Poor Water Soluble Drugs Research Articles

Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.

In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p < 0.05). Subsequent investigations in biorelevant media containing either the trihydroxy bile salt sodium taurocholate (TCA) or the dihydroxy bile salt sodium taurodeoxycholate (TDCA) revealed altered drug solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs, providing impetus to consider the gut microbiota in the drug absorption process. In the clinical setting, disruption of the gut microbial ecosystem, through disease or antibiotic treatment, could transform the bile acid pool with potential implications for drug absorption and bioavailability.

Creatinine-based non-phospholipid vesicular carrier for improved oral bioavailability of Azithromycin

Context: Novel, safe, efficient and cost effective nano-carriers from renewable resources have got greater interest for enhancing solubility and bioavailability of hydrophobic dugs.Objectives: This study reports the synthesis of a novel biocompatible non-phospholipid human metabolite "Creatinine" based niosomal delivery system for Azithromycin improved oral bioavailability.Methods: Synthesized surfactant was characterized through spectroscopic and spectrometric techniques and then the potential for niosomal vesicle formation was evaluated using Azithromycin as model drug. Drug loaded vesicles were characterized for size, polydispersity index (PDI), shape, drug encapsulation efficiency (EE), in vitro release and drug–excipient interaction using zetasizer, atomic force microscope (AFM), LC–MS/MS and FTIR. The biocompatibility of surfactant was investigated through cells cytotoxicity, blood hemolysis and acute toxicity. Azithromycin encapsulated in niosomes was investigated for in vivo bioavailability in rabbits.Results: The vesicles were spherical with 247 ± 4.67 nm diameter hosting 73.29 ± 3.51% of the drug. Surfactant was nontoxic against cell cultures and caused 5.80 ± 0.51% hemolysis at 1000 µg/mL. It was also found safe in mice up to 2.5 g/kg body weight. Synthesized surfactant based niosomal vesicles revealed enhanced oral bioavailability of Azithromycin in rabbits.Conclusions: The results of the present study confirm that the novel surfactant is highly biocompatible and the niosomal vesicles can be efficiently used for improving the oral bioavailability of poor water soluble drugs.

Challenges and Future Prospects of Nanoemulsion as a Drug Delivery System.

Nanoemulsion has the potential to overcome several disadvantages in drug formulation. Loading poor water-soluble drugs in the appropriate nanoemulsions enhances their wettability and/or solubility. Consequently, this improves their pharmacokinetics and pharmacodynamics by different routes of administration. Associated with the optimum nanodroplets size or even combined with key components, the droplets act as a reservoir of drugs, enabling nanoemulsion to be multifunctional platform to treat diverse diseases. A number of important advantages, which comprise nanoemulsion attributes, such as efficient drug release with appropriate rate, prolonged efficacy, drug uptake control, low side effects and drug protection properties from enzymatic or oxidative processes, have been reported in last decade. The high flexibility of nanoemulsion includes also a variety of manufacturing process options and a combination of widely assorted components such as surfactants, liquid lipids or even drug-conjugates. These features provide alternatives for designing innovative nanoemulsions aiming at high-value applications. This review presents the challenges and prospects of different nanoemulsion types and its application. The drug interaction with the components of the formulation, as well as the drug mechanistic interaction with the biological environment of different routes of administration are also presented.

Preparation and characterization of camptothecin-loaded alginate/poly[N-(2-hydroxypropyl) methacrylamide] hydrogel beads for anticancer treatment

ABSTRACTEncapsulation of poor water-soluble drugs into a biocompatible polymeric matrix is a good strategy for in vitro drug delivery. Present study deals with the preparation and optimization of alginate/poly[N-(2-hydroxypropyl) methacrylamide] beads (SA/pHPMA) for the delivery of an anticancer drug such as camptothecin (CPT). Beads were prepared by ionotropic gelation technique using calcium chloride and optimized concentrations of 10 w/v% of sodium alginate beads and 10:10 w/v% of poly[N-(2-hydroxypropyl) methacrylamide]:sodium alginate (SA/pHPMA) beads were prepared. Twenty ppm of CPT was incorporated into the beads by the imbibition method. XRD, thermogravimetric analysis, and differential scanning calorimetry studies of the beads showed no free pHPMA and CPT indicating their uniform dispersion into the matrix. FTIR analysis showed weak interaction between CPT and polymers. In vitro release of CPT from SA/pHPMA beads showed slow and sustained release of 80% while SA beads showed 62% retaining the shape of the beads in phosphate-buffered saline at pH 7.4. The presence of CPT inside the prepared beads has the potential to be used as soft bandages for treatment of cancer.

