Development and Evaluation of a Novel Drug in Adhesive Transdermal System of Levodopa and Carbidopa

Purpose

Administration of levodopa along with carbidopa increases the availability of dopamine in the mid-brain, and this combination thereby is used in the treatment of parkinsonism. However, concomitant delivery of levodopa with carbidopa in oral therapy is limited by several issues and an alternative route would be advantageous. The current study assesses the feasibility of co-administration of levodopa and carbidopa through skin using a drug in adhesive transdermal system.

Methods

Drug in adhesive transdermal system containing levodopa (5 % w/w) and carbidopa (2.5 % w/w) (1 cm² area) was fabricated and assessed for in vitro drug release, ex vivo permeation, and in vivo pharmacokinetics in rat model.

Results

In vitro dissolution profiles indicated a biphasic pattern with an initial burst effect for both levodopa and carbidopa, although the drug release rate was relatively higher for carbidopa. Ex vivo permeation studies showed higher steady-state flux for levodopa (53.77?±?6.94 μg/cm²/h) and carbidopa (23.81?±?4.06 μg/cm²/h). In vivo studies revealed that the concomitant transdermal delivery of levodopa with carbidopa significantly changed the pharmacokinetic parameters of levodopa.

Conclusions

Given the promising results, this study concludes that the transdermal delivery route could be a feasible alternative to oral therapy for the successful delivery of levodopa in Parkinson’s disorder.     

In Vitro,In Vivo,and In Silico Evaluation of the Bioresponsive Behavior of an Intelligent Intraocular Implant

Purpose

An autofeedback complex polymeric platform was used in the design of an intelligent intraocular implant—the I³—using stimuli-responsive polymers, producing a smart release system capable of delivering therapeutic levels of an anti-inflammatory agent (indomethacin) and antibiotic (ciprofloxacin) for posterior segment disorders of the eye in response to inflammation.

Methods

Physicochemical and physicomechanical analysis of the I³ was undertaken to explicate the highly crosslinked make-up and ‘on-off’ inflammation-responsive performance of the I³. In addition, energetic profiles for important complexation reactions were generated using Molecular Mechanics Energy Relationships by exploring the spatial disposition of energy minimized molecular structures. Furthermore, preliminary in vivo determination of the inflammation-responsiveness of the I³ was ascertained following implantation in the normal and inflamed rabbit eye.

Results

In silico modeling simulating a pathological inflammatory intraocular state highlighted the interaction potential of hydroxyl radicals with the selected polysaccharides comprising the I³. The intricately crosslinked polymeric system forming the I³ thus responded at an innate level predicted by its molecular make-up to inflammatory conditions as indicated by the results of the drug release studies, rheological analysis, magnetic resonance imaging and scanning electron microscopic imaging. In vivo drug release analysis demonstrated indomethacin levels of 0.749?±?0.126 μg/mL and 1.168?±?0.186 μg/mL, and ciprofloxacin levels of 1.181?±?0.150 μg/mL and 6.653?±?0.605 μg/mL in the normal and inflamed eye, respectively.

Conclusions

Extensive in vitro, molecular, and in vivo characterization therefore highlighted successful inflammation-responsiveness of the I³. The I³ is a proposed step forward from other described ocular systems owing to its combined bioresponsive, nano-enabled architecture.     

Triggered In Situ Drug Supersaturation and Hydrophilic Matrix Self-Assembly

Purpose

To understand in situ drug thermodynamic activity when embedded in a supramolecular structured hydrophilic matrix that simultaneously self-assembled during drug supersaturation.

Methods

A propylene glycol (PG)/water, hydroxypropyl methyl cellulose matrix containing ethanol was used to support diclofenac supersaturation. Phase behaviour, thermodynamics and drug transport were assessed through the determination of evaporation kinetics, supersaturation kinetics and transmembrane penetration.

Results

Initial ethanol evaporation from the drug loaded matrix (2.9?±?0.4?mg.min^?1.cm^?2) was comparable to that of the pure solvent (ca. 3?mg.min^?1.cm^?2). When 25% w/w of the total ethanol from the applied phase was lost (ethanol/water/PG molar ratio of 7:5:1.2), an inflection point in the evaporation profile and a sudden decrease in drug solubility demonstrated that a defined supramolecular structure was formed. The 55-fold decrease in drug solubility observed over the subsequent 8?h drove in situ supersaturation, the rate of which was a function of the drug load in the matrix (y?=?0.0078x, R²?<?0.99).

