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At present, a significant research activity is being undertaken to develop biologically compatible and degradable scaffolds for various biomedical applications. An ideal scaffolding material would act as a temporary replacement for the tissue that is lost or damaged while promoting its healing/regeneration. Amongst diverse group of materials, polymers are the most widely investigated for various applications. The popularity of polymers is attributed to the ability to control their properties by preparing scaffolds with varying porosity, geometry, surface area, mechanical and surface characteristics. Today, polymer based materials are an integral part of numerous applications such as drug delivery, tissue engineering, etc. No single material is suitable for all these applications each with explicit requisites. Hence, selection of biomaterials should be based on how far the scaffolding materials meet the requisite properties of the intended application. Polymers based on lactic and glycolic acids are extensively used biodegradable materials with long history of use in a variety of applications. The present review aims to provide an insight into biodegradable polymers based on lactic and glycolic acids, their biodegradation principles and behavior along with various problems encountered during their use and various methods used to overcome the shortcomings of these materials.

Aim The aim of the present study was to develop nanoproliposomes of lercanidipine, in order to overcome its poor biopharmaceutical properties and to improve its therapeutic efficacy in treating hypertension. Main methods The nanoproliposomes were prepared using a modified thin-film hydration method, and the formula was optimized by varying the ratio of lipids and the types of cryoprotectants. This optimized formulation was characterized in terms of its particle size, solid-state, drug release, in-situ absorption, in-vivo pharmacokinetics, and in-vivo anti-hypertensive activity in DOCA-salt induced hypertensive rats. Finally, a PK-PD correlation was established in order to understand the clinical implications of the developed novel nanoproliposomes. Key findings The nanoproliposomes showed a particle size of 174.7 nm and an entrapment efficiency of 85.4%. The in-vitro release displayed initial rapid release (19.33%) followed by a sustained release profile, releasing 88.37% of the encapsulated drug. The in-situ studies showed a significant increase in absorption rate across the rat intestinal membrane. The pharmacokinetics of this novel form indicated a 2.75-fold increase in the absolute bioavailability as compared to pure lercanidipine. In addition, the nanoproliposomes were found to be efficient in treating hypertension in DOCA-salt induced hypertensive rats. The PK-PD correlation demonstrated no time lag between effect and exposure, indicating that a direct PK-PD relationship can be expected in the clinic. Significance These findings suggest that nanoproliposomes are promising carriers in improving the oral bioavailability and bioactivity of lercanidipine, and can be an effective therapy in the management of hypertension.

The aim of this study was to prepare and characterize biodegradable scaffolds of poly(lactic-co-glycolic acid) (PLGA 85:15) and nano-hydroxyapatite (HA) containing magnesium carbonate (MC) as acidic microclimate controlling additive. Porous and nonporous scaffolds of PLGA 85:15 and nano-HA containing MC were prepared by solvent casting and particulate leaching method. Scaffolds were degraded at pH 7.4 phosphate buffer for 90 days. At regular intervals, pH of the degradation medium, release of degradation products, mass loss, water sorption, and tensile strength were measured. The results showed that the pH of the degradation medium significantly decreased with control specimens, whereas the scaffolds with MC did not show significant changes. In addition, acidic monomer release from the scaffolds with MC was found to be less, whereas the water sorption was found to be significantly higher. The tensile strength of the scaffold was found to be dependent on the concentration of HA and porosity. These results indicate that incorporation of MC to PLGA 85:15 scaffolds reduces the acidic microclimate with changes in mass loss, water sorption, and strength properties. POLYM. COMPOS., 2015. © 2015 Society of Plastics Engineers

In the present study, biodegradable scaffolds of poly(lactide-co-glycolide) PLGA 50:50 with acidic microclimate controlling additives were prepared and characterized for their degradation behavior, physical, and mechanical properties. Results indicate that scaffolds with acidic microclimate controlling additives undergo degradation without large variation in pH of the surrounding medium. Results also indicated that microclimate controlling additives did not significantly alter the physical and mechanical properties of the scaffolds. From the results, it can be concluded that PLGA 50:50 scaffolds with acidic microclimate controlling additives can be used as root replicas after the tooth extraction.

