Browsing by Author "Taylor, Lynne S."

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    Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: Investigation of relationships between polymer structure and performance
    Wilson, Venecia R.; Lou, Xiaochun; Osterling, Donald J.; Stolarik, DeAnne F.; Jenkins, Gary J.; Nichols, Brittany L. B.; Dong, Yifan; Edgar, Kevin J.; Zhang, Geoff G. Z.; Taylor, Lynne S. (Springer Nature, 2020-10-28)
    Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.
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    Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performance
    Wilson, Venecia R.; Lou, Xiaochun; Osterling, Donald J.; Stolarik, DeAnne F.; Jenkins, Gary J.; Nichols, Brittany L. B.; Dong, Yifan; Edgar, Kevin J.; Zhang, Geoff G. Z.; Taylor, Lynne S. (Nature Research, 2020-10-28)
    Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.
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    Amphiphilic hydroxyalkyl cellulose derivatives for amorphous solid dispersion prepared by olefin cross-metathesis
    Dong, Yifan; Mosquera-Giraldo, Laura I.; Troutman, Jacob; Skogstad, Brittny; Taylor, Lynne S.; Edgar, Kevin J. (Royal Society of Chemistry, 2016-07-07)
    Olefin cross-metathesis (CM) has enabled design and synthesis of diverse, amphiphilic cellulose ether derivatives (e.g. of ethyl and methyl cellulose). In this paper, hydroxyalkyl cellulose was selected as a hydrophilic starting material, with the additional advantage that it has DS (OH) 3.0 that allows targeting of a full range of DS of selected functional groups. Hydroxypropyl cellulose (HPC) was first etherified with 5-bromopent-1-ene to attach olefin “handles” for metathesis, whereby control of molar ratios of sodium hydride and 5-bromopent-1-ene permits full DS control of appended olefin. These olefin-terminated HPC ethers then were subjected to CM with acrylic acid and different acrylates, followed by diimide hydrogenation to reduce the resulting α,β-unsaturation. NMR and FT-IR spectroscopies were useful tools for following reaction progress. One of the product carboxyl-functionalized HPC derivatives, designated HPC-Pen106-AA-H, showed high promise as a crystallization inhibitor of the antiviral drug telaprevir. Its nucleation-induction inhibitory ability was compared to those of commercial controls, HPC and HPMCAS. All three polymers were very effective for inhibiting telaprevir crystallization, increasing induction time up to 8-fold. HPC did not effectively prevent amorphous particle growth, whereas the carboxyl-containing HPC-Pen106-AA-H and HPMCAS were able to prevent formation of agglomerates of amorphous drugs.
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    Cellulose Esters and Cellulose Ether Esters for Oral  Drug Delivery Systems
    Arca, Hale Cigdem (Virginia Tech, 2016-11-01)
    Amorphous solid dispersion (ASD) is a popular method to increase drug solubility and consequently poor drug bioavailability. Cellulose ω-carboxyesters were designed and synthesized specifically for ASD preparations in Edgar lab that can meet the ASD expectations such as high Tg, recrystallization prevention and pH-triggered release due to the free -COOH groups. Rifampicin (Rif), Ritonavir (Rit), Efavirenz (Efa), Etravirine (Etra) and Quercetin (Que) cellulose ester ASDs were investigated in order to increase drug solubility, prevent release at low pH and controlled release of the drug at small intestine pH that can improve drug bioavailability, decrease needed drug content and medication price to make it affordable in third world countries, and extent pill efficiency period to improve patient quality of life and adherence to the treatment schedule. The studies were compared with cellulose based commercial polymers to prove the impact of the investigation and potential for the application. Furthermore, the in vitro results obtained were further supported by in vivo studies to prove the significant increase in bioavailability and show the extended release. The need of new cellulose derivatives for ASD applications extended the research area, the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters for ASD formulations investigated and the efficiency of the polymers were summarized to show that they have the anticipated properties. The polymers were synthesized by the reaction of commercial cellulose alkyl ethers with benzyl ester protected, monofunctional hydrocarbon chain acid chlorides, followed by removal of protecting group using palladium hydroxide catalyzed hydrogenolysis to form the alkyl cellulose wcarboxyalkanoate. Having been tested for ASD preparation, it was proven that the polymers were efficient in maintaining the drug in amorphous solid state, release the drug at neutral pH and prevent the recrystallization for hours, as predicted.
