Topotecan hydrochloride liposomes incorporated into thermosensitive hydrogel for sustained and efficient in situ therapy of H22 tumor in Kunming mice

Abstract

Topotecan hydrochloride (TPT) has potential for the treatment of ovarian cancer, but the activity of TPT tends to decrease due to the ring-opening at physiological pH. In this study, we proposed to incorporate TPT liposomes into injectable thermosensitive in situ hydrogel, consisting of chitosan (CS) and β-glycerophosphate (β-GP), for sustained release and preservation of active lactone form of TPT. The rheology studies were carried out to investigate the sol–gel temperature, flow behavior and viscosity of these CS/β-GP systems. The optimized formulation exhibited sol–gel transition at 40.2?±?0.4?°C, with pseudoplastic flow behavior. The drug release rate of TPT liposomes loaded CS/β-GP hydrogel in phosphate buffer saline (pH?=?7.4) was found to be slowed down, and the lactone fraction of TPT in the hydrogel matrix was maintaining 40% after 50?h. In addition, the antitumor efficacy in Kunming mice bearing Hepatoma-22 tumor, after intratumoral injection of TPT liposomes loaded CS/β-GP hydrogel, was higher than that of TPT in saline and TPT in CS/β-GP hydrogel. Those results demonstrated that TPT liposomes loaded CS/β-GP hydrogel could become a potential formulation for improving the antitumor efficacy of TPT and suggested an important technology platform for intratumoral administration of derivative of camptothecin-family drugs.     

Development and anti-Candida evaluation of the vaginal delivery system of amphotericin B nanosuspension-loaded thermogel

Vulvovaginal candidiasis (VVC) is a typical kind of vaginal mucosal infection. Herein, we developed a novel vaginal delivery system of amphotericin B (AmB) nanosuspension-loaded thermogel (AmB NPs/thermogel) utilising pharmaceutical technique of high-pressure homogenisation and Poloxamer P407/P188 hydrogel. The stabiliser and hydrogel materials of the formulation were tested to maintain proper sol–gel transition as well as the relative stability of the particle size of AmB nanosuspension in the thermogel. The particle size of AmB nanosuspensions in the hydrogel was ～247?nm. Transmission electron microscopy images confirmed the round-shape morphology of AmB nanoparticles in AmB NPs/thermogel, while that of irregular morphology of merely AmB nanosuspensions without stabiliser and hydrogel materials. AmB could be sustained release for ～12?h in vitro. In vivo drug content in the vaginal tissue was also evaluated with 87, 47, 33 and 6.7% drug remaining after 1, 3, 6 and 12?h, respectively. The in vivo anti-Candida test was conducted on candidiasis-infected mice model. In the same drug dose of 2.5?mg/kg, AmB NPs/thermogel showed better anti-Candida efficiency compared with commercial AmB effervescent tablet. This delivery system might show some insights for the vaginal formulation development of other hydrophobic antifungal drugs.     

pH-and thermo-sensitive pluronic/poly(acrylic acid) in situ hydrogels for sustained release of an anticancer drug

In this study, we developed oral in situ gelling formulations composed of pluronic (Plu) and polyacrylic acid (PAA) for the delivery of an anticancer drug, epirubicin (Epi). We investigated various Plu/PAA/Epi formulations for their physicochemical properties and in vitro permeation and accumulation, as well as for in vivo pharmacokinetic and antitumor efficacy. A scanning electron microscopic (SEM) image of Plu 14%/PAA 0.75%/Epi hydrogel showed a sponge-like structure. This formulation has suitable gelation time, water content, bioadhesive force, structural stability, and a high permeation percentage of Epi, with sustained drug release characteristics for 96?h. This hydrogel was retained at the end of the ileum near the colon of Sprague-Dawley (SD) rats for at least 12?h. An in vivo pharmacokinetic study using SD rats showed that after oral administration in this formulation, Epi had prolonged half-life, greater area under the curve, and higher relative bioavailability than in an oral Epi solution. In vivo tumor growth inhibition of Epi in this formulation was more pronounced compared with oral Epi and intravenous Epi solutions in CT-26 mouse colon adenocarcinoma bearing Balb/c mice. This study highlights the advantages of using oral in situ temperature- and pH-sensitive hydrogels for future cancer therapy.     

