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Design of new biodegradable polymer matrices for controlled drug delivery
KTH, Superseded Departments, Polymer Technology.ORCID iD: 0000-0002-1631-1781
2000 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Conventional drug administration technologies display poorcontrollability, and lead to high plasma concentrations andshort duration times, which frequently lead to adverse effects.Controlled release technology aims at predictable andreproducible delivery of an active substance over an extendedperiod of time, yielding optimal response and prolongedefficiency, and thus offering considerable improvement of manytreatments. A powerful approach to controlled drug delivery isthe incorporation of the drug into a biodegradable polymericmatrix, which distributes the active substance in a controlledand sustained fashion as the polymer erodes.

This thesis describes the design of novel biodegradablepolymer matrices for controlled and sustained drug delivery.New functional and biodegradable materials with variableproperties were obtained by homopolymer blending andcopolymerization of building blocks with specific, desirableproperties; poly(adipic anhydride) (PAA), poly(trimethylenecarbonate) (PTMC), poly(1,5-dioxepan-2-one) (PDXO),poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), andpoly(L-lactide-co-1,5-dioxepan-2-one) (P(L-LA-co-DXO).Techniques were developed for the preparation of drug-releasingmatrices in the form of films and microspheres. Variousanalysis techniques, including Differential ScanningCalorimetry,1H-Nuclear Magnetic Resonance, InfraredSpectrometry, Scanning Electron Microscopy, Size ExclusionChromatography and UV-VIS Spectroscopy, were used forcharacterization.

Microspheres encapsulating therapeutic substances wereprepared from P(L-LA-co-DXO) and blends of PDXO with PLLA orPDLLA. The properties, storage stability,degradation and drugrelease characteristics of these matrices were explored,compared and evaluated with special regard to the morphologyand its impact on thein vitrobehavior. Sustained release of drugs wasobtained. The mode of release was strongly influenced by thehydrophilicity of the drug, and by the copolymer/blendcomposition and morphology. The lactide:DXO composition wasproven to be a versatile tool to control the morphology and inturn the rates and pattern of erosion and diffusion ofencapsulated agents from the matrices.

Films were prepared from PTMC-PAA blends, in which PAA actedas a plasticizer. Loss of the fast-degrading PAA componentenhanced the porosity and hydration of the slow-degrading PTMC.A statistical full factorial model was designed to elucidatethe influence of matrix parameters and their interactions. ThePTMC-PAA ratio, the molecular weight of the PTMC, andinteractions amongst these factors significantly influenced therelease performance, mass loss and degree of plasticization andthe relationships obtained enabled the erosion and drug releasepattern to be predicted and controlled. Moisture uptake,storage stability at different relative humidities, and thesterilizability were determined to further explore theversatility of PTMC-PAA matrices. Thein vivolocal tissue response and biocompatibility ofPTMC-PAA implants was assessed in the anterior chamber ofrabbits eyes for 1 month. PTMC-rich matrices displayed goodbiocompatibility.

Key factors that regulate the biological activity of thesepolymeric vehicles were identified as drug solubility,composition, molecular weight, stereochemical configuration,and morphology. By careful design, the degradation and drugrelease characteristics, e.g. kinetics and duration, can bealtered over a broad spectrum. This study shows that structuralchanges of the polymer backbone, and the modeling ofcomposition and morphology provide powerful means of tailoringsystems for specific applications.

Keywords: controlled release, drug delivery, microspheres,polylactide, poly(1,5-dioxepan-2-one), poly(adipic anhydride),poly(trimethylene carbonate), degradation, blends

Place, publisher, year, edition, pages
Stockholm: KTH , 2000. , 118 p.
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-2949ISBN: 91-7170-534-1 (print)OAI: oai:DiVA.org:kth-2949DiVA: diva2:8688
Public defence
2000-04-14, 00:00 (English)
Note
QC 20100528Available from: 2000-04-18 Created: 2000-04-18 Last updated: 2010-05-28Bibliographically approved
List of papers
1. Novel drug delivery microspheres from poly(1,5-dioxepan-2-one-co-L-lactide)
Open this publication in new window or tab >>Novel drug delivery microspheres from poly(1,5-dioxepan-2-one-co-L-lactide)
1999 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 37, no 12, 1877-1884 p.Article in journal (Refereed) Published
Abstract [en]

Novel microspheres from copolymers of 1,5-dioxepan-2-one (DXO) and L-lactide (L-LA) were prepared by oil-in-water solvent evaporation and oil-in-oil solvent removal. The two preparation techniques were evaluated for sphere formulation and incorporation of two different drugs. Sustained release of these therapeutic substances was obtained. The consequences of altering the DXO : LA ratio, preparation method, and drug hydrophilicity were explored and identified as factors governing sphere quality, in vitro degradation, and drug release characteristics. We show that these relationships provide a powerful means of controlling the microsphere performance.

