Current Drug Delivery (v.12, #5)

Meet Our Editorial Board Member: by Hae-Won Kim (473-473).

A Physicochemical and Pharmacological Study of the Newly Synthesized Complex of Albendazole and the Polysaccharide Arabinogalactan from Larch Wood by Yulia S. Chistyachenko, Elizaveta S. Meteleva, Maria Y. Pakharukova, Aleksey V. Katokhin, Mikhail V. Khvostov, Anastasiya I. Varlamova, Igor I. Glamazdin, Salavat S. Khalikov, Nikolay E. Polyakov, Ivan A. Arkhipov, Tatyana G. Tolstikova, Viatcheslav A. Mordvinov, Alexander V. Dushkin, Nikolay Z. Lyakhov (477-490).
Inclusion complexes of albendazole (ABZ) with the polysaccharide arabinogalactan from larch wood Larix sibirica and Larix gmelinii were synthesized using a solid-state mechanochemical technology. We investigated physicochemical properties of the synthesized complexes in the solid state and in aqueous solutions as well as their anthelmintic activity against Trichinella spiralis, Hymenolepis n?na, Fasciola hepatica, Opisthorchis felineus, and mixed nematodoses of sheep. Formation of the complexes was demonstrated by means of intrinsic solubility and the NMR relaxation method. The mechanochemically synthesized complexes were more stable in comparison with the complex produced by mixing solutions of the components. The complexes of ABZ showed anthelmintic activity at 10-fold lower doses than did free ABZ. The complexes also showed lower acute toxicity and hepatotoxicity. These results suggest that it is possible to design new drugs on the basis of the ABZ:arabinogalactan complex that are safer and more effective than albendazole.

Preparation and Evaluation of Chitosan Submicroparticles Containing Pilocarpine for Glaucoma Therapy by Cleonice Marques Costa, Leticia Coli Louvisse de Abreu, Elisabete Pereira dos Santos, Octavio Augusto Franca Presgrave, Anna Paola Trindade Rocha Pierucci, Carlos Rangel Rodrigues, Valeria Pereira de Sousa, Sara Nicoli, Eduardo Ricci Junior, Lucio Mendes Cabral (491-503).
The objective of the present study was to optimize the preparation of chitosan submicroparticles and to assess whether they enhanced ocular permeation of pilocarpine. Submicroparticles were produced by spray drying and characterized to determine process yield, encapsulation efficiency, morphology, size distribution, drug-polymeric matrix interaction, porcine sclera permeation as well as ocular irritancy and drug retention. Quantification of pilocarpine using High Performance Liquid Chromatography was found to be selective, linear, precise, accurate and robust. The spray drying method proved to be simple and reproducibly produced particles with satisfactory yields, thus showing potential for industrial scale applications. The pilocarpine-loaded chitosan particles exhibited adequate morphological characteristics as well as high encapsulation efficiency. The particles produced were on a submicrometric scale and compatible with intraocular administration. In pilocarpine-loaded particles, the interaction between pilocarpine and chitosan polymeric matrix resulted in delayed release of the drug, attributed to formation of a reservoir system. The best fit for drug release was obtained using the Higuchi equation. The chitosan submicroparticles enhanced the permeation effect and increased the passage of pilocarpine through porcine sclera and also demonstrated low irritancy potential. Therefore, the particles produced can be considered a promising system for the ocular delivery of pilocarpine.

Novel Cream Containing Microsponges of Anti-Acne Agent: Formulation Development and Evaluation by Riyaz Ali M. Osmani, Nagesh H. Aloorkar, Ajit S. Kulkarni, Parthasarathi K. Kulkarni, Umme Hani, Shailesh Thirumaleshwar, Rohit R. Bhosale (504-516).
The rationale behind present work was to formulate a novel cream containing microsponges of miconazole nitrate to provide prolonged release. By means of quasi-emulsion solvent diffusion method using Eudragit RS-100 with different drug-polymer ratios microsponges were prepared. In the direction of optimizing microsponge formulation, diverse factors that affect microparticles physical properties were also investigated. Microsponges were characterized by SEM, DSC, FT-IR and particle size analysis, and also evaluated for morphology, drug loading and in vitro drug release. The drug polymer ratio reflected notable effect on drug content, encapsulation efficiency and particle size. It has been found that there was no chemical interaction between drug and polymers used as revealed by FT-IR and DSC spectra. SEM micrographs exposed that microsponges were spherical, with porous surface and have had 26.23 ?m mean particle size. The microsponges were then incorporated in cream; which showed viscous modulus along with pseudoplastic behavior. In vitro drug release results depicted that microsponge with drug-polymer ratio of 1:2 was more efficient to give extended drug release of 78.28% at the end of 8 h; while conventional formulations get exhausted incredibly earlier by releasing 83.09% drug at the end of 4 h only. Thus the formulated cream containing microsponges of miconazole nitrate would be a promising alternative as compared to conventional therapy for secure and efficient treatment of acne and other topical infections.

