Biopharmaceutics Classification System Class Research Articles

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Moxifloxacin Hydrochloride

In this monograph, literature data is reviewed to evaluate the feasibility of waiving in vivo bioequivalence testing and instead applying the Biopharmaceutics Classification System (BCS) based methods to the approval of immediate-release solid oral dosage forms containing moxifloxacin hydrochloride as the sole active pharmaceutical ingredient. To facilitate the feasibility decision, solubility and permeability and dissolution characteristics in the context of the BCS, therapeutic index, therapeutic use, pharmacokinetic parameters, bioequivalence/bioavailability issues, drug-excipient interactions and other relevant data were taken into consideration. Moxifloxacin is a BCS class I drug with a wide therapeutic index. Bioequivalence risks arising from the presence of different excipients in the formulation and due to manufacturing variables were deemed to be low. The risks can be further reduced if the choice of excipients is limited to those present in products already approved in International Conference on Harmonisation or associated countries and if the results of in vitro dissolution studies comply with the specifications stipulated in the appropriate biowaiver guidelines. Under these conditions, we conclude that a BCS-based biowaiver can be recommended for moxifloxacin immediate-release solid oral dosage forms.

Copolymeric Micelles Overcome the Oral Delivery Challenges of Amphotericin B.

Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (Soluplus®) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr®) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index <0.2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 ± 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation.

Development of effective AmB/AmB–αCD complex double loaded liposomes using a factorial design for systemic fungal infection treatment

Amphotericin B (AmB) is a very potent antibiotic which still remains as the gold standard for the treatment of systemic fungal infections. AmB is a member of Biopharmaceutical Classification System Class IV, mainly characterized by its poor solubility and low permeability. In this study, AmB/AmB-α cyclodextrin complex double loaded liposomes (DLLs) were developed using the design of experiments (DoE®) approach to optimize/determine the effects of lipid composition and other parameters on final product properties such as encapsulation efficacy, particle size, polydispersity index, and zeta potential. Experimental design 24 was used for optimization of these properties in which four factors were studied in two levels. DLLs showed much higher physical stability than liposomes loaded only with free AmB by the means of particle size, zeta potential and encapsulation efficiency, in addition exhibited sustained release of AmB over 72 h (26.7%) with faster onset time. On the other hand, fourfold improved antimicrobial efficiency, minimum inhibitory concentration (0.125 µg/ml), and minimum fungicidal concentration (0.5 µg/ml) was determined by DLLs against C. albicans compared to Ambisome®. Dose dependent effects of the DLLs were investigated by cytotoxicity studies on Vero and L-929 cells. No significant cytotoxicity observed for AmB/AmB–αCD complex DLLs and Ambisome at tested concentrations while free AmB caused severe cytotoxicity. Lastly the developed DLLs did not cause an increase in NGAL (an early biomarker for acute kidney toxicity) levels for both Vero and HK-2 cell lines compared to free AmB.

DEVELOPMENT OF AMORPHOUS BINARY AND TERNARY SOLID DISPERSIONS OF NATEGLINIDE FOR IMPROVED SOLUBILITY AND DISSOLUTION

Objective: Nateglinide is a commonly used oral hypoglycemic, biopharmaceutical classification system Class II drug, which shows relatively poor water solubility and variable bioavailability. The objective of the present investigation was to develop the binary and ternary solid dispersions of nateglinide for improved solubility and dissolution.&#x0D; Methods: Nateglinide solid dispersions were prepared by a common solvent evaporation method. Polymers like soluplus, kolliphor P188, sylloid 244FP, gelucire 48/16, affinisol (HPMCAS), HPβCD, βCD were used in different combinations. The physicochemical characterization of the optimized ternary dispersion was studied by using FT-IR, DSC, and PXRD. Solubility and dissolution behavior of all dispersions were studied.&#x0D; Result: From all prepared ternary solid dispersions, nateglinide dissolution was significantly faster than pure nateglinide. With ternary solid dispersion of NTG, soluplus and kolliphor P188 there was a big improvement in solubility and dissolution. This combination enhanced the solubility of NTG by 23 folds. Another ternary dispersion of NTG with soluplus and gelucire 48/16 enhanced solubility by 25 fold.&#x0D; Conclusion: Ternary solid dispersion found superior over binary dispersions. For the ternary dispersions, showing the best solubility, tablets were prepared. Dissolution and drug release from the formulated tablet was as good as a marketed product.