Poly(N-vinylcaprolactam-co-methacrylic acid) hydrogel microparticles for oral insulin delivery

pH-sensitive copolymeric hydrogels prepared from N-vinylcaprolactam and methacrylic acid monomers by free radical polymerization offered 52% encapsulation efficiency and evaluated for oral delivery of human insulin. The in vitro experiments performed on insulin-loaded microparticles in pH 1.2 media (stomach condition) demonstrated no release of insulin in the first 2?h, but almost 100% insulin was released in pH 7.4 media (intestinal condition) in 6?h. The carrier was characterized by Fourier transform infrared, differential scanning calorimeter, thermogravimetry and nuclear magnetic resonance techniques to confirm the formation of copolymer, while scanning electron microscopy was used to assess the morphology of hydrogel microparticles. The in vivo experiments on alloxan-induced diabetic rats showed the biological inhibition up to 50% and glucose tolerance tests exhibited 44% inhibition. The formulations of this study are the promising carriers for oral delivery of insulin.     

Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles

ABSTRACT

Objective: Oral insulin administration suffers gastrointestinal tract (GIT) degradation and inadequate absorption from the intestinal epithelium resulting in poor bioavailability. This study entails in vitro and in vivo assessment of stimuli-responsive hydrogel microparticles (MPs) in an attempt to circumvent GI barrier and enhance oral insulin bioavailability.

Methods: Bacterial cellulose-g-poly(acrylic acid) (BC-g-P(AA)) hydrogel MPs were evaluated for morphology, swelling, entrapment efficiency (EE), in vitro insulin release and enzyme inhibition. The ex vivo mucoadhesion, insulin degradation and transport were investigated in excised intestinal tissues. The effect of MPs on paracellular transport was studied in Caco-2/HT29-MTX monolayers. The in vivo hypoglycemic effect and pharmacokinetics of insulin-loaded MPs were investigated in diabetic rats.

Results: Hydrogel MPs efficiently entrapped insulin (EE up to 84%) and exhibited pH-responsive in vitro release. The MPs decreased the proteolytic activity of trypsin (up to 60%). Insulin transport across monolayers was increased up to 5.9-times by MPs. Histological assessment of GI tissues confirmed the non-toxicity of MPs. Orally administered insulin-loaded MPs showed higher hypoglycemic effect as compared to insulin solution and enhanced relative oral bioavailability of insulin up to 7.45-times.

Conclusion: These findings suggest that BC-g-P(AA) MPs are promising biomaterials to overcome the barriers of oral insulin delivery and enhancing its bioavailability.     

Alendronate-loaded,biodegradable smart hydrogel: a promising injectable depot formulation for osteoporosis

Alendronate (ALN) is a BCS III bone resorption inhibitor, with very poor oral bioavailability. Our approach is to develop a minimally invasive thermogelling system for prolonged local delivery of ALN. For this, different chitosan-based thermogels were developed and characterised in terms of gelation time, injectability, pH, viscosity and thermoreversibility. Chitosan/β-glycerophosphate (CS/βGP) hydrogel pursued temperature-dependent, thermoreversible gelation behaviour and was thus selected for drug loading. Increasing ALN concentration resulted in hydrogels with lower porosity and higher density. FTIR and DSC proved interaction between ALN, CS with βGP. CS/βGP hydrogel ensured controlled ALN release over 45–65?days depending on initial ALN loading. Freeze drying improved the shelf-life stability with minor impact on thermogelling character. In vivo injection of plain and ALN-loaded hydrogel in rats rapidly gelled 15?min post-injection. Based on histological examination, ALN-loaded thermogel showed less inflammatory response, faster proliferation and maturation of granulation tissue relative to plain thermogel. Hydrogels excised 21-days post-injection proved the biocompatibility and biodegradability of the system. The presented chitosan-based thermogel has significant positive attributes for site-specific, time-controlled, intra-articular delivery of ALN.     