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    Chemical Modification of Cellulose Esters for Oral Drug Delivery
    Meng, Xiangtao (Virginia Tech, 2016-06-20)
    Polymer functional groups have critical impacts upon physical, chemical and mechanical properties, and thus affect the specific applications of the polymer. Functionalization of cellulose esters and ethers has been under extensive investigation for applications including drug delivery, cosmetics, food ingredients, and automobile coating. In oral delivery of poorly water-soluble drugs, amorphous solid dispersion (ASD) formulations have been used, prepared by forming miscible blends of polymers and drugs to inhibit crystallization and enhance bioavailability of the drug. The Edgar and Taylor groups have revealed that some cellulose omega-carboxyalkanoates were highly effective as ASD polymers, with the pendant carboxylic acid groups providing both specific polymer-drug interactions and pH-triggered release through swelling of the ionized polymer matrix. While a variety of functional groups such as hydroxyl and amide groups are also of interest, cellulose functionalization has relied heavily on classical methods such as esterification and etherification for appending functional groups. These methods, although they have been very useful, are limited in two respects. First, they typically employ harsh reaction conditions. Secondly, each synthetic pathway is only applicable for one or a narrow group of functionalities due to restrictions imposed by the required reaction conditions. To this end, there is a great impetus to identify novel reactions in cellulose modification that are mild, efficient and ideally modular. In the initial effort to design and synthesize cellulose esters for oral drug delivery, we developed several new methods in cellulose functionalization, which can overcome drawbacks of conventional synthetic pathways, provide novel cellulose derivatives that are otherwise inaccessible, and present a platform for structure-property relationship study. Cellulose omega-hydroxyalkanoates were previously difficult to access as the hydroxyl groups, if not protected, react with carboxylic acid/carbonyl during a typical esterification reaction or ring opening of lactones, producing cellulose-g-polyester and homopolyester. We demonstrated the viability of chemoselective olefin hydroboration-oxidation in the synthesis of cellulose omega]-hydroxyesters in the presence of ester groups. Cellulose esters with terminally olefinic side chains were transformed to the target products by two-step, one-pot hydroboration-oxidation reactions, using 9-borabicyclo[3.3.1]nonane (9-BBN) as hydroboration agent, followed by oxidizing the organoborane intermediate to a primary alcohol using mildly alkaline H2O2. The use of 9-BBN as hydroboration agent and sodium acetate as base catalyst in oxidation successfully avoided cleavage of ester linkages by borane reduction and base catalyzed hydrolysis. With the impetus of modular and efficient synthesis, we introduced olefin cross-metathesis (CM) in polysaccharide functionalization. Using Grubbs type catalyst, cellulose esters with terminally olefinic side chains were reacted with various CM partners including acrylic acid, acrylates and acrylamides to afford families of functionalized cellulose esters. Molar excesses of CM partners were used in order to suppress potential crosslinking caused by self-metathesis between terminally olefinic side chains. Amide CM partners can chelate with the ruthenium catalyst and cause low conversions in conventional solvents such as THF. While the inherent reactivity toward CM and tendency of acrylamides to chelate Ru is influenced by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides. We observed that the CM products are prone to crosslinking during storage, and found that the crosslinking is likely caused by free radical abstraction of gamma-hydrogen of the alpha, beta-unsaturation and subsequent recombination. We further demonstrated successful hydrogenation of these alpha, beta-unsaturated acids, esters, and amides, thereby eliminating the potential for radical-induced crosslinking during storage. The alpha, beta-unsaturation on CM products can cause crosslinking due to gamma-H abstraction and recombination if not reduced immediately after reaction. Instead of eliminating the double bond by hydrogenation, we described a method to make use of these reactive conjugated olefins by post-CM thiol-Michael addition. Under amine catalysis, different CM products and thiols were combined and reacted. Using proper thiols and catalyst, complete conversion can be achieved under mild reaction conditions. The combination of the two modular reactions creates versatile access to multi-functionalized cellulose derivatives. Compared with conventional reactions, these reactions enable click or click-like conjugation of functional groups onto cellulose backbone. The modular profile of the reactions enables clean and informative structure-property relationship studies for ASD. These approaches also provide opportunities for the synthesis of chemically and architecturally diverse cellulosic polymers that are otherwise difficult to access, opening doors for many other applications such as antimicrobial, antifouling, in vivo drug delivery, and bioconjugation. We believe that the cellulose functionalization approaches we pioneered can be expanded to the modification of other polysaccharides and polymers, and that these reactions will become useful tools in the toolbox of polymer/polysaccharide chemists.
