Current Drug Delivery (v.11, #2)

Solid Dispersion in Pharmaceutical Drug Development: From Basics to Clinical Applications by Punit Bhatnagar, Vinod Dhote, Suresh Chandra Mahajan, Pradyumna Kumar Mishra, Dinesh Kumar Mishra (155-171).
The solubility of drugs is one of the most challenging aspects in developing formulations for novel drug discovery.Myriad of approaches have been developed and tested to overcome the associated intricacies involved with poorwater soluble drugs. Out of the available technologies, solid dispersion (SD) method that significantly enhances the solubilityand bioavailability by reducing particle size to a micro-molecular level is often viewed as a promising strategy. Althoughconceptual basis of manufacturing processes involved in SD method have been reported, formulation characteristicsaddressing solubility issues remains yet elusive. The current review portray the historical milestones, classification,probable mechanisms for enhancement of solubility, manufacturing processes at commercial level along with pioneerbreakthroughs in field that enunciates the versatile pharmaceutical application for categories including anti-cancer andanti-retroviral drugs. Besides, our article also highlights the translational implications of drug development by SD methodhitherto unreported.

Transmucosal Delivery of Metformin- A Comprehensive Study by M. Sushma, Y. Prasanna Raju, C.R. Sundaresan, K.R. Vandana, N. Vijay Kumar, V. Harini Chowdary (172-178).
Discovered in the 1920s, the biguanide metformin hydrochloride is still the first line drug in the management ofType 2 diabetes mellitus. Metformin hydrochloride is absorbed slowly and incompletely from the gastrointestinal tract.The present research work was undertaken with the aim of developing a fast dissolving film of metformin hydrochloride,suitable for oral trans mucosal administration. Fast dissolving films allow rapid drug dissolution in the oral cavity, ensuringbypass of first pass metabolism resulting in rapid absorption. Films of metformin were prepared by solvent castingmethod using Hydroxypropyl methylcellulose K15 (HPMC). Six formulations (F1-F6) of metformin hydrochloride wereprepared and evaluated for their physical characteristics such as tackiness, thickness, tensile strength, elongation, weightvariation, folding endurance, drug content and surface pH. The compatibility of the drug with HPMC was confirmed byFTIR studies. The formulations were subjected to disintegration, in-vitro drug release and the optimised formulation wasevaluated for pharmacodynamic studies in diabetic rats. Among the formulations (F1-F6) F4 was found to be the bestformulation which contained Hydroxypropyl methyl cellulose K15 at weight ratios of 1:4 and showed excellent film formingcharacteristics such as disintegration time at 42 sec and percentage drug release of 94.2% within 5 minutes. Pharmacodynamicassessment in diabetes induced rats demonstrated that the fast dissolving films of metformin had a quicker onsetof action compared to conventional formulation.

In direct compression (DC), the significance of usual flow properties of powder from the hopper to the dies ofthe tablet machine cannot be overstressed. Ensuring the free flow of powder presents a number of challenges to the pharmaceuticalformulator in case of high speed tabletting. This research work was conceived to obtain directly compressibleagglomerates by spherical crystallization technique and were comparatively evaluated for physicochemical properties aswell as tableting properties of agglomerates and unprocessed aceclofenac. Agglomerates of aceclofenac were developedvia spherical crystallization method by a solvent arrangement containing dichloromethane (DCM) as a good solvent, wateras a bad solvent and acetone as a bridging liquid. Hydroxypropyl cellulose (HPC) in variable quantity was implemented ashydrophilic polymer. The agglomerates were evaluated for yield, solubility, drug content, FTIR spectroscopy, porosity,particle size, micromeritic properties, differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanningelectron microscopy (SEM), and dissolution studies. The agglomerates expressed improved micromeritic and dissolutionproperties, in equivalence to pure drug. Formulation F3 (optimized agglomerates) exposed estimable rotundity, better drugrelease, and easily compression into tablets by high speed DC Technique. The tablets showed acceptable physicochemicalproperties and complied with the pharmacopoeial specifications. The dissolution rate of prepared tablets from agglomerateswas better than the tablets of pure drug. The F3 agglomerates show splendid physicochemical and micromeritic properties.Agglomerated compression mix also showed good tableting properties as needed for high speed compression andenough stability under accelerated conditions at least for 1 month.