Paediatric drug development of ramipril: reformulation,in vitro and in vivo evaluation

Ramipril is used mainly for the treatment of hypertension and to reduce incidence of fatality following heart attacks in patients who develop indications of congestive heart failure. In the paediatric population, it is used most commonly for the treatment of heart failure, hypertension in type 1 diabetes and diabetic nephropathy. Due to the lack of a suitable liquid formulation, the current study evaluates the development of a range of oral liquid formulations of ramipril along with their in vitro and in vivo absorption studies. Three different formulation development approaches were studied: solubilisation using acetic acid as a co-solvent, complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) and suspension development using xanthan gum. Systematic optimisation of formulation parameters for the different strategies resulted in the development of products stable for 12 months at long-term stability conditions. In vivo evaluation showed C_max of 10.48?µg/ml for co-solvent, 13.04?µg/ml for the suspension and 29.58?µg/ml for the cyclodextrin-based ramipril solution. Interestingly, both ramipril solution (co-solvent) and the suspension showed a T_max of 2.5?h, however, cyclodextrin-based ramipril produced T_max at 0.75?h following administration. The results presented in this study provide translatable products for oral liquid ramipril which offer preferential paediatric use over existing alternatives.     

Injectable and biodegradable poly(organophosphazene) hydrogel as a delivery system of docetaxel for cancer treatment

Abstract

Although docetaxel (DTX) is an advanced taxoid, further augmentation of its properties is still required, such as improvement in its low aqueous solubility. Herein, we report the development of biodegradable/injectable poly(organophosphazene) (PPZ) hydrogels for the delivery of DTX without the use of organic solvents. An aqueous solution of PPZ containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 was prepared, thereby increasing the erosion capacity of the hydrogel by judicious balance of the hydrophobic/hydrophilic moieties. The safety of the hydrogel was demonstrated using a biocompatibility test. The PPZ aqueous solution (8?wt%) containing DTX exhibited a thermosensitive sol–gel–sol transition that was independent of the concentration of DTX (1–3?mg/mL). The in vitro release study indicated that the dominant release mechanism was either erosion or diffusion/erosion-controlled release depending on the DTX content of the hydrogel. The in vivo anticancer effect of the intratumorally injected PPZ system in human gastric cancer cell-xenografted mice was evaluated, which demonstrated a significantly (p?<?0.01) enhanced effect of the DTX-PPZ hydrogel system compared to the control (DTX solution, i.v.). In conclusion, the PPZ hydrogel may be a promising candidate for DTX delivery, affecting a decrease in the size of tumors with little toxicity prior to exeresis.     

Incorporation of rosuvastatin-loaded chitosan/chondroitin sulfate nanoparticles into a thermosensitive hydrogel for bone tissue engineering: preparation,characterization, and cellular behavior

Rosuvastatin (RSV) has been shown to have significant impact on the simulation of bone regeneration after local injection. The current study aimed to develop a localized controlled delivery system from RSV by incorporating RSV-loaded chitosan/chondroitin sulfate (CTS/CS) nanoparticles into thermosensitive Pluronic F127/hyaluronic acid (PF127/HA) hydrogel. RSV-loaded CTS/CS nanoparticles were prepared by ionic gelation, and the impact of various formulation variables was assessed using the Box–Behnken design. Consequently, optimized RSV-loaded nanoparticles were incorporated into the PF127/HA hydrogel. Rheological properties, degradation rates of hydrogels, and the release rate of RSV from hydrogel were examined. Mean particle size, zeta potential, entrapment efficiency, and mean release time of the optimized RSV-loaded nanoparticles were confirmed as 283.2?±?16?nm, –31.2?±?6.8?mV, 63.1?±?4.2%, and 6.14?±?0.3?h, respectively. The hydrogel containing 3% w/v CTS/CS nanoparticles existed as a solution with low viscosity at room temperature converted to a semisolid upon increasing the temperature to 35?°C. Hydrogel engrafted with CTS/CS showed controlled release of RSV during 48?h with superior in vitro gel stability. As revealed by cytotoxicity and mineralization assays, incorporation of RSV-loaded particles into PF127/HA hydrogel led to improvement in osteoblast viability and proliferation.     