Glutathione disulfide (GSSG) is an endogenous peptide and the oxidized form of glutathione. The impacts of GSSG on cell function/dysfunction remain largely unexplored due to a lack of method to specifically increase intracellular GSSG. We recently developed GSSG liposomes that can specifically increase intracellular GSSG. The increase affected 3 of the 4 essential steps (cell detachment, migration, invasion, and adhesion) of cancer metastasis in vitro and, accordingly, produced a significant inhibition of cancer metastasis in vivo. In this investigation, the effect of GSSG liposomes on cancer growth was investigated with B16-F10 and NCI-H226 cells in vitro and with B16-F10 cells in C57BL/6 mice in vivo. Experiments were conducted to elucidate the effect on cell death through promotion of apoptosis and the effect on the cell cycle. The in vivo results with C57BL/6 mice implanted subcutaneously with B16-F10 cells showed that GSSG liposomes retarded tumor proliferation more effectively than that of dacarbazine, a chemotherapeutic drug for the treatment of melanoma. The GSSG liposomes by intravenous injection (GLS IV) and GSSG liposomes by intratumoral injection (GLS IT) showed a tumor proliferation retardation of 85% ± 5.7% and 90% ± 3.9%, respectively, compared with the phosphate-buffered saline (PBS) control group. The median survival rates for mice treated with PBS, blank liposomes, aqueous GSSG, dacarbazine, GLS IV, and GLS IT were 7, 7, 7.5, 7.75, 11.5, and 16.5 days, respectively. The effective antimetastatic and antigrowth activities warrant further investigation of the GSSG liposomes as a potentially effective therapeutic treatment for cancer.

Celecoxib has been found to be effective in cancer prevention and treatment. Its combination with other chemotherapeutic agents was reported to produce synergistic/additive effects on various cancers. Dacarbazine (DTIC) is one of the most commonly used drugs in the treatment of metastatic melanoma. This investigation aimed to determine the in-vitro and in-vivo effects of the drug combination of celecoxib and DTIC on melanoma growth and metastasis. Melanoma cells B16-F10 and SK-MEL-28, and female C57BL/6 mice were used for the study. Our in-vitro data showed that significant synergistic effects were obtained when celecoxib was used together with various concentrations of DTIC. A study with B16-F10 cells using flow cytometry analysis showed that the drug combination induced significantly more apoptosis than each drug used individually. Our in-vivo results showed that the drug combination was much more effective than each drug used alone for the inhibition of both melanoma growth and metastasis in the B16-F10+C57BL/6 mouse models. For melanoma growth, the median survival rates for phosphate-buffered saline (PBS) (control), celecoxib (30 mg/kg), DTIC-1 (10 mg/kg), DTIC-2 (positive control, 50 mg/kg), and the drug combination (DTIC 10 mg/kg+celecoxib 30 mg/kg) were 6, 6.5, 7.5, 7.5, and 9 days, respectively. For melanoma metastasis, the average number of metastatic tumors in murine lungs was 53.7±10.7, 31.8±18.6, 21.2±21.7, 7.0±9.0, and 0.8±2.0 for PBS, DTIC-1, celecoxib, the drug combination, and DTIC-2. Our results warrant further investigation of the combination as an effective treatment for melanoma patients.

