Alia A. Badawi

Chitosan based nanocarriers for indomethacin ocular delivery

Two different chitosan (CS) nanocarriers namely nanoparticles and nanoemulsion were developed to prolong Indomethacin (IM) precorneal residence time and to improve its ocular bioavailability the main limitations in its management of post-operative inflammation and intraocular irritation after cataract extraction. CS-nanoparticles were developed by modified ionic gelation of CS with tripolyphosphate while nanoemulsion was prepared by spontaneous emulsification technique. Transmission electron microscopy revealed regular well-identified spherical shape. The nanoparticles had a mean size of 280 nm, a zeta potential of + 17 mV and high loading efficiency of 84.8 % while the mean size of nanoemulsion was affected by the nature of the surfactant used and varies between 220–690 nm. In vitro release studies, performed under sink conditions, revealed small initial burst release during the first hour followed by slow gradual drug release of 76 and 86% from nanoparticles and nanoemulsion respectively during a 24 h peroid. In vivo studies and histopathological examination revealed that eyes of rabbits treated with nanoemulsion showed clearer healing of corneal chemical ulcer with moderate effective inhibition of polymorph nuclear leuckocytic infiltration (PMNLs) compared with nanoparticles preparation. Moreover, following topical instillation of CS-nanoemulsion to rabbits, it was possible to achieve therapeutic concentration of IM in the cornea through out the duration of the study and fairly high IM level in inner ocular structure, aqueous humor. These levels were significantly higher than those obtained following instillation of IM solution. Therefore, CS nanocarriers developed in this study were able to contact intimately with the cornea providing slow gradual IM release with long-term drug level thereby increasing delivery to both external and internal ocular tissues.

Optimization of a Reconstitutable Suspension of Rifampicin Using 24 Factorial Design

In this study 24 factorial design associated with surface response methodology was used to develop and optimize a reconstitutable suspension of rifampicin. The study illustrated the effect of the percentage of each of sucrose, avicel RC-591, hydrophilic aerosil, and aerosol-OT on the flowability and the bulk density of the dry mixture as well as the viscosity, the sedimentation volume, and the redispersibility of the suspension. An empirical equation developed for each of the above responses was used with the aid of computer software to plot a contour map of the most significant effects and interactions. Five replicates at the center of the design were used to independently calculate the experimental error and to detect any curvature in the response surface. Three formulas which are not included in the design were prepared to check the validity of the model equation.

Studies on spironolactone polymorphic forms

AbstractThe phenomenon of polymorphism of spironolactone was studied using melting point and aqueous solubility determinations, infrared spectroscopy, differential thermal analysis, X-ray powder diffraction and powder dissolution. The results showed that spironolactone crystals obtained from ethyl acetate had the lowest melting range, while those obtained from acetonitrile had the highest range. The aqueous solubility data indicated the presence of different forms of spironolactone, each with a specific solubility, although practically all of these forms could be considered to be water-insoluble. The infrared spectra were not useful in clearly distinguishing between the different forms. Differential thermal analysis curves indicated that some of the forms obtained by treating spironolactone with different solvents were somewhat similar, others were variable, but all of them were different from the original form of the drug. Moreover, the thermal study proved the absence of any solvates. X-ray patterns wer...

Provesicular granisetron hydrochloride buccal formulations: In vitro evaluation and preliminary investigation of in vivo performance

Granisetron hydrochloride (granisetron) is a potent antiemetic that has been proven to be effective in acute and delayed emesis in cancer chemotherapy. Granisetron suffers from reduced oral bioavailability (≈60%) due to hepatic metabolism. In this study the combined advantage of provesicular carriers and buccal drug delivery has been explored aiming to sustain effect and improve bioavailability of granisetron via development of granisetron provesicular buccoadhesive tablets with suitable quality characteristics (hardness, drug content, in vitro release pattern, exvivo bioadhesion and in vivo bioadhesion behavior). Composition of the reconstituted niosomes from different prepared provesicular carriers regarding type of surfactant used and cholesterol concentration significantly affected both entrapment efficiency (%EE) and vesicle size. Span 80 proniosome-derived niosomes exhibited higher encapsulation efficiency and smaller particle size than those derived from span 20. Also, the effect of %EE and bioadhesive polymer type on in vitro drug release and in vivo performance of buccoadhesive tablets was investigated. Based on achievement of required in vitro release pattern (20-30% at 2h, 40-65% at 6h and 80-95% at 12h), in vivo swelling behavior, and in vivo adhesion time (>14 h) granisetron formulation (F19, 1.4 mg) comprising HPMC:carbopol 974P (7:3) and maltodextrin coated with the vesicular precursors span 80 and cholesterol (9:1) was chosen for in vivo study. In vivo pharmacokinetic study revealed higher bioavailability of buccal formulation relative to conventional oral formulation of granisetron (AUC0-∞ is 89.97 and 38.18 ng h/ml for buccal and oral formulation, respectively). A significantly lower and delayed Cmax (12.09±4.47 ng/ml, at 8h) was observed after buccal application compared to conventional oral tablet (31.66±10.15 ng/ml, at 0.5 h). The prepared provesicular buccoadhesive tablet of granisetron (F19) might help bypass hepatic first-pass metabolism and improve bioavailability of granisetron with the possibility of reducing reported daily dose (2mg) and reducing dosing frequency.

