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Drug Dev Ind Pharm [journal]
- Development and evaluation of orally disintegrating tablets of cilostazol-β-cyclodextrin inclusion complexes. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 28.:1-19.
Abstract Context: The clinical applications of cilostazol (CLZ) are limited by its low aqueous solubility (<5 µg/ml) and high biovariability. Objective: The aim of this study was to enhance the solubility of CLZ by forming inclusion complexes (ICs) with beta cyclodextrin (β-CD) and formulating them into oral disintegrating tablets. Methods: Phase solubility study of CLZ with β-CD was performed in water. Job's plot was constructed to determine the stoichiometry of ICs. ICs, prepared by spray-drying technique, were characterized using Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy, powder X-ray diffraction and nuclear magnetic resonance. Molecular modeling studies were performed to understand the mode of interaction of CLZ with β-CD. The formulation process was undertaken using a reproducible design of experiment generated model, attained by variation of diluents and disintegrants at three levels. Tablets were evaluated for drug content, hardness, friability, disintegration time (DT), wetting time (WT) and dissolution profiles. Results and discussion: Phase solubility studies suggested an AL type curve with stability constant (Ks) of 922.52 M(-1). Job's plot revealed 1:2 stoichiometry. All analytical techniques confirmed inclusion complexation. Molecular modeling revealed dispersive van der Waals interaction energy as a major contributor for stabilization of complex. The spray-dried complexes showed higher solubility and faster dissolution compared to plain CLZ. The optimized formulation showed DT of 11.1 ± 0.8 s, WT of 8.7 ± 0.9 s and almost complete dissolution of CLZ in 15 min. Conclusion: The prepared tablets with low DT and fast dissolution will prove to be a promising drug delivery system with improved bioavailability and better patient compliance.
- Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving, high drug-loaded, surfactant-free nanocomposites. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 27.:1-15.
Abstract Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.
- Development of gel-forming lyophilized formulation with recombinant human thrombin. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 27.:1-8.
Abstract The objective of this work was development and evaluation of gel-forming lyophilized formulation with recombinant human thrombin for topical administration. The influence of pH, ionic strength and buffer type on protein stability was evaluated as part of the pre-formulation screening studies. Results indicated an optimal pH from 6.0 to 7.0 and increased stability with increasing content of sodium chloride. The tested buffer types had no significant effect on thrombin stability. For further development, thermosensitive Pluronic® F-127 was employed as a bulking and gelling agent. Physical and mechanical characterization and viscosity measurement confirmed the gel-forming properties of the formulation at the application temperature of 32 °C. Several techniques (addition of well-soluble polyols, different freezing protocols and reconstitution under vacuum) were tested to decrease the reconstitution time. The obtained results revealed that a vacuum in the vial headspace is crucial for acceptable reconstitution. The freeze drying process has no negative impact on recombinant thrombin stability, and this was confirmed by reverse-phase-HPLC, activity assay and optical density measurements.
- Solubility and dissolution enhancement strategies: current understanding and recent trends. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 24.:1-13.
Abstract Identification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.
- In vitro lipolysis tests on lipid nanoparticles: comparison between lipase/co-lipase and pancreatic extract. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 24.:1-7.
Abstract Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLC) are lipid nanocarriers aimed to the delivery of drugs characterized by a low bioavailability, such as poorly water-soluble drugs and peptides or proteins. The oral administration of these lipid nanocarriers implies the study of their lipolysis in presence of enzymes that are commonly involved in dietary lipid digestion in the gastrointestinal tract. In this study, a comparison between two methods was performed: on one hand, the lipase/co-lipase assay, commonly described in the literature to study the digestion of lipid nanocarriers, and on the other hand, the lipolysis test using porcine pancreatic extract and the pH-stat apparatus. This pancreatic extract contains both the pancreatic lipase and carboxyl ester hydrolase (CEH) that permit to mimic in a biorelevant manner the duodenal digestive lipolysis. The test was performed by means of a pH-stat apparatus to work at constant pH, 5.5 or 6.25, representing respectively the fasted or fed state pH conditions. The evolution of all acylglycerol entities was monitored during the digestion by sampling the reaction vessel at different time points, until 60 min, and the lipid composition of the digest was analyzed by gas chromatography. SLN and NLC systems obtained with long-chain saturated acylglycerols were rapidly and completely digested by pancreatic enzymes. The pH-stat titration method appears to be a powerful technique to follow the digestibility of these solid lipid-based nanoparticles.
- Aloin delivery on buccal mucosa: ex vivo studies and design of a new locoregional dosing system. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 14.:1-7.
Abstract Context: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose. Objective: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system. Materials and methods: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudragit® RS 100 as, biocompatible, low permeable, pH-independent, and non-swelling polymer. The prepared tablets were evaluated for drug-polymer compatibility, weight variation, drug uniformity content, diameter, thickness, hardness, friability, swelling, mucoadhesive strength, and drug release. Results: Aloin has low tendency to cross buccal mucosa, permeation is marginal, and high drug amounts remain entrapped into the epithelium. Matrix tablets characteristics were in agreement with pharmacopoeial requirements. Drug release showed highly reproducible Higuchian profile. Delivery through matrix tablets promoted drug accumulation in the mucosal tissue. Discussion and conclusion: Following application of matrix tablets on porcine buccal mucosa, the amount of discharged drug recovered in the tissue should be sufficient to produce the desired effects, providing therapeutic drug levels directly at the site of action. Aloin-loaded tablets are valid candidates for prevention/treatment of potentially malignant disorders and oral cancer and could potentially lead to clinically relevant drug delivery system as coadjuvant of conventional chemotherapy/radiation therapy.
- Fusogenic liposomal formulation of sirolimus: improvement of drug anti-proliferative effect on human T-cells. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 14.:1-8.
