore, a qualitative in vitro-in vivo correlation was observed, possibly facilitating future optimization of the Triptorelin-hexPLA sustained-release formulations.


Subject(s)
Antineoplastic Agents, Hormonal/administration & dosage , Drug Carriers/administration & dosage , Lactic Acid/chemistry , Polymers/chemistry , Triptorelin Pamoate/administration & dosage , Animals , Antineoplastic Agents, Hormonal/chemistry , Antineoplastic Agents, Hormonal/pharmacokinetics , Biocompatible Materials/administration & dosage , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacokinetics , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Stability , Injections, Subcutaneous , Polyesters , Rats , Rats, Sprague-Dawley , Triptorelin Pamoate/chemistry , Triptorelin Pamoate/pharmacokinetics
9.
Eur J Pharm Biopharm ; 81(3): 591-9, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22561956

ABSTRACT

Poly(lactic acid) is a widely used polymer for parenteral sustained-release formulations. But its solid state at room-temperature complicates the formulation process, and elaborate formulation systems like microparticles and self-precipitating implants are required for administration. In contrast, hexylsubstituted poly(lactic acid) (hexPLA) is a viscous, biodegradable liquid, which can simply be mixed with the active compound. In this study, the feasibility to prepare injectable suspension formulations with peptides was addressed on the example of the GnRH-agonist Triptorelin. Two formulation procedures, of which one was a straight forward one-step cryo-milling-mixing process, were compared regarding the particle size of the peptide in the polymer matrix, distribution, and drug release. This beneficial method resulted in a homogeneous formulation with an average particle diameter of the incorporated Triptorelin of only 4.1 µm. The rheological behavior of the Triptorelin-hexPLA formulations was assessed and showed thixotropic and shear-thinning behavior. Viscosity and injectability were highly dependent on the drug loading, polymer molecular weight, and temperature. Nine formulations with drug loadings from 2.5% to 10% and hexPLA molecular weights between 1500 and 5000 g/mol were investigated in release experiments, and all displayed a long-term release for over 3 months. Formulations with hexPLA of 1500 g/mol showed a viscosity-dependent release and hexPLA-Triptorelin formulations of over 2500 g/mol a molecular weight-dependent release profile. In consequence, the burst release and rate of release were controllable by adapting the drug loading and the molecular weight of the hexPLA. The degradation characteristics of the hexPLA polymer during the in vitro release experiment were studied by following the molecular weight decrease and weight loss. Triptorelin-hexPLA formulations had interesting sustained-release characteristics justifying further investigations in the drug-polymer interactions and the in vivo behavior.


Subject(s)
Antineoplastic Agents, Hormonal/administration & dosage , Drug Carriers/chemistry , Lactic Acid/chemistry , Polymers/chemistry , Triptorelin Pamoate/administration & dosage , Delayed-Action Preparations , Injections , Molecular Weight , Particle Size , Polyesters , Rheology , Suspensions , Temperature , Time Factors , Viscosity
10.
Eur J Pharm Biopharm ; 57(3): 441-6, 2004 May.
Article in English | MEDLINE | ID: mdl-15093591

ABSTRACT

Poly (DL-lactide-co-glycolide) microparticles (MP) containing a highly potent peptidic gonadotropin releasing hormone antagonist (degarelix) of interest in the prostate cancer indication were screened for biological performance. Efficacy was tested in a castrated male rat model at 3 doses (0.4, 1.0 and 1.5 mg/kg) and assessed as inhibition of luteinizing hormone (LH) secretion. When increasing the dose, onset of inhibition was faster, inhibition was more intense, and duration of action was prolonged. The MP type was also highly influent. If spray-dried and microextrusion particles exhibited comparable potencies, double emulsion microspheres were significantly less potent, both for onset and duration of inhibition. Interestingly, for the latter type it was found that the degarelix fraction released upon reconstitution in the solution for injection was significantly lower (max 0.3%), in comparison to spray-dried MP (max 2%) or microextrusion (max 4%). With the three types of particles, increasing peptide content was detrimental for duration of action, but only little difference was noticed between particles based on different polymers. At 1.5 mg/kg, LH inhibition was achieved over 36 days with spray-dried MP based on 75/25 lactate/glycolate copolymer. This was superior by 1 week to the performance of unformulated degarelix given at the same dose.


