Current Drug Delivery (v.6, #1)

Aceclofenac Organogels: In Vitro and In Vivo Characterization by I. Shaikh, S. Jadhav, K. Jadhav, V. Kadam, S. Pisal (1-7).
Purpose: To develop and evaluate the suitability of lecithin organogels containing aceclofenac for topical application and compare its In vitro and In vivo effects with conventionally used hydrogels. Methods: The components and their concentration necessary for organogels formation were evaluated using phase diagram. Solubility of aceclofenac was determined. The In vitro skin permeation ability of aceclofenac from ethyl oleate based lecithin organogels [EO/lecithin organogel] and hydrogel was investigated. The In vivo characterization of ethyl oleate based organogel study was compared with that of hydrogel.The alterations in microstructure of organogels during diffusion study were elucidated. Viscosity and micellar size of the organogel sample were estimated. The safety of optimized organogel was determined using histopathological investigation. Results: The flux calculated for skin permeation ability of aceclofenac was in the order EO/lecithin organogel > hydrogel. The In vivo results also demonstrated that organogels are more effective in faster drug release as compared to hydrogels. It was observed that viscosity of gels decreased with increasing stress .The size of micellar aggregation increased with water added and has been revealed in dynamic light scattering (DLS) study. The histopathological data showed that EO/lecithin organogel were safe enough for topical purpose.

The purpose of the present study was to investigate the influence of method of preparation of large respirable particles of amikacin sulphate on traits and topography and in-vitro aerosol performance. Large respirable particles of amikacin sulfate (50and#x25;w/w) were produced by spray-drying and freeze-drying processes using hydrogenated soyaphosphatidylcholine, L-leucine and Poloxamer 188. Particles exhibited 0.04 - 0.08 g/cm3 tap densities, 7-20 and#956;m geometric particle size, and 1 to 5 and#956;m of mean aerodynamic diameter. Apart from the morphology and topographical features, spraydried and freeze- dried particles had marginal difference in their solid-state characteristics. Spray-dried particles were dimpled spherical shape with roundness value close to 1(1.066 and#xB1; 0.028), relatively smooth surface texture and produced greater aerosol dispersion with 20and#x25; higher fine particle fraction, 6.92and#x25; lower impaction loss and 13and#x25; less capsule and device retention than freeze dried particles. Traits and topographical features, such as particle size, polydispersity, elongation ratio, roundness, shape, and degree of surface roughness were found to be influenced significantly by spray-drying process and particles produced by spray-drying process showed better aerosol performance due to these differences.

Fluconazole Mucoadhesive Buccal Films: In Vitro/In Vivo Performance by Soad Yehia, Omaima El-Gazayerly, Emad Basalious (17-27).
Fluconazole mucoadhesive buccal films were prepared using film forming polymers namely; hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), chitosan, Eudragit and sodium alginate (SALG) either alone or in combination with bioadhesive polymers. The bioadhesive polymers studied were sodium carboxymethyl cellulose (SCMC), Carbopol 974P, and polycarbophil (AA-A). The prepared films were characterized by means of film thickness, surface pH, swelling capacity, in vitro adhesion, in vivo residence time, in vitro drug release and in vivo drug release to determine the amount of drug release from selected film formulae using microbiological assay and HPLC. Optimum release behavior, convenient bioadhesion, acceptable elasticity were exhibited by film containing 2and#x25; HPMC and 1and#x25; SCMC (fresh or stored for 6 months). Determination of the amount of drug released in saliva after application of the selected fluconazole films confirmed the ability of the film to deliver the drug over a period of approximately 300 minutes and to reduce side effects and possibility of drug interaction encountered during systemic therapy of fluconazole, which would be beneficial in the case of oral candidiasis.

