Academic literature on the topic 'Polymeric drug delivery systems'

The interaction of binary copolymers poly(maleic anhydride-co-poly(ethylene glycol) methyl ether methacrylate) with cholesterol results in formation of cholesterol containing polymers, which contain from 4.6 to 46.0 mol % monocholesteryl maleic links. Their structure was confirmed using functional analysis and IR spectroscopy. Acidic and anhydride links of these copolymers form polymeric salts if react with alkali. These salts are surfactants which in aqueous medium form a hierarchy micelles and micellar aggregates depending on the copolymer concentration. Using conductometry it was found that preferably monomolecular micelles are formed in dilute solutions, and micellar aggregates begin to form at higher concentrations. In aqueous media polymeric salts are able to solubilize such lipophilic substances as Sudan III dye and anticancer drug curcumin. Efficiency of solubilization towards Sudan III grows if the content of monocholesteryl maleic fragment in surfactant increases.

Pulsatile Drug Delivery Systems are gaining a lot of interest as they deliver the drug at the right place, at the right time and in the right amount, thus providing spatial, temporal and smart delivery and increasing patient compliance. The use of pulsatile release of the drugs is desirable where constant drug release is not desired. These systems are designed according to the circadian rhythm of the body. According to Latin literature circa means about and Diem means day. This could be advantageous for many drugs or therapies including asthma, peptic ulcer & arthritis etc. To correlate with our biological needs, “precisely timed drug delivery,” which could be accomplished with “programmable dosage forms,” is desirable. Precisely timed drug delivery may maximize therapeutic efficacy, minimize dose frequency, and may reduce toxicity. This paper outlines the concepts that have been proposed to release drugs in a pulsed manner from pharmaceutical device.

Pulsatile Drug Delivery Systems are gaining a lot of interest as they deliver the drug at the right place, at the right time and in the right amount, thus providing spatial, temporal and smart delivery and increasing patient compliance. The use of pulsatile release of the drugs is desirable where constant drug release is not desired. These systems are designed according to the circadian rhythm of the body. According to Latin literature circa means about and Diem means day. This could be advantageous for many drugs or therapies including asthma, peptic ulcer & arthritis etc. To correlate with our biological needs, “precisely timed drug delivery,” which could be accomplished with “programmable dosage forms,” is desirable. Precisely timed drug delivery may maximize therapeutic efficacy, minimize dose frequency, and may reduce toxicity. This paper outlines the concepts that have been proposed to release drugs in a pulsed manner from pharmaceutical device.

Delivery across skin offers many advantages compared to oral or parenteral routes e.g. non-invasive, avoiding first-past metabolism, improved bioavailability and reduction of systemic side effects. Microneedle (MN) are minimally-invasive devices that painlessly by-pass the skin's stratum corneum, which is the principal barrier to topically-applied drugs. Polymeric MN delivery systems were designed and evaluated to transdermally deliver two model drugs, the small water soluble drug ibuprofen sodium and the large protein ovalbumin (OVA). A range of hydrogel forming materials for MN production was evaluated to identify the most suitable super swelling hydrogel MN array that are hard in the dry state but, upon insertion into skin, rapidly take up interstitial fluid. The MN themselves contain no drug, but instead drug are loaded into lyophilized patches. Novel super swelling hydrogel forming MN arrays were fabricated from aqueous blends containing 20% w/w poly(methyl vinyl ether co maleic acid) (Gantrez® S97), 7.5% w/w poly(ethylene glycol) (PEG) and 3% sodium carbonate (Na2C03). In addition, dissolving MN arrays loaded with a high dose of non-potent therapeutic drug were fabricated from aqueous blends of 70% w/w Gantrez® AN139 (PH 7) and 30% ibuprofen sodium. Successful drug delivery was achieved in this research work using novel polymeric MN, super swelling hydrogel MN and dissolving MN. The in vitro studies has been shown first ever example of polymeric MN being loaded with a NSAIDs. The novel concept of super swelling hydrogel MN integrated with lyophilized patches loaded with ovalbumin was evaluated. They enabled the sustained delivery of the ibuprofen sodium and ovalbumin both in vitro and in vivo. Gamma sterilization can be done without compromising polymeric MN properties. Finally, hydrogel forming MN arrays can be successfully and reproducibly applied by human volunteers given appropriate instruction so the use of MN applicator devices may not be necessary, thus possibly enhancing patient compliance.