Multivesicular liposomes for sustained release of naltrexone hydrochloride: design,characterization and in vitro/in vivo evaluation

Multivesicular liposomes containing naltrexone hydrochloride (DepoNTX) was prepared by using the traditional DepoFoam technology and the key formulation factors on encapsulation efficiency and particle size were investigated. A morphological characterization and in vitro/in vivo release assay was also carried out. NTX was successfully encapsulated in DepoNTX with good yield and showing the spherical, smooth and multivesicular characteristics of particle by a light microscope. The in vitro studies in human plasma and sodium chloride showed that 80–85% of NTX encapsulated in MVLs released slowly from particles over 5 days. In vivo study, after a single dose of 2.0?mg/kg of DepoNTX formulation administered subcutaneously in rats, plasma NTX levels were maintained at a relatively constant level above 10?ng/mL for approximately 120?h, while after administered NTX solution, NTX level was quickly decreased below 10?ng/mL within 20?h. The results of the study demonstrated that DepoNTX was very promising candidate for sustained release delivery of naltrexone hydrochloride.     

Dermal delivery of doxorubicin-loaded solid lipid nanoparticles for the treatment of skin cancer

Objective: Dermal delivery of Doxorubicin (Dox) would be an ideal way in maximising drug efficiency against skin cancer accompanying with minimising side effects. We investigated the potential of Dox-loaded Solid lipid nanoparticles (SLNs) for topical delivery against skin cancer.

Methods: In vitro and in vivo cytotoxicity of optimised formulation were evaluated on murine melanoma (B16F10) cells by MTT assay and melanoma induced Balb/C mice, respectively. Animal study followed by histological analysis.

Results: Optimised formulation showed mean particle size and encapsulation efficiency (EE) of 92?nm and 86% w/w (0.86% w/w value of encapsulated Dox in the lipid matrix), respectively. FTIR experiment confirmed drug–lipid interaction interpreting the observed high EE value for Dox. In vitro and in vivo results indicated the superiority of cytotoxic performance of Dox-loaded SLN compared to Dox solution.

Conclusion: Our findings may open the possibilities for the topical delivery of Dox to the skin cancerous tissues.     

Poly(ester amine) constructed from polyethylenimine and pluronic for gene delivery in vitro and in vivo

A series of poly (ester amines) (PEAs) constructed from low molecular weight polyethyleneimine (LPEI, Mw: 0.8k, 1.2k Da) and Pluronic (different molecular weight (Mw) and hydrophilic-lipophilic-balance (HLB)) components were synthesized, and evaluated in vitro and in vivo as gene delivery carriers. Most PEA polymers were able to bind and condense plasmid DNA effectively into particles of approximately 150?nm in solution at the polymer/DNA ratio of 5 and above. Transfection efficiency of the PEA polymers depends on particle size of the polymer/DNA complex, molecular weight and HLB of the Pluronics and the size of PEI within PEA composition, as well as the cell type. Significant improvement in gene delivery efficacy was achieved with PEA01/04/05 composed of Pluronic size (Mw: 3000–5000?Da), and HLB (12–18) in CHO, C2C12 and HSkM cell lines; and the effective transfection was reflected with PEA 01/04/07 composed of Pluronics with size (2000–5000?Da) and HLB (12–23) in mdx mice. The best formulation for pDNA delivery was obtained with PEA 01 producing transgene expression efficiency 5, 19-folds of that of PEI 25k in vitro and in vivo, respectively. These results potent some of these PEA polymers as attractive vehicles for gene or oligonucleotide delivery.     

