OPTIMIZATION AND IN VITRO EVALUATION OF THE RELEASE OF CLASS II DRUG FROM ITS NANOCUBOSOMAL DISPERSION

Objective: This work involves investigation and evaluation of the factors that affect the preparation and the release of the model class II drug (erythromycin) to optimize the efficiency of its prepared nanocubosomal dispersion to give very fast initial burst effect within the first hour that can continue for further two hours. Methods: The work involved preparation of ten formulas of cubosomal dispersion by emulsifying different concentrations of glyceryl monooleate (GMO) (lipid content)/surfactant mixtures which were nano-sized and characterized morphologically by Transmission electronic microscopic (TEM), zeta potential, particle size, polydispersity index (pdI), pH, entrapment efficiency, conductivity test, dilution test and in vitro drug release. Results: The selected nanocubosomal formula (F1) showed pH (7.41), particle size (315.05 nm), pdI (0.194), zeta potential (-30.852), entrapment efficiency (91%) and gave a 70% drug release within the first hour of the in vitro test and continued until it gave 96.3% drug release with further 2 h. Conclusion: this work succeeded in preparing optimized cubosomal dispersion for erythromycin using different GMO/poloxamer 407 percent. The optimum formula gave an immediate release of the model drug (erythromycin) and it was ready to be incorporated in any suitable dosage form to give fast onset of action

ABSOLUTE AND RELATIVE BIOAVAILABILITY STUDY FOR THE NEWLY DEVELOPED NASAL NANOEMULSION IN SITU GEL OF ONDANSETRON HCl IN COMPARISON TO CONVENTIONALLY PREPARED IN SITU GEL AND INTRAVENOUS DOSAGES FORMS

Objective: The aim of the work was to study the absolute and relative bioavailability (using rabbits) of ondansetron HCl (ONH)from our newly prepared intranasal mucoadhesive nanoemulsion in situ gel (NIG) in comparison to intranasal mucoadhesive in situ gel (IG) prepared by the conventional method and intravenous injection.Methods: Six male rabbits weighing 2.5-3 kg were used in this study, where the dose of ondansetron HCl (ONH) was calculated based on the body surface area (BSA) which is equivalent to 140μl (containing 10 mg/ml) of NIG and IG and 700μl of intravenous Zofran® injection (containing 2 mg/ml) were given to the rabbits, separated with one week washout period. Serial blood samples were withdrawn and analyzed for simultaneous determination of the drug using HPLC (Knaure; 150 ×4.6 mm; 5 μm particle size; 25 cm length) supported by guard column C18-4 mm diameter.Results: The pharmacokinetics parameters for NIG; Cmax, Tmax, AUC0-t, AUC0-∞were found to be greater than conventional in situ gel (IG). In vivo pharmacokinetic studies in rabbits showed a significant increase in Cmax and AUC 0-α(P<0.001) with shorter Tmaxusing NIG compared to IG containing the same NIG excipients, while the absolute bioavailability for NIG and IG (was 80.541 and 51.068 respectively).Conclusion: The present studies ratify the bioavailability enhancement potential of NE used to prepare NIG for the drug and significantly high absolute bioavailability to be used as a successful alternative route to the IV injection and improve patient compliance

LOADING OF CLARITHROMYCIN AND PACLITAXEL ON SYNTHESIZED CdS/NiO NANOPARTICLES AS PROMISING NANOCARRIERS

Objective: In this study cadmium sulfide (CdS) and nickel oxide (NiO) nanoparticles were synthesized and applied as novel nanocarriers for antibacterial drug clarithromycin (CLA) and anticancer drug paclitaxel (PTX) to improve their physical properties and biological activities.Methods: Cadmium sulfide (CdS) and nickel oxide (NiO) nanoparticles were synthesized by chemical co-precipitation and thermochemical processing techniques respectively and loaded with clarithromycin (CLA) and paclitaxel (PTX) by simple new one-step reaction. Analytical measures including FTIR, PXRD, SEM, AFM, TGA, DSC and zeta potential where used for characterization. The in vitro release, antibacterial as well as anticancer activities were evaluated.Results: Analytical measures revealed that the loading involved physical complex formation rather than chemical modification with the high percent surface loading of the drugs on the nanoparticles. Solubility/dissolution study revealed higher significant* improvement in the solubility of CLA from NiO nanoparticles than that from CdS nanoparticles while the antibacterial activity of CLA was non-significantly improved. For PTX loaded on CdS and NiO nanoparticles showed non-significant change in its solubility, but remarkable significant* increase in its antitumor activity on MCF-7 cell line accompanied with significant* reduction in its cytotoxicity on normal mammary cell line (MCF-10A) indicating the selectivity and targeting of PTX-CdS/NiO nanocarriers with reduced side effects of the drug and the used metal nanocarriers.Conclusion: This work provided most selective and safe delivery system for PTX and best method for enhancement of CLA solubility.Keywords: Clarithromycin (CLA), Paclitaxel (PTX), Cadmium sulfide (CdS) nanoparticles, Nickel oxide (NiO) nanoparticlesÂ