Conclusion

The self-assembling supramolecular matrix prevented drug re-crystallisation for >24?h, but did not hinder mobility and this allowed the thermodynamic activity of the drug to be directly translated into highly efficient transmembrane penetration.     

Nano Composite Emulsion for Sustained Drug Release and Improved Bioavailability

Purpose

To propose a novel composite nanoemulsion formulation that contains no surfactant, but offers great stability and improved oral absorption capabilities.

Methods

The nanoemulsions were prepared by dispersing the oil phase into aqueous solutions containing different amounts of the PMMA/silica composite nanoparticles. The stability was tested under extreme conditions. The structure features of the nanoemulsion droplets were investigated using Electron microscope. The in vitro drug release and in vivo drug absorption profiles after oral administration were investigated using Cyclosporin A as a model drug.

Results

The composite nanoemulsion demonstrated great stability under various disruptive conditions. Electron microscopy studies indicated the existence of internal and surface domains in the nano-droplet structure. In vitro drug release and in vivo uptake characterizations also confirmed the unique interfacial properties of such nanoemulsion structures.

Conclusions

The novel nanoemulsion formulation may have modulated drug release profiles and alternative oral absorption mechanisms, which could offer significant advantages compared to traditional emulsion formulations.     

Pharmaceutical Differences Between Block Copolymer Self-Assembled and Cross-Linked Nanoassemblies as Carriers for Tunable Drug Release

Purpose

To identify the effects of cross-linkers and drug-binding linkers on physicochemical and biological properties of polymer nanoassembly drug carriers.

Methods

Four types of polymer nanoassemblies were synthesized from poly(ethylene glycol)-poly(aspartate) [PEG-p(Asp)] block copolymers: self-assembled nanoassemblies (SNAs) and cross-linked nanoassemblies (CNAs) to each of which an anticancer drug doxorubicin (DOX) was loaded by either physical entrapment or chemical conjugation (through acid-sensitive hydrazone linkers).

Results

Drug loading in nanoassemblies was 27?~?56% by weight. The particle size of SNA changed after drug and drug-binding linker entrapment (20?~?100 nm), whereas CNAs remained 30?~?40 nm. Drug release rates were fine-tunable by using amide cross-linkers and hydrazone drug-binding linkers in combination. In vitro cytotoxicity assays using a human lung cancer A549 cell line revealed that DOX-loaded nanoassemblies were equally potent as free DOX with a wide range of drug release half-life (t_1/2?=?3.24?~?18.48 h, at pH 5.0), but 5 times less effective when t_1/2?=?44.52 h.

Conclusion

Nanoassemblies that incorporate cross-linkers and drug-binding linkers in combination have pharmaceutical advantages such as uniform particle size, physicochemical stability, fine-tunable drug release rates, and maximum cytotoxicity of entrapped drug payloads.     

Feasibility of Capsule Endoscopy for Direct Imaging of Drug Delivery Systems in the Fasted Upper-Gastrointestinal Tract

Purpose

To develop a minimally-invasive method for direct visualization of drug delivery systems in the human stomach and to compare the obtained results with an established in vitro model. The method should provide the capsule rupture, dispersion characteristics, and knowledge regarding the surrounding physiological environment in the stomach.

Methods

A capsule endoscopic method was developed. The disintegration time, dispersion characteristics and the impact of the physiological environment on different lipid based delivery systems in different gelatin capsules in the fasted stomach of nine healthy volunteers were visualized. Biorelevant dissolution studies using a USP II apparatus and a droplet size analysis of the released SNEDDS were performed.

Results

Visualization of the behavior of both hard and soft gelatin capsules formulations was possible. The disintegration and dispersion of EP oil in a soft capsule and SNEDDS in a hard shell capsule were visualized. The in vitro release rates were different from the in vivo release rates of the soft capsule due to volume, fluid composition and motility differences but not for the hard capsule containing SNEDDS.

Conclusions

A minimally-invasive capsule endoscopic method was developed for direct visualizing of drug delivery systems in the human stomach and maybe later, in the duodenum.     

Folate-Targeted Nanoparticles Based on Albumin and Albumin/Alginate Mixtures as Controlled Release Systems of Tamoxifen: Synthesis and In Vitro Characterization

Purpose

Preparation and in vitro characterization of tamoxifen (TMX)-loaded folate-targeted nanoparticles based on disulfide bond reduced bovine serum albumin (BSA-SH) and BSA-SH/alginate-cysteine (BSA-SH/ALG-CYS) mixtures as drug delivery systems.