Permeation Studies of Captopril Transdermal Films Through Human Cadaver Skin by Rajesh Sreedharan Nair, Sujith Nair (517-523).
Mortality rate due to heart diseases increases dramatically with age. Captopril is an angiotensin converting enzyme inhibitor (ACE) used effectively for the management of hypertension. Due to short elimination half-life of captopril the oral dose is very high. Captopril is prone to oxidation and it has been reported that the oxidation rate of captopril in skin tissues is considerably low when compared to intestinal tissues. All these factors make captopril an ideal drug candidate for transdermal delivery. In this research work an effort was made to formulate transdermal films of captopril by utilizing polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) as film formers and polyethylene glycol 400 (PEG400) as a plasticizer. Dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) were used as permeation enhancers. Physicochemical parameters of the films such as appearance, thickness, weight variation and drug content were evaluated. The invitro permeation studies were carried out through excised human cadaver skin using Franz diffusion cells. The in-vitro permeation studies demonstrated that the film (P4) having the polymer ratio (PVP:PVA = 80:20) with DMSO (10%) resulted a promising drug release of 79.58% at 24 hours with a flux of 70.0 µg/cm2/hr. No signs of erythema or oedema were observed on the rabbit skin as a result of skin irritation study by Draize test. Based on the stability report it was confirmed that the films were physically and chemically stable, hence the prepared films are very well suited for transdermal application.

The Fate of Exogenous Human HSP70 Introduced into Animal Cells by Different Means by Marina Yurinskaya, Olga G. Zatsepina, Maxim G. Vinokurov, Natalia V. Bobkova, David G. Garbuz, Alexei V. Morozov, Dina A. Kulikova, Vladimir A. Mitkevich, Alexander A. Makarov, Sergei Yu. Funikov, Michael B. Evgen'ev (524-532).
Over the last decade, it has become evident that in mammals, including humans, heat shock protein 70 (HSP70), apart from its intracellular localization, is found in extracellular space, where it may execute various protective functions. Furthermore, the upregulation of HSP70 family members can be beneficial in the prevention and treatment of various human neurodegenerative diseases and cancer. Here, we demonstrate that recombinant human HSP70 after intranasal administration can penetrate various brain regions of mice in its native form and subsequently undergo rapid degradation. It was also shown that labeled HSP70 added to culture medium of different human and mouse cell lines enters the cells with strikingly different kinetics, which positively correlates with the basic levels of membrane bound Toll-like receptors (TLR) that are characteristic of these cell lines. HSP70 administration does not significantly modulate the level of TLR expression at the protein or RNA level. The degradation of the introduced recombinant HSP70 after entering the cells is likely proteasome-dependent and varies significantly depending on the cells type and origin. These results should be considered when developing HSP70-based therapies.

The aim of the present research work is to develop carbo-protein polymeric complex based sustain release microspheres of losartan potassium and investigate the ability of this dosage form to improve the flowability, compressibility and tableting properties of losartan potassium. The influence of silk sericin, alginate and its blend on various physicochemical parameters and in vitro drug release pattern were studied to optimize the concentration of polymeric blend required for 12 h. sustain release. Optimized batch was subjected to different flowability, compressibility and tableting properties studies to observe the effects of carbo-protein microspheres on flow properties. Results indicated that the concentration of sericin was found to be the main influential factor for prolonged drug release. Different micromeritic studies revealed that the poor flowability and compressibility properties of pure losartan potassium were significantly improved by this algino-sericin microspheric dosage form. Research findings also revealed that plasticity, die filling behavior and tableting properties of the pure drug were significantly improved by this microsphere formulation. So these prospective results concluded that carboprotein polymeric microspheres helps to sustain the drug release for prolong hours as well as improve the flowability, compressibility and tableting properties of losartan potassium.

