Current Drug Delivery (v.12, #6)

Meet Our Editorial Board Member by Ben Boyd (641-641).

Chemical penetration enhancers (CPEs), which are also referred to as sorption promoters or accelerants have several advantages in transdermal drug delivery. These are painlessness, noninvasiveness and the capacity to increase in transdermal flux in comparison with passive diffusion. Several investigators have used a number of chemical enhancers to demonstrate these important properties. Studies have also been carried out to have a better understanding of the mechanisms of penetration enhancement. It has been postulated that these compounds can enhance transdermal drug delivery by perturbing the stratum corneum, increasing partition coefficient or increasing solubility. In this paper, several compounds used in facilitating percutaneous penetration of drugs have been described and the potential of using them for transdermal drug delivery highlighted. Special attention has been paid to cell-penetrating proteins (protein transduction domains) as well as skin penetrating peptides. Ironically, these are substances that possess high molecular weight themselves but are capable of creating pores through which drugs can penetrate into and through the skin. Concerns relating to irritation and cytotoxicity and efforts to overcome them are discussed.

New Generation of Orally Disintegrating Tablets for Sustained Drug Release: A Propitious Outlook by Arwa Matoug Elwerfalli, Zabir Ghanchi, Fatema Rashid, Raid G. Alany, Amr ElShaer (652-667).
Orally disintegrating tablets (ODTs) or orodispersible tablets are solid dosage forms that disintegrate within 3 minutes in the mouth into a paste that can be easily swallowed. ODTs have improved over the past years, in an attempt to produce a safe and efficient substitute to the conventional oral dosage forms, particularly for dysphagia patients. Since its introduction in the market in the 1980s, ODTs expanded rapidly and achieved revenues over $3 billion in 2006 and sustaining 20% annual growth. It is therefore evident that ODTs carry good commercial value, however there is potential for improvement. Current sustained-release technologies may be exploited and incorporated into an ODT to provide greater therapeutic value by reducing the need for multiple daily dosing regimens and improving patient adherence. A number of technologies such as polymer coated nanoparticles, stimuli-responsive polymers and ion-exchange resins have emerged to produce robust, sustained release orally disintegrating tablets (SR-ODT). The purpose of this review is to highlight these various approaches and techniques and how they have been utilised in an ODT formulation to extend differentiated line, market exclusivity and patent life. The review also explores future perspective and the potential challenges that SR-ODTs will face.

Assessment of Aprotinin Loaded Microemulsion Formulations for Parenteral Drug Delivery: Preparation, Characterization, in vitro Release and Cytotoxicity Studies by Neslihan Üstünda| Okur, Derya |lem Özdemir, |ennur Görgülü Kahyao|lu, Zeynep Ay |enyi|it, Makbule A||ko|lu, Lütfi Genç, H. Ye|im Karasulu (668-679).
The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m (99mTc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with 99mTc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of 99mTc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of 99mTc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of 99mTc- Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized microemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies, the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

Benzocaine loaded solid lipid nanoparticles: Formulation design, in vitro and in vivo evaluation of local anesthetic effect by Mona Basha, Sameh Hosam Abd El-Alim, Ahmed Alaa Kassem, Sally El Awdan, Gamal Awad (680-692).
The aim of the present work is the development and evaluation of solid lipid nanoparticles (SLNs) as carrier system for topical delivery of benzocaine (BZC) improving its local anesthesia aiming to produce a fast acting and long lasting topical formulation. BZC loaded SLNs were prepared using a full factorial design to study the influence of the type of polyoxyethylene sorbitan ester surfactants as well as their concentration as independent variables on the particle size, entrapment efficacy and zeta potential selected as dependent variables. Design of experiment (DOE) and the analysis of variance (ANOVA) were conducted to assess the optimization of the developed formulations. The results indicated that the fatty acid chain length of tested surfactants and their concentration had a significant effect on the studied responses. The optimized formulations were spherical in shape of mean particle diameters<350 nm with negatively charged surface <-20mV. Particles were characterized using differential scanning calorimetry and X-ray powder diffraction confirming the amorphous nature and the uniformity of drug inclusion in the lipid matrix. Optimized BZC-SLNs were incorporated into hydrogels characterized by a pseudoplastic non-Newtonian behavior. In vitro release study revealed an apparently biphasic release process with sustained release profile following Higuchi kinetics. BZC loaded SLNs hydrogels showed more potent anesthetic effect compared to BZC hydrogel evaluated using tail-flick analgesimeter, confirming significant improvement in both the intensity and duration of anesthetic effect. The above results proved that SLNs represent good candidates to encapsulate BZC improving its therapeutic efficacy for the topical treatment of pain.