Organogel Nanoparticles as a New Way to Improve Oral Bioavailability of Poorly Soluble Compounds.

The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. Organogel nanoparticles loaded with EFV were formulated with sunflower oil, 12-hydroxystearic acid (HSA) and polyvinyl alcohol (PVA). Various parameters have been investigated in the current study such as (i) the release profile of organogel assessed by USP 4 cell flow dialysis, (ii) the impact of organogel on intestinal absorption, using Caco-2 cells as in vitro model and jejunum segments as ex vivo assay and (iii) the bioavailability of organogel following oral pharmacokinetic study. 250-300nm spherical particles with a final concentration of 4.75mg/mL drug loading were obtained, corresponding to a thousand fold increase in EFV solubility, combined to a very high encapsulation efficiency (>99.8%). Due to rapid diffusion, drug was immediately released from the nanoparticles. The biopharmaceutical evaluation on ex vivo jejunum segments demonstrated an increased absorption of EFV from organogel nanoparticles compare to a native EFV suspension. In vitro assays combining Caco-2 cell cultures with TEM and confocal microscopy demonstrated passive diffusion, while paracellular integrity and endocytosis activity remain expelled. Oral pharmacokinetics of EFV organogel nanoparticles improve oral bioavailability (Fr: 249%) and quick absorption compared to EFV suspension. Organogel nanoparticles increase the bioavailability of BCS Class II drugs. The main phenomena is simply oil transfer from the gelled particles through the cell membrane.

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor.

Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (Tmax) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concentrations were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5–300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an absolute bioavailability of ~ 100% under fasted conditions. Administration of the ertugliflozin 15 mg commercial tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concentration–time curve (AUC), but decreased peak concentrations (Cmax) by 29%. The effect on Cmax is not clinically relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were associated with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was observed and not considered clinically relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clinically meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and Cmax by 39% and 15%, respectively, and is not expected to affect efficacy in a clinically meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.

Dissolution and Permeability Properties of Co-Amorphous Formulations of Hydrochlorothiazide

A biopharmaceutics classification system class IV drug, hydrochlorothiazide (HCT), was combined with co-formers of L-and d-arginine (ARG) and sodium lauryl sulphate (SLS) by cryomilling in 1:1 molar ratio. Co-amorphization was observed with L- and D-ARG. These mixtures showed a single glass transition, evidence of possible salt formation and improved physical stability at elevated temperatures and/or humidity when compared with amorphous HCT. The co-amorphous formulations, along with the combinations of HCT and HCT:L-ARG with polyvinylpyrrolidone (PVP) in 1:1 mass ratio, were investigated with a simultaneous dissolution/permeation setup using parallel artificial membrane permeability assay (PAMPA) or Madine Darby kidney cells (MDCKII) as the permeation barrier. It was observed that co-amorphization with L-ARG and D-ARG was able to induce a supersaturated state for HCT, possibly through intermolecular interactions, but there was virtually no difference between the dissolution properties of the mixtures formed with the 2 optical isomers of ARG. The permeability of HCT was found to be dependent on the dissolution properties of the formulations in both PAMPA and cellular barrier experiments. Thus, co-amorphization of HCT with L- and D-ARG demonstrated the possibility to enhance the dissolution and thereby the permeation potential of a BCS class IV drug.

Interpreting In Vitro Release Performance from Long-Acting Parenteral Nanosuspensions Using USP-4 Dissolution and Spectroscopic Techniques.