The objective of the present work undertaken was to enhance the solubility and dissolution rate of valsartan a poorly water soluble antihypertensive, by preparation of solid dispersion granules which would additionally allow easy compression into tablets. The dispersion granules were prepared using a hot melt granulation technique which involved preparation of a homogenous dispersion of valsartan in gelucire-50/13 melt, followed by its adsorption on to the surface of aeroperl-300pharmaand#174;, an inert adsorbent. A two-factor, three-level (32) statistical design was implemented to quantitate the influence of gelucire-50/13 and aeroperl-300pharma on the dissolution profile and flow properties of the dispersion granules, where gelucire-50/13 and aeroperl-300pharmaand#174; were chosen as independent variables, while dissolution and flow properties were chosen as dependent variables. The dispersion granules were characterized for their in-vitro dissolution rate and flow properties. An appropriate statistical model was arrived at and a significantly enhanced dissolution rate and flow properties were exhibited with the optimized formulation. The formulation was further characterized by FTIR, DSC, XRD and SEM analysis. FTIR spectrum revealed some drug excipient interactions. DSC and XRD data indicated the retention of amorphous form of valsartan. SEM confirmed the homogeneity and surface adsorption of the gelucire- 50/13 melt on aeroperl-300pharmaand#174; leading to enhanced surface area and thus dissolution rate. The tablets of optimized dispersion granules were formulated and evaluated. The in-vitro dissolution rate of these tablets was significantly better in comparison with marketed formulation. In conclusion the statistical model enabled us to understand the effects of formulation variables on the dispersion granules of valsartan.

Aerosol Devices and Asthma Therapy by William Berger (38-49).
Aerosol delivery of asthma medications maximizes local effects in the lung and minimizes systemic effects compared with oral therapy. Both corticosteroids and bronchodilators are available in a variety of delivery devices for the treatment of asthma. The 1987 Montreal protocol requiring the phasing out of the chlorofluorocarbon (CFC) propellant in commonly used pressurized metered-dose inhalers (pMDIs) provided an impetus for the development of new technologies for the delivery of inhaled asthma medications. For pMDIs, CFC has been replaced with hydrofluoroalkane (HFA) propellant. New types of dry powder inhalers (DPIs) and nebulizers, aerosol delivery devices that do not use propellants, also have been introduced. Drug delivery varies based on the device type, the product formulation and patient-related factors. Thus, drug delivery can differ when the same medication is delivered via an HFA pMDI, a CFC pMDI, a DPI or a nebulizer. Even among the same type of device (eg. DPIs, pMDIs), inhaler designs and drug formulations differ. Drug and device selection should be based on consideration of the patient's ability to use the device properly, the availability of a desired drug or drugs (ie. maintenance and rescue) in a particular inhaler device and patient preference. This review describes key characteristics for each device type, explains differences in markers of lung deposition, lists potential advantages and disadvantages of the different devices and discusses how these and other factors need to be considered when selecting an inhaler device that meets the individual needs of a patient.

Design and Evaluation of a Bioadhesive Patch for Topical Delivery of Gentamicin Sulphate by N. El-Gendy, G. Abdelbary, M. EL-Komy, A. Saafan (50-57).
The use of aminoglycoside antibiotics for the topical treatment of gram positive and gram negative infections especially burns and wounds has increased markedly in recent years. Patch formulation for topical delivery can be advantageously used as an alternative to conventional topical dosage forms. The present study aims to prepare and evaluate gentamicin sulphate patches for topical application and to study the effect of different bioadhesive polymers on diverse characteristics of prepared patches. Drug patches were evaluated for weight and thickness uniformity, moisture absorption capacity, tensile strength and percentage elongation. In vitro release patterns of these patches were studied and analyzed. Skin irritation and susceptibility testing of gentamicin sulphate formulae were also evaluated and compared to commercially available gentamicin sulphate cream. The thickness of the films was found to be uniform. Tensile strength of the patches prepared using HPMC as bioadhesive polymer was the lowest compared to the other patches. The in vitro release of the patches followed a pattern close to diffusion model. Patches formulated using HPMC gave the most superior results as compared to other compositions.

Malignant vascular tumors are exceedingly rare in childhood. Generally, their prognosis is dependent from a microscopically complete surgical resection. We observed the case of a 4-year-old boy affected by malignant endovascular papillary angioendothelioma, a rare vascular tumor of intermediate malignancy, involving all his left leg and partially the pelvis. Its very large size hampered any surgical intervention. However, we could demonstrate high sensitivity of the tumor to lyposomal anthracyclines and the child was eventually cured by the intra-arterial administration of carboplatin and doxorubicin coupled with local hyperthermia. This experience probably represents the first step toward an effective treatment of malignant vascular tumors in infancy.