QbD-Oriented Development of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) of Valsartan with Improved Biopharmaceutical Performance by Shantanu Bandyopadhyay, Sarwar Beg, O. P. Katare, Gajanand Sharma, Bhupinder Singh (544-563).
The objectives of the present studies were to develop the systematically optimized selfnanoemulsifying drug delivery systems (SNEDDS) of valsartan employing the holistic QbD approach. The quality profile target product (QTPP) was defined and critical quality attributes (CQAs) earmarked. Preformulation studies including the equilibrium solubility and pseudoternary phase titration studies facilitated the selection of suitable lipids and emulgents for formulation of SNEDDS. Risk assessment and factor screening studies facilitated the selection of Lauroglycol FCC and Capmul MCM L8 (i.e., lipid), Tween 40 and Tween 80 (i.e., emulgent) as the critical material attributes (CMAs) for SNEDDS prepared using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). A central composite design (CCD) was employed for systematic optimization of SNEDDS, taking globule size (Dnm), drug release in 10 min (Q10min) and amount permeated in 45 min (%Perm45min) as the CQAs. Design space was generated using apt mathematical models to embark upon the optimized formulations and validation of the QbD. In situ SPIP studies revealed significant improvement in the absorptivity and permeability parameters of SNEDDS owing to the inhibition of P-gp/MRP2 efflux vis-a-vis the conventional marketed formulation and pure drug. In vivo pharmacokinetic studies corroborated marked enhancement in the oral bioavailability drug from SNEDDS vis-a-vis the marketed formulation. Establishment of various levels of in vitro/in vivo correlations (IVIVC) indicated excellent goodness of fit between the in vitro drug release data with the in vivo absorption parameters. In a nutshell, the present studies report successful QbD-based development of MCT and LCT-SNEDDS of valsartan with improved biopharmaceutical performance.

Development and Characterization of Novel Medicated Nanofibers Against Periodontitis by Deeksha Joshi, Tarun Garg, Amit K Goyal, Goutam Rath (564-577).
Periodontitis is an inflammatory disease of gums involving degeneration of periodontal ligaments, creation of periodontal pocket and resorption of alveolar bone, thus disrupting the support structure of teeth causing their loosening and finally removal. Since this disease is mainly confined to the periodontal pocket, so site specific drug delivery of an antibiotic is the best suitable option. This also eradicates the demerits of oral dosing like low drug concentration reaching the target site and the various systemic side effects. In the present work, an efficient and easy technique of electrospinning has been used to develop non-woven drug loaded and biodegradable nanofiber patch with inbuilt property of high surface area to volume ratio. Hyaluronic acid (HA) has been used specifically as the polymer since it possesses remarkable properties like providing an extracellular matrix supporting tissue regeneration, anti-inflammation and mucoadhesion. A blend of this natural polymer with another polymer (Polyvinyl alcohol) has been tried since HA alone cannot be electrospun efficiently as it shows very high viscosity at very low polymer concentration. The developed formulation presented controlled release behavior with good mucoadhesive strength. The in vivo studies confirmed the maintenance of minimum inhibitory concentration (MIC) over an extended period of time in addition to a significant antiinflammatory effect. All these observations suggested that the above formulation forms a stable intra periodontal pocket drug delivery system.

Ranitidine HCl is an H2-antagonist that suffers from low oral bioavailability of 50%. The site-specific absorption from the upper part of the small intestine and the colonic metabolism of the drug could partially contribute to its reduced bioavailability. To surmount these drawbacks, this work aimed at the formulation of Ranitidine HCl gastroretentive floating-biaodhesive tablets. A 32 factorial design was applied to assess the effects of matrix former (HPMC K100M): drug ratio, and the release retardant (Carbopol 971) amount on the characteristics of the tablets prepared using direct compression technique. The prepared tablets were thoroughly evaluated for physical properties, floating, swelling, bioadhesive and in vitro release behaviors. Statistical analysis of the results revealed significant effects for both formulation variables on the swelling index, maximum detachment force and cumulative percent drug released after 6 hours. In addition, the matrix- former: drug ratio showed a statistically significant effect on the floating lag time. Kinetic analysis of the release data indicated Higuchi diffusion kinetics and anomalous transport mechanism for all formulations. Scanning electron micrographs of the selected tablet formulation; F8, revealed intact surface without any perforations or channels in the dry state, while polymer expansion (relaxation) with some perforated areas were observed on the surface of the tablets after 12 hours dissolution in 0.1 N HCl. Furthermore, in vivo abdominal x-ray imaging showed good floating behavior of the selected formulation; F8, for up to 6 hours with appropriate bioadhesive property. In conclusion, the selected ranitidine HCl floating-bioadhesive tablets could be regarded as a promising gastroretentive drug delivery system that could deliver the drug at a controlled rate.

Investigation of Drug Release from PEO Tablet Matrices in the Presence of Vitamin E as Antioxidant by Saeed Shojaee, Ali Nokhodchi, Iain Cumming, Amjad Alhalaweh, Waseem Kaialy (591-599).
The objective of this study was to investigate the influence of drug type on the release of drug from PEO matrix tablets accompanied with the impact of vitamin E succinate as antioxidant. The result showed that the presence of vitamin E promoted a stable release rate of soluble drug propranolol HCl from aged PEO matrix tablets, which was similar to fresh sample, regardless of molecular weight (MW) of PEO. However, the influence of the presence of vitamin E on the release rate of partially soluble drug, theophylline, was dependent on the MW of PEO; i.e., fast and unstable drug release was obtained in the case of low MW PEO 750 whereas stable drug release was obtained in the case of high MW PEO 303. The release of low water-soluble drug zonisamide was stable regardless of both the presence of vitamin E and the MW of PEO. The presence of vitamin E slightly slowed the release of zonisamide from aged PEO 303 matrices but not PEO 750 matrices. Therefore, in order to achieve a suitable controlled release profile from PEO matrices, not only the presence of vitamin E but also the solubility of the drug and the MW of polyox should be considered.