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    Design and Synthesis of Cellulose Ether Derivatives for Oral Drug Delivery
    Dong, Yifan (Virginia Tech, 2017-05-31)
    Chemical modification of naturally occurring cellulose into ester and ether derivatives has been of growing interest due to inexhaustible cellulose resources, and to excellent properties and extremely broad applications of these derivatives. However, traditional esterification and etherification involve relatively harsh conditions (strongly acidic or strongly alkaline), greatly limiting the content and range of functional groups that may be installed onto the cellulose backbone. Amorphous solid dispersion (ASD) is an effective method to promote oral delivery of poorly-soluble drugs by dispersing crystalline drugs in a polymer matrix, creating drug supersaturation upon release. Cellulose 𝜔-carboxyesters have been proven to be effective ASD matrices for many different drugs; however, synthesis of such polymers involves protecting-deprotecting chemistry and one synthetic route only leads to one structure. Developing a new generation of cellulosic polymers for oral drug delivery such as ASD matrices requires new synthetic techniques and powerful tools. Olefin cross-metathesis (CM) is a mild, efficient and modular chemistry with extensive applications in organic, polymer, and polysaccharide chemistry. Successful CM can be achieved by appending olefin “handles” from cellulose esters and reacting with electron-deficient olefins like acrylic acid. Cellulose ethers have much better hydrolytic stability compared to esters and are also commercially very important. The overarching theme of this dissertation is to investigate modification of cellulose ether derivatives, and to design and synthesize effective ASD polymers by olefin CM. We first validated the strategy of performing CM by appending metathesis “handles” through etherification and then subjected these terminal olefins to various partners (acrylic acid and different acrylates). After demonstration of the concept, we applied different starting materials (e.g. ethyl cellulose, methyl cellulose, microcrystalline cellulose, and hydroxypropyl cellulose) with distinctive hydrophobicity/hydrophilicity balance. Furthermore, α,β-unsaturated CM products tended to undergo radical crosslinking through abstraction of 𝛾-protons and recombination of polymer radicals. In order to resolve this issue, we first applied post-CM hydrogenation and then explored a thiol-Michael addition to the α,β-unsaturation, which also incorporates an extra functional group through the thioether. We have successfully prepared a collection of cellulose 𝜔-carboxyether derivatives through the above-mentioned method and preliminary drug induction experiments also revealed that these derivatives hold high promise for ASD application. We also explored the possibility of conducting CM in a reverse order: i.e. appending electron-deficient acrylate groups to the polymer, then subjecting it to electron-rich small molecule terminal olefins. The failure of this metathesis approach was speculated to be due mainly to low acrylate reactivity on an already crowded polymer backbone and the high reactivity of rapidly diffusing, small molecule terminal olefins. Last but not least, we further utilized olefin CM to conjugate bile salt derivatives (e.g. lithocholic acid and deoxycholic acid) to a cellulose backbone by converting bile salts into acrylate substrates. Successful CM of bile salt acrylates to cellulose olefin “handles” further demonstrated the great versatility, excellent tolerance, and very broad applicability of this strategy. Overall, we have founded the strategy for performing successful olefin CM in many cellulose ether derivatives with acrylic acid and a variety of different acrylates. Post-CM hydrogenation efficiently removes the α,β-unsaturation and provides stable and effective cellulose 𝜔-carboxyether derivatives for ASD application. Tandem CM/thiol-Michael addition not only eliminates the crosslinking tendency but also enables an even broader library of polymer structures and architectures for structure-property investigations. We anticipate these methods can be readily adapted by polysaccharide chemists and applied with numerous complex structures, which would greatly broaden the range of cellulose and other polysaccharide derivatives for applications including ASDs, P-glycoprotein inhibition, antimicrobial, coating, and other biomedical applications.