Cancer metastasis is the major cause of cancer mortality. Despite extensive research efforts, effective treatment for cancer metastasis is still lacking. Cancer metastasis involves 4 essential steps: cell detachment, migration, invasion, and adhesion. Detachment is the first and required step for metastasis. Glutathione disulfide (GSSG) is derived from the oxidation of glutathione (GSH), which is present in biological systems in millimolar concentration. Although GSSG is commercially available, the impact of GSSG on cell functions/dysfunctions has not been fully explored due to the fact that GSSG is not cell membrane permeable and a lack of method to specifically increase GSSG in cells. We have developed GSSG liposomes that effectively deliver GSSG to cells. Unexpectedly, cells treated with GSSG liposomes were resistant to detachment by trypsinization. This observation led to the investigation of the antimetastatic effect of GSSG liposomes. Our data demonstrate that GSSG liposomes at 1 mg/mL completely blocked cell detachment and migration, and significantly inhibited cancer cell invasion. Aqueous GSSG showed no such effect, confirming that the effects on cell detachment, migration, and invasion were caused by the intracellular delivery of GSSG. An in vivo experiment with a murine melanoma experimental metastasis model showed that GSSG liposomes prevented melanoma lung metastasis. The unique antimetastatic mechanism through the effects on detachment and migration, and effective in vitro and in vivo metastasis inhibition, warrants further investigation of the GSSG liposomes as a potential treatment for cancer metastasis.

The purpose of the present study was to fabricate PLGA 50:50 and PLA microspheres for controlled delivery of anastrozole. The microspheres were prepared by oil-in-water (o/w) emulsion/solvent evaporation technique and evaluated for particle size and encapsulation. The optimised formulations were studied for solid state characterization, in vitro release and pharmacokinetic studies. The maximum encapsulation efficiency for PLGA 50:50 and PLA microspheres with 40:1 polymer - drug ratio was observed to be 78.4 ± 2.5 and 87.7 ± 2.6%. The solid state characterization confirmed dispersion of drug at the molecular level in the polymeric matrix. Microspheres were spherical in shape with a very smooth surface texture. Drug release was found to be in a sustained fashion, releasing constantly up to 720 h (30 days) for PLGA and 60 days for PLA microspheres. The pharmacokinetic study data revealed that the intramuscular administration of PLA microspheres showed improved pharmacokinetic profile as compared to PLGA microspheres, and therefore this formulation can be considered as the best optimised formulation with sustained exposure of the drug in vivo compared to other microspheres. From experimental results, PLA microspheres demonstrate the feasibility of employing biodegradable depot polymeric microspheres of anastrozole for long-term treatment of breast cancer.

Novel biodegradable micelles were synthesized by conjugating methoxy poly(ethylene glycol) (mPEG) to zein, a biodegradable hydrophobic plant protein. The mPEG-zein micelles were in the size range of 95-125 nm with a low CMC (5.5 × 10(-2) g/L). The micelles were nonimmunogenic and were stable upon dilution with buffer as well as 10% serum. Curcumin, an anticancer agent with multiple delivery challenges, was encapsulated in mPEG-zein micelles. The micelles significantly enhanced the aqueous solubility (by 1000-2000-fold) and stability (by 6-fold) of curcumin. PEG-zein micelles sustained the release of curcumin up to 24 h in vitro. Curcumin-loaded mPEG-zein micelles showed significantly higher cell uptake than free curcumin in drug-resistant NCI/ADR-RES cancer cells in vitro. Micellar curcumin formulation was more potent than free curcumin in NCI/ADR-RES cancer cells, as evidenced from the 3-fold reduction in IC(50) value of curcumin. Overall, this study for the first time reports a natural protein core based polymeric micelle and demonstrates its application for the delivery of hydrophobic anticancer drugs such as curcumin.

Clinical administration of paclitaxel is hindered due to its poor solubility, which necessitates the formulation of novel drug delivery systems to deliver such extreme hydrophobic drug. To formulate nanoparticles which makes suitable to deliver hydrophobic drugs effectively (intravenous) with desired pharmacokinetic profile for breast cancer treatment; in this context in vitro cytotoxic activity was evaluated using BT-549 cell line. PLGA nanoparticles were prepared by emulsion solvent evaporation technique and evaluated for physicochemical parameters, in vitro anti-tumor activity and in vivo pharmacokinetic studies in rats. Particle size obtained in optimized formulation was