Current HIV-therapy recommends combination of stavudine, lamivudine and nevirapine. Stavudine and lamivudine are administered as fixed combination while nevirapine as separate dosage form which often results in poor compliance and adherence to therapy by patients and therefore, there is a need to develop dosage forms that can overcome the problems of currently available dosage forms for treatment of HIV infection. The present study developed a single unit osmotic system for simultaneous and extended delivery of stavudine, lamivudine and nevirapine that can ensure patients compliance and adherence to HIV-therapy. Sandwich osmotic pump tablets (SOPTs) of stavudine, lamivudine and nevirapine in fixed dose combination were designed and evaluated for the effect of variables such as PEO (polymer), KCl (osmogen), and orifice diameter on the physicochemical characteristics and the release behavior of the drugs. A 24 h zero order release of stavudine, lamivudine and nevirapine from the formulations was observed and the release rate of the drugs was found to be affected by PEO, KCl, and orifice diameter. The in vitro release data of SOPT correlated with in vivo predictions by super - position method. The results of the study propose that a single unit osmotic system (SOPT) of stavudine, lamivudine and nevirapine is beneficial to overcome the disadvantages of currently available dosage forms for effective control of HIV infection.

Nanoparticles based on oleate alginate ester as curcumin delivery system by Mazhar Ali Raja, Chenguang Liu, Zhenhua Huang (613-627).
Hydrophobic alginate derivative was prepared by the modification of alginate with methyl oleate. The synthesized oleate alginate ester (OAE) conjugate was characterized by FTIR and 1HNMR analysis. Results of critical aggregation concentration (CAC) revealed that OAE conjugate had low CAC and was prone to form self-assembled nanoparticles in aqueous medium. Curcumin loaded OAE nanoparticles (Cur-OAE Nps) were developed by a simple sonication method and the physicochemical parameters of the nanoparticles such as zeta potential, size distribution and drug encapsulation were characterized. The results showed that zeta potential of the prepared nanoparticles was -55.4±0.91 mV and the average size was about 200 nm. A significant enhancement in aqueous solubility and stability of curcumin were observed after encapsulation into OAE nanoparticles. With the increase of curcumin concentration, loading efficiency increased but encapsulation efficiency decreased. The in vitro release profile exhibited significant sustained release pattern with initial burst release followed by a slower release over a period of one week. Cytotoxicity assay against MCF-7cells showed that Cur-OAE Nps had slow and continuous cytotoxic effect. Furthermore, in vitro cell uptake study revealed that cell uptake of curcumin from OAE nanoparticles was sustained and both were time and concentration dependent. Therefore, the developed Cur-OAE Nps might be promising candidates for curcumin delivery to cancer cells.

In vitro characterisation of Span™ 65 niosomal formulations containing proteins by Rita Rochdy Haj-Ahmad, Amal Ali Elkordy, Cheng Shu Chaw (628-639).
Proteins can be encapsulated in niosomes as they are known to protect proteins against the surrounding env ironment. Niosomes of Span 65/cholesterol/pluronic® F -127 were prepared by thin film hydration method. Insulin and lysozyme were chosen as model proteins. Niosomes were chara c-terised for morphology by Transmission Electron M icroscopy (TEM) and vesicles size using Dynamic Light Scattering. The entrapment efficiency of protein in niosomes was determined by complete vesi-cle disruption using 50:50% isopropanol:buf fer, followed by analysis of the resulting so lutions by HPLC method. Thermal behaviour of the niosomes was investigated using Differential Scanning Calo-rimetry (DSC). Protection of proteins against simulated gastric fluid (SGF) and simu lated intestinal fluid (SIF) were also assessed. The results showed that niosomes prepared with diffe r ent molar ratios % of Span 65, cholesterol and pluronic®F -127 successfully produced with insulin and lysozyme. For insulin co n taining niosomes, the ratio % of 64.7 (Span 65): 32.3 (cholesterol): 3.0 (pluronic® F - 127) produced the highest protein encapsulation eff i-ciency and the smallest vesicle size of 653.6 nm. For lysozyme containing niosomes, the maximum pr o tein encapsulation was found in 72.75/24.25/3.00% molar ratio of Span 65/cholesterol/pluronic® F -127 niosomes with vesi cle size of 627.3 nm. The release study of proteins from the niosomal preparations in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) revealed that insulin and lysozyme efflux from the niosomes is a biphasic process. The results indicate that Span 65 niosomes could be developed as controlled release dosage forms for delivery of peptides and proteins such as insulin and lysozyme.