The objective of this work was to develop suitable delivery systems for biological agents that have antimicrobial activities using biocompatible polymers, aiming to reduce their toxicity when administered. Two biological agents, colistin as an antibacterial agent and nystatin (Nys) as an antifungal agent, are the focus of this thesis as they are potent treatments for current pathogen infections, especially to the multidrug-resistant (MDR) bacteria/fungi, but have potential toxicity to human. Polymeric drug delivery systems, including prodrug, hydrogel and micelle formulations, have been developed and discussed for their potential as topical and systemic regimes. The majority of the work was focused on the effect of the covalently attachment of synthetic polymers onto the biological agents upon their antimicrobial activities and the toxicity. The conjugation between colistin and polymers was achieved successfully through either irreversible or releasable linkages. Although irreversible polymer modifications on colistin showed no antimicrobial activity (chapter 2), an acceptable antibacterial activity was observed from the polymer-colistin conjugates with a releasable linkage through either ‘grafting-to’ (chapter 3) or ‘grafting-from’ (chapter 4) approaches. On the other hand, even though the pure polymer-Nys conjugate with a releasable imine linkage cannot be obtained due to the nature of the labile imine bond, the crude conjugate showed an excellent antifungal activity and a reduced toxicity compared to the native Nys (chapter 6). Other polymeric delivery systems were also discussed in this thesis. The incorporation of colistin within a developed hydrogel delivery system as an antibacterial patch for burn infections was investigated through in vitro and in vivo studies, showing a similar antibacterial activity as the native colistin solution against MDR Gram-negative bacteria with no systemic toxicity (chapter 5). Finally, an amphiphilic polymer containing boronic acid groups on the side chains was synthesised and used to target the hydroxyl groups on Nys, expecting to build up an environmental responsive micelle through dynamic boronate ester bond (chapter 7). Although more work is still needed, this system showed a potential to improve Nys solubility.

Introduction: Embolic agents are used to block blood flow of hypervascular tumours, ultimately resulting in target tissue necrosis. However, this therapy is limited by the formation of new blood vessels within the tumour, a process known as angiogenesis. Targeting angiogenesis led to the discovery of anti-angiogenic factors, large molecular weight proteins that can block the angiogenic process. The aim of this research is development of poly (vinyl alcohol) (PVA) aqueous solutions that cross-link in situ to form a hydrogel that functions as an embolic agent for delivery of macromolecular drugs. Methods: PVA (14 kDa, 83% hydrolysed), functionalised by 7 acrylamide groups per chain, was used to prepare 10, 15, and 20wt% non-degradable hydrogels, cured by UV or redox initiation. Structural properties were characterised and the release of FITCDextran (20kDa) was quantified. Degradable networks were then prepared by attaching to PVA (83% and 98 % hydrolysed) ester linkages with an acrylate end group. The effect on degradation profiles was assessed by varying parameters such as macromer concentration, cross-linking density, polymer backbone and curing method. To further enhance the technology, radiopaque degradable PVA was synthesised, and degradation profiles were determined. Cell growth inhibition of modified PVA and degradable products were also investigated. Results: Redox initiation resulted in non-degradable PVA networks of well-controlled structural properties. Increasing the solid content from 10 to 20wt% prolonged the release time from few hours to ~ 2 days but had no effect on the percent release, with only a maximum release of 65% achieved. Ester attachment to the PVA allowed flexibility in designing networks of variable swelling behaviors and degradation times allowing ease of tailoring for specific clinical requirements. Synthesis of radiopaque degradable PVA hydrogels was successful without affecting the polymer solubility in water or its ability to polymerize by redox. This suggested that this novel hydrogel is a potential liquid embolic with enhanced X-ray visibility. Degradable products had negligible cytotoxicity. Conclusion: Novel non-degradable and radiopaque degradable PVA hydrogels cured by redox initiation were developed in this research. The developed PVA hydrogels showed characteristics in vitro that are desirable for the in vivo application as release systems for anti-angiogenic factors.

