S. Shawky Tous

Improvement of availability of allopurinol from pharmaceutical dosage forms I : suppositories

Solid dispersion and crystallization of a very slightly water-soluble drug, allopurinol, were prepared using urea, sodium salicylate and beta-cyclodextrin (beta-CD) as carriers. The spectroscopic infra-red (IR), differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) data indicate a role of these carriers in decreasing the crystallinity of allopurinol and complexing abilities. Solid dispersion and crystallization of the drug with these carriers were used in suppository formulations to investigate their role in enhancement of drug release through the membrane barrier. The bases used included Suppocire AM and the mixture of polyethylene glycols (PEGs). The release rates of allopurinol from lipophilic and hydrophilic suppository bases were examined and compared with those obtained for their inclusion compounds incorporated in the same bases. The prepared suppositories were evaluated for in-vitro drug release, when fresh and on storage. The release of pure allopurinol from the lipophilic base was remarkably higher than that from the hydrophilic one. The release of allopurinol from lipophilic as well as hydrophilic bases was significantly enhanced by crystallization of the drug from 5% w/v of sodium salicylate. Allopurinol crystallized from sodium salicylate, showed enhanced release reaching about 100% in 1 h from the Suppocire AM base. The obtained data from these experiments proved the superiority of the PEG formulations containing coevaporates of the drug to sodium salicylate, ratio 1:1, or of the drug to beta-CD, ratio 1:2; T(90%),12 and 36 min, respectively. A significant decrease of uric acid excretion in rabbits was observed after rectal administration of suppositories containing allopurinol crystallized from sodium salicylate.

Formulation release characteristics and evaluation of ibuprofen suppositories

Abstract Suppositories of ibuprofen were formulated using cocoa butter, witepsol E 75 and polyethylene glycol (PEG) bases. Cocoa butter suppositories showed the best permeation of the drug (indicated by their k value being the highest) and the fastest dissolution rate. The four PEGs formulae and witepsol followed in order. Ibuprofen in cocoa butter and PEG ‘A’ was physiologically evaluated in albino rats using local vascular permeability and pain sensation as parameters. The results obtained from both methods revealed that cocoa butter was more efficient than PEG as a base for ibuprofen suppositories, in agreement with the in vitro release studies.

Development and evaluation of viscosity-enhanced nanocarrier (VEN) for oral insulin delivery

Solid lipid nanoparticles (SLN) have demonstrated good potential for oral peptide delivery. However, their hydrophobic nature generally accounts for low peptide entrapment efficiency (EE%). In this study, a new strategy was adopted to improve peptide EE% by incorporating a hydrophilic viscosity-enhancing agent (VA) within SLN cores to develop viscosity enhanced nanocarriers (VEN). Three agents namely, propylene glycol (PG), polyethylene glycol (PEG) 400 and PEG 600, were tested with human insulin serving as a model peptide drug. The effects of VA were both concentration- and type-dependent. 70% w/w PG had achieved the highest EE% (54.5%), versus the two PEGs, compared to only 20.4% in unmodified SLN. PG based VEN had demonstrated good dispersion stability at gastrointestinal (GI) pHs and preferential uptake by intestinal Caco2 cells while showing low cytotoxicity. Additionally, they preserved the integrity of insulin and significantly protected it against GI enzymatic degradation. Freeze dried VEN had shown good stability upon storage at -20°C. Orally administered insulin-VEN had achieved good hypoglycemic effect in fasted rats with relative bioavailability of 5.1%. To conclude, an easily implementable technique to improve peptide entrapment within SLN has been validated, and the resulting VEN had proved promising efficacy for oral peptide delivery.

Methocel-Lipid Hybrid Nanocarrier for Efficient Oral Insulin Delivery

Even with the use of double-emulsion technique for preparation, the hydrophobic nature of solid lipid nanoparticles (SLNs) limits their encapsulation efficiency (EE%) for peptides such as insulin. In this study, we hypothesize that inclusion of Methocel into SLN to form Methocel-lipid hybrid nanocarriers (MLNs) will significantly enhance insulin EE% without compromising the various characteristics of SLN favorable for oral drug delivery. Our data show that incorporation of 2% wt/wt of Methocel A15C had doubled insulin EE% (around 40%) versus conventional SLN prepared using standard double emulsion technique. MLN significantly protected the entrapped insulin against chymotrypsin degradation at gastrointestinal pH. Using intestinal epithelial cells Caco2 as a model, it was shown that MLN could be extensively taken up by Caco2 cells while demonstrating low cytotoxicity. The results indicate that MLN have preserved the key advantages of SLN (biocompatibility, low cytotoxicity, good drug protection, and good interaction with cells) while overcoming their key limitation for efficient peptide entrapment. Based on this, MLN may serve as a promising nanocarrier for oral delivery of peptides.