Keyword
1, 5-dioxepan-2-one, L-lactic acid, microspheres, drug delivery, controlled release, RELEASE
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-13120 (URN)000080345100017 ()
Note
QC 20100528Available from: 2010-05-28 Created: 2010-05-28 Last updated: 2017-12-12Bibliographically approved
2. Copolymerization and polymer blending of trimethylene carbonate and adipic anhydride for tailored drug delivery
Open this publication in new window or tab >>Copolymerization and polymer blending of trimethylene carbonate and adipic anhydride for tailored drug delivery
1999 (English)In: Journal of Applied Polymer Science, ISSN 0021-8995, E-ISSN 1097-4628, Vol. 72, no 2, 227-239 p.Article in journal (Refereed) Published
Abstract [en]

The copolymerization in bulk and solution of trimethylene carbonate (TMC) with adipic anhydride (AA) as well as the blending of homopolymers are described. We show experimentally that the components are not copolymerizable but partially miscible, forming a microscopic dispersion without any visible signs of phase separation. Poly(adipic anhydride) (PAA) functions as a plasticizer, permitting an increase in the erosion rate by increasing the porosity and hydration. Drug delivery from the blends was evaluated. A statistical factorial model was designed to explore the influence of three important blend parameters and their interactions, making it possible to predict the erosion and drug-release behavior of the blend matrices. The PAA:poly(trimethylene carbonate) (PTMC) ratio and molecular weight of the polycarbonate component significantly influence the drug-release performance, mass loss, and degree of plasticization. The interaction among these factors also influences the blend properties. Plasticization of PTMC enhances the drug release to an extent that is dependent on the amount of PAA used. We demonstrate that blending offers a convenient alternative to copolymerization for the preparation of polymer matrices with predictable drug delivery.

Keyword
screening design, poly(trimethylene carbonate), poly(adipic acid), drug delivery, degradable blend, copolymerization, RELEASE CHARACTERISTICS, POLY(ADIPIC ANHYDRIDE), DEGRADATION, MICROSPHERES, POLYANHYDRIDES, MATRICES
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-13121 (URN)000078984800008 ()
Note
QC 20100528Available from: 2010-05-28 Created: 2010-05-28 Last updated: 2017-12-12Bibliographically approved
3. Sterilization, storage stability and in vivo biocompatibility of poly(trimethylene carbonate)/poly(adipic anhydride) blends
Open this publication in new window or tab >>Sterilization, storage stability and in vivo biocompatibility of poly(trimethylene carbonate)/poly(adipic anhydride) blends
Show others...
2000 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 21, no 9, 945-955 p.Article in journal (Refereed) Published
Abstract [en]

Biodegradable blends of poly(trimethylene carbonate) (PTMC) and poly(adipic anhydride) (PAA) have been proven to be strong candidates for controlled drug delivery polymers in vitro. We now report on the stability, sterilizability and in vivo local tissue response of these matrices. Blend matrices were sterilized by beta-radiation or ethylene oxide gas treatment, stored at different times and temperatures, and analyzed for changes in physicochemical properties. Moisture uptake at different relative humidities and storage times was determined. Sterilization procedures induced hydrolysis of the matrices. Ethylene oxide gas sterilization had a significantly more marked effect upon the matrix properties than radiation treatment. The onset of degradation was reflected in a decrease of crystallinity and molecular weight along with a change of blend composition. A similar onset of matrix degradation was observed upon storage in air. The physicochemical properties of the blends were well preserved upon storage under argon atmosphere. Biocompatibility of PTMC/PAA implants was assessed in the anterior chamber of rabbits eyes for 1 month. At selected post-operative time points, aqueous humor was analyzed for white blood cells and the corneal thickness was measured. The results suggest good biocompatability of PTMC-rich matrices, whereas fast eroding PAA-rich matrices caused inflammatory responses, due to a burst release of degradation products.