De nos jours, les maladies inflammatoires chroniques de l'intestin (MICI) comme la rectocolite hémorragique et la maladie de Crohn touchent près de 200 000 personnes en France. Elles se caractérisent par l'inflammation de la paroi de différentes régions du tractus gastro-intestinal (TGI). Les deux sont des maladies chroniques qui impliquent une inflammation de la muqueuse colique. La principale différence entre la maladie de Crohn et la rectocolite hémorragique réside dans la localisation et la nature de l’inflammation. La maladie de Crohn peut toucher n’importe quelle partie du tractus gastro-intestinal (TGI), de la bouche à l’anus, mais dans la plupart des cas, elle atteint l’iléon. En revanche, la rectocolite hémorragique est limitée au côlon et au rectum.Le ciblage du colon peut offrir des avantages majeurs pour le traitement des MICI. Les formes galéniques conventionnelles entraînent une libération prématurée de la substance active dans l'estomac et l’intestin grêle. La substance active est alors absorbée dans la circulation sanguine ce qui provoque de sérieux effets secondaires. De ce fait la concentration de substance active qui arrive au site d’action (partie distale du TGI) est très faible, ce qui entraîne une faible efficacité thérapeutique voire échec de la thérapie.Pour pallier ce problème, une forme galénique idéale devrait effectivement protéger la substance active dans le haut TGI, puis la libérer dans la partie distale du TGI de manière contrôlée. Des systèmes réservoirs (granules enrobés, capsules…) ou des systèmes matriciels (comprimés, extrudats…) peuvent être utilisés pour protéger la substance active dans le haut TGI. Les polysaccharides qui ne sont dégradés que par des enzymes bactériennes localisées dans le colon peuvent être utilisés dans le développement des formes galéniques pour le traitement des MICI. L’objectif de ce travail était de développer de nouvelles formes galéniques contenant un polysaccharide (pectine, gomme de guar…) dégradable par la flore colique et d’un polymère thermoplastique hydrophobe (éthylcellulose, HPMC…) qui vas réduire l’hydrophilicité du polysaccharide. Or, le mélange des deux polymères ne doit pas enrober le polysaccharide qui va servir pour le ciblage de la partie distale du TGI
Chronic inflammatory bowel diseases (IBD) today affects close to 200,000 people in France. They are characterized by the inflammation of the wall of a part of the digestive tract. They usually include Ulcerative Colitis and Crohn’s disease. Both are chronic diseases that involve inflammation of the colonic mucosa. The main difference between Crohn’s disease and Ulcerative Colitis is the location and nature of inflammation. Crohn’s disease can affect any part of the GIT from mouth to anus but in most cases attacks the terminal ileum. In contrast, Ulcerative Colitis is restricted to the colon and the rectum. An ideal dosage form should effectively protect the drug in the stomach and small intestine and subsequently release the drug in the colon in a targeted and controlled manner. The objective of this work was to develop new drug delivery systems containing a polysaccharide (pectin, guar gum, inulin ...), which are degradable by the colonic bacteria and a hydrophobic thermoplastic polymer (ethylcellulose, polyurethane, polyvinyl acetate ...), which will reduce the hydrophilicity of the polysaccharide. The technique used for the preparation of these dosage forms is hot-melt extrusion. It is a continuous and free solvent process that allows the manufacturing of a dosage form called "extrudate" by forcing the soften material through an orifice. It has been demonstrated that extrudates based on polyvinyl acetate/polyurethane and inulin can minimize the release of a model active substance in the upper part of GIT due to the hydrophobic properties of polyvinyl acetate. Indeed, these extrudates uptake low amount of water and lose low dry mass upon exposure to media simulating the stomach and the small intestine. However, once in contact with the colonic flora, these systems show a considerable loss of mass due to the degradation of inulin by enzymes secreted by colonic bacteria. In another study, hot melt extrudates based