Risperidone, an and#x201C;atypicaland#x201D; antipsychotic drug, having large scope for prolonged psychotic treatments through novel parenteral drug delivery systems. Polymeric nanoparticles suspensions containing risperidone made of poly (D, LLactide) were designed by nanoprecipitation method using polymeric stabilizer (Pluronicand#174; F-68 or Pluronicand#174; F-127). The prepared nanosuspensions were characterized for particle size by photon correlation spectroscopy and scanning electron microscopy. The free dissolved drug in the nanosuspension was determined by bulk equilibrium reverse dialysis bag technique. In vitro release studies were carried out using dialysis bag diffusion technique. The particle size of the prepared nanoparticles in the nanosuspensions ranged between 78-184 nm. Nanoparticles of risperidone in the nanosuspensions were obtained with high encapsulation efficiency (91 - 94 and#x25;). The drug release from the risperidone nanosuspension was sustained in some batches for more than 24 h with 75and#x25; drug release whereas release from risperidone solution showed release within 1.5 h. The release pattern of drug is analyzed and found to follow first order equation and Fickian diffusion kinetics. These studies suggest the feasibility of formulating risperidone loaded poly (D, L-Lactide) nanoparticles suspension for the treatment of psychotic disorders.

Preparation and Characterization of Cephalexin Loaded PLGA Microspheres by Wasana Chaisri, Wim Hennink, Siriporn Okonogi (69-75).
The aim of this study was to evaluate the effects of emulsion type and process parameters on the properties of CPX-loaded PLGA microspheres in order to obtain delivery systems suitable for the treatment of dairy mastitis. The microsphere size was analyzed by photon correlation spectrophotometry. Determination of the drug loading was achieved by HPLC. It was found that CPX-loaded PLGA microspheres prepared using a w/o/w double emulsion technology were slightly larger (and#x223C; 3-5 and#956;m) but much higher in drug content (and#x223C; 18 and#x25; w/w) than those obtained using o/w single emulsion preparation technology (average size was 2 and#956;m, encapsulation efficiency was less than 2 and#x25;). It was also demonstrated that stirring during emulsification and a change in both the internal and external phase of the emulsion, affected the size and the drug entrapment efficiency of the microspheres obtained. A 60/40 v/v mixture of chloroform and acetone was found to be the best organic solvent system for creating the primary emulsion. To obtain a high yield ( > 90and#x25;) of microspheres with a desirable size and high drug entrapment efficacy, a stirring rate of 8,000-10,000 rpm gave the best results. It is concluded CPX-loaded PLGA microspheres with suitable characteristics for the treatment of cows with dairy mastitis can be prepared by a w/o/w double emulsion preparation method.

Enhancement of Immunoprotective Effect of CpG-ODN by Formulation with Polyphosphazenes Against E. coli Septicemia in Neonatal Chickens by Azita Taghavi, Brenda Allan, George Mutwiri, Marianna Foldvari, Andrew Kessel, Philip Willson, Lorne Babiuk, Andrew Potter, Susantha Gomis (76-82).
Synthetic oligodeoxynucleotides (ODN) containing CpG motifs (CpG-ODN) have been shown to be effective immunoprotective agents and vaccine adjuvants in a variety of bacterial and protozoan diseases in different animal species. The objective of this study was to investigate the immunoprotective effect of formulated CpG-ODN with polyphosphazene, liposome or oil-in-water emulsion against E. coli infections in neonatal chickens. Eighteen-day-old embryonating eggs were inoculated with 50 and#956;g CpG-ODN or formulated CpG-ODN with polyphophazene, liposome or oil-in-water emulsion. Four days after exposure to formulated CpG-ODN or day-1 post-hatch, 1x104 or 1x105 cfu of a virulent isolate of E. coli was inoculated by the subcutaneous route in the neck. Clinical signs, pathology, bacterial isolations from the air sacs, and mortality were observed for eight days following challenge with E. coli. The survival rate of birds following E. coli infection was 0and#x25; in groups receiving either non-CpG-ODN or saline. In contrast, birds receiving either CpG-ODN or CpG-ODN formulated with polyphosphazene had significantly higher survival of 55and#x25; (P andlt; 0.0001). The relative risk of mortality was significantly reduced for birds treated with CpG-ODN formulated in PCPP (0.25), in PCEP (0.33), or unformulated CpG-ODN (0.39) in comparison to the group treated with saline (p andlt; 0.01). Although formulation of CpG-ODN with liposomes or oil-in-water emulsion did not increase the immunoprotective effect against E. coli infection, no adverse reactions or poor hatchability were observed in embryos. This is the first time that CpG-ODN formulated with polyphosphazene has been demonstrated to have an immunoprotective effect against an extra cellular bacterial infection in neonatal broiler chickens following in ovo delivery.