Subject(s)
Gonadotropin-Releasing Hormone/antagonists & inhibitors , Hormone Antagonists/metabolism , Lactic Acid/metabolism , Microspheres , Polyglycolic Acid/metabolism , Polymers/metabolism , Animals , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/metabolism , Gonadotropin-Releasing Hormone/metabolism , Hormone Antagonists/administration & dosage , Lactic Acid/administration & dosage , Luteinizing Hormone/antagonists & inhibitors , Luteinizing Hormone/metabolism , Male , Polyglycolic Acid/administration & dosage , Polylactic Acid-Polyglycolic Acid Copolymer , Polymers/administration & dosage , Rats , Rats, Sprague-Dawley
11.
Eur J Pharm Biopharm ; 56(3): 327-36, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14602174

ABSTRACT

The formulation of a new GnRH antagonist (degarelix) in biodegradable poly(DL-lactide-co-glycolide) (PLGA) microparticles was investigated for the development of a 3-month sustained release formulation to treat prostate cancer. The aim was to screen formulation technologies and distinct copolymers to produce microparticles (MP) of different types with good entrapment efficiency (>85%) and peptide purity (>95%) after gamma sterilization. Basically, three types of degarelix-loaded MP (4, 8 and 16% w/w nominal content) were produced with solvent and non-solvent technologies, namely double-emulsion solvent evaporation, spray-drying and two extrusion methods. Besides composition, commercial copolymers differing in residual monomer content and functional group at the carboxylic terminus (acid or ester) were characterized and employed. Peptide loading capacity and purity, as well as shape, size characteristics, and porosity of the produced microparticles were discussed in relation to technology and copolymer choice. Spray-drying and micro-extrusion were the two preferred formulation technologies because of higher entrapment efficiency and better preservation of peptide purity during production and gamma-sterilization. The impact of formulation technologies on the MP characteristics overwhelmed the impact of copolymer selection. Nevertheless, one particular polymer was discarded since it was more susceptible towards radiolytic degradation. The resulting degarelix-MP will be tested in a biological assay for selection of the formulation based on performance.


Subject(s)
Gonadotropin-Releasing Hormone/antagonists & inhibitors , Hormone Antagonists/chemistry , Lactic Acid/chemistry , Microspheres , Oligopeptides/administration & dosage , Oligopeptides/pharmacokinetics , Polyglycolic Acid/chemistry , Polymers/chemistry , Biotransformation , Chemistry, Pharmaceutical , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Hormone Antagonists/administration & dosage , Hormone Antagonists/pharmacokinetics , Lactic Acid/administration & dosage , Lactic Acid/pharmacokinetics , Oligopeptides/chemistry , Polyglycolic Acid/administration & dosage , Polyglycolic Acid/pharmacokinetics , Polylactic Acid-Polyglycolic Acid Copolymer , Polymers/administration & dosage , Polymers/pharmacokinetics
12.
Eur J Pharm Sci ; 20(2): 217-22, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14550888

ABSTRACT

A new fluorescent polymer based on D,L-lactic acid units end-capped with 1-pyrenebutanol (PLAP) was synthesized by ring-opening polymerization. PLAP having different molecular weight could be obtained by varying the ratio of D,L-lactide and 1-pyrenebutanol. Fluorescent nanoparticles (NP) were prepared using blends of poly(D,L-lactic acid) (PLA) and the new PLAP of 6 kDa by the salting-out process. Incubation of these nanoparticles with human blood monocytes was performed in serum and the cell-associated fluorescence was analysed by flow cytometry. Monocytes in contact with NP containing increasing amounts of PLAP showed a regular increase of the fluorescence. Cells incubated with NP containing 5% (w/w) of PLAP showed high signals of fluorescence with no possible overlap with those given by blank monocytes. This demonstrated that flow cytometry performed in the UV domain was very specific. In addition, the results of cytotoxicity tests using a MTT assay method indicated that PLAP did not increase the cytotoxicity when incorporated into PLA nanoparticles.