on ethylcellulose blended with different types of polysaccharides (guar gum, inulin, corn starch, maltodextrin, pectin and chitosan) were studied for the development of controlled drug delivery systems. Anhydrous theophylline and diprophylline have been used as model drugs. This study was useful to set the extrusion parameters: temperature 100 °C; screw speed 30 rpm; feed rate 3 cc/min; 30 % dibutyl sebacate as a plasticizer. Importantly, hot melt extrudates based on ethylcellulose:guar gum blends offer an interesting potential as controlled drug delivery systems: They can be prepared at temperatures of about 100 °C, provide broad spectra of drug release patterns (in particular about constant drug release rates). Finally, hot melt extrudates remained stable after 1 year storage at ambient conditions

Since the early 80’s the forward steps in genetics and proteomics, have led a particular interest to biotech products, such as DNA and proteins. Although difficult, their large-scale production enabled the therapeutic use of this compounds. Proteins and DNA sequences can be very interesting therapeutic molecules owing to their high selectivity/affinity for the receptor or the specific site of action. Unfortunately, some issues still limit their pharmaceutical use, such as the susceptibility to enzymatic degradation, rapid renal clearance and immunogenicity. To overcome these limitations, many researchers are seeking solutions in the field of drug delivery systems (DDSs). In this respect, many systems have been developed and conjugation with PEG (polyethylene glycol) can be considered one of the leading approaches. PEGylation brings to the conjugated molecule great solubility and stability to proteolytic digestion, furthermore it reduces the tendency to aggregate and reduces the immunogenicity. Thanks to these advantages and the particular characteristics of PEG, to date, there are on the market 12 pegylated compounds: 9 are proteins, one peptide, one aptamer and a liposomal formulation, containing doxorubicin. The improvements in the pharmacokinetic profile of these drugs, thanks to the use of drug delivery systems, can be also applied in the field of tissue engineering, where the same issues are of fundamental importance for the development of scaffolds for cells capable of releasing growth factors. In the last years various polymers have been studied by many research groups to find an alternative to PEG, but its excellent biocompatibility and the know-how in its use has not brought any polymer to be truly competitive against PEG. Nevertheless, PEG presents some limits such as its non-biodegradability and in some case there are reports of antibodies against PEG. Therefore, there is an increased need for a PEG substitute. In the first section of this work hyaluronic acid (HA) has been studied as a candidate polymer for bioconjugation of proteins (HAylation). HA, being biodegradable can compensate this limit of PEG. HA, is also present in humans and is metabolized by hyaluronidase. Moreover, HA has the advantage of a high loading compared to PEG, thanks to the presence of repetitive functional groups in each monomer. This part of the work was focused on the study of HA conjugation (HAylation) to two model enzymes, trypsin and Ribonuclease A, and then to an interesting protein in pharmaceutical field, insulin. In order to avoid cross-linking phenomena, only a fraction of all carboxyl groups of the polymer has been modified to aldehyde allowing the conjugation with the amino groups of the protein models. Furthermore, by modulating the pH of reaction two protein-HA conjugates were obtained, selective N-terminal (pH 6) or random (pH 8), this taking advantage of the different pKa values of the amino groups in the proteins. The first products obtained with the enzymes Ribonuclease A and trypsin were tested verifying the residual activity compared to the native proteins. All conjugates, in particular those obtained by N-terminal selective conjugation, maintain a good activity on small substrates (30% decrease); only the HA-derived trypsin retains about 60% of residual activity against the substrate with a high weight molecular. Furthermore, enhanced stability