Mucoadhesivity Characterization of Isabgol Husk Mucilage Microspheres Crosslinked by Glutaraldehyde by Vipin Kumar Sharma, Prince Prashant Sharma, Bhasker Mazumder, Aseem Bhatnagar, Thakuri Singh (693-702).
The microspheres of Isabgol husk were prepared by emulsification-crosslinking technique and the gastrointestinal transition behavior of the formulation was studied by gamma scintigraphy. The impact of different process variables such as amount of glutaraldehyde, concentration of Isabgol husk and temperature was studied on surface morphology and mucoadhesion. In vitro mucoadhesive testing of formulations was performed by determination of zeta potential, mucus glycoprotein assay and mucus adsorption isotherms. The effect of feeding on retention of microspheres in the gastrointestinal track (GIT) was studied in albino rabbits by gamma scintigraphy study. The results indicated the formation of microspheres as observed by scanning electron microscopy. The smooth and round surfaces of microspheres were obtained on increasing Isabgol husk and glutaraldehyde amount. The positive zeta potential of all formulations indicated the electrostatic interaction as a mechanism of mucoadhesion between the mucus of GIT membranes and the microspheres surfaces. The influence of electrostatic interaction on mucoadhesion of microspheres was again ascertained when the mucin equilibrium adsorption on preparations indicated well fitness in Langmuir and Freundlich adsorption isotherms. During gamma scintigraphy, the stability of 99mTc-sodium pertechnetate was found 98.82% at pH 6.8 and 96.78% at pH 7.2, respectively. It indicated the minimal leaching of bound radionuclide from microspheres during gastrointestinal transition as observed in gamma scintigraphic images of the rabbits. The microspheres retained in GIT even after 24 hrs of oral administration. The results indicated the applicability of Isabgol husk mucilage in the development of mucoadhesive microspheres.

Formulation and Characterization of Aceclofenac -Aloe vera Transemulgel by Y. Prasanna Raju, K. Haritha, Rao P. Satyanarayana, K.R. Vandana, D. Thushara Bindu, V. Vinesha, V. Harini Chowdary (703-708).
The present research was aimed to formulate aceclofenac transemulgel using Aloe vera as gel base. The prepared formulations were subjected to physical characterization, in-vitro and in-vivo assessment. Aceclofenac, a hydrophobic potential non steroidal anti inflammatory drug, causes ulceration upon chronic oral administration, could be formulated into transemulgel to enhance therapeutic efficacy and to lower the unwanted side effects. The transemulgel was prepared from aqueous Aloe vera gel and aceclofenac emulsion. The prepared transemulgel was evaluated for its pH, viscosity, drug content, skin irritation, in-vitro diffusion and accelerated stability studies. The prepared aceclofenac-Aloe vera tranemulgel and commercial aceclofenac gel were subjected to pharmacodynamic studies in albino rats of Wistar strain employing carrageenan induced left hind paw edema method to assess the anti-inflammatory effect. The transemulgel showed a pH of 6.78 and viscosity of 18 cps. In-vitro diffusion data revealed better permeation characteristics. Topical application of formulation found no skin irritation. Stability study has proved the integrity of the formulation. The prepared aceclofenac Aloe vera transemulgel showed better in-vitro drug release when compared with the commercial aceclofenac gel formulation. Anti-inflammatory activity in treated rats showed the significant paw volume reduction at p<0.05 compared with that of control. Thus, it is concluded that aceclofenac, a potential non steroidal anti inflammatory drug, showed high therapeutic efficiency when formulated into transemulgel using aqueous Aloe vera as gel base.

