Khaled M. Aiedeh

Synthesis of Chitosan Succinate and Chitosan Phthalate and Their Evaluation as Suggested Matrices in Orally Administered, Colon‐Specific Drug Delivery Systems

The naturally occurring polymer chitosan was reacted separately with succinic and phthalic anhydrides. The resulting semisynthetic polymers were assessed as potential matrices for colon‐specific, orally administered drug delivery. Sodium diclofenac was used as the dispersed model drug. The prepared matrices were incorporated into tablets, which were evaluated in vitro. The evaluation included dissolution studies conducted under simulated gastrointestinal conditions of pH and transit times. The percentage fluid uptake was used to indicate the ability of the matrix to protect an embedded drug from gastric juices. The prepared matrices resisted dissolution under acidic conditions. On the other hand, improved drug release profiles were observed under basic conditions. Therefore, the results suggest the suitability of the prepared matrices in colon specific, orally administered drug delivery system. However, future in vivo testing is planned to fully establish the suitability of the prepared polymers for colon‐specific drug delivery.

Synthesis of iron-crosslinked chitosan succinate and iron-crosslinked hydroxamated chitosan succinate and their in vitro evaluation as potential matrix materials for oral theophylline sustained-release beads

Chitosan succinate (CS) and hydroxamated chitosan succinate (HCS) were prepared. The generated semisynthetic polymers were employed in the formation of drug-loaded, iron(III)-crosslinked polymeric beads. Infrared spectroscopy was employed to prove the crosslinking. The produced beads were evaluated in vitro as drug prolonging and potentially orally administered delivery system. Theophylline was used as the loaded model drug. The generated beads proved to be successful in prolonging drug release. Iron leaching from the generated beads was minimal (<2%), and it only took place under acidic conditions (pH 1).

Colloidal Stability of Citrate and Mercaptoacetic Acid Capped Gold Nanoparticles upon Lyophilization: Effect of Capping Ligand Attachment and Type of Cryoprotectants

For various applications of gold nanotechnology, long-term nanoparticle stability in solution is a major challenge. Lyophilization (freeze-drying) is a widely used process to convert labile protein and various colloidal systems into powder for improved long-term stability. However, the lyophilization process itself may induce various stresses resulting in nanoparticle aggregation. Despite a plethora of studies evaluating lyophilization of proteins, liposomes, and polymeric nanoparticles, little is known about the stability of gold nanoparticles (GNPs) upon lyophilization. Herein, the effects of lyophilization and freeze-thaw cycles on the stability of two types of GNPs: Citrate-capped GNPs (stabilized via weakly physisorbed citrate ions, Cit-GNPs) and mercaptoacetic acid-capped GNPs (stabilized via strongly chemisorbed mercaptoacetic acid, MAA-GNPs) are investigated. Both types of GNPs have similar core size and effective surface charge as evident from transmission electron microscopy and zeta potential measurements, respectively. Plasmon absorption of GNPs and its dependence on nanoparticle aggregation was employed to follow stability of GNPs in combination with dynamic light scattering analysis. Plasmon peak broadening index (PPBI) is proposed herein for the first time to quantify GNPs aggregation using nonlinear Gaussian fitting of GNPs UV-vis spectra. Our results indicate that Cit-GNPs aggregate irreversibly upon freeze-thaw cycles and lyophilization. In contrast, MAA-GNPs exhibits remarkable stability under the same conditions. Cit-GNPs exhibit no significant aggregation in the presence of cryoprotectants (molecules that are typically used to protect labile ingredients during lyophilization) upon freeze-thaw cycles and lyophilization. The effectiveness of the cyroprotectants evaluated was on the order of trehalose or sucrose > sorbitol > mannitol. The ability of cryoprotectants to prevent GNPs aggregation was dependent on their chemical structure and their ability to interact with the GNPs as assessed with zeta potential analysis.

Sustained-release of buspirone HCl by co spray-drying with aqueous polymeric dispersions

Sustained-release of buspirone HCl (BUH) was attempted by spray drying after dissolving in two commercially available aqueous polymeric dispersions (Eudragit RS 30 D or Kollicoat SR 30 D) at five different drug:polymer ratios (1:1, 1:2, 1:3, 1:6 and 1:9). The produced spray-dried agglomerates were evaluated in terms of their particle size and morphology, production yield, encapsulation efficiency and in-vitro release of BUH. Possible drug-polymer interactions were checked by Differential Scanning Calorimetry (DSC) and FT-IR spectroscopy. Scanning electron microscopy (SEM) was employed for the qualitative characterization of particle size and morphology. Encapsulation efficiency was generally high (around 100%) and independent of the polymeric dispersion type, while production yield was generally low (7.2-31.0%) and significantly lower for the case of Kollicoat SR 30 D (KSR) than for Eudragit RS 30 D (ERS). Scanning electron micrographs showed remarkable changes in size and shape of agglomerates due to the type of aqueous polymeric dispersion and drug:polymer ratio. In-vitro release of BUH from compacted co spray-dried agglomerates was remarkably slower and incomplete for the case of Kollicoat at drug:polymer ratio below 1, presumably due to increased plastic deformation of the developed coating instead of fragmentation in the case of Eudragit coating during compaction.