over time was found for HA-trypsin respect to the free enzyme (45% on average) and also susceptibility to hyaluronidase was confirmed for both conjugates. Polymer validation as potential protein carrier was then evaluated by preparing conjugates with bovine insulin, as an example of pharmacologically active protein. Two conjugates were synthesized by N-terminal selective conjugation starting from polymers with different degree of aldehyde derivatization, 4% and 21%, yielding products with a protein loading of 17% and 32% (w/w), respectively. The therapeutic efficacy of the conjugates in comparison with insulin was tested in Sprague Dawley rats with induced diabetes. The conjugate with a lower protein loading was more effective and with a longer pharmacodynamic effect on the reduction on blood glucose level. The second section of the work was focused on an innovative strategy of enzymatic PEGylation of oligonucleotides. Briefly, the method investigated on model oligonucleotides is composed of two steps: the first consists in the chemical conjugation of a short oligonucleotide to a PEG chain, the second step is the enzymatic-mediated conjuagation of the PEGylated oligonucleotide with a DNA sequence by the DNA T4 ligase. To study the enzymatic PEGylation, 4 oligo sequences have been prepared as ligation model: two complementary pairs ending with sticky-ends in turn complementary (18-mer + 21-mer and 16-mer + 19-mer). The 18-mer has a thiol group in 5’-ending, in order to perform the coupling with PEG. Applying some modifications to ligation classical protocols, excellent results were obtained: PEGylated portion completely ligate the other ds-DNA and no undesired products were found. To further confirm the effective ligation, the ligated and PEGylated sequence was restricted with EcoRI. Indeed, the EcoRI recognized a sequence that is present only the ligated DNA. Complete restriction was found in absence and even in the presence of the polymer, further confirming the successes of ligation. Furthermore it was investigated if a reduced number of bases coupled to PEG can still preserve the requirements for the ligase enzyme activity. Thus, the pair of the complementary sequences then coupled to PEG has been reduced to half (9-mer + 12-mer). Even with a shorter PEGylated sequence a complete ligation was obtained. In conclusion in this thesis it has been demonstrated that HA can be a valid alternative to PEG for protein conjugation. In the field of oligonucleotide delivery an enzymatic approach of oligonucleotide conjugation can open new horizons that so far have not been completely explored.
Dai primi anni 80 i passi avanti fatti nel campo della genetica e della proteomica, hanno portato ad un particolare interesse nei confronti dei prodotti biotecnologici, quali DNA e proteine. L’utilizzo terapeutico di queste entità, seppur non privo di difficoltà, è stato facilitato dalla loro produzione su larga scala. Proteine e sequenze oligonucleotidiche si sono rivelate interessanti come agenti terapeutici essendo molecole dotate d’elevatissima selettività/affinità per il recettore o il sito d’azione specifico. L’impiego farmaceutico può evidenziare alcuni svantaggi che ne possono limitare l’utilizzo, come ad esempio la suscettibilità alla degradazione da parte di proteasi e DNasi, la rapida clearance renale e l’immunogenicità. Per affrontare tali limiti, molti ricercatori hanno cercano soluzioni nel campo dei drug delivery sistems (DDSs). A tal proposito, sono stati sviluppati molti sistemi e la coniugazione al PEG (polietilen glicole) è risultata essere una delle più promettenti. La PEGhilazione, infatti, conferisce alle molecole coniugate maggiore solubilità e stabilità nei confronti della digestione proteolitica, una ridotta tendenza all’aggregazione ed una ridotta immunogenicità. Grazie a questi vantaggi ed alle particolari caratteristiche del PEG, ad oggi sono presenti nel mercato 12 composti PEGhilati: 9 sono proteine, un peptide, un aptamero ed una formulazione liposomiale (contenente doxorubicina). Le migliorie apportate ai profili farmacocinetici di questi farmaci biotech grazie all’uso di DDSs possono essere anche impiegate nel campo dell’ingegneria