Rheological Properties of Vaginal Hydrophilic Polymer Gels by Jose Neves, Marta da Silva, Maria Goncalves, Maria Amaral, Maria Bahia (83-92).
The objective of this work was to investigate the main rheological features of vaginal hydrophilic polymer gels and to elucidate about the relationship between these characteristics and gels composition, and their general influence in therapeutic/usage purpose. Flow and dynamic oscillatory properties of four commercially available (Conceptroland#174;, Gynol IIand#174;, RepHreshand#174;, and Replensand#174;) and two investigational vaginal gels were determined by cone-and-plate rheometry, at body temperature. Several parameters (apparent viscosity, complex viscosity, storage modulus, loss modulus, critical oscillatory stress, tan and#948;, thixotropy and yield stress) were measured and/or calculated. Gels presented non-Newtonian, pseudoplastic, thixotropic behavior, with yield stress. Overall viscosities varied between 13500 Pa.s and approximately 80 Pa.s within a biologically relevant shear rate interval (0.01-100 s-1). Yield stress values were variable between different determination methods but coherent in terms of ranking. Also, tested gels showed viscoelastic properties, being characterized by predominant elastic solid-like behavior. Rheological behavior of vaginal gels strongly depended on the type of gelling agent used, which potentially influences their spreading and retention properties when administered in the vaginal canal. Small variations in gels composition can result in substantial changes in their features, namely viscosity, yield stress and thixotropy. Rheological properties of tested gels appeared to be correlated with their therapeutic/usage purpose.

In this study the effect of vehicle on in vitro diffusion of diclofenac sodium (DS) from new different formulations such as Carbopol gel (A), Sodium lauryl sulphate cream (B) and Carbopol cream (C) was evaluated with Franz diffusion cells using hydrophilic and hydrophobic synthetic membranes. The commercial formulation Voltarenand#174; Emulgel was used as reference. Furthermore, the in vivo efficacy of topical formulations was studied in the carrageenan-induced edema and hyperalgesia, whereas the antinociceptive effect was evaluated on thermal pain threshold in rat paw. The flux of DS across hydrophilic membranes showed this rank order: Control and#x2249; C > A and#x2249; B. On the other hand, the diffusion rate of DS across hydrophobic membranes resulted in the following order: Control > B > A and#x2249; C; this suggested a lower interaction between the vehicles and these membranes. The in vivo results indicated that the prepared formulations failed in the inflammatory tests to reduce the development of edema. Nevertheless, treatment with B formulation inhibited the development of acute hyperalgesia induced by carrageenan, and elicited a significant increase in paw withdrawal latencies whereas other formulations were ineffective. The results obtained in this study suggest that Sodium lauryl sulphate cream might be useful in local pain conditions and may be an effective alternative to the presently used systemic routes.

Improvement in Chemical and Physical Stability of Fluvastatin Drug Through Hydrogen Bonding Interactions with Different Polymer Matrices by G. Papageorgiou, S. Papadimitriou, E. Karavas, E. Georgarakis, A. Docoslis, D. Bikiaris (101-112).
Solid dispersions of Fluvastatin with polyvinylpyrrolidone (PVP), eudragit RS100 (Eud), and chitosan (CS) as drug carrier matrices, were prepared using different techniques in order to evaluate their effect on Fluvastatin stability during storage. The characterization of the three different systems was performed with the use of differential scanning calorimetry (DSC) and wide angle X-ray diffractometry (WAXD). It was revealed that amorphization of the drug occurred in all of the solid dispersions of Fluvastatin as a result of drug dissolution into polymer matrices and due to physical interactions (hydrogen bonding) between the polymer matrix and Fluvastatin. This was established through the use of FTIR spectroscopy. SEM and micro-Raman spectroscopy showed that Fluvastatin was interspersed to the polymer matrices in the form of molecular dispersion and nanodispersion, too. The finding that completely different polymer matrices, used here as drug carriers, produce completely different dissolution profiles for each one of the solid dispersions, suggests that each matrix follows a different drug release mechanism. Hydrogen bonding interactions as in the case of CS/Fluva solid dispersions lead to controlled release profiles. All formulations were subjected to accelerated aging in order to evaluate Fluvastatin stability. From by-products analysis it was found that Fluvastatin is very unstable during storage and anti-isomer as well as lactones are the main formed by-products. On the other hand, solid dispersions due to the evolved interactions of their reactive groups with Fluvastatin provide a sufficient physical and chemical stability. The extent of interactions seems to play the most important role in the drug stabilization.