Review on the formulation considerations needed to produce a stable Self micro Emulsifying Drug Delivery System (SMEDDS)

Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modifications and lipid based delivery systems finding increased appliance with the apparent increase in absorption of drug. Among lipid based formulations, self-micro emulsifying formulations (droplet size < 100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented. Various components that are used to formulate these dosage forms like surfactants and lipids contribute to the overall improvement in oral bioavailability via promoting the lymphatic transport; thereby hepatic first pass metabolism can be surmounted. The present article gives exhaustive information on the formulation design and characterization of SMEDDS by which the bioavailability can be improved. In this review article, the various aspects of pharmaceutical SMEDDS where compiled together and target audience are specifically the B. Pharm and M. Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publication.

Development and characterization of ternary system for solubility enhancement of a second-generation COX-II inhibitor

Etoricoxib is a highly selective COX-II inhibitor, used to treat pains of different etiologies. Etoricoxib has low aqueous solubility (201g/ml) and high permeability and therefore classified as BCS class II drug. By formulating these drugs with cyclodextrins as inclusion complexes have shown to increase the bioavailability. Cyclodextrins when used as complexing agents, enhance the solubility of poor water soluble lipophilic drugs. The objective of the present work is to formulate Etoricoxibcyclodextrin complexes by using ternary systems as Citric acid, Tartaric acid and PVP K-30 in order to enhance solubility and evaluate the enhanced solubility by in-vitro dissolution.

FABRICATION AND EVALUATION OF SMART NANOCRYSTALS OF ARTEMISININ FOR ANTIMALARIAL AND ANTIBACTERIAL EFFICACY.

Background:Nanocrystals have the potential to substantially increase dissolution rate, solubility with subsequent enhanced bioavailability via the oral route of a range of poor water soluble drugs. Regardless of other issues, scale up of the batch size is the main issue associated with bottom up approach.Material and Methods:Smart nanocrystals of artemisinin (ARM) was produced relatively at large batch sizes (100, 200, 300 and 400ml) compared to our previously reported study by (Shah, et al., 2016). ARM nanosuspensions/nanocrystals were characterised using zeta sizer, SEM, TEM, DSC, PXRD and RP-HPLC. The nanosuspensions were finally subjected to in vitro antimalarial and antimicrobial activity.Results:The average particle size (PS) for 400 ml batches was 126.5 ±1.02 nm, and the polydispersity index (PI) was 0.194 ± 0.04. The saturation solubility of the ARM nanocrystals was substantially increased to (725.4± 2.0 μg/ml) compared to the raw ARM in water 177.4± 1.3 μg/ml and stabilizer solution (385.3± 2.0 μg/ml). The IC50 value of ARM nanosuspension against P. vivax was 65 and 21 folds lower than micronized 19.5 ng/mL and unprocessed drug (6.4 ng/mL) respectively. The ARM nanosuspension was found highly effective compared to unprocessed drug against all the tested microorganism except E. coli, Shigella and C. albican.Conclusion:The simple precipitation-ultrasonication approach was efficiently employed for fabrication of ARM nanosuspension to scale up the batch size. Similarly, the solubility, antimalarial potential and antimicrobial efficacy of ARM in the form of nanosuspension were significantly enhanced. Findings from this study can persuade research interest for further comprehensive studies using animals model.

Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene-polypropylene block copolymer for maximized disintegration and dissolution.

The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs) with an optimized disintegration and dissolution characteristics. Polyoxyethylene–polypropylene block copolymer (poloxamer 188) was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs). Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 32 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT’s porosity and to fasten disintegration rather than swelling action by croscarmellose sodium. On the other hand, croscarmellose sodium was most important for the initial simvastatin release. The results suggest the potential use of poloxamer 188-based SD in RDT for the oral delivery of poor water-soluble antihyperlipidemic drug, simvastatin.