tessutale, dove le medesime problematiche sono di basilare importanza per lo sviluppo di scaffold per cellule, in grado di rilasciare fattori di crescita. Il polietilen glicole (PEG) è il polimero leader per la coniugazione di proteine. Negli ultimi anni diversi polimeri sono stati studiati per trovare una valida alternativa a questo polimero, ma la sua eccellente biocompatibilità e la conoscenza nel suo utilizzo non ha ancora portato nessun polimero ad essere realmente competitivo nei suoi confronti. Nonostante tutto, anche l’utilizzo del PEG presenta alcuni limiti, quali la non-biodegradabilità e la documentata presenza di anticorpi anti-PEG sviluppati in alcuni casi specifici. Per questo motivo si è alla ricerca di un polimero che possa validamente sostituire il PEG. Nella prima parte di questo lavoro di tesi è stato studiato l’acido ialuronico (HA) per la bioconiugazione di proteine (HAylation). Essendo biodegradabile, l’HA può essere vantaggioso rispetto al PEG. L’HA è un polimero endogeno ed è metabolizzato dalle ialuronidasi, inoltre ha il vantaggio di poter raggiungere una capacità di loading elevate rispetto al PEG, grazie alla presenza di gruppi funzionali ripetitivi in ciascun monomero. In questa parte del lavoro di tesi, la ricerca si è concentrata sullo studio della coniugazione dell’HA a due enzimi modello, Ribonuclease A e tripsina, e poi ad un interessante proteina per uso farmaceutico, l’insulina. Per evitare fenomeni di cross-linking, solo una parte dei gruppi carbossilici del polimero è stata coniugata ad uno spacer aldeidico, consentendo la coniugazione con i gruppi amminici delle proteine. Inoltre, modulando il pH di reazione si sono potuti ottenere coniugati con legame selettivo all’N-terminale (pH 6) oppure random (pH 8), sfruttando la differente pKa degli ammino gruppi nelle proteine. I primi coniugati ottenuti con gli enzimi Ribonuclease A e tripsina sono stati studiati verificandone l’attività residua rispetto alle proteine native. Tutti i coniugati, in particolare quelli ottenuti per legame selettivo all’N-terminale, mantengono una buona attività su piccoli substrati (diminuzione del 30%); solo il derivato HA-tripsina mantiene circa il 60% di attività residua nei confronti del substrato ad alto peso molecolare. Inoltre, sempre per HA-tripsina, si è trovata una maggiore stabilità nel tempo rispetto l’enzima nativo (mediamente 45%) e si è confermata la suscettibilità di entrambe i coniugati nei confronti della ialuronidasi. La valutazione del polimero come potenziale carrier per proteine è proseguita preparando dei coniugati con l’insulina bovina, come esempio di proteina farmacologicamente attiva. Sono stati sintetizzati due coniugati con modalità selettiva all’N-terminale a partire da polimeri con diverso grado di modifica con gruppi aldeidici, pari a 4 e 21% e si sono ottenuti prodotti con il 17 e 32% (p/p), rispettivamente, di loading proteico. L’efficacia terapeutica dei coniugati in comparazione con l’insulina è stata testata su ratti Sprague Dawley con diabete indotto. Il coniugato con un minore loading proteico si è rivelato essere più efficace e con una riduzione dei livelli di glucosio nel sangue più prolungata. Nella seconda parte di questo lavoro di tesi si è studiata un’innovativa strategia di PEGhilazione enzimatica di sequenze oligonucleotidiche al fine di sviluppare questo approccio per il delivery di oligonucleotidi. Il metodo è stato messo a punto con sequenze nucleotidiche modello e l’approccio è stato il seguente: una breve sequenza oligonucleotica viene legata chimicamente ad una catena di PEG. Poi, mediante l’azione catalitica della T4 DNA ligase la porzione di PEG-DNA viene coniugata ad un’altra sequenza oligonucleotidica. Per lo studio di PEGhilazione enzimatica si è ideato un modello costituito da 4 sequenze oligonucleotidiche di riferimento: due coppie complementari terminanti con sticky-ends complementari a loro volta (18-mer + 21-mer e 16-mer + 19-mer). L’oligo di 18 nucleotidi portava in posizione 5’ una funzione tiolica, che è stata impiegata per la coniugazione col polimero. Dopo aver apportato alcune variazioni ai protocolli classici di ligazione si sono ottenuti ottimi risultati: completa