Vaginal delivery of carboplatin-loaded thermosensitive hydrogel to prevent local cervical cancer recurrence in mice

Local tumor recurrence after cervical cancer surgery remains a clinical problem. Vaginal delivery of thermosensitive hydrogel may be suited to reduce tumor relapse rate with more efficacy and safety. A pilot study was carried out to evaluate the efficacy of carboplatin-loaded poloxamer hydrogel to prevent local recurrence of cervical cancer after surgery. In vivo vaginal retention evaluation of 27% poloxamer hydrogel in mice was proven to be a suitable vaginal drug delivery formulation due to its low gelation temperature. A mimic orthotopic cervical/vaginal cancer recurrence model after surgery was established by injecting murine cervical cancer cell line U14 into the vaginal submucosa to simulate the residual tumor cells infiltrated in the surgical site, followed by drug administration 24?h later to interfere with the formation/recurrence of the tumor. By infusing fluorescein sodium-loaded hydrogel into the vagina of mice, a maximized accumulation of fluorescein sodium (Flu) in the vagina was achieved and few signals were observed in other organs. When used in the prevention of the cervical cancer formation/recurrence in mice, the carboplatin-loaded poloxamer hydrogel exhibited great efficacy and systemic safety. In conclusion, thermosensitive hydrogel presents a simple, practical approach for the local drug delivery via vagina against cervical cancer recurrence.     

Bioadhesive Chitosan-Coated Cationic Nanoliposomes With Improved Insulin Encapsulation and Prolonged Oral Hypoglycemic Effect in Diabetic Mice

Oral administration of insulin is hampered by the lack of carriers that can efficiently achieve high encapsulation, avoid gastric degradation, overcome mucosal barriers, and prolong the hypoglycemic effect. Chitosan (CS)-coated insulin-loaded cationic liposomes have been developed and optimized for improved oral delivery. Liposomes were prepared cationic to improve insulin encapsulation. CS was selected as a mucoadhesive coat to prolong the system's residence and absorption. The performance of CS-coated liposomes compared with uncoated liposomes was examined in vitro, ex vivo, and in vivo in streptozotocin-induced diabetic mice. Free uncoated liposomes showed high positive zeta potential of +58.8 ± 2.2 mV that reduced (+29.9 ± 1.4 mV) after insulin encapsulation, confirming the obtained high entrapment efficiency of 87.5 ± 0.6%. CS-coated liposomes showed nanosize of 439.0 ± 12.3 nm and zeta potential of +60.5 ± 1.9 mV. In vitro insulin release was limited to 18.9 ± 0.35% in simulated gastric fluid, whereas in simulated intestinal fluid, 73.33 ± 0.68% was released after 48 h from CS-coated liposomes. Ex vivo intestinal mucoadhesion showed increased tissue residence of CS-coated liposomes compared with uncoated liposomes. A striking reduction in the glucose level was observed 1 h after oral administration of CS-coated liposomes and maintained up to 8 h (p <0.01 vs. insulin solution or uncoated liposomes) within the normal value 129.29 ± 3.15 mg/dL. In conclusion, CS-coated insulin-loaded cationic liposomes improved loading efficiency with promising prolonged pharmacological effect.     

Local release of gemcitabine via in situ UV-crosslinked lipid-strengthened hydrogel for inhibiting osteosarcoma

Osteosarcoma is among the most common malignant bone tumors in human skeletal system. The conventional treatment of osteosarcoma mainly consists of combining neoadjuvant chemotherapy with surgical approach. However, it is crucial to design an artificial implant that possesses excellent biomechanical properties and is capable of sustaining local release of chemotherapeutics. In this study, we envision that the highly efficient combination of gemcitabine (GEM) hydrochloride loaded liposomes with gelatin methacryloyl (GelMA) of in situ photocrosslinkable hydrogel will lead to a multifunctional implant with unique antitumor, mechanical, and biodegradable properties. A sustained controlled release was observed; more specifically, the release of GEM in vitro lasted for 4?days long. Furthermore, its capability in killing MG63 cells was further explored by using the lixivium of GEM-Lip@Gel and GEM-GelMA hydrogel in vitro (composite hydrogel by GEM loaded liposomes blending with GelMA, short for GEM-Lip@Gel), which agreed with the drug release outcome. In addition, these hydrogel showed excellent ability in inhibiting osteosarcoma in vivo by Balb/c mice bearing MG63 cells. Therefore, GEM-loaded lipo-hydrogel certainly has presented itself as a promising strategy for the development of implant in the field of osteosarcoma treatment.     