Novel paclitaxel formulations solubilized by parenteral nutrition nanoemulsions for application against glioma cell lines

The aim of this study is to investigate using nanoemulsion formulations as drug-delivery vehicles of paclitaxel (PX), a poor water-soluble anticancer drug. Two commercially available nanoemulsion fat formulations (Clinoleic 20% and Intralipid 20%) were loaded with PX and characterised based on their size, zeta potential, pH and loading efficiency. The effect of formulation on the cytotoxicity of PX was also evaluated using MTT assay.The droplet size of the Clinoleic emulsion increased from 254.1nm to 264.7nm when paclitaxel (6mg/ml) was loaded into the formulation, compared to the drug-free formulation. Similarly, the droplet size of Intralipid increased from 283.3 to 294.6nm on inclusion of 6mg/ml paclitaxel. The Polydispersity Indexes (PDIs) of all the nanoemulsion formulations (Clinoleic and Intralipid) were less than 0.2 irrespective of paclitaxel concentration indicating that all nanoemulsion formulations used were homogeneously sized. The pH range for the Clinoleic formulations (7.1–7.5) was slightly higher than that of the Intralipid formulations (6.5–6.9). The zeta potential of linoleic had a greater negative value than that of Intralipid.Loading efficiencies for paclitaxel were 70.4–80.2% and 44.2–57.4% for Clinoleic and Intralipid formulations, respectively. Clinoleic loaded with paclitaxel decreased the viability of U87-MG cell to 6.4±2.3%, compared to Intralipid loaded with paclitaxel (21.29±3.82%). Both nanoemulsions were less toxic to the normal glial cells (SVG-P12), decreasing the cell viability to 25–35%. This study suggests that nanoemulsions are useful and potentially applicable vehicles of paclitaxel for treatment of glioma.

Transdermal film-loaded finasteride microplates to enhance drug skin permeation: Two-step optimization study

The goal was to develop an optimized transdermal finasteride (FNS) film loaded with drug microplates (MIC), utilizing two-step optimization, to decrease the dosing schedule and inconsistency in gastrointestinal absorption. First; 3-level factorial design was implemented to prepare optimized FNS-MIC of minimum particle size. Second; Box–Behnken design matrix was used to develop optimized transdermal FNS-MIC film. Interaction among MIC components was studied using physicochemical characterization tools. Film components namely; hydroxypropyl methyl cellulose (X1), dimethyl sulfoxide (X2) and propylene glycol (X3) were optimized for their effects on the film thickness (Y1) and elongation percent (Y2), and for FNS steady state flux (Y3), permeability coefficient (Y4), and diffusion coefficient (Y5) following ex-vivo permeation through the rat skin. Morphological study of the optimized MIC and transdermal film was also investigated. Results revealed that stabilizer concentration and anti-solvent percent were significantly affecting MIC formulation. Optimized FNS-MIC of particle size 0.93μm was successfully prepared in which there was no interaction observed among their components. An enhancement in the aqueous solubility of FNS-MIC by more than 23% was achieved. All the studied variables, most of their interaction and quadratic effects were significantly affecting the studied variables (Y1–Y5). Morphological observation illustrated non-spherical, short rods, flakes like small plates that were homogeneously distributed in the optimized transdermal film. Ex-vivo study showed enhanced FNS permeation from film loaded MIC when compared to that contains pure drug. So, MIC is a successful technique to enhance aqueous solubility and skin permeation of poor water soluble drug especially when loaded into transdermal films.