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    Design and Synthesis of Complex and Fluorescent Labeled Cellulose-Based Derivatives for Orally Administered Drug Delivery Systems
    Novo, Diana Cecilia (Virginia Tech, 2023-09-11)
    Cellulose ethers are valuable matrices for drug-delivery systems (DDS), namely amorphous solid dispersions (ASD). ASD are efficient vehicles that can solubilize and stabilize poorly soluble drugs by increasing the time that it takes for drugs to crystallize, thereby allowing higher drug concentrations and providing increased bioavailability. However, most commercially available cellulose derivatives were not specifically designed for this application, leading to gaps in understanding the key mechanisms by which ASD operate. This creates the need for polysaccharide derivatives specifically conceptualized for ASD and for elucidating structure-property relationships. In this dissertation, I successfully demonstrated regioselective and chemoselective techniques to functionalize cellulose to prepare new ASD as well as smart tracking devices. I efficiently and successfully create complex structures via appending bile salt substituents using olefin cross-metathesis. I ascertained that high performance crystallization inhibitors can be achieved with enhanced hydrophilicity by the marriage of two classes crystallization inhibitors (cellulose and bile salts), as illustrated with the commercial, fast crystallizing prostate cancer drug, enzalutamide. I obtained ketone-functionalized cellulose derivatives using oxidation chemistry to produce fluorescent poly- and oligosaccharides (hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl beta cyclodextrin). Schiff-base chemistry was then explored to append a commercially available fluorescent label, Nile Blue. Due to the dynamic nature and hydrolytic lability of Schiff-bases, I applied reductive-amination chemistry with either one pot, or two-step techniques and evaluated the efficiency of these approaches. I characterized the new fluorescent polymers, and with the objective of elucidating ASD mechanisms, I investigated their response in solvents of different polarities to probe environment-sensitivity. Flavonoids are interesting drug candidates; they have been explored for many biomedical applications, including as inducers of apoptosis and functioning as antioxidants by radical scavenging. I prepared high-performance ASD polymer candidates, then prepared and characterized ASDs with different loadings of the flavonoids, genistein and quercetin. I explored the performance of polymers with different functionalities, hydrophilicity/hydrophobicity, and carboxylic acid content (cellulose acetate glutarate, 5-carboxypentyl hydroxypropyl cellulose, and hydroxypropyl methyl cellulose acetate succinate as positive control) by using in vitro dissolution studies. In this screening process, I determined that cellulose acetate glutarate provides the most advantageous enhancement, possessing the appropriate amphiphilicity to increase drug concentration in this study, supported by the similarity of the polymer and drug solubility parameters. I was further able to confirm via polarized light microscopy that advantageous nanodroplet formation occurs during the drug-release process.
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    Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity
    Novo, Diana C.; Gao, Chengzhe; Qi, Qingqing; Mosquera-Giraldo, Laura I.; Spiering, Glenn A.; Moore, Robert B.; Taylor, Lynne S.; Edgar, Kevin J. (Elsevier, 2022-09-15)
    Crystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone.
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    Mixed Polysaccharide Esters for Amorphous Solid Dispersion Oral Drug Delivery Vehicles
    Petrova, Stella (Virginia Tech, 2023-12-04)
    Using various synthetic strategies, we designed several libraries of novel polysaccharide mixed ester derivatives for oral drug delivery applications. Cellulose and cellulose esters have been extensively studied and utilized for different applications such as separation membranes, sustainable plastics, and enteric coatings in oral drug delivery carriers. We sought to exploit the ring-opening of cyclic anhydrides, succinic and glutaric anhydride, to append ω-carboxyl groups to commercially available cellulose and cellulose ester substrates. We used scalable synthetic strategies and widely available and cheap reagents to show a proof-of-concept for the manufacturability of these different polymer derivatives. We incorporated different degrees of substitution of ω-carboxyl groups to impart a range of water solubility in these polymers. The derivatives displayed excellent Tg values for ASD applications, adequate water solubility, and good amphiphilic properties. We designed very effective amorphous solid dispersion (ASD) oral drug delivery polymers that prevented recrystallization of felodipine for hours and had excellent congruent polymer-drug release from the formulation at 20% drug loading. During the ring-opening reactions of the cellulose derivatives with glutaric anhydride we discovered that crosslinking and gelation can occur, especially with cellulose and cellulose ester substrates with a high degree of substitution (DS) of hydroxy groups. We isolated and characterized these gelled products using rheology, and solid-state 1D and 2D NMR spectroscopy, to evaluate whether the gels are physical or chemical in nature and proposed a mechanism for gelation. We determined that the gels are mostly physical but can proceed to chemical crosslinking over time. We designed a library of cellulose ester derivatives, and we investigated their performance as amorphous solid dispersion (ASD) drug delivery vehicles for the lipophilic drug felodipine, through in vitro experiments. Aside from felodipine, many other active pharmaceutical ingredients (APIs) are also highly crystalline and poorly water-soluble. ASDs are used to disrupt the crystalline packing of these drugs through dispersing them in amorphous polymeric carriers, facilitating their water-solubility, and preventing their recrystallization. We showed that our polymers performed remarkably well in the in vitro