Preparation and in Vitro/in Vivo Evaluation of Insulin-Loaded Poly(Acryloyl-Hydroxyethyl Starch)-PLGA Composite Microspheres

Purpose. The purpose of this study was to develop and evaluate a novel composite microsphere delivery system composed of poly(D,L-lactide-co-glycolide) (PLGA) and poly(acryloyl hydroxyethyl starch) (acryloyl derivatized HES; AcHES) hydrogel using bovine insulin as a model therapeutic protein. Methods. Insulin was incorporated into the AcHES hydrogel microparticles by a swelling technique, and then the insulin-containing AcHES microparticles were encapsulated in a PLGA matrix using a solvent extraction/evaporation method. The composite microspheres were characterized for loading efficiency, particle size, and in vitro protein release. Protein stability was examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, high-performance liquid chromatography, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The hydrogel dispersion process was optimized to reduce the burst effect of microspheres and avoid hypoglycemic shock in the animal studies in which the serum glucose and insulin levels as well as animal body weight were monitored using a diabetic animal model. Results. Both the drug incorporation efficiency and the in vitro release profiles were found to depend upon the preparation conditions. Sonication effectively dispersed the hydrogel particles in the PLGA polymer solution, and the higher energy resulted in microspheres with a lower burst and sustained in vitro release. Average size of the microspheres was around 22 m and the size distribution was not influenced by sonication level. High-performance liquid chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, along with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry showed the retention of insulin stability in the microspheres. Subcutaneous administration of microspheres provided glucose suppression <200 mg/dL for 810 days with hyperglycemia recurring by day 16. During the treatment, the time points with higher serum insulin level were consistent with a more significant glucose suppression. The microsphere-treated rats also grew virtually at the same rate as normal control until the insulin level declined and hyperglycemia returned. Multiple dosing given every 10 days demonstrated that the pharmacological effect and serum insulin levels from second or third doses were similar and comparable to that of the first dose. Conclusion. The AcHES-PLGA composite microsphere system provides satisfactory in vitro and in vivo sustained release performance for a model protein, insulin, to achieve 10-day glucose suppression.     

PHARMACEUTICAL NANOTECHNOLOGY: A Novel Composite Hydrogel Based on Chitosan and Inorganic Phosphate for Local Drug Delivery of Camptothecin Nanocolloids

In attempt to overcome the problem of low water solubility and severe toxicity of camptothecin (CPT) after intravenous administration, a novel drug carrier system based on chitosan (CS) and dibasic sodium phosphate (DSP) has been developed in this paper to encapsulate CPT intending for local administration. Nanocolloids of CPT with size about 500 nm were first prepared, followed by encapsulation in the chitosan/dibasic sodium phosphate (CS/DSP) formulation. The formulation was sol state below 37°C and transformed to nonflowing gel state at 37°C. Encapsulation of CPT nanocolloids had greatly effect on the gelling time as well as the micro-structure of hydrogel. In vitro and in vivo degradation studies revealed that the developed CS/DSP hydrogel was biodegradable and biocompatible. In vitro release study revealed that CPT released from CS/DSP hydrogel in an extended period with about 70% of total CPT released from hydrogel after 18 days. Furthermore, nearly 90% of CPT in the chitosan hydrogels could be preserved in the lactone form (active form) even after 7 days's storage at 37°C. Furthermore, in vitro cytotoxicity of CPT nanocolloids on SKOV3 human ovarian cancer cells suggested the well anti-tumor cell efficiency could be gained at a lower concentration.     