Electrospun pH-sensitive core–shell polymer nanocomposites fabricated using a tri-axial process

A modified tri-axial electrospinning process was developed for the generation of a new type of pH-sensitive polymer/lipid nanocomposite. The systems produced are able to promote both dissolution and permeation of a model poorly water-soluble drug. First, we show that it is possible to run a tri-axial process with only one of the three fluids being electrospinnable. Using an electrospinnable middle fluid of Eudragit S100 (ES100) with pure ethanol as the outer solvent and an unspinnable lecithin-diclofenac sodium (PL–DS) core solution, nanofibers with linear morphology and clear core/shell structures can be fabricated continuously and smoothly. X-ray diffraction proved that these nanofibers are structural nanocomposites with the drug present in an amorphous state. In vitro dissolution tests demonstrated that the formulations could preclude release in acidic conditions, and that the drug was released from the fibers in two successive steps at neutral pH. The first step is the dissolution of the shell ES100 and the conversion of the core PL–DS into sub-micron sized particles. This frees some DS into solution, and later the remaining DS is gradually released from the PL–DS particles through diffusion. Ex vivo permeation results showed that the composite nanofibers give a more than twofold uplift in the amount of DS passing through the colonic membrane as compared to pure DS; 74% of the transmitted drug was in the form of PL–DS particles. The new tri-axial electrospinning process developed in this work provides a platform to fabricate structural nanomaterials, and the core–shell polymer-PL nanocomposites we have produced have significant potential applications for oral colon-targeted drug delivery. Statement of SignificanceA modified tri-axial electrospinning is demonstrated to create a new type of core–shell pH-sensitive polymer/lipid nanocomposites, in which an electrospinnable middle fluid is exploited to support the un-spinnable outer and inner fluids. The structural nanocomposites are able to provide a colon-targeted sustained release and an enhanced permeation performance of diclofenac sodium. The developed tri-axial process can provide a platform for fabricating new structural nanomaterials with high quality. The strategy of a combined usage of polymeric excipients and phospholipid in a core–shell format should provide new possibilities of developing novel drug delivery systems for efficacious oral administration of poorly-water soluble drugs.

Mechanistic insights into acyclovir-polyethylene glycol 20000 binary dispersions.

Objective:The objective of this study is to provide a mechanistic insight into solubility enhancement and dissolution of acyclovir (ACY) by polyethylene glycol20000 (PEG20000).Materials and Methods:Solid dispersions with differing ratios of drug (ACY) and carrier (PEG20000) were prepared and evaluated by phase solubility, in vitro release studies, kinetic analysis, in situ perfusion, and in vitro permeation studies. Solid state characterization was also done by Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FT-IR) analysis and surface morphology was assessed by Polarizing Microscopic Image (PMI) analysis, Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), and Nuclear Magnetic Resonance (NMR) analysis.Results:Thermodynamic parameters proved the solubilization effect of carrier. The aqueous solubility and dissolution of ACY were increased in all samples. Formation of solid solution, crystallinity reduction, and absence of interaction between drug and carrier was proved by XRD, DSC, and FTIR analysis. The particle size reduction and change in surface morphology were confirmed by SEM and AFM and analysis. The permeation coefficient and amount of drug diffused was higher in samples as compared to ACY. The stability was high in dispersions, and it was proved by NMR analysis.Conclusion:The mechanical insights into the enhancement of solubility and dissolution could be used as a platform to improve the aqueous solubility for other poor water soluble drugs.

Carbamazepine-Fumaric Acid Co-Crystal Screening Using Solution Based Method

Co-crystals is a multi-component system which connected by non-covalent interactions, present physically as a solid form under ambient conditions. Nowadays, co-crystal has becoming as an alternative approach to improve the bioavailability of poor water soluble drugs especially for a weakly ionisable groups or neutral compounds. In this study the co-crystal screening was carried out for carbamazepine (CBZ) and fumaric acid (FUM) co-crystal former (CCF) using non-stoichiometric method (addition of CBZ to CCF saturated solution) and stoichiometric method (evaporation of 1:1 molar ratio of CBZ to CCF) in acetonitrile, ethyl acetate, propanol, ethanol and formic acid solvent systems. The crystals produced from the screening were characterized using Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared (FT-IR). The PXRD analysis had confirmed that the co-crystal was successfully formed in both methods for all of the solvent system studied with an exception to formic acid in the stoichiometric method where no crystal was found precipitate. The findings from this study revealed that Form A and Form B of CBZ-FUM co-crystal had been successfully formed from different solvent systems.

Carbohydrate-based amphiphilic nano delivery systems for cancer therapy.

