Current Drug Delivery - Volume 6, Issue 2, 2009

The research presented in this paper discusses the potential of iontophoresis facilitated transdermal delivery of glycine. Iontophoresis has been widely investigated as a noninvasive transdermal drug delivery system. Iontophoresis is the use of a low electric current to carry ionized as well as unionized drug molecules across tissues (like skin) in a noninvasive technique. In the present paper, a custom made low cost, battery powered, portable transdermal iontophoretic system has been investigated for the various parameters of transdermal iontophoretic drug delivery namely drug density in donor formulation, current density, current profile, presence of competitive ions and type of electrode material. In vitro release studies of glycine, as a drug, were done using a modified Franz type glass diffusion cell through excised mouse skin. Factors affecting the delivery of glycine (a non-essential amino acid used to treat schizophrenia, anxiety, insomnia, hypoglycemia etc.) by iontophoresis include concentration of glycine in donor solution, ionic strength of donor solution, density of applied current & its aspect ratio. The change in frequency and electrode type (Ag/AgCl & stainless steel) did not have any significant effect on glycine delivery. In conclusion it could be stated that it is possible to achieve appreciable control over the transdermal delivery of glycine by the low-cost portable iontophoretic drug delivery system developed.

The purpose of the present study was to formulate and systematically evaluate in vitro, ex vivo and in vivo performances of itraconazole containing bioadhesive vaginal film. We introduce here a novel intravaginal delivery system for itraconazole based on solid dispersion of itraconazole and hydroxypropyl methylcellulose E15 that improve drug solubility and produce bioadhesive system in presence of other ingredients. Solid dispersions of itraconazole were prepared with hydroxypropyl methylcellulose by a spray drying method and characterized by X-ray diffraction and differential scanning calorimetry. The film was prepared using a solvent evaporation technique. In the in vitro antimicrobial study, it was found that solid dispersion containing formulation improves antimicrobial action of itraconazole. From the ex vivo retention study, it was found that the bioadhesive polymers hold the film upto 7 hours on the vaginal mucosa. In vivo antifungal activity tested against Candida albicans vaginitis in female rats, was found to significantly improve the therapeutic benefit of the drug. At 6 days post-dose, the c.f.u. of Candida albicans was more than 103 fold decreased in film treated groups without affecting the morphology of vaginal mucosa. These studies suggested that bioadhesive vaginal film is a novel approach for delivery of itraconazole as topical drug delivery system for treating vaginal candidiasis.

Carbamazepine indicated for the control of epilepsy, undergoes extensive hepatic first-pass metabolism after oral administration. A vaginal dosage form of carbamazepine is not commercially available. Conventional suppository having poor retention in the vaginal tract, as they are removed in a short time by the tract's self-cleansing action, having poor patient compliance. To overcome such problems, delivery system with mucoadhesive polymers polyox WSR N-60K and Ucarflock 302 that prolong drug permanence on the vaginal mucosa were developed. In the present study the suitability of gelucires to formulate vaginal pesseries was investigated. The possible modification of carbamazepine release kinetics by using gelucires blends and hydrophilic additives in the pesseries was evaluated. It was observed that among gelucire grades melting point higher than 37 °C, the release rate proved to be highly dependant on HLB value and matrix composition. In most of the formulations carbamazepine release occurred by disintegration and erosion of the matrices which is depending upon the vehicle employed. The aging study revealed that the formulations containing G50/13 and G50/13- G44/14 blends undergo some changes during one year of shelf aging. From the results obtained it can be concluded that different gelucire grades and their blends along with hydrophilic polymer could be successesively used to formulate prolong release carbamazepine pesseries.

Pulmonary insulin delivery is steadily emerging as a promising solution for the treatment of diabetes mellitus. The large as well as thin absorptive area of the lungs has not been explored until now for the treatment of systemic disease like diabetes. With an understanding of the lung anatomy and physiology and the transport mechanism of insulin through lungs, diabetic treatment through the pulmonary route may well become the reality of the 21st century. Though the transport of insulin through the lungs itself appears quite encouraging, potential problems concerning the formulation of a peptide like insulin in the form of an aerosol seem to be the most challenging. Stability aspects, stringent control of Mass Median Aerodynamic Diameter, antigenicity, insulin losses due to the device and impaction, sedimentation and diffusion in the nonabsorptive areas of the airway system (especially in the oropharynx) emerge as major concerns. This is in addition to the problems of lack of reproducibility of dose delivery by an inhaler where individual variations due to inspiratory differences and method of use of device come into play. Lung diseases and smoking may alter lung mechanisms and dose alterations are to be studied in such cases. Though almost equally effective, if not more, than the subcutaneous insulin route, even with proved short-term efficacy, insulin delivery through lungs is a potential but not a wholly proven means for blood glucose control.

The purpose of the present study was to develop and investigate the suitability of microemulsion based lecithin organogel formulations for topical delivery of fluconazole in order to bypass its gastrointestinal adverse effects. The ternary phase diagrams were developed and various organogel formulations were prepared using pharmaceutically acceptable surfactant (lecithin) and ethyl oleate (EO). Solubility of fluconazole in EO and EO-lecithin reverse micellar system was determined. The transdermal permeability of fluconazole from different concentrations of lecithin organogels containing EO as oil phase was analyzed using Keshary-Chien diffusion cell through excised rat skin. Solubility of fluconazole in EO-lecithin reverse micellar system was almost 3 folds higher than that in EO. Gelation and immobilization of oil require critical solubility-insolubility balance of gelator. The occurrence of gel phase was lecithin concentration dependent and was observed in 10-60% w/v of system. Organogel containing 300 mM of lecithin showed the higher drug release and better relative consistency. Hence, it was selected for antifungal activity. The increase in antifungal activity of fluconazole in lecithin organogel may be because of the surfactant action of the lecithin and EO that may help in the diffusion of drug. The histopathological data showed that EO-lecithin organogels were safe enough for the topical purpose. Hence, the present lecithin based organogel appears beneficial for topical delivery of fluconazole in terms of easy preparation, safety, stability and low cost.