Formulation of tretinoin-loaded topical proniosomes for treatment of acne: in-vitro characterization, skin irritation test and comparative clinical study

Abstract Tretinoin (TRT) is a widely used retinoid for the topical treatment of acne, photo-aged skin, psoriasis and skin cancer which makes it a good candidate for topical formulation. Yet side effects, like redness, swelling, peeling, blistering and, erythema, in addition to its high lipophilicity make this challenging. Therefore, the aim of this study was the development of TRT-loaded proniosomes to improve the drug efficacy and to increase user acceptability and compliance by reducing its side effects. Nine formulae were prepared according to 32 factorial design and were evaluated for their morphology, vesicle size, entrapment efficiency (EE %), and% of drug released after 5 h. Hydrogel of the candidate formula, N8G (proniosomes prepared with 0.025% TRT, and Span60: cholesterol molar ratio of 3:1 and incorporated in 1% carbopol gel) was developed and evaluated for skin irritation test and clinical study in acne patients compared to marketed product. Candidate formula showed higher efficacy and very low irritation potential when compared to marketed product in human volunteers.

Tretinoin-loaded liposomal formulations: from lab to comparative clinical study in acne patients

Abstract Topical tretinoin is the most commonly used retinoid for acne. However, its irritative potential on the applied area and the barrier properties of the stratum corneum limit its use. The objective of the present study was to formulate tretinoin liposomal gel to obtain a formula with lower skin irritation potential and greater clinical effect. A statistical 24 factorial design was adopted. Sixteen formulae prepared and were properly evaluated. A candidate formula (F13G) prepared with 0.025% tretinoin, phospholipid– cholesterol–dicetylphosphate (9:1:0.01) and incorporated in 1% carbopol gel was selected for skin irritation test. Clinical study was conducted on acne patients and compared to marketed product. All liposomes formulations were spherical in shape. The addition of cholesterol in the film hydration method significantly decreased the vesicle size, and increased the percentage of incorporation efficiency at (p < 0.05). The presence of dicetylphosphate significantly increased drug release but did not affect the percentage of incorporation efficiency and vesicle size. The results of the clinical study in acne patients revealed that F13G showed significantly higher efficacy when compared to marketed product (p < 0.05).

Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well.

Improvement of the microbiological activity of topical ketoconazole using microemulsion systems

The present study aimed to develop microemulsion formulae for topical delivery of ketoconazole (KTZ) with enhanced microbiological activity to avoid the systemic side effects. Different oils were screened for drug solubility and two oils, namely Labrafil M 2125 and IPM, were selected. Different surfactants and cosurfactants were screened for development of microemulsions. Pseudoternary phase diagrams of the selected oils were constructed using Tween 80 as surfactant and isopropanol as cosurfactant in the ratio of 3:1. Various KTZ microemulsions were prepared and characterized for their physical stability, microbiological activity, and rheological properties. The prepared microemulsions were clear and the fluid showed Newtonian flow. Assessment of microbiological activity using agar cup diffusion method showed a marked enhancement of antifungal activity compared to a marketed product. Accelerated stability showed that KTZ subjected to severe degradation in microemulsions prepared using Labrafil M 2125 and was more stable in microemulsions prepared using IPM.

Pharmaceutical and medical aspects of hyaluronic acid–ketorolac combination therapy in osteoarthritis treatment: radiographic imaging and bone mineral density

Abstract The objective of this study was to formulate novel painless combined hyaluronic acid (HA)–ketorolac (KT) membrane for the management of osteoarthritis with rapid analgesic onset, thus avoiding HA frequent invasive intra-articular injections and KT gastrointestinal complaints associated with all non-steroidal anti-inflammatory drugs. HA was chemically crosslinked with carbodiimide/glutaraldehyde to yield membrane of low water content. Different in vitro aspects (mechanical properties, water content and in vitro release) were studied leading to an optimized soft, flexible K8 HA membrane containing 30 mg KT that achieved the desired balance of excellent elasticity and low water content. Moreover, a successful retardation of KT release rate was achieved (82%) after 48 h with favored initial fast drug release in the first hour (32.7%) to attain rapid analgesic effect. The clinical assessments in arthritic rats revealed apparent improvement in joint space narrowing, highest increase in bone mineral density at the proximal tibia and distal femur joints with the absence of osteophytosis only in animal group treated with combined HA–KT membrane. Application of K8 membrane was able to preserve KT plasma concentration above its minimum effective concentration for 48 h therefore, would able to replace six commercial tablets each of 10 mg KT.

Comparative study on the in vitro performance of blister molded and conventional lornoxicam immediate release liquitablets: accelerated stability study and anti-inflammatory and ulcerogenic effects.

Abstract Context: Lornoxicam is a potent non-steroidal anti-inflammatory drug (NSAID). It shows limited solubility in the gastric pH, delayed bioavailability and pharmacodynamic effects with aggravated gastric side effects (due to longer residence in the stomach wall). Objective: To enhance dissolution of lornoxicam in the gastric fluid and expectedly absorption and pharmacological action, with less ulcerogenic effects. Materials and methods: Formulation of immediate release (IR) lornoxicam liquitablets containing both liquid and solid release modulators (wetting agent, solubilizers and microenvironmental pH modifiers). Beside the traditional direct compression technique employed for the preparation of liquitablets a new technique, blister molding, was also used. The effect of the two different manufacturing methods on the fast release characteristics (rapid disintegration and dissolution) was studied. Stability and pharmacological activity of the optimum formula were also explored. Results: Similarity factor pointed out the superiority of molding technique in enhancing dissolution of lornoxicam owing to significant crystallinity reduction (XRD). Optimum formula showed negligible change in drug content and dissolution profiles over 12 weeks, significantly improved anti-inflammatory activity and significantly reduced gastric ulcerative effect over pure lornoxicam and commercial formula. Discussion and conclusion: Blister molded lornoxicam liquitablet of improved dissolution and pharmacological activity and less gastric erosion was successfully prepared.