Injectable sustained release dosage forms have emerged as desirable therapeutic routes for patients that require life-long treatments. The prevalence of drug molecules with low aqueous solubility and bioavailability has added momentum toward the development of suspension-based long-acting parenteral (LAP) formulations; the previously undesirable physicochemical properties of Biopharmaceutics Classification System (BCS) Class II/IV compounds are best suited for extended release applications. Effective in vitro release (IVR) testing of crystalline suspensions affirms product quality during early-stage development and provides connections with in vivo performance. However, before in vitro-in vivo correlations (IVIVCs) can be established, it is necessary to evaluate formulation attributes that directly affect IVR properties. In this work, a series of crystalline LAP nanosuspensions were formulated with different stabilizing polymers and applied to a continuous flow-through (USP-4) dissolution method. This technique confirmed the role of salt effects on the stability of polymer-coated nanoparticles through the detection of disparate active pharmaceutical ingredient (API) release profiles. The polymer stabilizers with extended hydrophilic chains exhibited elevated intrapolymer activity from the loss of hydrogen-bond cushioning in dissolution media with heightened ionic strength, confirmed through one-dimensional (1D) 1H NMR and two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY) experiments. Thus, steric repulsion within the affected nanosuspensions was limited and release rates decreased. Additionally, the strength of interaction between hydrophobic polymer components and the API crystalline surface contributed to suspension dissolution properties, confirmed through solution- and solid-state spectroscopic analyses. This study provides a unique perspective on the dynamic interface between the crystalline drug and aqueous microenvironment during dissolution.

Development and evaluation of TPGS/PVA-based nanosuspension for enhancing dissolution and oral bioavailability of ticagrelor.

In this study, we developed ticagrelor-dispersed nanosuspension (TCG-NSP) to enhance the dissolution and oral bioavailability of ticagrelor (TCG) through a statistical design approach. TCG, a reversible P2Y12 receptor antagonist, is classified as a biopharmaceutics classification system (BCS) class IV drug with low solubility and permeability, resulting in low oral bioavailability. Nanosuspension (NSP) is an efficient pharmaceutical technique for overcoming the disadvantages. First, we optimized TCG-NSP consisting of D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and polyvinyl alcohol (PVA), which exhibited homogeneously dispersed TCG particle (233nm) and low precipitation (3%). Characterization studies demonstrated that TCG-NSP provided amorphous TCG particles and supersaturation effect, resulting in higher dissolution than a commercial product. In addition, everted gut sac and pharmacokinetic studies confirmed that TCG-NSP improved the gastrointestinal permeation of TCG by 2.8-fold compared to commercial product, thereby enhancing the oral bioavailability (2.2-fold). These results suggested that TCG-NSP could be successfully used as an efficient pharmaceutical formulation to achieve the enhanced dissolution and oral bioavailability of TCG.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate

Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the Food and Drug Administration, World Health Organization and European Medicines Agency, taking the degradation at some pH values into consideration. Together with solubility and permeability data for cephalexin monohydrate from the literature, it was demonstrated to be a Biopharmaceutics Classification System Class 1 drug. The pharmacokinetic behavior, results of bioequivalence studies published in the literature, as well as the therapeutic uses, potential toxicity and potential excipient effects on bioavailability were also assessed. Cephalexin has a wide therapeutic index and no bioequivalence problems have been reported. Dissolution studies were run under Biopharmaceutics Classification System–biowaiver conditions for the pure drug and 2 generic formulations available on the German market. Considering all relevant aspects, it was concluded that a biowaiver-based approval for products containing cephalexin monohydrate as the single active pharmaceutical ingredient is scientifically justified, provided that well-established excipients are used in usual amounts and that both test and reference dosage forms meet the guideline criteria of either “rapidly dissolving” or “very rapidly dissolving.”