Novel Interpenetrating Polymer Matrix Network Microparticles for Intestinal Drug Delivery by Jagadeeswara Reddy, B. Nagashubha, Mahesh Reddy, Afrasim Moin, H.G. Shivakumar (191-199).
This paper deals with the synthesis and characterization of Ghatti gum (GG) and chitosan (CS) IPN MP preparedby emulsion-cross-linking method. Glutaraldehyde (GA) was used as a cross-linker. IPN microparticles were usedto deliver (DS) Diclofenac sodium (Model anti inflammatory drug) to the intestine. IPN MP were characterized by Scanningelectron microscopy (SEM), differential scanning calorimetric (DSC), Fourier Transform Infrared Spectroscopy(FTIR) and evaluated for in vitro dissolution rate. FTIR studies assessed the formation of IPN structure. The surface morphologywas studied by SEM. Particle sizes ranged between 294 to 366 ?m. After encapsulation into IPN microparticlesDSC studies were performed to recognize the crystalline nature of drug. DS percentage encapsulation efficiency (%EE)ranged from 84.09 to 96.81%. Equilibrium swelling was performed in buffer solution (pH 7.4). In-vitro release studies indicatedthe dependence of drug release rates on both the amount of chitosan and GG used in grounding of microparticles.The release was extended up to 12 hrs and release rates were fitted into an empirical equation to work out the diffusion parameterwhich indicates a Non-Fickian release. Continuous dissolution-absorption studies were carried out using evertedrat intestine for optimized formulation (F9).

New Insights into the Diagnosis and Chemotheraphy for Visceral Leishmaniasis by V. Dinesh Kumar, Priya Ranjan Prasad Verma, Sandeep Kumar Singh (200-213).
Visceral leishmaniasis (VL) is a severe form of leishmaniasis - a disease caused by protozoan parasites andtransmitted by the bite of certain species of sand fly. In VL, parasites migrate to the vital organs and bone marrow, destroyingwhite and red blood cells. VL has been called the parasitic version of HIV/AIDs (Human immunodeficiencyvirus infection / acquired immunodeficiency syndrome), as it attacks the immune system. The most common form of thedisease is cutaneous leishmaniasis, which causes skin lesions and often leaves the infected individual permanently disfigured.Even though the disease is treatable, current treatments are difficult to administer, too expensive, or toxic for extensiveuse in developing nations. Furthermore, resistance to treatment is an increasing problem, particularly in India. 90% ofpeople with VL die if the infection is left untreated, and death can come within 2 years, significantly faster than AIDS.The search for new drugs continues, with new chemical and natural compounds. Many potential drug targets have beenidentified in biochemical and molecular studies, and some have been validated. Attempts to exploit these targets are inprogress. This article reviews the epidemiology, clinical features, control Strategies, diagnosis and current treatment aboutvisceral leishmaniasis.

Most of the classical drugs used today to destroy cancer cells lead to the development of acquired resistance inthose cells by limiting cellular entry of the drugs or exporting them out by efflux pumps. As a result, higher doses of drugsare usually required to kill the cancer cells affecting normal cells and causing numerous side effects. Accumulation of thetherapeutic level of drugs inside the cancer cells is thus required for an adequate period of time to get drugs' completetherapeutic efficacy minimizing the side effects on normal cells. In order to improve the efficacy of chemotherapeuticdrugs, nanoparticles of carbonate apatite and its strontium (Sr2+)-substituted derivative were used in this study to makecomplexes with three classical anticancer drugs, methotrexate, cyclophosphamide and 5-flurouracil. The binding affinitiesof these drugs to apatite were evaluated by absorbance and HPLC analysis and the therapeutic efficacy of drug-apatitecomplexes was determined by cell viability assay. Carbonate apatite demonstrated significant binding affinity towardsmethotrexate and cyclophosphamide leading to more cellular toxicity than free drugs in MCF-7 and 4T1 breast cancercells. Moreover, Sr2+ substitution in carbonate apatite with resulting tiny particles less than 100 nm in diameter furtherpromoted binding of methotrexate to the nanocarriers indicating that Sr2+-substituted apatite nanoparticles have the highpotential for loading substantial amount of anti-cancer drugs with eventual more therapeutic effectiveness.