Methods

Folate-nanoparticles were characterized in terms of folate content, morphology, size, zeta potential, TMX load and drug release kinetics. Additionally, cell viability and cellular uptake of nanoparticles were determined using different cancer cell lines.

Results

Folic acid (FOL) was successfully attached to nanoparticles (ranging between 79 and170 μmol folate/g NP). Nanoparticles with 76–417 nm mean size were obtained and loaded with TMX (4.2–7.7 μg/mg NP). Zeta potential and drug extraction revealed major superficial placement of the drug, especially in the case of BSA/ALG-FOL systems. Drug release studies in the presence of surfactant showed a gradual release of the drug between 4–7 h. In general, low cytotoxicity of unloaded systems was found. Internalization of the systems was achieved and mediated by folate receptor, especially in the case of BSA NP-FOL. The administration of 10 μM TMX by TMX-FOL NP showed their efficacy as controlled TMX release systems.

Conclusions

Promising anticancer action of these new TMX-loaded folate-targeted systems was demonstrated, allowing a new administration route to be studied in further in vivo studies in order to improve current TMX therapy.     

The Acoustic Features of Inhalation can be Used to Quantify Aerosol Delivery from a Diskus™ Dry Powder Inhaler

Purpose

Some patients are unable to generate the peak inspiratory flow rate (PIFR) necessary to de-agglomerate drug particles from dry powder inhalers (DPIs). In this study we tested the hypothesis that the acoustic parameters of an inhalation are related to the PIFR and hence reflect drug delivery.

Methods

A sensitivity analysis of the relationship of the acoustics of inhalation to simultaneously recorded airflow, in a cohort of volunteers (n?=?92) was performed. The Next Generation Impactor (NGI) was used to assess in vitro drug delivery from salmeterol/fluticasone and salbutamol Diskus? DPIs. Fine particle fraction, FPF, (<5 μm) was measured at 30–90 l/min for 2–6 s and correlated with acoustically determined flow rate (IFRc). In pharmacokinetic studies using a salbutamol (200 μg) Diskus?, volunteers inhaled either at maximal or minimal effort on separate days.

Results

PIFRc was correlated with spirometrically determined values (R ²?=?0.88). In in vitro studies, FPF increased as both flow rate and inhalation duration increased for the salmeterol/fluticasone Diskus? (Adjusted R ²?=?0.95) and was proportional to flow rate only for the salbutamol Diskus? (Adjusted R ²?=?0.71). In pharmacokinetic studies, blood salbutamol levels measured at 20 min were significantly lower when PIFRc was less than 60 l/min, p?Conclusion Acoustically-determined PIFR is a suitable method for estimating drug delivery and for monitoring inhalation technique over time.     

On-Command Drug Release from Nanochains Inhibits Growth of Breast Tumors

Purpose

To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor.

Methods

A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the 4T1-Luc-GFP orthotopic mouse model, which is a highly aggressive breast cancer model. The 4T1-Luc-GFP cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI).

Results

Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n?=?5 animals per group).

Conclusions

These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival.     

Multicompartimental Nanoparticles for Co-Encapsulation and Multimodal Drug Delivery to Tumor Cells and Neovasculature

Purpose

The purpose of this work was the development of a multicompartimental nanocarrier for the simultaneous encapsulation of paclitaxel (PTX) and genistein (GEN), associating antiangiogenic and cytotoxic properties in order to potentiate antitumoral activity.

Method

Polymeric nanocapsules containing PTX were obtained by interfacial deposition of preformed polymer and coated with a phospholipid bilayer entrapping GEN. Physical-chemical and morphological characteristics were characterized, including size and size distribution, drug entrapment efficiency and drug release profile. In vivo studies were performed in EAT bearing Swiss mice.

Results

Entrapment efficiency for both drugs in the nanoparticles was approximately 98%. Average particle diameter was 150 nm with a monomodal distribution. In vitro assays showed distinct temporal drug release profiles for each drug. The dose of 0.2 mg/kg/day of PTX resulted in 11% tumor inhibition, however the association of 12 mg/kg/day of GEN promoted 44% tumor inhibition and a 58% decrease in VEGF levels.

Conclusions

Nanoparticles containing GEN and PTX with a temporal pattern of drug release indicated that the combined effect of cytotoxic and antiangiogenic drugs present in the formulation contributed to the overall enhanced antitumor activity of the nanomedicine.     