Modified-chitosan nanoparticles: Novel drug delivery systems improve oral bioavailability of doxorubicin.

The efficacy of most anticancer drugs is highly limited in vivo due mainly to poor pharmacokinetics behavior including poor bioavailability after extravascular administration. We have developed novel chitosan-modified polymeric nanoparticles for oral as well as i.v. administration. Nanoparticles were developed utilizing the double emulsion solvent evaporation technique for sustained delivery of various anticancer drugs. Chitosan diacetate (CDA) and chitosan triacetate (CTA) polymers were previously modified in our laboratory and used as novel matrix. Nanoparticles, loaded with various anticancer drugs, were characterized for particle size using dynamic light scattering as well as transmission electron microscopy and net surface charge using dynamic light scattering. Particles size was below 100nm in diameter and zeta potential ranged - (25-30). Encapsulation efficiency of anticancer drugs varied considerably and was dependent on the physicochemical characteristics of the encapsulated drug. However, chitosan triacetate nanoparticles showed relatively higher encapsulation efficiency than chitosan diacetate nanoparticles. In vitro release of encapsulated drugs was sustained over a period of 14days. Nanoparticles enhanced cellular accumulation of encapsulated drugs, compared to the free drugs, in vitro in MCF-7 and Caco-II tumor cell lines. In conclusion, diacetate and triacetate chitosan are novel polymers that can be used to formulate nanoparticles which efficiently encapsulated anticancer drugs, and sustained the release and enhanced tumor cellular uptake of these drugs. Further, chitosan triacetate nanoparticles enhanced oral bioavailability of doxorubicin. CDA and CTA nanoparticles can be used to efficiently deliver anticancer drugs and improve their in vivo profile.

Modulation of buspirone HCl release from hypromellose matrices using chitosan succinate: implications for pH-independent release.

Chitosan succinate (CS) was synthesized through the acylation of chitosan with succinic anhydride. The interaction of CS with buspirone HCl (BUSP) was evaluated using dialysis experiments and shown to result in complex with a stability constant of 2.26 mM and a capacity of 0.0362 micromol BUSP/mg CS. The extent of complexation upon dry and wet mixing of CS and BUSP was determined quantitatively using differential scanning calorimetry. The extent of the interaction was highest in wet mixtures and was found to be dependent on the pH of the granulation liquid. CS was incorporated in BUSP-containing hypromellose (HPMC) tablets using dry mixing and wet granulation with BUSP. Tablet dissolution was tested in 0.1N HCl and phosphate buffer, pH 6.8. According to f(2) and mean dissolution time results, the similarity of profiles increased as CS content increased with the highest f(2) value observed when CS was wet granulated with BUSP. Dissolution was also tested in deionized water and 5% NaCl; where increased ionic strength resulted in faster dissolution suggesting an ion exchange involvement in drug release. CS was proved effective in modulating BUSP release from HPMC matrices for pH-independent release through ionic complex formation.

Effects of Thermal Curing Conditions on Drug Release from Polyvinyl Acetate–Polyvinyl Pyrrolidone Matrices

This study aimed to investigate the effects of dry and humid heat curing on the physical and drug release properties of polyvinyl acetate–polyvinyl pyrrolidone matrices. Both conditions resulted in increased tablet hardness; tablets stored under humid conditions showed high plasticity and deformed during hardness testing. Release from the matrices was dependent on the fillers type and level. Release profiles showed significant changes, as a result of exposure to thermal stress, none of the fillers used stabilized matrices against these changes. Density of neat polymeric compacts increased upon exposure to heat; the effect of humid heat was more evident than dry heat. Thermograms of samples cured under dry heat did not show changes, while those of samples stored under high humidity showed significant enlargement of the dehydration endotherm masking the glass transition of polyvinyl acetate. The change of the physical and release properties of matrices could be explained by the hygroscopic nature of polyvinyl pyrrolidone causing water uptake; absorbed water then acts as a plasticizer of polyvinyl acetate promoting plastic flow, deformation, and coalescence of particles, and altering the matrices internal structure. Results suggest that humid heat is more effective as a curing environment than dry heat for polyvinyl acetate–polyvinyl pyrrolidone matrices.

Application of active layering and coating techniques in the development of a multiparticulate, controlled release dosage form of a high-dose, highly soluble drug

Abstract Context: The success of the development of controlled release, multilayered, multiparticulate dosage form of a high-dose, highly-soluble drug is dependent upon proper material and processing choices. Objective: To develop a controlled release dosage form of diltiazem hydrochloride using active layering and coating. Methods: Active layering was achieved by spraying a drug solution onto sugar cores using polyvinyl alcohol – polyethylene glycol as a binder. Layered pellets with highest loading and lowest binder content were coated using aqueous dispersions of polyvinyl acetate (PVAc). The effects of the plasticizer and curing on drug release were evaluated. Results and discussion: The binder level had no effect on the process efficiency. Drug release from PVAc-coated pellets was slowed by increasing PVAc level. Plasticization slowed drug release in comparison to nonplasticized formulations. Curing affected drug release of nonplasticized formulations only. Protection against humidity was essential in stabilizing drug release under stability study conditions. Conclusion: Materials and process used were suitable to face the challenge posed by the high dose of the water-soluble drug on the success of the formulation. The effects of the plasticizer, curing and ability of packaging to protect against elevated humidity on the performance of the studied system should be considered in development.