Design and Evaluation of HP-β-CD Based Voriconazole Formulations for Ocular Drug Delivery by Priyanka Pahuja, Heena Kashyap, Pravin Pawar (223-232).
Systemic administration of voriconazole, a novel anti-fungal agent, is associated with adverse effects includingvisual disturbances and hepatic abnormalities. The purpose of this study was to improve the aqueous solubility of voriconazoleusing 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and to study the effect of addition of viscosity modifiers tothese solutions. Statistical analysis was done by one-way analysis of variance followed by Dunnett's test. The phase solubilitystudies indicated that voriconazole solubility increased with increase in HP-β-CD concentration. Using a combinationof chitosan 0.2%, BAK 0.01% and EDTA 0.01% in voriconazole- HP-β-CD based aqueous drops (1.5%, pH 7.0), a3.9 times and 5.4 times higher Papp was obtained than with formulation without chitosan and control formulation (withoutchitosan and preservative), respectively. Thus, it could be concluded voriconazole aqueous drops formulated usingHP-β-CD can be used topically for the treatment of fungal keratitis and the addition of chitosan to the voriconazole aqueousdrops can produce significantly higher permeation.

Gene Delivery for Cancer Therapy by Teng Zhang (233-242).
Gene therapy has potential in the treatment of human cancers. However, its clinical implication has onlyachieved little success due to the lack of an efficient gene delivery system. A major hurdle in the current availableapproaches is in the ability to transduce target tissues at very high efficiencies that ultimately lead to therapeutic levels oftransgene expression. This review outlines the characteristics and utilities of several available gene delivery systems,including their advantages and drawbacks in the context of cancer treatment. A perspective of existing challenges andfuture directions is also included.

Nanomulsion as a Carrier for Efficient Delivery of Metformin by Juber Akhtar, Hefazat Hussain Siddiqui, Badruddeen, Sheeba Fareed, Mohd. Aqil (243-252).
Metformin (MTF) improves hyperglycemia primarily by suppressing glucose production by the liver. The objectiveof our investigation was to evaluate nanoemulsion as a promising carrier for MTF for sustained hypoglycemic effect.The drug was incorporated into oil phase of nanoemulsion, which finally improved biopharmaceutical propertiesachieved when compared with lipid based systems. Pseudo ternary phase diagrams were prepared by aqueous titrationmethod. Formulations were selected at a difference of 5% v/v of oil from the o/w nanoemulsion region of phase diagrams,and then thermodynamic stability and dispersibility tests were performed. The composition of optimized formulation washydrogenated castor oil (5% v/v), 30% v/v of surfactant (tween 80), co-surfactant (transcutol) and distilled water (65%v/v) as an aqueous phase. The preparation showed maximum drug release (98.70%), optimal globule size (92.25 nm), lowestpolydispersity value (0.172), lesser viscosity (22.124 cps) and infinite dilution capability. The antidiabetic activity of optimizedMTF nanoemulsion formulation evaluated by blood glucose estimation showed significant hypoglycemic effectwhich was comparable to that observed with conventional marketed formulation in experimental diabetic rats. Optimizedformulation was subjected to stability studies at different temperature and relative humidity and was found to be stable.No significant variations were observed in the formulation over a period of 3 months at accelerated storage conditions.