COMPARATIVE BIOAVAILABILITY (BIOEQUIVALENCE) STUDY FOR FIXED DOSE COMBINATION TABLET CONTAINING AMLODIPINE, VALSARTAN, AND HYDROCHLOROTHIAZIDE USING A NEWLY DEVELOPED HPLC-MS/MS METHOD

Objective: The aim of the study was to evaluate the bioequivalence between a newly developed generic tablet containing fixed-dose combination of amlodipine besylate, valsartan and hydrochlorothiazide (10/160/25 mg), and the reference brand product Exforge HCT® tablet; using a newly developed HPLC-MS/MS method for simultaneous determination of these drugs in human plasma.Methods: The brand (reference) and the test (generic) products were administered to thirty-nine healthy subjects. A fasting, laboratory blind, single-dose, two-treatment, two-period, two-sequence, randomized crossover design was conducted with 14 d washout period between dosing. Serial blood samples were withdrawn from each subject immediately before dosing (zero time), and then at 0.33, 0.66, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 14, 16, 24, 48 and eventually at 72 h post dosing. Plasma samples were analyzed for simultaneous determination of amlodipine, valsartan and hydrochlorothiazide by a newly developed HPLC coupled with MS/MS detector. The linearity of the method was established for plasma concentration ranges of 0.2-12 ng/ml, 50-8000 ng/ml, and 2-250 ng/ml for amlodipine, valsartan, and hydrochlorothiazide, respectively.Results: Plasma concentration-time data of each individual were analyzed by non-compartmental method to measure the pharmacokinetics parameters; Cmax, Tmax, AUC0-t, AUC0-¥, lZ, T1/2. For amlodipine truncated AUC72hr was calculated. The 90% confidence interval for the pharmacokinetic parameters used for bioequivalence evaluation (Cmax and AUC) for amlodipine, valsartan, and hydrochlorothiazide were well within FDA acceptable ranges of 80-125%.Conclusion: It is concluded that the newly devolved generic product is bioequivalent with the brand product Exforge HCT® tablet. Thus, both products are clinically interchangeable.Keywords: Amlodipine, Valsartan, Hydrochlorothiazide, Pharmacokinetics, Bioequivalence, HPLC-MS/M

PREPARATION AND IN VITRO EVALUATION OF MONTELUKAST SODIUM ORAL NANOEMULSION

Objective: Oral nanoemulsion (NE) represent one of the newest technology to enhance intestinal drug permeability, bioavailability and facilitate swallowing of the oral dosage form. Methods: In this study, montelukast sodium (MS) nanoemulsions (NEs) were formulated by ultra-sonication using different surfactants (tween 20, tween 60 and tween 80) in different surfactant: co-surfactant (ethanol) ratios (Smix). The prepared NEs were evaluated for different parameters including droplet size (DS) using zetasizer as a function of ultra-sonication time, dispersibility, phase separation, conductivity, percent transmittance, optical transparency, in vitro release in addition to morphology using transmission electron microscopic (TEM). Results: The results revealed that F3 was the optimum formula having an average DS 32.95±2.8 nm after 5 min ultra-sonication assured by zetasizer and TEM, furthermore, a clear to bluish NE was formed after aqueous dilution with high conductivity (59.2±1.76 μs/cm) which indicated the formation of O/W NE. In addition, an optically clear NE was formed with (88.6±2.1) % transmittance with no sedimentation, creaming or separation after centrifugation signifying the formation of a stable NE. Finally, F3 showed faster dissolution rate (92.45%±1.66) after 30 min compared to other formulas. Conclusion: The net result of this study is the formulation of a stable oral NE containing MS which presents new easily swallowed dosage form that may enhance drug permeability as well as it may reduce drug metabolism leading to improving bioavailability for asthmatic patients

APPLICATION OF LIQUISOLID TECHNOLOGY TO ENHANCE THE DISSOLUTION OF CEFIXIME FROM ITS ORAL CAPSULES

Objective: Oral drug delivery is the most desired route for drug administration for its well-known features. Therefore, many attempts were implemented to improve the poor solubility of many active ingredients in order to enhance their dissolution and absorption via the oral route. From these, the liquisolid system is a very promising technology for enhancing solubility and bioavailability of poorly soluble drugs.Methods: In this research, oral capsules of cefixime were prepared by liquisolid technique after mixing different concentrations of the drug with propylene glycol (non-volatile solvent), followed by their addition to different proportions of microcrystalline cellulose and aerosil i.e. different carrier: coating (R-value). The liquisolid capsules were evaluated for In vitro disintegration and dissolution in addition to content uniformity and weight variations. Furthermore, solubility studies, scanning electron microscope (SEM) were performed to the optimum formula. Finally, the release profile of the optimum formula was compared with the marketed cefixime capsules.Results: Liquisolid formula (F3) with 70% cefixime and R-value equals 10 was selected as the optimum formula having higher % release in 45 min (99.5%±0.53) compared to other formulas with faster release rate in the first 20 min than marketed capsules. It had an acceptable disintegration time (25 min±0.76), content uniformity (197.6±0.92) and weight variation (698.04±0.16). Results of solubility study, SEM assured enhancement in solubility and dispersibility of the drug.Conclusion: This research proved that liquisolid system is a promising technology in improving the solubility and dissolution of cefixime from its capsules and hence it may improve its absorption and oral bioavailability