ligazione del modello PEGhilato ed assenza di prodotti indesiderati. Un’ulteriore conferma di ligazione del modello PEGhilato si è ottenuta tramite digestione con EcoRI. Infatti, solamente dopo la ligazione è possibile trovare nella sequenza oligonucleotidica il sito di restrizione dell’enzima. In presenza o in assenza di polimero la restrizione è avvenuta completamente. Si è poi voluto indagare se una sequenza PEGhilata con un numero di basi ridotto potesse comunque mantenere i requisiti per essere substrato della T4 DNA ligase. Così, la coppia di sequenze complementari designata alla PEGhilazione è stata ridotta alla meta della sua lunghezza (9-mer + 12-mer). Anche con la sequenza PEGhilata così accorciata la ligazione è avvenuta completamente. In conclusione questo lavoro di tesi ha dimostrato che l’HA può essere una promettente alternativa al più noto PEG per la modifica di proteine. Nell’ambito del delivery di oligonucleotidi lo sviluppo di un approccio enzimatico di coniugazione può aprire nuovi orizzonti in questo settore il cui potenziale non è stato ancora esplorato.

Various drug delivery systems are developed to deliver therapeutic and diagnostic agents to tissues covered with mucus, such as airways, nasal cavity, or oral cavity [1]. However, the mucus, which present for protection of the tissues, significantly hinders the transport of these agents and ultimately mitigates their efficacy [2]. Several studies have been performed to improve the transmucosal transport by studying the transport rates of polymeric nanoparticles with various sizes and surface chemistry [3–5]. However, drug delivery systems with improved transmucosal transport capability are still highly desired.

Controlled and targeted drug delivery systems have gained a lot of interest as they offer numerous benefits such as precise dosing, reduced side-effects and increased patient compliance. We have designed a microelectromechanical systems (MEMS) drug delivery device that is capable of releasing drugs in a controlled and programmable manner. This self-powered device does not require any external stimulation or control to achieve pulsatile release of drugs. The device consists of multiple reservoirs containing the drug embedded together with a water-swellable polymer. The swelling of the polymer upon contact with water and the resulting pressure generated is used as an actuation mechanism to release drugs from each reservoir. The programmable release of the drug from the device is achieved by controlling the diffusion rate of water from the surrounding environment into each reservoir. The drug is released from the reservoir when the swellable polymer absorbs water from the environment and generates enough pressure to break an overlying rupturable membrane. We have demonstrated that controlled and pulsatile drug delivery can be achieved using this delivery device, without any external power or control.

Hydrogels are the promising classes of polymeric drug delivery systems with the controlled release rates. Among them, injectable thermosensitive hydrogels with transition temperature around the body temperature have been wildly considered. Chitosan is one of the most abundant natural polymers, and its biocompatibility and biodegradability makes it a favorable thermosensitive hydrogel that has been attracted much attention in biomedical field worldwide. In this work, a thermosensitive and injectable hydrogel was prepared using chitosan and β-glycerophosphate (β-GP) incorporated with an antibacterial drug (gentamycin). This drug loaded hydrogel is liquid at room temperature, and becomes more solidified gel when heated to the body temperature. Adding β-GP into chitosan and drug molecules and heating the overall solution makes the whole homogenous liquid into gel through a 3D network formation. The gelation time was found to be a function of temperature and concentration of β-GP. This thermosensitive chitosan based hydrogel system was characterized using FTIR and visual observation to determine the chemical structure and morphology. The results confirmed that chitosan/(β-GP) hydrogels could be a promising controlled-release drug delivery system for many deadly diseases.