Current Drug Delivery - Volume 5, Issue 2, 2008

Microwave has received a widespread application in pharmaceuticals and food processing, microbial sterilization, biomedical therapy, scientific and biomedical analysis, as well as, drug synthesis. This paper reviews the basis of application of microwave to prepare pharmaceutical dosage forms such as agglomerates, gel beads, microspheres, nanomatrix, solid dispersion, tablets and film coat. The microwave could induce drying, polymeric crosslinkages as well as drug-polymer interaction, and modify the structure of drug crystallites via its effects of heating and/or electromagnetic field on the dosage forms. The use of microwave opens a new approach to control the physicochemical properties and drug delivery profiles of pharmaceutical dosage forms without the need for excessive heat, lengthy process or toxic reactants. Alternatively, the microwave can be utilized to process excipients prior to their use in the formulation of drug delivery systems. The intended release characteristics of drugs in dosage forms can be met through modifying the physicochemical properties of excipients using the microwave.

Molecular imprinting is an efficient technique for introducing regions with a highly specific molecular arrangement into a polymeric matrix. The first example of a molecularly imprinted polymer (MIP) was reported half a century ago; however, the use of molecular imprinting has become a well established practical tool only in the last decade. Recently, MIPs are widely used, for example, in chromatographic applications or enzyme antibody mimics. MIPs have also been used in biological applications such as drug delivery systems (DDS), and they have also been successfully applied as excipients in controlled delivery systems. Their huge potential could bring about intelligent drug release; this refers to the release, in a predictable way, of therapeutic agents in response to specific environmental stimuli (the presence of another molecule, pH changes, temperature, etc.). This review is focused on particular intelligent devices of this type that exhibit selective recognition (traps for toxic molecules) and release (of drugs in order to prolong the duration of pharmacological action) in response to specific stimuli. The “stimuli-responsive molecularly imprinted polymers” reviewed in this paper are expected to contribute significantly to the exploration and development of new generations of intelligent and self-regulated drug delivery systems.

Gelrite® is an ion-activated polymer prepared by partial acetylation of gellan gum, an exogeneous polysaccharide present in Pseudomonas elodea. Its unique cation-dependent gelling property at 33°C has been exploited for the formulation of in situ gelling hydrogels for ophthalmic and oral drug delivery. Gelrite® based oral formulations are known to sustain the drug levels at acidic pH due to the formation of 3D-lattice by cross-linking of uronic acid groups with cations. An extrusion method for formation of microspheres has been reported for Gelrite®. The method cannot be successfully applied for encapsulation of hydrophilic moieties and has thus been modified in the present study. The microparticles prepared were optimized for various encapsulation variables such as particle size, shape, drug entrapment efficiency and in vitro drug release. A maximum of 41.87 +0.2 % drug loading was obtained for the improved method. The drug release was found to be sustained in acidic medium (50% in SGF pH 1.2) for a period of 4 hours while burst release was observed in SIF pH 7.4. The work thus, presents a simplified microencapsulation method for hydrophilic drugs with higher entrapment efficiency for Gelrite®, taking rifampicin as the model drug.

In this work the possibility of impregnating P(MMA-EHA-EGDMA) with flurbiprofen using a clean and environmentally friendly technology, namely supercritical fluid technology was evaluated. P(MMA-EHA-EGDMA) has been proposed as a promising matrix to be used for intraocular delivery of anti-inflammatory drugs used in eye surgery and flurbiprofen is a non-steroidal antiinflammatory agent. Fundamental studies like, the solubility of the drug in carbon dioxide, as well as the sorption degree of this polymeric matrix in the presence of carbon dioxide have been previously carried out. The aim of this research was to evaluate the effects of these two variables in the impregnation process. Different experimental conditions were tested and the results obtained suggest that the best impregnating conditions for this system are low temperatures and pressures, which at the same time correspond to a lower solubility of the drug in the supercritical fluid and a low swelling of the polymeric matrix. Experiments performed also indicate that the batch impregnation process leads to higher yields of impregnation and according to the release profiles obtained the drug can be released from the matrix up to three months, which presents great advantages for post-surgical treatments.