The aim of this study was to develop an enteric-coated multiunit dosage form containing aceclofenac, a nonsteroidal anti-inflammatory drug. The pellets were prepared by using extrusion/spheronization method, and the core pellets were coated with a pH-sensitive poly(meth) acrylate copolymer (Eudragit L100-55) to achieve site-specific drug release. The formulated pellets were characterized for percentage yield, size distribution, surface morphology studies, drug content, and flow properties. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. The practical yield was found to be 90-95%. The particle size of enteric-coated pellets was found to be in the range of 0.59-0.71 mm. The pellets were spherical in shape and surfaces of pellets were found to be rough and showing micropores. Enteric-coated pellets showed good flow properties and in vitro dissolution profile. Dissolution tests were carried out in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The release of the aceclofenac from formulated pellets was established to be minimum in the pH 1.2 (5%) for a period of 2 h, and at pH 6.8, it shows the maximum release (85 +/- 5% release within 1 h) which indicates gastric resistance of the formulated pellets. The 20% wt/wt enteric-coated pellets were compared to that of marketed product (tablets), it was observed that pellets showed better release profile. The study concluded that the formulated multiparticulate dosage forms can be used as an ideal drug delivery system for the aceclofenac.

A study of rivastigmine liposomes for delivery into the brain through intranasal routeThe present study is mainly aimed at delivering a drug into the brainviathe intranasal route using a liposomal formulation. For this purpose, rivastigmine, which is used in the management of Alzheimer's disease, was selected as a model drug. Conventional liposomes were formulated by the lipid layer hydration method using cholesterol and soya lecithin as lipid components. The concentration of rivastigmine in brain and plasma after intranasal liposomes, free drug and per oral administration was studied in rat models. A significantly higher level of drug was found in the brain with intranasal liposomes of rivastigmine compared to the intranasal free drug and the oral route. Intranasal liposomes had a longer half-life in the brain than intranasally or orally administered free drug. Delivering rivastigmine liposomes through the intranasal route for the treatment of Alzheimer's disease might be a new approach to the management of this condition.

The aim of this study was to formulate and evaluate gliclazide (GLC) loaded chitosan nanoparticles (NP's). GLC is a hypoglycemic agent, stimulates insulin secretion from functional pancreatic beta-cells and increases the sensitivity of the beta cells to glucose. In the present study GLC loaded chitosan NP's were prepared by salting out of chitosan with sodium citrate. The influence of various formulation factors (stirring speed, drug: polymer ratio) on particle size, drug loading, and encapsulation efficiency were investigated. The particle size analysis was determined by dynamic light scattering technique. The developed NP's showed high drug loading and encapsulation efficiency. FT-IR and DSC studies showed no interaction of GLC with polymers. The release of drug from NP's exhibited over a period of 24 h with an initial burst effect followed by sustained release. The rate and amount of the drug release was decreased as the polymer content increased. The optimum ratio was found to be 1:2.5 with high encapsulation efficiency with sustained drug release. Stability studies revealed that the GLC-loaded NP's were stable for the period of three months.

The purpose of the study was to formulate and evaluate controlled release chitosan microspheres of mirtazapine (MTZ) to improve the bioavailability by altering the pharmacokinetic profiles of the drug. Chitosan microspheres were prepared to prolong the release of the drug into the systemic circulation. Microspheres were prepared by a single water in oil (w/o) emulsion technique varying the chitosan/drug ratio, stirring speed and concentration of the crosslinking agent (glutaraldehyde). Drug-polymer compatibility studies were carried out using fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The microspheres were evaluated for encapsulation efficiency, particle size, surface morphology, swelling index, in vitro release, as well as erosion and in vivo studies in rats. The FT-IR and DSC studies revealed no interaction between drug and polymer. The encapsulation efficiency of different formulation varied from 53 ± 1.2% to 78 ± 1.5%. The mean particle size of the optimized formulation F-14 was 106.4 ± 0.5 μm. Surface morphology revealed that chitosan microspheres were discrete and spherical in shape with a porous surface. The release of MTZ from chitosan microspheres was rapid up to 4 h, and then it was continuously and slowly released up to 48 h. Optimized formulation (F-14) was found to be stable under accelerated storage conditions based on International Conference on Harmonisation guidelines. Pharmacokinetic studies revealed that the optimized formulation showed significant increases in systemic exposure (AUC = 177.70 ± 7.39 μg·h/mL), half-life (4.72 ± 0.46 h) and reduced clearance (0.009 ± 0.0001 L/h) compared to pure drug administration. Hence, the present study demonstrates that controlled release formulation of MTZ microspheres using chitosan can improve pharmacokinetic profiles of MTZ.

