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OXFORD, MS, United States

Hefnawy M.,King Saud University | Al-Omar M.,King Saud University | Julkhuf S.,King Saud University | Attia S.,King Saud University | And 2 more authors.
Analytica Chimica Acta | Year: 2010

Microemulsion electrokinetic capillary chromatography (MEEKC) with sample stacking induced by reverse migrating pseudostationary phase (SRMP) technique in a suppressed electro-osmotic flow (EOF) strategy was investigated for analysing the new ultra-short hypnotic HIE-124 in mice serum. The proposed method utilized fused-silica capillary with a total length of 50cm (effective length 40cm), applied voltages for stacking and separation were 5.0kV for 4.30min and subsequently 25kV, respectively, with a sample injection of 0.5psi for 90s. All the runs were carried out at 25°C and detected at 213nm. The optimum microemulsion background electrolyte (BGE) solution consisted of 0.8% (v/v) ethyl acetate, 6.6% (v/v) butan-2-ol, 1.0% (v/v) acetonitrile, 2.0% (w/v) sodium dodecyl sulfate (SDS), and 89.6mL with 25mM phosphate buffer pH 8. When this preconcentration technique was used, the sample stacking and the separation processes took place successively with changing the voltage with an intermediate polarity switching step. The proposed method was validated carefully with respect to high specificity of the method, good linearity (r=0.9994), fair wide linear concentration range (66-1500ngmL-1), limit of detection and quantitation were 21.6 and 65.5ngmL-1, respectively. The mean relative standard deviation (RSD) of the results of intra- and inter-day precision and accuracy were less than 6.0%, and overall recovery higher than 95% of HIE-124 in mice serum. The developed method could be used for the trace analyses of HIE-124 in serum and was finally used for the pharmacokinetic study investigation of HIE-124 in mice serum. © 2010 Elsevier B.V. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 167.38K | Year: 2011

DESCRIPTION (provided by applicant): Currently, FDA approved clinical applications of 9-Tetrahydrocannabinol (THC) include control of nausea and vomiting associated with chemotherapy and for appetite stimulation for AIDS patients suffering from anorexia and wasting syndrome. However, THC also has significant potential in the treatment of glaucoma, the second largest cause of blindness, by decreasing intraocular pressure and by acting as a retinal neuroprotectant, through an interaction with the cannabinoid receptors expressed on the ocular tissues. To date, however, lack of an appropriate mechanism for effective topical delivery of THC has been a limiting factor. We propose to broaden the paradigm of THC research to appropriate drug design and deliverystrategies to enhance ocular bioavailability, through topical administration, of this valuable medicinal compound. This project will test the hypothesis that selected novel hydrophilic amino acid (AA), dicarboxylic acid (DCA) or combination (AA-AA, AA-DCA)based THC prodrugs will improve transcorneal penetration and will demonstrate optimal resistance to enzymatic and chemical hydrolysis. Our approach in Aim 1 will be to select and synthesize THC prodrugs and their salts. Specifically, amino and/or dicarboxylic acids will be linked to THC in a manner to yield THC prodrugs (THC-AA, THC-AA-AA, THC-DCA, and THC-AA-DCA) representing a variety of computed logP values, charge and chain length and their salts. The identity of the prodrugs synthesized will be established using analytical tools such as HPLC-MS and NMR (1H and 13C). Under Aim 2, physicochemical characteristics, aqueous solubility, pH dependent solubility and stability in aqueous solutions, as well as bioreversion of the prodrugs in ocular tissue homogenates and aqueous and vitreous humor will be determined. In vitro permeability will be evaluated using isolated rabbit corneas. Finally, Aim 3 will determine ocular bioavailability and pharmacological activity of selected THC prodrugs in vivo in New Zealand albino rabbits. Intraocular pressure (IOP) lowering properties of the selected prodrugs will be compared to that of the parent drug, THC. Suitable formulations for topical delivery will be prepared. In addition to evaluating the effect on the IOP, ocularbioavailability of the most effective prodrug/dose will be determined in the anesthetized rabbit model using a dual probe ocular microdialysis technique to sample the aqueous and vitreous humor. Plasma THC levels, as well as THC acid and 11-hydroxy THC metabolite levels, at the final time point, will also be determined in these studies to estimate systemic exposure. It is expected that the innovative THC prodrugs proposed in this application will be markedly more hydrophilic and stable, compared to THC, and will show significant IOP lowering activity following topical application. Additionally, this study will provide a better understanding of the physicochemical and formulation characteristics necessary for drug penetration into the back-of-the eye tissuesfollowing topical administration and thus help improve treatment options for glaucoma as well as a host of other ocular diseases. PUBLIC HEALTH RELEVANCE: This STTR Phase I application is directed towards the development of hydrophilic tetrahydrocannabinol (THC) prodrugs for topical administration as eyedrops. Such prodrugs will be of great value in the prevention of loss or deterioration of vision in patients suffering from glaucoma.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 743.61K | Year: 2008