APPLICATION OF THE NEW OROSLIPPERY TECHNOLOGY IN THE PREPARATION OF ENTERIC SLIPPERY COATED TABLET OF NAPROXEN

Objective: The aim of this study was to formulate enteric coated oroslippery tablets (OSTs) of naproxen to overcome the common problems of stomach irritation and swallowing difficulties which accompanied the administration of naproxen tablets.Methods: Different formulas of enteric slippery tablets were prepared by direct compression method. Various parameters were investigated like the effect of eudragit L-100 (eud.) concentration (as an enteric polymer), coating level and effect of different concentrations of croscarmellose sodium CCS (as super disintegrant) on the physical properties. Finally, in an in vitro disintegration and release study was carried out.Results: The enteric slippery optimal formula (F8) was selected to consist of double coat (17.5% eudragit (eud.)) with core tablet containing (6% CCS). It was found that this optimal formula having an acceptable physical property (friability, hardness, thickness and weight variation). Besides, the best acid resistant potential represented by the protection of the OSTs for 2 h in 0.1 N HCl without any sign of disintegration and drug release. Moreover, it was found that (F8) has a disintegration time equal to (8±1.36 min) and release of 80% (20±0.18 min) in phosphate buffer pH 6.8.Conclusion: The result revealed the successful preparation of naproxen tablets using enteric slippery coating that can be easily swallowed and prevent direct irritation of the stomach with acceptable tablet weight

Lomustine’s nanoemulsion as nose-to-brain drug delivery system for CNS tumor treatment

Nose-to-brain delivery allows the direct targeting of drug molecules bypassing the Blood Brain Barrier and systemic effect. Nanoemulsion is one of the novel strategies to deliver drug in this route due to its simplicity in manufacturing, long-term stability, and strong solubilization property for drug. The anticancer drug lomustine had poor oral bioavailability in addition to its serious side effect, therefore, developing more effective drug delivery with direct targeting towards the brain through intra-nasal administration applying nanoemulsion technology is a promising alternative. The work involved lomustine solubility screening in oils, surfactants and cosurfactants as well as emulsifier ratio (Smix) nanoemulsion area was identified using pseudo-ternary phase diagrams. Eighteen nanoemulsion formulas were produced for optimization, then characterized for droplet size, polydispersity index, zeta potential, entrapment efficiency, conductivity, transmittance, dilution, visual transparency, physical stability and in vitro release. The optimum NE formula showed droplet size, zeta potential, polydispersity index, entrapment efficiency, %transmittance, conductivity of 31.31 nm, −30.65 mV, 0.159, 98.12%, 99.08%, and 951 us/cm, respectively. The best formula released 100% lomustine within 15 min which is a promising potential drug delivery system that may deliver the drug quickly and directly to the brain as a safe and effective alternative to oral delivery

DESIGN AND CHARACTERIZATION OF OROSLIPPERY BUOYANT TABLETS FOR RANITIDINE HYDROCHLORIDE

  Objective: The goal behind of performing this study was to come out with an oroslippery buoyant ranitidine hydrochloride tablet to ease the swallowing process. Hence, the drug is released controllably in the stomach regardless of the effect on gastric emptying time.Materials and Methods: The core of the buoyant containing 150 mg of the drug was compressed directly, and sodium bicarbonate was employed as an effervescent agent, besides, hydroxyl propyl methyl cellulose (HPMC) polymer was utilized in different grades in the formulation process. The prepared core was immersed in the coating dispersion, which was formulated using xanthan gum (slipping agent) and Kollicoat instant release (IR) (for film formation). According to the variables in the formulation process, floating properties varies along with the release profile of the drug; therefore, investigation of the effects of variables was conducted, including polymer type and concentration in the core part, and the effect of Kollicoat IR amount as well as the level of coating.Results: According to this study, it was clearly obvious that T4 formulation, that consisted of HPMC K4M, after being dipped 2 times in dispersion of 0.3% xanthan gum and 14% Kollicoat IR, had provided an instant floating, moreover, the in vivo slipperiness was quite acceptable as well as the taste masking. Nevertheless, the percentage of drug release measured after 6 h was 90.15%.Conclusion: The resultant formulas is quite promising to take the lead as new approach to easy swallowing tablets without need of water especially for patients with swallowing problems as well as it is floating tablet that can retain the drug in gastric cavity to be continuously released to ensure its maximum absorption and may improve its bioavailability.Â