Plumbagin Nanoparticles Induce Dose and pH Dependent Toxicity on Prostate Cancer Cells. by Harikrishnan A. Nair, K. S. Snima, Ravindranath C. Kamath, Shantikumar V. Nair, Vinoth-Kumar Lakshmanan (709-716).
Stable nano-formulation of Plumbagin nanoparticles from Plumbago zeylanica root extract was explored as a potential natural drug against prostate cancer. Size and morphology analysis by DLS, SEM and AFM revealed the average size of nanoparticles prepared was 100±50nm. In vitro cytotoxicity showed concentration and time dependent toxicity on prostate cancer cells. However, plumbagin crude extract found to be highly toxic to normal cells when compared to plumbagin nanoformulation, thus confirming nano plumbagin cytocompatibility with normal cells and dose dependent toxicity to prostate cells. In vitro hemolysis assay confirmed the blood biocompatibility of the plumbagin nanoparticles. In wound healing assay, plumbagin nanoparticles provided clues that it might play an important role in the anti-migration of prostate cancer cells. DNA fragmentation revealed that partial apoptosis induction by plumbagin nanoparticles could be expected as a potent anti-cancer effect towards prostate cancer.

Brimonidine Imprinted Hydrogels and Evaluation of Their Binding and Releasing Properties as New Ocular Drug Delivery Systems by Hediye Moghadam Omranipour, Sayyed Abolghasem Sajadi Tabassi, Reza Kowsari, Maryam Shayani Rad, Seyed Ahmad Mohajeri (717-725).
Molecular imprinting is a technique for preparation of specific polymeric receptors for recognition and selective binding of chemicals. Recently, molecularly imprinted soft contact lenses have been studied as novel ocular drug delivery systems. The aim of this work was to prepare, for the first time, a brimonidine (BRN) imprinted soft contact lens material and study of its binding and releasing properties in aqueous media. The hydrogels were prepared using hydroxyethyl methacrylate (HEMA) as a backbone monomer, methacrylic acid (MAA), methacrylamide (MAAM) and 4-vinylpyridine (4VP) as the functional monomers and ethylene glycol dimethacrylate (EGDMA) as a cross linker monomer. Different BRN: MAA molar ratios were also applied in feed composition of monomers to study the influence of molecular imprinting technique on their binding properties. The hydrogels were characterized by determination of their swelling and binding properties in water. Their loading and release properties were also studied using Korsmeyer-Peppas equation in normal saline (NaCl 0.9%) and artificial tear solution. Poly (HEMA-co-MAA) showed superior binding properties compared to other copolymers. Also molecular imprinting technique significantly increased the hydrogel affinity to drug. It was found that all molecularly imprinted polymers (MIPs) had higher affinity to BRN in comparison with nonimprinted polymers (NIPs). The optimized MIP hydrogel with BRN: MAA molar ratio of 1: 8 showed greater ability to drug loading and controlled release compared to other MIPs. The results of the present work indicated that molecular imprinting technique had a significant effect on improving loading capacity and sustaining drug release from hydrogels.

Improving Protein Stability and Controlling Protein Release by Adding Poly (Cyclohexane -1, 4 -Diyl Acetone Dimethylene Ketal) to PLGA Microspheres by Chenhui Wang, Changhui Yu, Kongtong Yu, Lesheng Teng, Jiaxin Liu, Xuesong Wang, Fengying Sun, Youxin Li (726-735).
The use of biodegradable polymers such as PLGA to encapsulate therapeutic proteins for their controlled release has received tremendous interest. However, an acidic environment caused by PLGA degradation productions leads to protein incomplete release and chemical degradation. The aim of this study was to develop novel PCADK/PLGA microspheres to improve protein stability and release behavior. Bovine serum albumin (BSA) incubated in PCADK and PLGA degradation products was investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size exclusion chromatography (SEC-HPLC), circular dichroism (CD) and fluorescence spectroscopy. Blended microspheres of PCADK/PLGA were prepared in different ratios and the release behaviors of the microspheres and the protein stability were then measured. The degradation properties of the microspheres and the pH inside the microspheres were systematically investigated by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) to examine the mechanism of autocatalytic degradation and protein stability. BSA was more stable in the presence of PCADK monomers than it was in the presence of PLGA monomers, revealing that PCADK is highly compatible with this protein. PCADK/PLGA microspheres were successfully prepared, and 2/8 was determined to be the optimal ratio. Further, 43% of the BSA formed water-insoluble aggregates in the presence of PCADK/PLGA microspheres, compared with 57% for the PLGA microspheres, demonstrating that the BSA encapsulated in PCADK/PLGA blended microspheres was more stable than in PLGA microspheres. The PCADK/PLGA blended microspheres improved protein stability and release behavior, providing a promising protein drug delivery system.