Enhancement Solubilization of Dutasteride using Microsponge Formulation

Dutasteride (DU) (5α-reductase inhibitor) that is used for the treatment of benign prostate hyperplasia (BPH), DU has low water solubility and poor oral absorption that classified as Biopharmaceutics Classification System (BCS) class II. This study aims to improve the physical properties of Dutasteride (DU) like solubility by the preparation of microsponge (MS). Microsponges are spherical in shape, sponge-like structure, polymeric delivery systems composed of porous microspheres with a large internal surface area. Nine formulations of DU MS had been prepared by the technique of quasi-emulsion solvent diffusion (QESD) and utilizing Eudragit S100 as major polymer and glycerol as a plasticizer that dissolved in dichloromethane where polyvinyl alcohol PVA serves as a stabilizer in the external phase. The formulas were employed to optimize preparation variable factors include; different drug to polymer ratio, the addition of different concentrations of PVA, and stirring rate. Optimization was done using the response of production yield (PY), entrapment efficiency EE), particle size, and in vitro drug release; The results display that the best ratio of (drug: polymer) was 5:1, and the best rate of stirring was 1,000 rpm respecting the optimum characteristics of microsponge. The best-selected formula prepared (F2) was underwent to evaluation regarding saturated solubility, FTIR, DSC, and SEM and showed 1.28 folds enhancement in saturated solubility compared to plain DU, and was well fabricated with high entrapment efficiency (83.7% ± 1.37), production yield (85.61% ± 0.6), and particle size of 77μm. Moreover, the percent release of DU was 75.74 ± 1.5 after 4 hours, with good compatibility as confirmed by XRD, SEM, DSC, and fourier-transform infrared spectroscopy (FTIR) analysis. It can be concluded that the selected formula prepared (F2) of DU microsponge is reassuring and promising drug delivery with improved pharmaceutical physical properties.

Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development.

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high Peff marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol’s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product.

DISSOLUTION ENHANCEMENT OF LANSOPRAZOLE USING COCRYSTALLIZATION

Objective: Lansoprazole (LPZ) is a Biopharmaceutics Classification System Class II drug. It has low solubility and high permeability, so its rate ofdissolution is a rate-limiting step for drug absorption. This study aimed to improve the dissolution rate of LPZ by forming cocrystals, using nicotinamide(NCT) as the conformer.Methods: Cocrystals of LPZ were produced using the solvent evaporation and solvent-drop grinding methods with a molar ratio of 1:1 and 1:2.The cocrystals were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), and differential scanningcalorimetry (DSC). The solubility and dissolution of the LPZ cocrystals were examined in distilled water.Results: FTIR was used to confirm the formation of hydrogen bonds between LPZ and NCT. DSC and XRD studies showed the formation of crystalsfrom cocrystals and a decrease of the melting point of the cocrystals. The dissolution study revealed that the cocrystals could increase the LPZdissolution rate by up to 8.4-fold compared with pure LPZ.Conclusion: LPZ cocrystal formation with NCT was successful in increasing the dissolution rate of LPZ.

Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin.

The Biopharmaceutics Classification System (BCS) categorizes active pharmaceutical ingredients according to their solubility and permeability properties, which are susceptible to matrix or formulation effects. The aim of this research was to evaluate the matrix effects of a hydroethanolic extract of calyces from Physalis peruviana L. (HEE) and its butanol fraction (BF), on the biopharmaceutics classification of their major compound, quercetin-3-O-rutinoside (rutin, RU). Rutin was quantified by HPLC-UV, and Caco-2 cell monolayer transport studies were performed to obtain the apparent permeability values (Papp ). Aqueous solubility was determined at pH 6.8 and 7.4. The Papp values followed this order: BF>HEE>RU (1.77±0.02>1.53±0.07>0.90±0.03×10-5 cm/s). The lowest solubility values followed this order: HEE>RU>BF (2.988±0.07>0.205±0.002>0.189±0.005mg/ml). According to these results, rutin could be classified as BCS classes III (high solubility/low permeability) and IV (low solubility/low permeability), depending on the plant matrix. Further work needs to be done in order to establish how apply the BCS for research and development of new botanical drugs or for bioequivalence purposes.