Subject(s)
Fluorescent Dyes/chemical synthesis , Polyesters/chemical synthesis , Pyrenes/chemistry , Cell Survival/drug effects , Chemical Phenomena , Chemistry, Physical , Fluorescent Dyes/pharmacology , Humans , In Vitro Techniques , Kinetics , Magnetic Resonance Spectroscopy , Microspheres , Molecular Weight , Monocytes/drug effects , Phagocytosis , Polyesters/pharmacology , Pyrenes/pharmacology , Spectrophotometry, Ultraviolet , Tetrazolium Salts , Thiazoles
13.
Int J Pharm ; 254(1): 69-72, 2003 Mar 18.
Article in English | MEDLINE | ID: mdl-12615412

ABSTRACT

Poly(D,L-lactic acid)-methoxypoly(ethylene glycol) (PLA-MePEG) copolymers were synthesized by ring-opening polymerization of D,L-lactide in the presence of MePEG of different molecular weights and stannous octoate as the catalyst. The chemical composition of the diblock-copolymer PLA-MePEG was confirmed by 1H-NMR and the molecular weight and distribution were assessed by gel permeation chromatography. Nanoparticles containing Nile red as a fluorescent dye were prepared using poly(D,L-lactic acid) (PLA), blends of PLA and PLA-MePEG or PLA-MePEG alone. Incubation of nanoparticles with human blood monocytes was performed in serum or in PBS and the cell-associated fluorescence was analyzed by flow cytometry. In serum, a protective effect was obtained and the interaction of particles with mononuclear leukocytes decreased to 40%.


Subject(s)
Leukocytes, Mononuclear/metabolism , Microspheres , Polyesters/chemistry , Polyethylene Glycols/chemistry , Biocompatible Materials , Blood/metabolism , Chromatography, Gel/instrumentation , Chromatography, Gel/methods , Drug Carriers , Flow Cytometry/instrumentation , Flow Cytometry/methods , Humans , In Vitro Techniques , Molecular Weight , Nanotechnology , Particle Size , Polyethylene Glycols/metabolism , Polymers/chemistry , Polymers/metabolism , Surface Properties
14.
Biomaterials ; 23(4): 993-1002, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11791933

ABSTRACT

Laboratory- and pilot-scale racemic polylactides (PLA50) were synthesized in the presence of stannous octoate (SnOct2) or zinc-metal as initiators in the absence of alcohol. The resulting polymers were processed by compression molding or injection molding depending on the batch scale. The hydrolytic degradation of compression-molded samples selected to be comparable was investigated first in order to show the influence of the initiator system. Differences in water uptake were found between PLA50-Zn (zinc-metal initiation) and PLA50-Sn (SnOct2 initiation). PLA50-Zn being much more hydrophilic. PLA50-Sn exhibited a slower molecular weight decrease and delayed onsets of weight loss, release of acidity and stereocomplex formation, with respect to PLA-Zn. The concentration in residual tin in PLA50-Sn increased from 306 to 795 ppm during aging. In the case of PLA50-Zn the residual metal remains constant at ca. 40 ppm. In a second series of experiments, high molecular weight PLA50 different in characteristics and in initiator, synthesized under pilot-scale, were compared. The effects of the initiator on the degradation of the polymers well agreed with laboratory-scale findings, differences in hydrophobicity being enlarged by the up scaling. PLA50-Sn polymers appeared much more degradation resistant than PLA50-Zn ones. Contributions of the other characteristics (e.g. molecular weight, purity, stereoregularity, processing) were shown to be important as well.


Subject(s)
Biocompatible Materials/chemistry , Polyesters/chemistry , Absorption , Biodegradation, Environmental , Caproates , Crystallization , Drug Stability , Hydrolysis , In Vitro Techniques , Materials Testing , Molecular Weight , Pilot Projects , Tin , Water , Zinc
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