Quality by Design: Discussing and Assessing the Solid Dispersions Risk by Luise L. Chaves, Alexandre C.C. Vieira, Salette Reis, Bruno Sarmento, Domingos C. Ferreira (253-269).
The poor water solubility tops the list of undesirable physicochemical properties in the drug discovery andSolid Dispersions (SDs) has been frequently used to enhance dissolution of such compounds. Although, some challengeslimit the studies of SD commercial application. During recent years, the Quality by Design (QbD) approach has begun tochange drug development, and focus on pharmaceutical production, which shifted from an univariate empirical understandingfor a systematic multivariate process. In this review, some possible variables during the development process,formulation and production of SDs were defined, introducing and applying the QbD concept. The proposed work presentedimportant definitions as well as its application in the pharmaceutical product and process design, especially thechallenges encountered during the development of formulations of poorly soluble drugs. In this aspect, the SD techniquewas deeply discussed, in which some important parameters during SD design and production were mentioned as methodof production, polymers commonly used, methods for characterization and stability evaluation, in addition of biopharmaceuticalconsiderations. Finally, a specific risk assessment for the design and production of SD and critical points werediscussed, which was a positive evolution and may lead to better understanding of SD for a rational formulation.

New Chitosan Nanospheres for the Delivery of 5-Fluorouracil: Preparation, Characterization and in vitro Studies by Roberta Cavalli, Federica Leone, Rosalba Minelli, Roberto Fantozzi, Chiara Dianzani (270-278).
The aim of this work was to develop new chitosan nanospheres for the delivery of 5-fluorouracil (5-FU). Drugloaded nanospheres were prepared using a technique derived from a combination of coacervation and emulsion dropletcoalescence methods. The size and morphology of nanospheres were characterized by laser light scattering and transmissionelectron microscopy. The 5-FU interaction with chitosan nanospheres was investigated by DSC analysis and FT-IRspectroscopy. The in vitro release was studied by dialysis bag technique. Cytotoxicity of 5-FU loaded chitosan nanosphereswas evaluated in vitro on HT29 and PC-3 cell lines. The effects of 5-FU loaded chitosan nanospheres on adhesionof tumor cells to human umbilical vein endothelial cells (HUVEC) were also investigated. 5-FU loaded chitosan nanospheresappeared with a spherical shape, with a mean diameter of about 200 nm and a negative zeta potential of about- 6.0 mV. The successful interaction between drug and chitosan nanosphere matrix was demonstrated by both DSC andFT-IR analyses. The quantitative determination of 5-FU was assayed by UV-Vis analysis. The encapsulation efficiency of5-FU content was about 70%. A kinetic study of in vitro release demonstrated that the percentages of 5-FU delivered fromnanospheres was approx. 10% after 3 hours. The in vitro studies showed that 5-FU loaded nanospheres were effective inreducing tumor cell proliferation in a time- and concentration-dependent manner. 5-FU nanospheres were also able to inhibitboth HT29 and PC-3 adhesion to HUVEC after 48 hours of treatment.

Assessment of PLGA-PEG-PLGA Copolymer Hydrogel for Sustained Drug Delivery in the Ear by Liang Feng, Jonette A. Ward, S. Kevin Li, Gaurav Tolia, Jinsong Hao, Daniel I. Choo (279-286).
Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanicinjection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery forseveral days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanicinjection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEGPLGAupon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safetyof PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of theadditives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cellsin vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in thepresence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did notaffect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study,the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decreasethe rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the oppositeeffect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose andcould provide sustained release that could be controlled by using the additives for inner ear applications.

Approach of novel drug delivery system (NDDS) overcomes the limitations of conventional dosage forms.However, this concept is still not practiced to a large extent in delivery of herbal drugs in Ayurveda. Thus, the potential ofherbal drugs has not been explored to its fullest. Hence, there is a growing need to amalgamate the concept of NDDS indelivery of herbal constituents. The present investigation is designed to deliver and retain two herbal constituents in stomachfor better action against Helicobacter pylori induced gastric ulcers. The objective was to develop a bilayer floatingtablet of ellagic acid and Aloe vera gel powder through rational combination of excipients to give the lowest possible lagtime with maximum drug release in the period of 4 h. Formulation F9 containing 100 mg of HPMC K15M, 27 mg ofcrospovidone, 80 mg of mannitol and effervescent agents in the ratio 1:2 gave 92% drug release and desired floatingproperties. In vivo studies showed that combination of ellagic acid and Aloe vera gave 75 % ulcer inhibition in comparisonto 57% ulcer inhibition in the group which was administered with ellagic acid alone. This suggests the use of bilayerfloating tablet in gastric ulcer treatment.