Preparation and Characterization of Solid Dispersion of Flufenamic Acid by Solvent Evaporation Method

The low aqueous solubility of Flufenamic acid (FFA), a Biopharmaceutics Classification System (BCS) II class drug, is a major challenge to overcome its low bioavailability. Poor solubility and low dissolution rate of the poorly aqueous solubility drugs in the aqueous gastrointestinal fluids (6.8 pH) often cause insufficient bioavailability. As for BCS class II drugs, dissolution rate having limiting step, increasing the solubility of drug leads to increases the bioavailability. Therefore, it is important to improve the solubility of flufenamic acid. Several methods such as salt formation, particle size reduction and solid dispersion are available to enhance the solubility of many drugs. In this work, solid dispersion of flufenamic acid with hydrophilic polymer Polyvinylpyrrolidone K 30 (PVP K 30) are produced by solvent evaporation technique. Raw FFA, PVP K-30 and solid dispersion containing FFA and PVP K-30 are characterized by SEM, FTIR. It was observed that morphology of raw FFA was rock like which changed when solid dispersion is formed with PVP K30. The FTIR spectroscopy showed that hydrogen bonding between FFA and PVP occurs in solid dispersion.

A novel and innovative drug delivery system in fast dissolving oral film of glimepiride-betacyclodextrin inclusion complexes

Delivery system in fast dissolving oral film is the system in which drug can be released immediately without drinking water and can be dissolved in saliva, then absorbed into the body through the oral cavity. Glimepiride is classified in the Biopharmaceutics Classification System class II which has a low solubility in water. Formation of glimepiride inclusion complexes using betacyclodextrin is known to increase solubility while suppressing the bitter taste of glimepiride. The purpose of this study was to develop FDOF preparations containing glimepiridebetacyclodextrin (1:2) inclusion complexes made by co-grinding technique. The development of the FDOF formula begins with the orientation of the formula which varies the concentration of crospovidone as superdisintegrant and PEG 400 as plasticizer. The FDOF were made from two formulas, with one formula containing glimepiride-betacyclodextrin (1:2) inclusion complexes and the other formula containing pure glimepiride as the active ingredient, using the solvent casting method with HPMC E5 LV as the film forming agent. The final evaluations of FDOF include organoleptic, weight variation, film thickness, surface pH, disintegration time, drug content, dissolution rate, percent elongation, tensile strength and folding endurance tests. The best FDOF formula from optimization process contain HPMC E5 LV 35% as film forming agent, PEG 400 15% as plasticizer and 8% crospovidone as superdisintegrant. From the results of final preparation evaluation, FDOF containing glimepiride-betacyclodextrin (1:2) inclusion complexes proved to be better than FDOF containing pure glimepiride.

Solubility enhancement of BCS classified IV drug - Apixaban by preparation and evaluation of Mesoporous Nanomatrix

Biopharmaceutics classification system (BCS) class IV compounds, exhibits low solubility, intestinal permeability and oral bioavailability among all the pharmaceutical class of drugs. Therefore, these drugs need a more compatible and efficient delivery system. Since, their solubility in various mediums will remains a limitation. Hence, the mesoporous Nanomatrix approach may prove to be a suitable solution ahead. Therefore, in the present study, the polymer-coated mesoporous material like Sylysia 350, Carbon, Tin Oxide are opted for the BCS class IV drug like Apixaban to attain higher solubility and dissolution. The prepared Nanomatrix was evaluated for its particle size, DSC, Solubility and dissolution studies. For this study, Apixaban was opted for formulating Sylysia 350, Carbon, Tin Oxide based Mesoporous Nanomatrix system. Nanomatrix was prepared by the Amorphous solid dispersion method using probe sonication. The mesoporous Nanomatrix of Apixaban showed improvement in the solubility in water by approx.7 folds when Apixaban used in combination with Sylysia 350 and Polymer HPMC K15M. From the present study, we can conclude that the optimized Apixaban mesoporous Nanomatrix may prove to be a suitable potential option for solubility enhancement, increase in-vitro drug release and effective delivery of BCS class IV drugs.