Utility of Mannitol and Citric Acid for Enhancing the Solubilizing and Taste Masking Properties of β-Cyclodextrin: Development of Fast-Dissolving Tablets Containing Extremely Bitter Drug

Introduction

Development of Fast dissolved tablets (FDTs) in which taste is masked, and drug dissolution is improved, is a major challenge especially in case of extremely bitter drug with poor water solubility such as aceclofenac.

Purpose

The purpose of this study was to enhance the taste masking and solubilizing properties of β-cyclodextrin using citric acid and mannitol through preparation of acid soluble taste masked granules of aceclofenac (ASTMGA).

Methods

General factorial design was applied to optimize FDTs containing ASTMGA so to have short disintegration time (<30 sec.), acceptable taste and enhanced drug dissolution in gastric fluid. Three formulation variables; the type of sugar / cellulose based diluents, X₁ (Galen IQ® and Prosolv®), superdisintegrant type, X₂ (Crospovidone®, Glycolys® and Ac-Di-Sol®) and superdisintegrant concentration, X₃ (10 % and 20 %) were included in the design. The systems were assessed for hardness, friability, in vitro disintegration, wetting time, in vitro dissolution and in vivo oral study.

Results

The combination of Prosolv® and Crospovidone® in the formulation of FDT gave optimum disintegration time. The stability of the optimized FDT in different package materials was retained after storage at 40 ?C/75 % RH for six months. Contrary to FDT containing conventional aceclofenac β-cyclodextrin inclusion complex, FDT containing ASTMGA showed highest dissolution rate in both simulated salivary and gastric fluids and excellent ability to mask the bitterness of drug.

Conclusions

Our results propose that the combination of citric acid, mannitol and β-cyclodextrin could be promising to improve taste masking and solubilizing properties of β-cyclodextrin.     

Photo-Inducible Crosslinked Nanoassemblies for pH-Controlled Drug Release

Purpose

To control drug release from block copolymer nanoassemblies by variation in the degree of photo-crosslinking and inclusion of acid sensitive linkers.

Methods

Poly(ethylene glycol)-poly(aspartate-hydrazide-cinnamate) (PEG-CNM) block copolymers were prepared and conjugated with a model drug, doxorubicin (DOX), through acid sensitive hydrazone linkers. The block copolymers formed photo-inducible, self-assembled nanoassemblies (piSNAs), which were used to produce photo-inducible crosslinked nanoassemblies (piCNAs) through UV crosslinking. The nanoassemblies were characterized to determine particle size, surface charge, pH- and crosslinking-dependent DOX release, in vitro cytotoxicity, and intracellular uptake as a function of photo-crosslinking degree.

Results

Nanoassemblies with varying photo-crosslinking degrees were successfully prepared while retaining particle size and surface charge. Photo-crosslinking caused no noticeable change in DOX release from the nanoassemblies at pH 7.4, but the DOX-loaded nanoassemblies modulated drug release as a function of crosslinking at pH 6.0. The nanoassemblies showed similar cytotoxicity regardless of crosslinking degrees, presumably due to the low cellular uptake and cell nucleus drug accumulation.

Conclusions

Photo-crosslinking is useful to control drug release from pH-sensitive block copolymer nanoassemblies as a function of crosslinking without altering the particle properties, and thus providing unique tools to investigate the pharmaceutical effects of drug release on cellular response.     

Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches

Purpose

Catalytic selectivity of human UGT1A9, an important membrane-bound enzyme catalyzing glucuronidation of xenobiotics, was determined experimentally using 145 phenolics and analyzed by 3D-QSAR methods.

Methods

Catalytic efficiency of UGT1A9 was determined by kinetic profiling. Quantitative structure activity relationships were analyzed using CoMFA and CoMSIA techniques. Molecular alignment of substrate structures was made by superimposing the glucuronidation site and its adjacent aromatic ring to achieve maximal steric overlap. For a substrate with multiple active glucuronidation sites, each site was considered a separate substrate.

Results

3D-QSAR analyses produced statistically reliable models with good predictive power (CoMFA: q²?=?0.548, r²?=?0.949, r _pred ² ?=?0.775; CoMSIA: q²?=?0.579, r²?=?0.876, r _pred ² ?=?0.700). Contour coefficient maps were applied to elucidate structural features among substrates that are responsible for selectivity differences. Contour coefficient maps were overlaid in the catalytic pocket of a homology model of UGT1A9, enabling identification of the UGT1A9 catalytic pocket with a high degree of confidence.