Nanoparticles (NPs) are novel drug delivery systems that have been attracting more and more attention in recent years, and have been used for the treatment of cancer, infection, inflammation and other diseases. Among the numerous classes of materials employed for constructing NPs, organic polymers are outstanding due to the flexibility of design and synthesis and the ease of modification and functionalization. In particular, NP based amphiphilic polymers make a great contribution to the delivery of poorly-water soluble drugs. For example, natural, biocompatible and biodegradable products like polysaccharides are widely used as building blocks for the preparation of such drug delivery vehicles. This review will detail carbohydrate based amphiphilic polymeric systems for cancer therapy. Specifically, it focuses on the nature of the polymer employed for the preparation of targeted nanocarriers, the synthetic methods, as well as strategies for the application and evaluation of biological activity. Applications of the amphiphilic polymer systems include drug delivery, gene delivery, photosensitizer delivery, diagnostic imaging and specific ligand-assisted cellular uptake. As a result, a thorough understanding of the relationship between chemical structure and biological properties facilitate the optimal design and rational clinical application of the resulting carbohydrate based nano delivery systems for cancer therapy.

Development and evaluation of solid dispersion of spironolactone using fusion method.

Introduction:Solubility and dissolution of a poor water-soluble drug are the two major barriers for formulation scientists in development of drug delivery. Many of the potent drugs do not show the therapeutic effects due to solubility issues but may show toxicity issues when used in high doses. Solid dispersion (SD) technology is an excellent tool for enhancing the solubility and dissolution and hence related bioavailability.Materials and Methods:SD of spironolactone (SPL) was developed using an inert carrier polyethylene glycol 4000 (PEG 4000) by the conventional fusion method and characterized for various characterization parameters.Results:Solubility of pure drug and SD of SPL in water was found to be 23.54 ± 1.75 μg/mL and 61.73 ± 1.26 μg/mL, respectively. The maximum cumulative percentage release from pure drug, SPL marketed product (tablet), physical mixture, and SPL SD at 60 min was 27.25 ± 1.83%, 35.64 ± 3.65%, 47.72 ± 2.45%, and 74.24 ± 3.25%, respectively in 0.1 N HCl.Conclusions:SD of SPL was developed successfully. The solubility of SPL SD was found to be significantly increased (P < 0.05) as compared to SPL active pharmaceutical ingredient (API) and physical mixture of PEG 4000 and SPL. The current study indicated that SD of SPL was a better option for enhancing solubility of a poorly soluble therapeutic agent.

A novel formulation for solubility and content uniformity enhancement of poorly water-soluble drugs using highly-porous mannitol

The present study investigates the enhancement of the dissolution rates for poorly-water soluble drugs by a new adsorption method. The results show that the current adsorption method enhanced the dissolution rate of both nifedipine and indomethacin to a significant extent by nano-confinement of drugs into the pore spaces of highly-porous excipients. Porous mannitol particles with a surface area and pore volume of 6.3±0.1m2g−1 and 0.036±0.002mlg−1, respectively, were drug loaded in two different concentrations of indomethacin and nifedipine. The results of drug loading for nifedipine showed an increase from 3.2±0.1% w/w for a 0.08M drug solution to 9.1±0.3% w/w drug loading for a 0.16M drug solution, while indomethacin had slightly better performance for the adsorption process, with 4.1±0.2% w/w and 12.6±0.4% w/w for 0.08M and 0.16M concentrations of indomethacin, respectively, in the final formulation. This result also indicated highly-uniform blends with a percentage relative standard deviation of less than 4% for drug-loaded mannitol in both nifedipine and indomethacin. This method gave a significant enhancement of the dissolution rate for both drugs due to nano-confinement of drugs into porous excipients and high solubility of porous mannitol, with 80% drug release within the first 15min for the drug-loaded samples.