The objective of the present study was to develop the mucoadhesive buccal film of valdecoxib for the treatment of oral sub mucous fibrosis, a localized buccal disease. Valdecoxib, a novel COX-2 inhibitor has been reported to be used in various osteopathic and rheumatoid conditions as oral therapy. The films were made out of chitosan and HPMC K4M as polymers. Sodium taurocholate was used as a permeation enhancer. All the formulations were examined for film thickness, swelling properties, drug content, weight variation, in vitro release studies, bioadhesive force, tensile strength, diffusion studies using pig mucosa and pharmacokinetic study in healthy male volunteers. Prepared films were thin, flexible, smooth and transparent. Bioadhesive force and tensile strength of the optimized formulation were found to be 75 +/- 4 kg m(-1) S(-2) and more than 2.5 kg/3 cm(2), respectively. The percent drug content was 98.5 +/- 1.3%. The in vitro drug release from the selected formulation showed that about 69.34% of the drug payload was released up to 6 hours. The drug permeation through the dialysis sac and pig buccal mucosa was found to be 62.70% and 54.39%, respectively. Pharmacokinetic studies of the buccal mucoadhesive film showed that the drug was released locally at the target site of action, and a very small amount might have absorbed systemically.

The present study is mainly aimed at delivering a drug into the brain via the intranasal route using a liposomal formulation. For this purpose, rivastigmine, which is used in the management of Alzheimer’s disease, was selectd as a model drug. Conventional liposomes were formulated by lipid layer hydration method using cholesterol and soya lecithin as lipid components. The concentration of rivastigmine in brain and plasma was studied in rat models after intranasal and oral administration of liposomes and free drug. A significantly higher level of drug was found in the brain with intranasal liposomes of rivastigmine compared to the intranasal free drug and the oral route. Intranasal liposomes had a longer half-life in the brain than intranasally or orally administered free drug. Delivering rivastigmine liposomes through the intranasal route for the treatment of Alzheimer’s disease might be a new approach to the management of this condition., Glavni cilj rada je razvoj liposoma za intranazalnu primjenu za isporuku lijeka u mozak. U tu svrhu izabran je rivastigmin kao modelni lijek koji se upotrebljava u terapiji Alzheimerove bolesti. Liposomi su pripravljeni metodom hidratacije lipidnog sloja koristeći kolesterol i lecitin iz soje kao lipidne komponente. Praćena je koncentracija rivastigmina u mozgu i plazmi nakon intranazalne i peroralne primjene liposoma i slobodnog lijeka. S intranazalnim liposomima rivastigmina postignuta je značajno veća koncentracija lijeka u mozgu. Osim toga intranazalni liposomi imaju dulje vrijeme poluživota u mozgu. Intranazalna primjena liposoma rivastigmina mogla bi predstavljati novi pristup terapiji Alzheimerove bolesti.

The study was aimed at investigating localized topical drug delivery to the breast via mammary papilla (nipple). 5-fluorouracil (5-FU) and estradiol (EST) were used as model hydrophilic and hydrophobic compounds respectively. Porcine and human nipple were used for in-vitro penetration studies. The removal of keratin plug enhanced the drug transport through the nipple. The drug penetration was significantly higher through the nipple compared to breast skin. The drug’s lipophilicity had a significant influence on drug penetration through nipple. The ducts in the nipple served as a major transport pathway to the underlying breast tissue. Results showed that porcine nipple could be a potential model for human nipple. The topical application of 5-FU on the rat nipple resulted in high drug concentration in the breast and minimal drug levels in plasma and other organs. Overall, the findings from this study demonstrate the feasibility of localized drug delivery to the breast through nipple.