Enhancing Docetaxel Delivery to Multidrug-Resistant Cancer Cells with Albumin-Coated Nanocrystals

Intravenous delivery of poorly water-soluble anticancer drugs such as docetaxel (DTX) is challenging due to the low bioavailability and the toxicity related to solubilizing excipients. Colloidal nanoparticles are used as alternative carriers, but low drug loading capacity and circulation instability limit their clinical translation. To address these challenges, DTX nanocrystals (NCs) were prepared using Pluronic F127 as an intermediate stabilizer and albumin as a functional surface modifier, which were previously found to be effective in producing small and stable NCs. We hypothesize that the albumin-coated DTX NCs (DTX-F-alb) will remain stable in serum-containing medium so as to effectively leverage the enhanced permeability and retention effect. In addition, the surface-bound albumin, in its native form, may contribute to cellular transport of NCs through interactions with albumin-binding proteins such as secreted protein acidic and rich in cysteine (SPARC). DTX-F-alb NCs showed sheet-like structure with an average length, width, and thickness of 284 ± 96, 173 ± 56, and 40 ± 8 nm and remained stable in 50% serum solution at a concentration greater than 10 μg/mL. Cytotoxicity and cellular uptake of DTX-F-alb and unformulated (free) DTX were compared on three cell lines with different levels of SPARC expression and DTX sensitivity. While the uptake of free DTX was highly dependent on DTX sensitivity, DTX-F-alb treatment resulted in relatively consistent cellular levels of DTX. Free DTX was more efficient in entering drug-sensitive B16F10 and SKOV-3 cells than DTX-F-alb, with consistent cytotoxic effects. In contrast, multidrug-resistant NCI/ADR-RES cells took up DTX-F-alb more than free DTX with time and responded better to the former. This difference was reduced by SPARC knockdown. The high SPARC expression level of NCI/ADR-RES cells, the known affinity of albumin for SPARC, and the opposing effect of SPARC knockdown support that DTX-F-alb have exploited the surface-bound albumin-SPARC interaction in entering NCI/ADR-RES cells. Albumin-coated NC system is a promising formulation for the delivery of hydrophobic anticancer drugs to multidrug-resistant tumors.

Enhancement of nalidixic acid solubility via cosolvency and solid dispersion

Nalidixic acid is practically insoluble in water therefore the aim of this study was to study the effect of both cosolvency and solid dispersion on its solubility. Among different cosolvents, the highest result was achieved by isopropanol (30 % v/v). Through all studied solid dispersion carriers in the ratio 1:1, sodium benzoate enhanced both the solubility and antibacterial activity of nalidixic acid and was therefore selected for further investigation. Increasing sodium benzoate ratio had significantly increased nalidixic acid solubility till a 1:8 ratio. Differential scanning calorimetry (DSC) showed a sharp endothermic peak of nalidixic acid which was slightly shifted to lower temperature accompanied by significant broadening in the case of solid dispersion. Further confirmation was obtained by X-ray powder diffraction (XRPD) whereas the peak heights were much reduced in the case of solid dispersion confirming the cause of increasing solubility.

Formulation and in vitro evaluation of nitrofurantoin floating matrix tablets

The aim of this study was to develop nitrofurantoin floating matrix tablets, which after oral administration will prolong the gastric residence time, control the drug delivery to the body, thus increase the drug bioavailability and diminish gastric irritating side effects. Hydroxypropyl methylcellulose (HPMC) of different viscosity grades together with a gas generating agent (sodium bicarbonate) and other optional additives were examined to optimize the floating characters of the prepared tablets. The in vitro study of the floating behavior of the prepared tablets in simulated gastric fluid (pH 1.2, enzyme free) at 37°C showed that tablets eroded upon contact with the release medium. The drug release rate, polymer swelling, and tablet erosion varied markedly with the type of matrix materials. The results also showed that tablet composition had profound effect on the floating behavior and drug release. All formulations prepared using HPMC E4M with the incorporation of sodium bicarbonate showed suitable floating lag time (20 s), with duration of floating more than 8 h. The drug release from those tablets was sustained over 8 h.