Particulate antigens are more effective than soluble antigens in induction of systemic and mucosal immunity; possibly because they are more efficiently endocytosed by mucosal-associated lymphoid tissue (MALT) M cells. In this study, we determined the systemic and mucosal immune responses in rabbits following intranasal immunization with tetanus toxoid (TT) entrapped in cationic, fusogenic and cationic-fusogenic liposomes. Liposomes containing TT were prepared by dehydration-rehydration method. The volume mean diameter of cationic, fusogenic and cationic-fusogenic liposomes were 3.4 ± 0.6, 4.3 ± 2.3 and 3.4 ± 1.5 μm, respectively. Encapsulation efficiency of TT in cationic, fusogenic and cationic-fusogenic liposomes was respectively determined as 49.1 ± 8.4%, 48.5 ± 2.1% and 50.8 ± 4.9%. After 3 months, the leaking of encapsulated TT from liposomes ranged between 2.02 - 5.46%. Immunoreactivities of encapsulated TT in all kinds of liposomes were completely preserved, as studied by Sodium Dodecyl Sulfate - Polyacrylamide Gel Electrophoresis (SDS-PAGE) and Enzyme-Linked Immunosorbent Assay (ELISA). The highest serum immunoglobulin G (IgG) and antitoxin titers were observed in groups immunized with solution formulation (P< 0.001). However, the highest mucosal secretory IgA (sIgA) titers were achieved by fusogenic liposomes (five times more titers compared with TT solution, and 15 times more titers compared with i.m. vaccine), followed by cationic-fusogenic liposomes. No hemolysis was occurred on incubation of liposomes and human erythrocytes. Also after nasal administration of plain liposomes to human volunteers, no local irritation was seen. This study suggests that intranasal administration of fusogenic and cationic-fusogenic liposomes encapsulated with vaccines could be an effective way for inducing mucosal immune responses.

Recent technological advances and improved nebulizer designs have overcome many limitations of jet nebulizers. Newer devices employ a vibrating mesh or aperture plate (VM/AP) for the generation of therapeutic aerosols with consistent, increased efficiency, predominant aerosol fine particle fractions, low residuals, and the ability to nebulize even microliter volumes. These enhancements are achieved through several different design features and include improvements that promote patient compliance, such as compact design, portability, shorter treatment durations, and quiet operation. Current VM/AP devices in clinical use are the Omron MicroAir, the Nektar Aeroneb, and the Pari eFlow. However, some devices are only approved for use with specific medications. Development of “smart nebulizers” such as the Respironics I-neb couple VM technologies with coordinated delivery and optimized inhalation patterns to enhance inhaled drug delivery of specialized, expensive formulations. Ongoing development of advanced aerosol technologies should improve clinical outcomes and continue to expand therapeutic options as newer inhaled drugs become available.

The present study evaluates the efficacy of drug polymer self folding nano-conjugates of pectin-cisplatin to enhance blood circulating levels of cisplatin. The binding of nano-conjugate was confirmed by a peak-shift in UV-spectra. Physical characterization was done by DLS and TEM. Pharmacokinetics and bio-distribution of the nano-conjugates were performed at various time points in normal, Balb-c mice. Zeta Potential showed the shielding effect on the negative potential of pectin that was ∼7 times more than the pectin chains when conjugated with cisplatin. TEM confirmed the formation of a hydrophilic, easily re-dispersible nano-conjugate in the size range of 100nm. Release kinetics in plasma showed that the pectin-cisplatin conjugate is a stable, slow and sustained system with no burst effect. Immunofluorescence analysis of J-774, a mouse macrophage cell line, was assessed after incubating the cells with pectin chains tagged with FITC as well as Pectin-Cisplatin-FITC conjugates. With the cellular uptake of these particles in J-774, 40% of the cells showed an uptake post 30 min of incubation. However, Pectin chains were clearly eliminated. The plasma proteins facilitate the release of cisplatin with 85-89% of the drug being released in 17 days, and only 57% of drug was released in ∼ 30 days without plasma. The reduced negative charge on the conjugate helps in adhesion to the cell surface and subsequent uptake by cells as evidenced by cell uptake studies on J-774 cell line. Nano-conjugates showed long blood retention profile in mice and the cisplatin was found in circulation even after 24 hrs. Pharmacokinetic study clearly indicates that it can form a novel anticancer drug that possesses good efficacy and has a safer profile than cisplatin.

An in situ formed non-disintegrating controlled release asymmetric membrane capsular system, offering improved osmotic effect, was used to deliver poorly water soluble drug flurbiprofen (model drug) to demonstrate how controlled release characteristics could be manipulated by design of polymeric capsule with an asymmetric membrane. In situ formed asymmetric membrane capsule was made by dry method via precipitation of asymmetric membrane on the walls of hard gelatin capsule. Effect of different formulation variables were studied based on 23 factorial design, namely, level of osmogen, ethylcellulose and pore former apart from studying the effect of varying osmotic pressure on drug release. Scanning Electron Microscopy showed an outer dense non porous region and an inner lighter porous region for the prepared asymmetric membrane inside and a gelatin layer outside. Statistical test (Dunnett Multiple Comparison Test) was applied for in vitro drug release at P>0.05. The best formulation closely corresponded to the extra design checkpoint formulation by a similarity (f2) value of 96.88. The drug release was independent of pH but dependent on the osmotic pressure of the dissolution medium. The release kinetics followed Higuchi model and mechanism of release was Fickian diffusion.