In situ forming biodegradable polymeric systems were prepared from Poly (DL-lactide-co-glycolide), RG504H (50:50, lactide:glycolide), RG756 (75:25) and mixture of them. They were dissolved in N-methyl-2-pyrrolidone (33% w/w) and mixed with betamethasone acetate (BTMA, 5 and 10% w/w) and ethyl heptanoate (5% w/w, as an additive). The effects of gamma irradiation, drug loading, type of polymers and solvent removal were evaluated on release profiles. Scanning electron microscopy (SEM) of RG756 samples loaded by BTMA did not show any degradation until two weeks. Differential scanning calorimeter (DSC) experiments confirmed insignificant decrease in Tg, and consequently release rate. Declining Tg of RG504H and RG756 after gamma irradiation was about 0.4 and 1.46°C, respectively. High performance liquid chromatography (HPLC) revealed that BTMA release is more rapid from the formulations prepared using the RG504H with lower molecular weight. The formulations prepared by RG756 had lower burst release (2.5-41%) than the samples based on RG504H (60-67%) and mixture of them (30-33%). Regarding this research three different kinds of steriled in situ forming systems were developed which can release BTMA for 24, 90 and 60 days.

Osteoclasts degrade bone through the creation of an enclosed, acidic extracellular microenvironment adjacent to the bone surface. Membrane bound proton pumps in the osteoclast cell membrane function to create this acidified environment. Accordingly, this H+ ion transport mechanism provides a potential target for a specific class of drugs, proton pump inhibitors (PPI), with a view to controlling osteoclast mediated bone resorption. Self setting calcium phosphate cements are common bone graft materials that are degraded by osteoclastic activity. We have already shown that incorporation of bafilomycin, a non-regulated PPI, within these cements prevents or delays osteoclast mediated resorption of the cement. We demonstrate here that two regulated proton pump inhibitors, Pantaprazole™ and Omeprazole™, currently used clinically to treat gastroesophageal reflux disorders, are effective in inhibiting osteoclast mediated resorption in-vivo when delivered to a bony defect in self setting calcium phosphate cements. As determined by qualitative histology, Pantaprazole ™ at a dose of 0.5mg/ml produced a delay in osteoclast resorption whilst this effect was not as evident using Omeprazole™ at an equivalent dose, but higher doses of Omeprazole™ (40mg/ml) did delay cement resorption. These data demonstrate, for the first time, the functional effect of blocking the H+/K+ ATPase pump in-vivo on the capacity of osteoclasts to resorb bone and the potential of this strategy to modulate osteoclast mediated resorption of calcium phosphate biomaterials.

Toothache is a serious problem worldwide. To give relief from this intolerable toothache, doctors prescribe painkillers along with antibiotics. Most of the painkillers, if not all, produce hyperacidity and gastric irritation upon oral administration. Oral antibiotics have slow onset of action and undergo hepatic “first-pass” effect. Moreover, available dental formulations are mostly liquid and last only few hours upon application, before being washed out by saliva. To overcome the above-mentioned problems, a soft polymeric mold containing antibiotic and analgesic drugs and having an appropriate consistency to adhere to the tooth, was developed for sustained drug release to provide better relief in dental patients. Eudragit L 100-55, carbopol 971 P, gum karaya powder and ethyl cellulose were used to prepare the mold “Denticaps” containing Lidocaine hydrochloride and Amoxicillin trihydrate individually and in combination, by mixing and solvent evaporation technique. Different physicochemical characterization studies such as mucoadhesion test, water absorption capacity and swelling index were carried out. In vitro drug release studies showed sustained release of Lidocaine hydrochloride and Amoxicillin trihydrate in simulated saliva for 24 h. Further studies are warranted to succeed with these formulations in humans. Upon success, this type of dosage form may open up new avenues towards dentistry.

The prodrugs designed by classical approach increase lipophilicity of the drug, which decreases the water solubility thus decreasing the concentration gradient, which controls drug absorption. To overcome the limitations of traditional prodrug approach, water soluble prodrugs can be designed by adding selected amino acid to the drug moiety that are the substrates for the enzyme located at the intestinal brush border thus overcoming pharmaceutical problem without compromising bioavailability. ACaa (Amino acid conjugate of Aceclofenac) was synthesized by conjugation with lphenylalanine by conventional coupling method using N, N-dicyclohexylcarbodiimide and ACaa was characterized by melting point, TLC, photomicrograph, UV, FT-IR, FT-NMR, MS-FAB, XRD and DSC. As a part of product development study ACaa was subjected to studies like In-vivo in albino rats and in-vitro like ACaa reversion to AC (Aceclofenac) in aqueous buffers of pH 1.21, 2.38. 3.10, 6.22 and 7.41, at a constant concentration (0.05M), ionic strength (μ = 0.5) and at a temperature of 37 oC ± 0.5 oC, ACaa showed negligible reversion (2.15 %) up to 24 hrs study at acidic pH thus suggesting stability in acidic environment of stomach, the rate of reversion increased as pH of medium increased. pH- partition profile, pH- solubility profile and micromeritic studies were also carried out in comparison to pure drug. The solubility and lipophilicity of ACaa exhibited higher values at all pH range when compared to AC. The micromeritic properties also evaluated in terms of particle shape and size, IQCS and kurtosis. Resulting IQCS value approached zero thus suggesting reducing in the degree of skewness.