Abstract Context: Fusogenic liposomes are unique delivery vehicles capable of introducing their contents directly and efficiently into the cytoplasm. Objective: The objective of this study was to evaluate the potential of fusogenic liposomes containing Sirolimus to improve its anti-proliferative effect on T-lymphocyte cells. Materials and methods: Conventional liposomes containing Sirolimus were prepared from Dipalmitoylphosphatidylcholine (DPPC) and cholesterol using the modified ethanol injection method. To prepare fusogenic liposomes, dioleoylphosphatidylethanolamine (DOPE) was added to the conventional liposome formulation. The liposomes were characterized by their size, zeta potential, encapsulation efficiency percent (EE%) and chemical stability during 6 months. The in vitro release of liposomes, anti-proliferative effect and liposome uptake of both types of liposomes with optimized formulations were studied on human T-lymphocyte cells employing the MTT assay and fluorescein isothiocyanate-loaded liposomes. Results and discussion: The particle size of the liposomes was evaluated between 138 and 650 nm and mean zeta potential was in the range of -32.95 to -45.60 mV. The average EE% of the prepared conventional and fusogenic liposomes were 76.9% and 80.5%, respectively. Liposomal formulations released only 10-20% of encapsulated drug without any burst effect. In vitro immunosuppressive evaluation on T-cells showed that fusogenic liposomes have the best anti-proliferative effects and uptake on T-lymphocyte cell compared to the conventional liposomes. Conclusion: Our results indicated that fusogenic liposomes can be useful carriers for improving the inhibition of T-cell proliferation.
- Development of a solid self-microemulsifying drug delivery system (SMEDDS) for solubility enhancement of naproxen. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 13.:1-10.
Abstract Context: Comparative evaluation of liquid and solid self-microemulsifying drug delivery systems (SMEDDS) as promising approaches for solubility enhancement. Objective: The aim of this work was to develop, characterize, and evaluate a solid SMEDDS prepared via spray-drying of a liquid SMEDDS based on Gelucire® 44/14 to improve the solubility and dissolution rate of naproxen. Material and methods: Various oils and co-surfactants in combination with Gelucire® 44/14 were evaluated during excipient selection study, solubility testing, and construction of (pseudo)ternary diagrams. The selected system was further evaluated for naproxen solubility, self-microemulsification ability, and in vitro dissolution of naproxen. In addition, its transformation into a solid SMEDDS by spray-drying using maltodextrin as a solid carrier was performed. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to evaluate the physical characteristics of the solid SMEDDS obtained. Results: The selected formulation of SMEDDS was comprised of Miglyol 812®, Peceol™, Gelucire® 44/14, and Solutol® HS 15. The liquid and solid SMEDDS formed a microemulsion after dilution with comparable average droplet size and exhibited uniform droplet size distribution. In the solid SMEDDS, liquid SMEDDS was adsorbed onto the surface of maltodextrin and formed smooth granular particles with the encapsulated drug predominantly in a dissolved state and partially in an amorphous state. Overall, incorporation of naproxen in SMEDDS, either liquid or solid, resulted in improved solubility and dissolution rate compared to pure naproxen. Conclusion: This study indicates that a liquid and solid SMEDDS is a strategy for solubility enhancement in the future development of orally delivered dosage forms.
- Mixture design approach for early stage formulation development of a transdermal delivery system. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 13.:1-9.
Abstract Transdermal delivery systems (TDS) consisting of mixtures of adhesives also named multiple polymer adhesive systems are rarely found in the market and research has only been performed on a few of them. Following the principles of ICH Q8, a Design of Experiments (DOE) approach was selected for the formulation development. For evaluation of the statistical method of "mixture design", blends of silicon adhesive, acrylic adhesive, oleyl alcohol as a surfactant and ibuprofen as a model drug were considered to be combined at different concentrations. A randomized design of 16 runs with five replicates and five runs to estimate the lack of fit (LOF) was generated. Samples were tested for adhesion properties, stability of the wet mixes, solubility of the API in the matrix and appearance of the matrix. After performing an ANOVA with the results, response surfaces of tack, shear adhesion, extent of creaming, crystallization behavior, droplet size and droplet size range were derived as contour plots. It could be shown that crystal growth of ibuprofen correlates well with droplet size and droplet size range, where lowest values for crystallization were found with mixtures containing small droplets. However, it was observed that oleyl alcohol showed no positive effect on the miscibility of the polymers and no improvement of the solubility of ibuprofen in the mixtures. With a reasonable number of experiments, the development of a design space for a TDS via mixture design gave valuable information on the product as well as on the interactions of the components.
- Effect of textured eye drop bottles on the photostability of pranoprofen 0.1% ophthalmic solution. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2014 Oct 13.:1-6.
Abstract Context: Ophthalmic solutions are usually filled in a plastic bottle due to its durability and disposability. In Japan, photostability is one of the concerns for the quality control because an eye drop bottle must be a transparent container. Objective: The present work studied the effect of textured eye drop bottles on its light blocking to improve the photostability of ophthalmic solutions. Materials and methods: We investigated the photostability of Pranoprofen ophthalmic solution filled in a variety of textured eye drop bottles. Pranoprofen content was analyzed by high-performance liquid chromatography and surface structure of textured eye drop bottles was evaluated by transmittance, calculated average roughness (Ra) and haze intensity. Results: We observed that eye drop bottle which had greater than Ra value of 1.0 µm and haze intensity 62% clearly showed photostability improvement. Conclusions: This report is the first one which shows that photostability of ophthalmic solution is improved by using textured eye drop bottle. Moreover, this approach is a simple and effective method to improve the photostability. This method is available for not only various ophthalmic applications but also other liquid pharmaceuticals or food products.