Conclusion

CoMFA/CoMSIA models can predict substrate selectivity and in vitro clearance of UGT1A9. Our findings also provide a possible molecular basis for understanding UGT1A9 functions and substrate selectivity.     

GFR may not accurately predict aspects of proximal tubule drug handling

Purpose

Dose modification in renal impairment has traditionally been based on changes in estimated glomerular filtration rate (eGFR; estimated by creatinine clearance). However, many drugs are eliminated by tubular anionic and cationic transport where changes in eGFR may not necessarily reflect changes in tubular function. This study investigated the relationship between GFR and renal tubular function with reference to drug handling by using accepted drug probes.

Methods

Three drug probes, ⁵¹Cr-EDTA, fluconazole, and pindolol, were administered to patients who had varying degrees of renal impairment. Blood sampling, assays, and a pharmacokinetic analysis were performed for all drug probes and endogenous urate. Measured GFR (⁵¹Cr-EDTA clearance; mGFR) was compared to tubular anionic transport (urate clearance), tubular reabsorption (fluconazole clearance), and tubular cationic transport (S-pindolol clearance).

Results

A moderately strong association was demonstrated between the measured isotopic GFR and creatinine clearance (R²?=?0.78). A moderate positive correlation was found between mGFR and proximal tubular anion transport and reabsorption (R²?=?0.40–0.44, p?2?=?0.11, p?=?0.036).

Conclusions

Given that drug dosing schedules utilise eGFR values as the basis for modifying drug dosing, our results would suggest that a recommendation of a dose reduction according to eGFR alone should be treated with caution.     

Mapping Ion-Induced Mesophasic Transformation in Lyotropic In Situ Gelling System and its Correlation with Pharmaceutical Performance

Purpose

To investigate influence of ion induced mesophasic transformation on pharmaceutical performance of in situ gelling system consisting of glyceryl monooleate.

Methods

The prepared system showed mesophasic transformation during its conversion from sol to gel upon controlled hydration. The process of mesophasic transformation was studied by SAXS, DSC, rheology and plane polarized light microscopy. Further the influence of additives i.e. naproxen salts (sodium and potassium) and naproxen (base) on the process of mesophasic transformation was also elucidated.

Results

It was observed that addition of salt form of naproxen transformed W/O emulsions into cubic mesophase whereas addition of base form of naproxen formed reverse hexagonal (H_II) phase upon controlled hydration. The cubic mesophase formed by naproxen salts retarded the drug release for initial 3 h whereas H_II phase showed sustained drug release characteristics for naproxen base following Higuchi drug release kinetics.

Conclusion

The current work suggests that formulations with tailor made pharmaceutical performance can be developed by selecting proper additives in the system so as to obtain the desired mesophase ‘on demand’ thereby controlling drug release characteristics.

Optimization of Novel Mucoadhesive In Situ Film Forming Periodontal Drug Delivery System for Chemotherapeutic Agents

Introduction

The objective of the present investigation was to develop and evaluate mucoadhesive in situ film forming periodontal drug delivery system (MIFPDDS) for local delivery of chemotherapeutic agents. Ethyl cellulose, a film forming release retardant, was used in combination with Eudragit RL100, a mucoadhesive polymer, and polyvinylpyrrolidone K-30 to develop MIFPDDS.

Materials and methods

A simplex lattice design was employed to achieve an optimum solvent blend (N-methyl-2-pyrrolidone, polyethylene glycol-200, and propylene glycol) which has rapid film formation capacity and low viscosity. The prepared MIFPDDS was evaluated for various parameters such as in vitro film forming capacity, viscosity, in vitro diffusion study, ex vivo mucoadhesion study, stability study, and compatibility. A 32 full-factorial design was used to investigate the influence of formulation variables.

Results and discussion

Drug release data from all formulations were fitted to different kinetic models, and the Korsmeyer–Peppas model was found the best fit model. Increasing the concentration of each polymeric component increases viscosity, and time for 50, 70, and 90 % drug release was observed and graphically represented by the surface response and contour plots. The formulation of batches MIF1—PCM4, MIF6, and MIF7 failed to give the desired results for the first hour drug release and MIF8 and MIF9 failed to show viscosity below 70 cPs.