DESCRIPTION (provided by applicant): Delta-9-Tetrahydrocannabinol (THC), the active ingredient in the cannabis plant, has a wide range of pharmacological properties of therapeutic value. The drug has been approved by the Food and Drug Administration (FDA) (Marinol(r) soft gelatin capsules) for the treatment of nausea and vomiting associated with chemotherapy and for appetite stimulation in AIDS patients suffering from the wasting syndrome. Other therapeutic possibilities include pain management (chronic pai n), glaucoma (lowering the intraocular pressure), and anxiety. The only formulation available in the United States is the soft gelatin oral capsule. This formulation suffers from several shortcomings including low and erratic bioavailability and first pass effect which results in relatively high levels of 11-OH-THC, a metabolite with much more prominent psychological properties which contribute to the side effects of the drug. In addition, multiple daily doses are required for therapeutic efficacy. The incr eased interest in THC (and other cannabinoids) therapeutic activities necessitated the search for alternative delivery systems, as was recommended in the Institute of Medicine (IOM) Report of 1999. We have, therefore, embarked on the development of a new f ormulation based on Hot Melt Extension (HME) to deliver THC from a Transmucosal Matrix Patch (TMP). During the Phase I period, and in efforts carried out thereafter (in preparation for this application), several formulations were prepared and tested that c ontained THC or a prodrug thereof. Although in vitro studies exhibited encouraging stability, bioadhesive, and permeation results for THC from TMP, bioavailability in the rabbit animal model was not observed. A prodrug of THC, THC-hemisuccinate (or THC-HS) , was investigated, and a formulation for incorporation into a TMP system was developed with positive stability, bioadhesive, and permeability profile. In vivo testing of the THC-HS formulation in the rabbit model demonstrated extremely promising results, where blood levels reached up to 6 ng/mL THC and 17 ng/mL of THC acid metabolite, with almost no 11-OH-THC, showing a true transmucosal absorption of the drug and bypassing of the first pass. The goal of this Phase II application is to capitalize on the re sults obtained during Phase I, and to develop a formulation for the effective, sustained delivery of THC from a TMP system incorporating the most suitable THC prodrug. Therefore, different prodrugs will be synthesized during Phase II and evaluated for the selection of the best prodrug/formulation(s) based on stability, bioadhesive, and permeation in vitro profiles. In vivo evaluation will include LD50 determinations for each prodrug, with only those having LD50 comparable to or higher than that of THC quali fying for further studies. Promising formulations will then be evaluated in vivo, first in the rabbit model and then in the pig model (more predictive of systemic absorption in humans). Finally, the selected prodrug will be cGMP produced, and stability dat a (at least three months) will be generated to support the use of the API in preparing TMP systems supply for Phase I clinical evaluation. Narrative: This Phase II application is directed toward the development of a Transmucosal Patch (TMP) System for the effective and sustained delivery of THC. Such delivery system will be of great value for patients suffering from conditions for which THC would be an effective drug (nausea and vomiting in cancer patients, appetite stimulation in AIDS patients, tre atment of chronic pain, glaucoma, and anxiety).