Design and Optimization of Domperidone Fast Dissolving Tablet Using Central Composite Design by Bhatt Shailendra, Mandge Shailendra, Jaimini Manish, Tanwar Yuveraj Singh, Trivedi Priti (736-744).
The main aim present work was to optimize fast dissolving tablet (FDT) formulation using response surface approach. The variables studied were sodium bicarbonate (X1), citric acid (X2), and superdisintegrant, Ac-Di-Sol (X3). The main aspect of present work was to develop FDT of Domperidone which possesses fast disintegration and high mechanical strength. It was found that the response was affected by all the three factors studied. The statistical models were successfully used to prepare FDT of Domperidone with fast disintegration (31.08 seconds) and adequate hardness (4.1 kg/cm2). Pharmacokinetic studies in rats showed statistically insignificant difference (p>0.05) between Domperidone fast dissolving tablet (DFDT) and market product. This concluded that optimized FDT is bioequivalent with the marketed formulation. The values of Tmax were found to be 0.5 h and 0.75 h for DFDT and reference product, respectively. Conditioned place aversion study was performed on Swiss Albino mice and the study showed the better anti emetic potency of optimized FDT in nauseated condition over market product (p<0.05). Thus, the present investigation conclusively demonstrates the potential role in terms of rapid disintegration and high mechanical strength.

The solid-self nanoemulsifying drug delivery system (S-SNEDDS) of Amiodarone hydrochloride (AH) was prepared and evaluated. AH exhibits poor aqueous solubility (0.3-0.5 mg/ml) and therefore variable oral bioavailability. Capmul MCM, Cremophor RH-40 and Propylene glycol were identified as oil, surfactant and co-surfactant for preparing L-SNEDDS. D-optimal design was used to optimize the amount of components in liquid self nanoemulsifying drug delivery system (L-SNEDDS). Optimized AH-L-SNEDDS having 15.8 nm globule size and 99.5 %transmittance was then adsorbed on Neusilin US2 to form solid self nanoemulsifying drug delivery system (AH-SSNEDDS). AH loaded L-SNEDDS and S-SNEDDS were characterized for various physicochemical properties and solid state properties. In vitro dissolution, ex vivo drug release study and In vivo study were performed for pure AH, AH-LSNEDDS and AH-S-SNEDDS. Both AH loaded L-SNEDDS and S-SNEDDS showed more than 95% drug release in 20 min during drug release studies. In vivo study revealed that release of AH from S-SNEDDS was 2.26 times and LSNEDDS was 1.83 times higher than that from suspension when given to rabbits (p < 0.01). The optimized S-SNEDDS was found to be stable and its shelf life was found to be 2.2 years. S-SNEDDS could serve as a potential drug delivery system for AH.

In Vitro Skin Permeation Enhancement of Sumatriptan by Microneedle Application by Buchi N. Nalluri, Sai Sri V. Anusha, Sri R. Bramhini, J. Amulya, Ashraf S.K. Sultana, Chandra U. Teja, Diganta B. Das (761-769).
Different dimensions of commercially available microneedle devices, namely, Admin- Patch® microneedle arrays (MN) (0.6, 0.9, 1.2 and 1.5 mm lengths) and Dermaroller® microneedle rollers (DR) (0.5 and 1mm lengths) were evaluated for their relative efficiency in enhancement of transdermal permeation of Sumatriptan (SMT). Solubility assessment of SMT was carried out using propylene glycol (PG), polyethylene glycol (PEG) in combination with saline (S) at different ratios and the order of solubility was found to be 70:30 > 80:20 > 90:10 %v/v in both PG:S and PEG:S. In vitro skin permeation studies were performed using PG:S (70:30 %v/v) as donor vehicle. A significant increase in cumulative amount of SMT permeated, steady state flux, permeability coefficient and diffusion coefficient values were observed after microneedle treatment, and the values were in the order of 1.5mm MN >1.2mm MN >0.9mm MN >1mm DR >0.6mm MN >0.5mm DR > passive permeation. Lag times were significantly shorter after longer microneedle application (0.24h for 1.5mm MN). Arrays were found to be superior to rollers with similar microneedle lengths in enhancing SMT permeation and may be attributed to higher density of microneedles and force of application onto skin. The in vitro flux values revealed that 2.5cm2 area patch is sufficient for effective therapy after treatment of skin with 1.5mm MN. It may be inferred that microneedle application significantly enhances the transdermal penetration of SMT and that it may be feasible to deliver clinically relevant therapeutic levels of SMT using microneedle assisted transdermal delivery systems.