Improved Dissolution Properties of Ketoconazole through Application of Liquisolid Techniques

In present investigation liquisolid compact technique is investigated as a tool for enhanced dissolution of poorly water-soluble drug Ketoconazole. The liquisolid tablets were formulated with liquid medications, namely Propylene Glycol (PG) drug concentrations, 60% w/w, 70% w/w and 80% w/w. Avicel pH102 was used as a carrier material, Aerosil 200 as a coating material and Sodium starch glycollate as a super-disintegrant. Quality control tests, such as uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test, disintegration and dissolution tests were performed to evaluate prepared tablets. For further confirmation of results the liquisolid compacts were evaluated by XRD and FTIR studies to prove that, solubility of Ketoconazole has been increased by liquisolid compact technique. From the results obtained, it was be speculated that such systems exhibit enhanced drug release profiles due to increased wetting properties and surface of drug available for dissolution. As liquisolid compacts demonstrated significantly higher drug release rates, in PG as compared to directly compressible tablets and conventional wet granulation, we lead to conclusion that it could be a promising strategy in improving the dissolution of poor water soluble drugs and formulating immediate release solid dosage forms.&#x0D;

Novel nanostructured supramolecular hydrogels for the topical delivery of anionic drugs

A bis-imidazolium-based amphiphilic molecule was used to form novel supramolecular gels in ethanol–water mixtures. The proportion of solvents, the concentration of gellant and the temperature are factors that strongly influence the gelling process. The physical gels that are formed comprise entangled fibers of around 100nm in diameter, able to incorporate anionic drugs, whose morphology varies depending on the drug they incorporate. These hydrogels are soft and therefore optimum for skin application. They show good stability when compared to previously reported gels. Suitable drug release and skin permeation profiles were obtained, and, moreover, they seem to promote the retention of the drug inside the skin. Finally, effective in vivo anti-inflammatory activity was observed, especially with the indomethacin-incorporated gel, which indicates that these supramolecular hydrogels are a good option for the delivery of poor water soluble drugs for the treatment of acute inflammation or other skin diseases.

Physical–chemical properties of furosemide nanocrystals developed using rotation revolution mixer

Recently, several approaches have been reported to improve the dissolution rate and bioavailability of furosemide, a class IV drug. However, to the best of our knowledge, none of them proposed nanocrystals. In the last decade, nanocrystals successfully addressed solubility issues by increasing surface area and saturation solubility, both leading to an increase in the dissolution rate of poor water soluble drugs. The preparation of furosemide nanocrystals was by a rotation revolution mixer method. Size distribution and morphology were performed using laser diffraction and scanning electron microscopy, respectively. In addition, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction (XRD) and low frequency shift-Raman spectroscopy allowed investigating the thermal properties and crystalline state. Solubility saturation and intrinsic dissolution rate (IDR) studies were conducted. The thermal analysis revealed lower melting range for the nanocrystals comparing to furosemide. Moreover, a slight crystalline structure change to the amorphous state was observed by XRD and confirmed by low frequency shift Raman. The particle size was reduced to 231 nm with a polydispersity index of 0.232, a 30-fold reduction from the original powder. Finally, the saturation solubility and IDR showed a significant increase. Furosemide nanocrystals showed potential for development of innovative formulations as an alternative to the commercial products.

Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments

Novel formulations that overcome the solubility limitations of poorly water soluble drugs (PWSD) are becoming ever more critical to a drug development process inundated with these compounds. There is a clear need for developing bio-enabling formulation approaches to improve oral bioavailability for PWSD, but also to establish a range of predictive in vitro and in silico biopharmaceutics based tools for guiding formulation design and forecasting in vivo effects. The dual aim of this study was to examine the potential for a novel lipid based formulation, termed a lipidic dispersion, to enhance fasted state oral bioavailability of fenofibrate, while also assessing the predictive ability of biorelevant in vitro and in silico testing. Formulation as a lipidic dispersion improved both dissolution and solubilisation of fenofibrate through a combination of altered solid state characteristics and incorporation of solubilising lipidic excipients. These changes resulted in an increased rate of absorption and increased maximal plasma concentrations compared to a commercial, micronised product (Lipantil® Micro) in a pig model. Combination of biorelevant in vitro measurements with in silico physiologically based pharmacokinetic (PBPK) modelling resulted in an accurate prediction of formulation performance and forecasts a reduction in food effects on fenofibrate bioavailability through maximising its fasted state dissolution.