Buccal bioadhesive tablets of clotrimazole (CTZ) and clotrimazole: hydroxypropyl-β-cyclodextrin (CTZ-HPβCD) complex were prepared by using polymer xanthan gum in combination with carbopol 974P. The prepared buccal bioadhesive tablet formulations were evaluated for physicochemical characteristics (weight, hardness, friability, diameter, and drug content), swelling index, microenvironment pH, in-vitro drug release, bioadhesion strength, residence time and duration of antifungal activity (in-vitro). The dissolution of CTZ from the prepared tablets into phosphate buffer (pH 6.8) was controlled up to 8 h. All the prepared tablets gave reasonable in-vitro residence time (7.13 - 9.34 h). X-ray diffraction (XRD) studies of the CTZ-HPβCD complex, made by kneading and freeze-dried method, showed no CTZ crystal signals, demonstrating the inclusion of CTZ in the hydrophobic cavity of hydroxypropyl-β-cyclodextrin (HPβCD) and formation of amorphous inclusion complex. Duration of the antifungal activity was measured by the inhibition zone of Candida albicans by agar diffusion assay. It is evident from the results obtained, the prepared buccal bioadhesive tablets of CTZ would markedly prolong the duration of the antifungal activity and may prove to be a viable alternative to the conventional local oral medication.

The therapeutic index (TI) of locally acting inhaled drug products depends on a number of parameters and processes: the particle size distribution of the inhaled aerosol, the dose-efficacy response curves at the deposition sites, the amount of drug absorbed into the systemic circulation from the lung as well as the gastrointestinal (GI) tract, and the dose-effect curves for the different adverse drug reactions. In this review, we present qualitative scenarios, combining these effects and showing the possible influence of an envisaged change in the particle size distribution in the inhaled dose of a locally acting drug product on the TI. These scenarios are a valuable tool in the development of inhalation drug products. As a surrogate for the inhaled dose in vivo, we use the fine particle mass (FPM), measured by in vitro measurements. Using these scenarios, we reviewed the literature on bronchodilators and corticosteroids for reported associations between a change in the FPM and/or particle size distribution within the FPM, and the TI. We conclude that decreasing the particle size of an inhalation product may alter the TI both in a positive as well as a negative sense. So, smaller particle are not always better.

The aim of this work was to formulate transdermal therapeutic system (TTS) of an antihypertensive drug, enalapril maleate (EM) using a new penetration enhancer, piperidine hydrochloride (PH), belonging to the class of Dihydropyridines. The TTS of EM was prepared by solvent evaporation technique using polymers Eudragit E100 and polyvinyl pyrrolidone K-30 in varying ratios, 5% w/w dibutylphthalate as plasticizer and 10% w/w PH as penetration enhancer. The TTS was evaluated for in-vitro drug release using paddle over disc method and ex-vivo skin permeation using modified Keshary and Chein diffusion cell. The interaction studies were carried out by comparing the results of assay, UV and TLC analysis for pure drug and medicated and TTS formulation. Skin irritation potential of TTS was assessed by visual examination of treated rat skin. Stability studies were conducted according to ICH guidelines at a temperature of 40±0.5°C and 75plusmn;5% RH. The optimized formulation was evaluated for preclinical bioavailability and antihypertensive efficacy using albino rat model. The optimized formulation provided 87.3% drug release in-vitro and a flux of 380 μg/cm2/hr over a period of 48 hours. No chemical interaction was found between the drug and excipients and there were no signs of skin irritation on application of patch. The optimized formulation was stable with a tentative shelf life of two years. Significant fall in BP (p<0.001) was observed in experimental hypertensive rats which was maintained for 2 days. There was 3 fold improvement in bioavailability with TTS vis-a-vis marketed tablet (AUC0 to t : 1253.9 ng.h/ml vs. 422.88 ng.h/ml). These preclinicial studies indicate the feasibility of matrix-type TTS of EM for 2 day management of hypertension. Further studies on human beings are warranted to establish clinical utility of the above TTS.