Purpose: Honokiol, a plant lignan isolated and purified from Magonila Officinalis has been shown to have chemopreventive effects in chemically induced and UV-B induced skin tumor development in SKH-1 mice. However poor solubility of honokiol greatly limits its clinical application. The key objectives of the present investigation are to improve the solubility and stability of honokiol by encapsulating in nanostructured lipid nanoparticles. Methods: Honokiol was incorporated into nanostructured lipid nanoparticles and cream using hot homogenization method. Compritol 888 ATO, Precirol ATO 5, and miglyol 812 as lipid matrices and poloxamer 188 as emulsifier. Lipid nanoparticles were characterized for size, zeta potential, shape and morphology using photon correlation spectroscopy (PCS) and atomic force microscopy (AFM). Honokiol was quantified by isocratic HPLC method using mobile phase of 60:40 (%v/v, acetonitrile:water) at a flow rate of 1 ml/min at a wavelength of 254 nm. Permeation studies were carried out using porcine dermatome skin in Franz diffusion cell. Honokiol concentration corresponding to 0.5 mg/ml in sesame oil, cream and lipid nanoparticles was dispersed in PBS pH 7.4. Permeation studies were performed till 24hrs; the samples (200 µl) were withdrawn at regular time intervals and replaced with fresh medium. Amount of honokiol permeated across porcine skin was quantified using HPLC method. Stability of cream and lipid nanoparticle formulations was studied at 30° C and 65 % relative humidity in a stability chamber for one month. Results: The size of the optimized honokiol loaded lipid nanoparticles was 145±7 nm with a polydispersity index of 0.24±0.02. The zeta potential and encapsulation efficiency was 0.34±0.02 mV and 97±2 %. The particle size of lipid nanoparticles measured in AFM was very close to size measured by PCS. In case of precirol cream, particle size was more than 20 µm with drug content of 89±5 %. Honokiol loaded nanostructured lipid nanoparticles, and cream were stable for about 30 days without any significant changes in particle size, and drug content at 30° C and 65 % relative humidity. Skin treated with honokiol entrapped in nanoparticles and cream has shown more retention of honokiol in the skin compared to plain honokiol in sesame oil. Proposed lipid cream and nanoparticles formulation has shown effective skin penetration of honkiol. From the data it is evident that nanoparticles has shown higher amount of honokiol in skin compared to cream formulation. Conclusions: Preliminary results of this study have shown the potential of lipid based formulations for topical delivery of honokiol. Chemopreventive potential and efficacy of honokiol encapsulated in lipid based formulations will be evaluated in UV-B induced skin cancer model. Acknowledgements: Supported by Translational Cancer Research Center funded by the South Dakota Governor's Office of Economic Development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5709. doi:1538-7445.AM2012-5709

Skin cancer is the most prevalent of all cancers and its incidence is expected to increase substantially. UVB is major etiologic factor in the skin cancer development. Honokiol, a plant ligan isolated from bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on UVB-induced skin cancer development in our laboratory. The objectives of this investigation are to study chemopreventive effects of dose response of honokiol on UVB-induced skin tumor development in SKH-1mice and to prepare topical formulations of honokiol that deliver effective concentration of drug locally. Female SKH-1 mice were divided into 4 groups. Group 1 received acetone one hour before UVB treatment; Group 2, 3 and 4 received honokiol (0.2 ml of 30, 45 and 60 μg in acetone, topical) before each UVB treatment. Mice were treated with UVB dose of 30 mJ/cm2/day for 25 weeks. Tumor counts and group weights were taken weekly. Honokiol pretreated groups resulted in 36-78% reduction in tumor multiplicity compared to control. Honokiol pretreatment (60 μg) decreased tumor incidence by 40 %. Topical formulation of honokiol gel was prepared by using carbomer 940 as base and propylene glycol as penetration enhancer. Drug content and content uniformity were determined. Release studies and permeation studies were studied in detail. This study is supported by Translational Cancer Research Center funded as 2010 Research Initiative Center by the State of South Dakota Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4620. doi:10.1158/1538-7445.AM2011-4620