The aim of the present study was to prepare mucoadhesive multiparticulate system for oral drug delivery using ionic gelation technique. Microspheres composed of various mucoadhesive polymers including HPMC of various grades like K4M, K15M, K100M, E50LV, Carbopol of grades 971P, 974P and polycarbophil were prepared. In this technique cross linking of sodium alginate with calcium chloride was done which retarded the release of drug from the mucoadhesive polymer. In the present work Metoprolol tararate was used as a model drug. Interaction studies performed using FTIR spectroscopy revealed that there was no drug to polymer interactions. The preliminary mucoadhesive strength studies performed for various polymers using rotating cylindrical method showed that HPMC had greater mucoadhesive properties than carbopol and polycarbophil. Microspheres so prepared were discrete, bulky, free flowing and showed an average encapsulation efficiency ranging from 50-60and#x25;. Particle size of the microspheres, as determined by the optical microscopy was found to be between 400-650and#956;m. The prepared formulations also exhibited a good mucoadhesive strength which was determined in in vitro conditions through falling film technique and was compared with ex vivo studies. The microspheres so prepared also exhibited a good swelling index which confirmed the strong mucoadhesive property of the formulation. Metoprolol release from the multiparticulate system was regulated and extended until 12 hours and exhibited a non fickian drug release kinetics approaching to zero order, as evident from the release rate exponent values which varied between 0.57 to 0.73. The stability studies performed on the optimized batches at 40and#176;C / 75and#x25; RH for 90 days indicated no significant change in the physicochemical properties.

Recent Advances in Pelletization Technique for Oral Drug Delivery: A Review by Md. Rahman, Alka Ahuja, S. Baboota, Bhavna, Vikas Bali, Nitin Saigal, Javed Ali (122-129).
Multiparticulate dosage forms are receiving a great deal of attention as alternative system for oral drug delivery. The present review outlines the recent findings on the manufacturing and evaluation of spherical pellets published over the past decade. The techniques namely extrusion-spheronization, hot melt extrusion, freeze pelletization, cryopelletization have been discussed along with parameters affecting pelletization. Evaluation of quality of the pellets is discussed with reference to the size distribution, shape, surface morphology, specific surface area, friability, tensile strength, density, porosity, disintegration time and in vitro dissolution studies of pellets. The use of multiparticulate dosage forms as a promising system for the oral delivery of many therapeutic agents has also been examined in the current review.

In the present study Elementary osmotic pump (EOP) of highly water soluble drug tramadol hydrochloride (TRH) was developed and evaluated. Target release profile was selected and different variables were optimized to achieve the same. Formulation variables like levels of swellable polymer (10-21.87 and#x25;) and plasticizer (0-20and#x25; w/w of polymer), and coat thickness of semipermeable membrane (SPM) were found to affect the drug release from the developed formulations. TRH release was directly proportional to the level of plasticizer and osmotic pressure generated by osmotic agent but inversely proportional to the level of swellable polymer within the core and coat thickness of SPM. Drug release from developed formulations was independent of pH and agitation intensities of release media. Burst strength of the exhausted shells increased with increase in coat thickness but decreased with increase in level of plasticizer. The in-vitro results of the developed formulations were compared with performance of standard marketed formulation of TRH. The developed formulation provided more prolonged and controlled TRH release as compared to marketed formulation. The manufacturing procedure was found to be stable during six months of accelerated stability study.

Mucoadhesive patch releasing the drug in the oral cavity at predetermined rate may present distinct advantages over traditional dosage forms such as tablets, gels and solutions. The present study was concerned with the preparation and evaluation of mucoadhesive buccal patches for the controlled systemic delivery of Salbutamol sulphate to avoid first pass hepatic metabolism. The developed patches were evaluated for the physicochemical, mechanical and drug release characteristics. The patches showed desired mechanical and physicochemical properties to withstand environment of oral cavity. The in-vitro release study showed that patches could deliver drug to the oral mucosa for a period of 7 h. the patches exhibited adequate stability when tested under accelerated conditions.