Injectable poly(organophosphazene) hydrogel system for effective paclitaxel and doxorubicin combination therapy

Abstract

Combination therapy is an important option for gastric cancer which is the second leading cause of cancer-related death worldwide. The administration schedule of cell cycle-specific drugs, such as doxorubicin (DOX) and paclitaxel (PTX), is important for therapeutic efficacy. However, to control the schedule is clinically inconvenient. Additionally, in vitro cytotoxicity tests against human gastric cancer cells (SNU-601) showed that the combination indices (CIs) of DOX and PTX were 1.43 (α?=?0) and 1.90 (α?=?1), respectively, indicating that the DOX and PTX interaction was antagonistic. Thus, based on the finding that the release rate of drugs from poly(organophosphazene) (PPZ) hydrogel is dependent on the hydrophobicity of the drugs, we used injectable PPZ hydrogel in combination therapy. In vivo anticancer activity test in human gastric cancer cell-xenografted mice showed that intratumoral injection with aqueous PPZ solution, containing DOX (15?mg/kg) and PTX (30?mg/kg), resulted in the highest tumor inhibition and safety (no mortality for approximately 3 months) in the experimental groups. Consequently, PPZ hydrogel is expected to be a promising drug delivery system for cell cycle-specific drugs, facilitating the control of their administration schedule for effective combination therapy.     

pH triggered delivery of curcumin from Eudragit-coated chitosan microspheres for inflammatory bowel disease: characterization and pharmacodynamic evaluation

Objective: This investigation deals with the development and evaluation (in vitro and in vivo) of pH triggered Eudragit-coated chitosan microspheres of curcumin (CUR) for treating ulcerative colitis.

Methods: CUR-loaded chitosan microspheres were initially prepared by emulsion cross linking method followed by coating with Eudragit S-100. The pharmacodynamics of the developed formulation was analyzed in mice by acetic acid induced colitis model.

Results: The developed microspheres were of uniform spherical shape with high entrapment efficiency. CUR-chitosan microspheres showed less intense peaks compared to free CUR confirming inclusion of drug within microspheres as revealed by X-ray diffractogram. Uncoated CUR-chitosan microspheres exhibited burst release within initial 4?h while microspheres coated with Eudragit S-100 prevented premature release of CUR and showed controlled release up to 12?h following Higuchi model. In vivo organ biodistribution study showed negligible amount of CUR in stomach and small intestine confirming integrity of microsphere in upper gastrointestinal tract (GIT). In vivo study revealed significant reduction in severity and extent of colonic damage with CUR-loaded microspheres as compared to pure CUR which was further confirmed by histopathological study.

Conclusion: In vitro and in vivo studies proved the developed formulations as a promising system for pH-dependent delivery of drug to colon in ulcerative colitis.     

A local drug delivery system based on visible light-cured glycol chitosan and doxorubicin⋅hydrochloride for thyroid cancer treatment in vitro and in vivo

Systemic drug delivery systems (SDDSs) for thyroid cancer treatment are associated with serious side effects including nausea, anorexia, and hair loss as a result of damage to normal tissues. In this study, we investigated the feasibility of a local DDS (LDDS) based on visible light-cured glycol chitosan (GC) hydrogel and doxorubicin?hydrochloride (DOX?HCl), called GC10/DOX, on thyroid cancer treatment in vivo. Visible light irradiation increased the storage modulus and swelling ratio of the GC10/DOX hydrogel precursor. The release of DOX?HCl from GC10/DOX exhibited two unique patterns comprising an initial burst within 18?hours, followed by a controlled and sustained release thereafter. In vitro cell viability testing showed that GC10/DOX had a greater antitumor effect than free DOX?HCl and GC10 hydrogel controls. In vivo, local injection of GC10/DOX near tumor tissue led to a superior antitumor effect compared with controls consisting of free DOX?HCl intravenously injected to the tail vein of thyroid cancer-bearing mouse and GC10 hydrogel subcutaneously injected near the tumor. Altogether, our results suggest that GC10/DOX may have clinical potential for thyroid cancer treatment.