Conclusion

The formulation of batch MIF5 containing 3 % (w/v) of ethyl cellulose and 8 % (w/v) of Eudragit RL100 was considered as optimum formulation.     

Potential of a Cyclone Prototype Spacer to Improve In Vitro Dry Powder Delivery

Purpose

Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrier-based DPIs was investigated.

Methods

Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30 and 60 Lmin^?1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography.

Results

Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89?±?6.51% at 30 Lmin^?1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08?±?0.05 μm vs. 3.00?±?0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates.

Conclusion

This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.     

Infection-Responsive Drug Delivery from Urinary Biomaterials Controlled by a Novel Kinetic and Thermodynamic Approach

Purpose

The pH-dependent physicochemical properties of the antimicrobial quinolone, nalidixic acid, were exploited to achieve ‘intelligent’ drug release from a potential urinary catheter coating, poly(2-hydroxyethylmethacrylate) (p(HEMA)), in direct response to the elevated pH which occurs at the onset of catheter infection.

Methods

p(HEMA) hydrogels, and reduced-hydrophilicity copolymers incorporating methyl methacrylate, were loaded with nalidixic acid by a novel, surface particulate localization method, and characterized in terms of pH-dependent drug release and microbiological activity against the common urease-producing urinary pathogen Proteus mirabilis.

Results

The pH-dependent release kinetics of surface-localized nalidixic acid were 50- and 10-fold faster at pH 9, representing the alkaline conditions induced by urease-producing urinary pathogens, compared to release at pH 5 and pH 7 respectively. Furthermore, microbiological activity against P. mirabilis was significantly enhanced after loading surface particulate nalidixic acid in comparison to p(HEMA) hydrogels conventionally loaded with dispersed drug. The more hydrophobic methyl methacrylate-containing copolymers also demonstrated this pH-responsive behavior, but additionally exhibited a sustained period of zero-order release.

Conclusions

The paradigm presented here provides a system with latent, immediate infection-responsive drug release followed by prolonged zero-order antimicrobial delivery, and represents an ‘intelligent’, infection-responsive, self-sterilizing biomaterial.     

Sterically Stabilized Liposomes Incorporating the Novel Anticancer Agent Phospho-Ibuprofen (MDC-917): Preparation, Characterization, and In Vitro/In Vivo Evaluation

Purpose

To incorporate phospho-ibuprofen (P-I), a lipophilic, water insoluble novel anti-cancer agent, into pegylated liposomes and upon formulation optimization to evaluate its antitumor activity in vitro and in vivo.

Methods

P-I loaded liposomes were prepared using the thin-film hydration method, and characterized for size, zeta potential, drug content and drug release. We examined their physical stability by particle size changes; their lyophilization ability in the presence of cryoprotectants; and their antitumor activity in vitro in human cancer cell lines and in vivo in a xenograft murine model.

Results

P-I was successfully loaded into liposomes consisting of soy-PC and PEG₂₀₀₀-PE. These liposomes were <150?nm in diameter; exhibited prolonged stability in suspension and can be lyophilized using sucrose as cryoprotectant. P-I liposomes inhibited the growth of human cancer cell lines in vitro and in vivo of xenograft in nude mice to a greater extent than free P-I.

Conclusions

High levels of P-I can be incorporated into liposomes which can be lyophilized in the presence of sucrose and showed good stability upon storage. Moreover, these drug-incorporating liposomes were capable of inhibiting the growth of xenografted tumors in mice more effectively than free P-I. These results justify further development of the P-I liposomes.     

Drug Delivery Using Platelet Cancer Cell Interaction

Purpose

To develop an efficient biocompatible and targeted drug delivery system in which platelets, an essential blood component having a natural affinity for cancer cells, are used as carrier of anticancer drug as delivery of drug to the targeted site is crucial for cancer treatment.

Methods

Doxorubicin hydrochloride, a potent anti cancer drug, was delivered in lung adenocarcinoma cell line (A549) using platelet as a delivery agent. This delivery mode was also tested in Ehrlich ascites carcinoma (EAC) bearing mice in presence and absence of platelets.

Results

The results show that platelets can uptake the drug and release the same upon activation. The efficiency of drug loaded platelets in inducing cytotoxicity was significantly higher in both in vitro and in vivo model, as compared to the free drug.

Conclusions

The proposed drug delivery strategy may lead to clinical improvement in the management of cancer treatment as lower drug concentration can be used in a targeted mode. Additionally the method can be personalized as patient's own platelet can be used for deliver various drugs.