studies and inhibited crystallization of model compound felodipine for several hours while providing optimal drug release, affording highly promising ASD polymers. If company formulators are unable to develop an effective oral-delivery carrier to prevent a drug from recrystallizing, then the drug cannot be tested in in vivo toxicology studies, and therefore cannot be brought to market because of its poor aqueous solubility and subsequent low bioavailability. To test the robustness of our polymers, we also performed in vitro ASD experiments at the pharmaceutical company AbbVie with their most rapidly crystallizing pipeline compounds, and several commercially available drugs (Compound A, axitinib, and ziprasidone). We demonstrated that our polymers could also prevent drug recrystallization with these rapid crystallizers, outperforming commercial polymers like FDA-approved hydroxypropyl methyl cellulose acetate succinate (HPMCAS (MF)), even at exceptionally high drug loading ratios of 40 times the concentration of polymer. α-1,3-Glucans are an emerging class of polysaccharides and are structurally different than cellulose due to their α (1→3) linkage versus the cellulose β (1→4) glycosidic linkage. We demonstrated that we could modify these derivatives using a variety of esterification strategies and TEMPO-mediated C6 selective oxidation, affording a myriad of different novel polymer products, some of which are structural analogs of the cellulose ester derivatives we previously created. The polymers had higher Tg values than the cellulose ester polymers, which may be useful for applications where heat resistance is desired. In the future, we will screen some of these α-1,3-glucan derivatives with poorly water-soluble enzalutamide, posaconazole and celecoxib model drugs, to evaluate their crystallization inhibition properties and the influence of polymer morphology upon structure-property relationships. We expect that these synthetic polymer strategies will offer scalable routes to novel ASD polymers, which we demonstrated to be highly effective drug crystallization inhibitors against a variety of different hydrophobic pharmaceutical compounds.
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    Pullulan w-carboxyalkanoates for Drug Nanodispersions
    Rolle, Jameison Theophilus (Virginia Tech, 2015-09-25)
    Pullulan is an exopolysaccharide secreted extracellularly by the black yeast-like fungi Aureobasidium pullulans. Due to an alpha-(1-->6) linked maltotriose repeat unit, which interferes with hydrogen bonding and crystallization, pullulan is completely water soluble unlike cellulose. It has also been tested and shown to possess non-toxic, biodegradable, non-mutagenic and non-carcinogenic properties. Chemical modification of polysaccharides to increased hydrophobicity and increase functionality has shown great promise in drug delivery systems. Particularly in amorphous solid dispersion (ASD) formulations, hydrophobicity increases miscibility with hydrophobic, crystalline drugs and carboxy functionality provides stabilization with drug moieties and well as pH specific release. Successful synthesis of cellulose w-carboxyalkanoates have been reported and showed great promise as ASD polymers based on their ability to retard the recrystallization of the HIV drug ritonavir and antibacterial clarithromycin. However, these cellulose derivatives have limitations due to their limited water solubility. Natural pullulan is water-soluble and modification with w-carboxyalkanoate groups would provide a unique set of derivatives with increased solubility therefore stronger polymer-drug interactions in solution. We have successfully prepared novel pullulan w-carboxyalkanoates, which exhibit good solubility in polar aprotic and polar protic solvents. All derivatives exhibit high thermal stability and most recorded high glass transition temperatures. Due to unknown impact of their three dimensional structure on miscibility and stabilization of drug against crystallization, each of these polymers possesses great potential for use in various drug delivery applications.
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    Synthesis and Applications of Cellulose Derivatives for Drug Delivery
    Marks, Joyann Audrene (Virginia Tech, 2015-09-14)
    In an effort to produce new derivatives of cellulose for drug delivery applications, methods were developed to regioselectively modify C-6 halo cellulose esters to produce cationic derivatives via nucleophilic substitution. Reaction of C-6 substituted bromo and iodo cellulose with trialkylated amines and phosphines produced new cationic ammonium and phosphonium cellulose derivatives which can be explored as delivery agents for nucleic acids, proteins and other anionic drug molecules. It was anticipated that these new derivatives would not only be capable of complexing anionic drug molecules but would have greatly improved aqueous solubility compared to their precursors. The phosphonium derivatives described in this work are an obvious example of such improved solubility properties. Given the importance of cellulose derivatives in making amorphous dispersions with critical drugs, it has also been important to analyze commercially available polymers for the potential impact in oral drug delivery formulations. To do so pairwise blends of cellulosics and synthetic polymers commonly used as excipients were tested for miscibility using techniques such as DSC, mDSC, FTIR and film clarity. Miscible combinations highlight the potential to use combinations of polymers currently available commercially to provide drug delivery solutions for specific drug formulations. The use of melt extrusion in processing some of these drug/polymer dispersions provides a means of highlighting the capability for the use of these cellulosics in melt extruded amorphous dispersions. This solvent free, high pressure method significantly reduces cost and time and can be applied on a large scale. The analysis of long chain cellulose esters and ultimately the novel omega carboxy esters for melt processability significantly impacts the possibilities available for use of those excellent drug delivery agents on a much larger scale.