Antifertility effect of orally formulated melatonin tablets in mice

Abstract Melatonin, a putative pineal hormone, has been proved to be active orally. In the present investigation the efficacy of melatonin as an oral antifertility agent in mice was investigated. Melatonin tablets prepared by the solvent deposition technique (SDT) were found to be superior in their physical properties and the release rate of melatonin from the tablets was higher than those prepared by the conventional mixing method (CMM). The interaction of melatonin with polyvinylpyrrolidone (PVP) and lactose may be responsible for its high release rate. Melatonin tablets prepared by the SDT were used to evaluate its antifertility effect in mice. This effect was compared with that of its intramuscular injection. Oral administration of melatonin on the proestrus day resulted in 100% reduction in the mean number of corpora lutea and lutein cells. The ovulation blockage ratio was 100%. The mean duration of the oestrus phase was significantly decreased. Absence of corpora lutea was evident histologically. On the 4th day of pregnancy, oral administration of melatonin led to 100% interruption of pregnancy and 100% reduction in the mean number of implantation sites. Also, the average number of the blood capillaries and their transverse diameter were significantly decreased. Histological examination of the interrupted pregnant uteri showed completely degenerated embryo. The result of oral administration of melatonin mimicked the known effects of its intramuscular injection.

Improvement of the in vitro dissolution rate of mebendazole via crystallization in aqueous surfactant solutions

The technique of crystallization from different aqueous surfactant solutions has been employed in the present study for the purpose of enhancing the solubility and dissolution rate of mebendazole (MBZ), thereby; the limited systemic availability could be improved. Crystallization was carried out using aqueous solutions of non-ionic surfactants (Tween 20, 40, 60 and 80) and ionic surfactants (sodium lauryl sulfate and cetrimide). The in vitro dissolution rates were determined for the untreated drug, the drug crystallized in water [0% surfactant] (control) and that treated with 1, 2, 3 and 4% w/v aqueous surfactant solutions. The dissolution was performed in 0.1N HCl at 37°C for 2 h. Certain factors affecting the dissolution rate enhancement namely, type and concentration of surfactant, concentration of MBZ in solution (saturated or supersaturated solution) and temperature of the crystallization medium were all investigated. The results showed higher dissolution rates for the treated samples as compared to the untreated drug with the exception of samples crystallized from cetrimide solutions which had no enhancing effect towards the dissolution rate. Samples precipitated with the non-ionic surfactants showed higher dissolution rates over those precipitated with the ionic surfactants. Moreover, samples crystallized with 3% aqueous solution of Tween 60 showed the highest dissolution rates among all the preparations. A study on the effect of aging on the dissolution rate of the sample crystallized with Tween 60 (3%) over a period of 7 months showed a slight decrease in the amount dissolved from 66.7 to 49.8% after a dissolution period of 2 h. Further evaluation was performed to study the physicochemical properties of the crystallized drug using IR spectroscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and microscopic examination.

Formulation and clinical evaluation of some new nalidixic acid topical formulations

In a novel attempt, nalidixic acid was formulated in different topical 1 % (w/w) gel and cream bases. The viscosity, pH and drug content of preparations were investigated. The highest in vitro release was achieved by (Na-CMC) gel base. The presence of isopropanol as a cosolvent and nalidixic acid sodium benzoate solid dispersion (1:8) in the selected formulae had enhanced both the in vitro release and antibacterial activity of nalidixic acid. Both DSC and FTIR spectroscopy had shown that the drug is compatible with selected excepients. All cream formulations had shown weaker antibacterial activity therefore only gel bases were further investigated for their stability. No significant change in pH or drug content had been observed in stored gel formulations. The best clinical result in impetigo was achieved after 4-7 days with treatment by gel containing isopropanol and nalidixic acid sodium benzoate solid dispersion (1:8).