Keyword
poly(trimethylene carbonate), poly(adipic acid), sterilization, in vivo, degradable blends, implant, DRUG-CARRIER MATRICES, IN-VITRO, BIOERODIBLE POLYANHYDRIDES, CONTROLLED-RELEASE, POLYMERS, DEGRADATION, CARBONATE)
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-13122 (URN)10.1016/S0142-9612(99)00268-9 (DOI)000085787000010 ()
Note
QC 20100528Available from: 2010-05-28 Created: 2010-05-28 Last updated: 2017-12-12Bibliographically approved
4. Morphology engineering of a novel poly(L-lactide)/poly(1,5-dioxepan-2-one) microsphere system for controlled drug delivery
Open this publication in new window or tab >>Morphology engineering of a novel poly(L-lactide)/poly(1,5-dioxepan-2-one) microsphere system for controlled drug delivery
2000 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 38, no 5, 786-796 p.Article in journal (Refereed) Published
Abstract [en]

Morphology is presented as a powerful tool to control the in vitro degradation and drug release characteristics of novel drug delivery microspheres prepared from homopolymer blends of 1,5-dioxepan-2-one, DXO, and L-lactide, L-LA. Their performance in this respect was compared to analogous P(L-LA-co-DXO) microspheres. Blends formed denser and less porous microspheres with a higher degree of matrix crystallinity than copolymers of corresponding L-LA:DXO composition. The morphology differences of blends and copolymers, further adjustable by means of component ratio, are shown to have a vital impact on the in vitro performance. Sustained drug delivery was obtained from both copolymers and blends. Molecular weight; loss was retarded and diffusion-mediated release was inhibited in the latter case, further delaying the release process. The effects of storage on the physicochemical properties of these systems were evaluated under desiccated and moist conditions for 5 months. Storage-induced physicochemical changes, such as matrix crystallization and molecular weight decrease, were accelerated at higher relative humidities. P(L-LA-co-DXO) demonstrated higher moisture sensitivity than a PLLA-PDXO blend of corresponding composition. The more crystalline and dense morphology of blend microspheres may thus be considered an improvement of the storage stability.

Keyword
poly(1, 5-dioxepan-2-one), poly(L-lactide), microspheres, biodegradable blends, drug delivery, storage stability, BEHAVIOR, RELEASE, 1, 5-DIOXEPAN-2-ONE, DEGRADATION, COPOLYMERS, STORAGE, BLENDS, ACID)
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-13123 (URN)10.1002/(SICI)1099-0518(20000301)38:5<786::AID-POLA2>3.0.CO;2-7 (DOI)000085290900001 ()
Note
QC 20100528Available from: 2010-05-28 Created: 2010-05-28 Last updated: 2017-12-12Bibliographically approved
5. Microspheres from poly(D,L-lactide)/poly(1,5-dioxepan-2-one) miscible blends for controlled drug delivery
Open this publication in new window or tab >>Microspheres from poly(D,L-lactide)/poly(1,5-dioxepan-2-one) miscible blends for controlled drug delivery
2000 (English)In: Journal of bioactive and compatible polymers (Print), ISSN 0883-9115, E-ISSN 1530-8030, Vol. 15, no 3, 214-229 p.Article in journal (Refereed) Published
Abstract [en]

Novel biodegradable microspheres were designed from blends of poly(D,L-lactide) (PDLLA) and poly(1,5-dioxepan-2-one) (PDXO). The addition of PDXO to PDLLA yielded a more pliable and versatile matrix, where the properties can be controlled by means of composition. The components were fully miscible and formed homogeneous, amorphous, smooth and dense microspheres. Blend composition was a vital factor in determining the blend properties, morphology and in vitro degradation. Diclofenac sodium, a non-steroidal anti-inflammatory drug, was incorporated into PDLLA-PDXO microspheres of various composition ratios. Sustained release of drug was obtained. The degradation and release rates of PDLLA-PDXO microspheres were dependent on the blend composition, providing a powerful means of controlling drug delivery.

Keyword
HYDROLYTIC DEGRADATION, DICLOFENAC SODIUM, MOLECULAR-WEIGHT, IN-VITRO, 1, 5-DIOXEPAN-2-ONE, COPOLYMERS, POLYMERIZATION, INDOMETHACIN, BEHAVIOR, RELEASE
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-13124 (URN)10.1177/088391150001500302 (DOI)000087509300002 ()
Note
QC 20102528Available from: 2010-05-28 Created: 2010-05-28 Last updated: 2017-12-12Bibliographically approved

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