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 205.51K | Year: 2013

DESCRIPTION (provided by applicant): The natural product artemisinin is a sesquiterpene endoperoxide with known anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant strains of the parasite Plasmodium falciparum. In addition to its anti-malarial activity, artemisinin was reported to have cytotoxic activity against several different tumor cell lines. Recently, artemisinin work conducted by our group has been extended to the preparation of a series of dihydroartemisinin dimers (DHA dimers) and the testing of these dimers against protozoal infections, as well as collaborative work with the National Cancer Institute (NCI) and the anti-tumor screening program. The analog DHA dimer oxime and its hemisuccinate ester (HS) have shown very promising results in the NCI screening program and strong activity against malaria in our initial in vitro and in vivo studies. However, the oral antimalarial dose needed was approximately 10-fold higher than the intraperitoneal dose. Several factors could be responsible for the observed limited oral absorption. These could include degradation of the drug/prodrug in the gastrointestinal tract, poor solubility in the gastrointestinal fluids, limited permeability across the gastro-intestinal walls or first-pass metabolism. Thus, the overall objective of this proposal is to elucidate the factor(s) behind the limited oral absorption and to develop formulation(s) that has high oral bioavailability, through strategies to overcome the challenges faced in oral absorption. This will be accomplished through a set of specific aims which include: 1: Synthesis of DHA dimer oxime and DHA dimer oxime hemisuccinate: These are the two compounds characterized as the lead dimers for oral bioavailability studies. 2: Evaluationof the biopharmaceutical characteristics of these DHA dimers: These studies will include solubility, logP, pH stability profile, metabolic stability in te presence of gastrointestinal and hepatic enzymes and in vitro permeability of the compounds. The data obtained will help identify the constraints in oral bioavailability of these compounds. 3: Development of formulation approaches: Based on the findings in Aim 2 various strategies to overcome the challenges including solubilization and stabilization approaches, inclusion of permeation enhancers and nanoparticle dosage forms will be investigated through in vitro permeability experiments. 4: Delineation of oral bioavailability in rats: Finally, promising formulations will be tested in vivo. The oral PK data will be compared to the intraperitoneal PK data. Blood samples will be analyzed using LC/MS/MS. It is anticipated that at least one formulation containing one of the dimers will be identified with high oral bioavailability and willbe progressed to developmental studies during phase II. This STTR application represents a collaborative effort between ElSohly Laboratories, Inc. (ELI), and the Department of Pharmaceutics at the University of Mississippi (UM). PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: This proposal is directed towards improving the oral bioavailability of DHA dimers with potential therapeutic applications in malaria. This novel class of compounds also shows a lot of promise in other infectious diseases and in several forms ofcancer. Development of an orally bioavailable formulation will significantly improve its therapeutic utility and will have a tremendous impact on public health.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 100.07K | Year: 2006

DESCRIPTION (provided by applicant): The long term objectives of this proposal are aimed at the development of new composition(s) to be used for the prophylactic treatment/prevention of poison ivy contact dermatitis in sensitive individuals. Poison ivy/poison oak and another related species poison sumac are the main cause of occupational hazards for outdoor workers in the United States. Most of the products on the market today are aimed at applying a chemical barrier prior to being exposed to these plants or directed toward symptomatic treatment of the dermatitis. The products proposed in this application will be directed towards treatment of individuals who have never been exposed to poison ivy and therefore inducing tolerance in these individuals (equivalent to immunization) and/or towards prophylactic treatment of already sensitive individuals, perhaps using a single injection prior to each season. The aims, therefore of this proposal will be to prepare (synthesize) different derivatives with enhanced physical and formulation characteristics, testing of these products (or at least one selected agent) in the guinea pig animal model for efficacy as a proof of concept. The results of this work will form the basis for a Phase II application directed toward optimization of formulation, dosage and route of administration as well as carrying out stability, pharmacokinetics and preclinical toxicology/developmental activities. This proposal addresses a major public health problem, namely contact allergic dermatitis and promises the development of an effective agent to address this problem.

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