Cancer in individuals suffering with HIV and AIDS has become a common source of morbidity and mortality, especially in the underdeveloped world in which Kaposi's sarcoma is the most occurring tumor of vascular endothelium frequently seen in patients suffering from AIDS. Suffering individuals are invariably co-infected with HIV and HHV-8 virus. The conventional modes for chemotherapies may be clinically useful in patients with Kaposi's sarcoma. Though advancements in treatment modalities of AIDS related Kaposi's sarcoma have been successfully achieved, till date an exclusive therapy of golden standard has not been principally defined that can deliver the drug via non-invasive route. Novel concepts of treatment primarily address the factors that are associated with the pathogenesis of critical disease. On the other hand local therapies are aimed at eradicating primary lesions; and systemic chemotherapies are aimed to treat widespread visceral involvement. Increased understanding of the mechanisms underlying viral tumorigenesis will hopefully portray new therapeutic strategies. This review discusses novel drug delivery strategies that have been investigated for the effective and safe management of AIDS related kaposi's sarcoma. The review also highlights, the lipid based ultradeformable vesicular system that offers attractive drug delivery platform capable of delivering its payload without using invasive technique. These systems offer advance models for efficacious treatment of the future therapy aiming Kaposi's sarcoma.

Dual Drug Conjugate Loaded Nanoparticles for the Treatment of Cancer by Megha Shyam Matlapudi, Afrasim Moin, Raghavender Medishetti, K. Rajendra, Ashok M. Raichur, B.R. Prashantha Kumar (782-794).
Two antineoplastic agents, Imatinib (IM) and 5-Fluorouracil (FU) were conjugated by hydrolysable linkers through an amide bond and entrapped in polymeric Human Serum Albumin (HSA) nanoparticles. The presence of dual drugs in a common carrier has the advantage of reaching the site of action simultaneously and acting at different phases of the cell cycle to arrest the growth of cancer cells before they develop chemoresistance. The study has demonstrated an enhanced anticancer activity of the conjugate, and conjugate loaded stealth HSA nanoparticles (NPs) in comparison to the free drug in A-549 human lung carcinoma cell line and Zebra fish embryos (Danio rerio). Hydrolysability of the conjugate has also been demonstrated with complete hydrolysis being observed after 12 h. In vivo pharmacodynamics study in terms of tumor volume and pharmacokinetics in mice for conjugate (IM-SC-FU) and conjugate loaded nanoparticles showed significant anti-cancer activity. The other parameters evaluated were particle size (86nm), Poly Dispersive Index (PDI) (0.209), zeta potential (-49mV), drug entrapment efficiency (96.73%) and drug loading efficiency (89%). Being in stealth mode gives the potential for the NPs to evade Reticulo-Endothelial system (RES), achieve passive targeting by Enhanced Permeation Retention (EPR) effect with controlled release of the therapeutic agent. As the conjugate cleaves into individual drugs in the tumor environment, this promises better suppression of cancer chemoresistance by delivering dual drugs with different modes of action at the same site, thereby synergistically inhibiting the growth of cancerous tissue.

Nanoemulsion-based Parenteral Drug Delivery System of Carbamazepine: Preparation, Characterization, Stability Evaluation and Blood-Brain Pharmacokinetics by Sim Ling Tan, Johnson Stanslas, Mahiran Basri, Abedi Karjiban R.A., Brian P. Kirby, Dahiru Sani, Hamidon Bin Basri (795-804).
Carbamzepine (CBZ) was encapsulated in a parenteral oil-in-water nanoemulsion, in an attempt to improve its bioavailability. The particle size, polydispersity index and zeta potential were measured using dynamic light scattering. Other parameters such as pH, osmolality, viscosity, drug loading efficiency and entrapment efficiency were also recorded. Transmission electron microscopy revealed that emulsion droplets were almost spherical in shape and in the nano-range. The in vitro release profile was best characterized by Higuchi's equation. The parenteral nanoemulsion of CBZ showed significantly higher AUC0→5, AUC0→?, AUMC0→5, AUMC0→?, Cmax and lower clearance than that of CBZ solution in plasma. Additionally, parenteral nanoemulsion of CBZ showed significantly higher AUC0→?, AUMC0→? and Cmaxthan that of CBZ solution in brain. The parenteral nanoemulsion of CBZ could therefore use as a carrier, worth exploring further for brain targeting.