Effects of a 10-day course of a high dose calciferol versus a single mega dose of ergocalciferol in correcting vitamin D deficiency.

BACKGROUND AND OBJECTIVES The correction of vitamin D deficiency is crucial for optimal skeletal and non-skeletal health. Most regimens in current use are based on daily dosing, which may raise concerns of dosage inadequacy and suboptimal patient compliance. Vitamin D is available in 2 forms: D2 (ergocalciferol) and D3 (cholecalciferol). It has been reported that D2 supplements are less effective and may enhance the degradation of 25-hydroxyvitamin D3 (25[OH]D3) metabolite. The aim of this study was to compare the effect of 2 high-dose oral vitamin D regimens—a 10-day course of D3 500 000 IU versus a single mega dose of 600 000 IU D2—on serum 25(OH)D levels. DESIGN AND SETTINGS A prospective cohort study was conducted from September 2010 to February 2011 in an urban university tertiary hospital in Amman, Jordan. PATIENTS AND METHODS A total of 109 patients aged 18 to 79 years were enrolled with severe vitamin D deficiency. Fifty-one subjects received 600 000 IU D2 orally and 54 subjects received a total dose of 500 000 IU D3 administered orally, as 50 000 IU D3 daily for 10 consecutive days. Baseline and follow-up total serum 25(OH)D, 25(OH)D2, and 25(OH)D3 levels were compared. RESULTS The mean total 25(OH)D increment from baseline was 10.33 (5.68) ng/mL over a mean of 43.08 (2.81) days for the D2 group. The mean increment in 25(OH)D for the D3 group was 47.03 (23.67) ng/mL over a mean of 36.9 (2.9) days. The difference between the 2 mean increments was highly significant: P=3.15×10−18. The 600 000 IU D2 single mega-dose decreased 25(OH)D3 levels by an average of 4 ng/mL in 37 subjects. CONCLUSION Overall, the 10-day oral D3 regimen rapidly and effectively normalized 25(OH)D levels. The shortened dosing interval over 10 consecutive days might result in higher compliance.

The Determination of 25-OHVitamin (D2/D3) in Human Serum by Liquid Chromatography Tandem Mass Spectrometry with Comparison to IDS Enzyme Immunoassay

The proper assessment of the status of vitamin D requires the accurate measurement of both 25-OH vitamin D2 and 25-OH vitamin D3, which collectively constitute 25-OH vitamin D, the best indicator of vitamin D status. Currently, numerous assay methods are available for 25-OH vitamin D measurement but their comparability is uncertain. We employed isotope dilution liquid chromatography coupled with tandem mass spectrometry (ID-LC-MS/MS) to quantify 25-OH vitamin D2 and 25-OH vitamin D3 in human serum. Hexadeuterium labeled 25-OH vitamin D3 internal standard was added to calibrators, controls prepared in 6% bovine serum albumin in phosphate buffered saline, and patients’ sera. Zinc sulphate was added to release 25-OH vitamin D metabolites for vitamin D binding protein, followed by a precipitation step withthe addition of acetonitrile. Subsequent online phase extraction by trap column followed by chromatographic separation on a C-8 column using a water/acetonitrile gradient was employed. Detection was performed using Atmospheric Pressure Chemical Ionization (AP-CI) in a Multiple Reaction Monitoring (MRM) mode. The method was linear from 4 to 70 ng/mL. The intra and inter-day CV% were ≤ 10 for both 25-OH vitamin D2 and 25-OH vitamin D3. Recoveries ranged between 39.09 % to 64.31 % for 25-OH vitamin D2 and 30.44 % to 58.66 % for 25-OH vitamin D3, while recoveries from hexadeuterium 25-OH vitamin D3 ranged from 44.11 % to 67.5%.We compared the newly validated LC-MS/MS with a commercial Enzyme Immunoassay from Immunodiagnostic Systems (IDS EIA) in terms of inter-method agreement, correlation, and impact of assay variation on the diagnostic categorization of vitamin D status through the measurement of 182 subjects’ sera. The mean bias % of the IDS EIA relative to the LC-MS/MS was -34.28 ± 10.15 (mean ± std) with 95% CI [-24.13 to 44.43]. The two methods were ingood agreement with reasonable correlation (r²=0.82, P value = 0.000). Inter-method diagnostic categorization was variableand depended on the type of assay method and the applied cut offs used. Cross calibration and standardization of vitamin D assay methods is crucial for proper clinical assessment of vitamin D status. This LC-MS/MS method is reliable and robust for the measurement of both 25-OH vitamin D2 and 25-OH vitamin D3 in human serum.