Tablets of "Hydrochlorothiazide in Cyclodextrin in Nanoclay": A New Nanohybrid System with Enhanced Dissolution Properties.

Hydrochlorothiazide (HCT), a Biopharmaceutical Classification System (BCS) class IV drug, is characterized by low solubility and permeability, that negatively affect its oral bioavailability, reducing its therapeutic efficacy. The combined use of cyclodextrins (CDs) and nanoclays (NCs) recently proved to be a successful strategy in developing delivery systems able to merge the potential benefits of both carriers. In this work, several binary systems of CDs or NCs with the drug were obtained, using different drug:carrier ratios and preparation techniques, and characterized in solution and in solid state, to properly select the most effective system and preparation method. Then, the best CD (RAMEB) and NC (sepiolite), at the best drug:carrier ratio, was selected for preparation of the ternary system by co-evaporation and emerged as the most effective preparation method. The combined presence of RAMEB and sepiolite gave rise to a synergistic improvement of drug dissolution properties, with a two-fold increase in the amount of drug dissolved as compared with the corresponding HCT-RAMEB system, resulting in an approximately 12-fold increase in drug solubility as compared with the drug alone. The ternary system that was co-evaporated was then selected for a tablet formulation. The obtained tablets were fully characterized for technological properties and clearly revealed a better drug dissolution performance than the commercial reference tablet (Esidrex®).

Formulation and evaluation of liquisolid compacts of itraconazole to enhance its oral bioavailability.

Aim: Formulate and evaluate liquisolid compacts of Itraconazole, a biopharmaceutical classification system class II drug, which has poor bioavailability. Materials & methods: PEG 600 was used as a nonvolatile solvent, Alfacel PH 200 as a carrier and Aerosil 200 as a coating material. The Itraconazole solution upon mixing with a carrier and coating material resulted in a dry powder, which was compressed into tablets. Results & conclusion: The optimized formulation exhibited a significantly higher drug dissolution (90.73% in 90 min) compared with conventional tablets and marketed capsules. The antifungal activity was retained in the formulation. Higher values of Cmax and AUC0-24 of the formulation compared with the plain drug indicated enhancement in oral bioavailability. The formulation was stable at room temperature as well as in accelerated conditions.

Dissolution enhancement of carbamazepine using twin-screw melt granulation

The current study explored the twin-screw melt granulation (TSMG) as a potential technology for the water solubility enhancement of biopharmaceutical classification system (BCS) class II drugs. As a model drug, carbamazepine (CBZ) was formulated with three different polymers as melt granules produced in a co-rotating twin-screw granulator. Polyethylene glycol 6000 (PEG 6000) and Kolliphor® (poloxamer) P407 were used as binding materials at two different granulation temperatures (Tmax: 70 °C; 100 °C). Additionally, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) was chosen as binder of higher melting/ granulation temperature (Tmax: 140 °C). Temperature dependent polymorphic transition of CBZ during melt granulation was observed and identified using XRPD- (X-ray powder diffraction) and FTIR- (Fourier transform infrared spectroscopy) analysis. The effects of polymer type, polymer content (10, 15, 20% (w/w)) and granulation temperature on polymorphic transition, their impact on wettability (contact angle via drop shape-analysis), and the resulting dissolution performance at non-sink conditions in phosphate buffer (pH 6.8), were studied. This study showed that TSMG led to a crystalline system facilitating supersaturation when brought in solution, even when high drug loads (up to 90% (w/w)) were used.In general, for all granules produced, the supersaturation level and its duration varied with the extent of polymorphic transition and binder concentration. The results of this study indicated the importance of temperature control and polymer selection for tailoring desired dissolution profiles.