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    Synthesis and Structure-property Evaluation of Novel Cellulosic Polymers as Amorphous Solid Dispersion Matrices for Enhanced Oral Drug Delivery
    Liu, Haoyu (Virginia Tech, 2014-02-03)
    The use of amorphous solid dispersions (ASDs) is an effective and increasingly widely adopted approach for solubility and bioavailability enhancement of hydrophobic drugs. Cellulose derivatives have strong potential as ASD polymers. We demonstrate herein design, synthesis and structure-property relationship characterization of a new series of organo-soluble cellulose omega-carboxyalkanoates for ASDs, by two different synthetic approaches. These carboxyl-containing cellulose mixed-esters possessed relatively high Tg values with sufficient differences versus ambient temperature, useful to prevent drug mobility and crystallization during storage or transport. Screening experiments were utilized to study the impact of ASD polymers including our new family of cellulose Ω-carboxyesters on both nucleation induction time and crystal growth rate of three poorly soluble model drugs from supersaturated solutions. Attributed to relatively rigid structures and bulky substituent groups, cellulose derivatives were more significant crystallization inhibitors compared to the synthetic polymers. The effective cellulose omega-carboxyesters were identified as possessing a similar hydrophobicity to the drug molecule and high number of ionization groups. Among them, cellulose acetate suberate prepared by us was an extraordinary solution crystal growth inhibitor for ritonavir and its formulated solid dispersions provided a substantial 15-fold enhancement of apparent solution concentration vs. the equilibrium solubility of the crystalline drug. To offset the issue of slow drug release from some cellulose omega-carboxyester based formulations, a new class of amphiphilic cellulosic polymers with hydrophilic oligo(ethylene oxide)-containing side chains was developed via versatile synthetic pathways, and the evaluation of these materials alone or by pairwise polymer blends will be performed as ASD matrices for the enhancement of drug solubility and stability.
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    Synthesis of New Pullulan Derivatives for Drug Delivery
    Pereira, Junia M. (Virginia Tech, 2013-10-07)
    Pullulan is a non-ionic water-soluble polysaccharide which is produced from starch by the yeast-like fungus Aureobasidium pullulans. Pullulan is known for its non-toxicity and biocompatibility. Most pullulan modifications are intended to reduce its water solubility or to introduce charged or reactive groups for functionality. Polysaccharides that have been hydrophobically modified and contain carboxyl groups are commonly used in drug delivery systems because of their ability to provide pH-controlled drug release. We demonstrated in this dissertation the regioselective synthesis of a range of 6-carboxypullulan ethers that are promising anionic derivatives for drug delivery applications. These compounds have also shown impressive surfactant properties. Another class of pullulan derivatives was synthesized by regioselective introduction of amine and amide groups to the pullulan backbone. These chemical groups are known to play a fundamental role in the biological activity of important polysaccharides, such as chitin and chitosan, therefore, the pullulan derivatives synthesized herein, which are structural isomers of those polymers, possess great potential for biomedical applications. Clarithromycin (CLA) is an aminomacrolide antibiotic whose physical properties are fascinating and challenging. It has very poor solubility at neutral intestinal pH, but much higher solubility under acidic conditions. Therefore, CLA dissolves better in the stomach than in the small intestine; but CLA is also quite labile towards acid-catalyzed degradation. We report herein a study on amorphous solid dispersion (ASD) of CLA with promising carboxyl-containing cellulose derivatives, both as macro and nanoparticles. This approach was intended to improve CLA solubility in neutral media, to protect it from acid degradation, and thereby increase its uptake from the small intestine and ultimately its bioavailability. We have also prepared ASDs of selected anti-HIV drugs, ritonavir (RTV), efavirenz (EFV) and etravirine (ETR) with the cellulosic derivative carboxymethyl cellulose acetate butyrate (CMCAB). This polymer was efficient in stabilizing RTV and EFV in their amorphous form in the solid phase and all ASDs provided significant enhancement of drug solution concentration.