Characterization and Crystal Structural Analysis of Novel Carvedilol Adipate and Succinate Ethanol-Solvated Salts.

Two ethanol-solvated adipate and succinate salts of carvedilol (CVD), a Biopharmaceutics Classification System class 2 drug, were synthesized by crystallizing ethanol with adipic acid (ADP) and succinic acid (SUA). Proton transfer from ADP and SUA to CVD and the presence of ethanol in the two novel compounds were confirmed using powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and single-crystal X-ray diffraction measurements. The two novel ethanol-solvated salts exhibited enhanced solubility and dissolution rates compared with pure carvedilol in phosphate buffer (pH 6.8). Additionally, the morphologies and attachment energies of the two novel compounds and pure CVD were calculated based on their single-crystal structures, revealing a correlation between attachment energy and dissolution rate.

Enantioselective binding of carvedilol to human serum albumin and alpha-1-acid glycoprotein.

Carvedilol, a highly protein-bound beta-blocker, is used in therapy as a racemic mixture of its two enantiomers that exhibit different pharmacological activity. The aim of this study was to evaluate the stereoselective nature of its binding to the two major plasma proteins: albumin and alpha-1-acid glycoprotein. The determination of the plasma protein-binding degree for carvedilol and its enantiomers was achieved using ultrafiltration for the separation of the free fraction, followed by LC-MS/MS quantification, using two different developed and validated methods in terms of stationary phase: achiral C18 type and chiral ovomucoid type. Furthermore, molecular docking methods were applied in order to investigate and to better understand the mechanism of protein-binding for S-(-)- and R-(+)-carvedilol. A difference in the binding behavior of the two enantiomers to the plasma proteins was observed when taken individually, with R-(+)-carvedilol having a higher affinity for albumin and S-(-)-carvedilol for alpha-1-acid glycoprotein. However, in the case of the racemic mixture, the binding of the S enantiomer to alpha-1-acid glycoprotein seemed to be influenced by the presence of its antipode, although no such influence was observed in the case of albumin. The results raise the question of a binding competition between the two enantiomers for alpha-1-acid glycoprotein.

Synthesis and Characterization of Carvedilol-Etched Halloysite Nanotubes Composites with Enhanced Drug Solubility and Dissolution Rate.

Carvedilol is a poorly water-soluble drug employed to treat chronic heart failure. In this study, we synthesize new carvedilol-etched halloysite nanotubes (HNTs) composites to enhance solubility and dissolution rate. The simple and feasible impregnation method is used for carvedilol loading (30-37% weight). Both the etched HNTs (acidic HCl and H2SO4 and alkaline NaOH treatments) and the carvedilol-loaded samples are characterized by various techniques (XRPD, FT-IR, solid-state NMR, SEM, TEM, DSC, and specific surface area). The etching and loading processes do not induce structural changes. The drug and carrier particles are in intimate contact and their morphology is preserved, as demonstrated by TEM images. The 27Al and 13C solid-state NMR and FT-IR findings show that carvedilol interactions involve the external siloxane surface, especially the aliphatic carbons, the functional groups, and, by inductive effect, the adjacent aromatic carbons. All the carvedilol-halloysite composites display enhanced dissolution rate, wettability, and solubility, as compared to carvedilol. The best performances are obtained for the carvedilol-halloysite system based on HNTs etched with HCl 8M, which exhibits the highest value of specific surface area (91 m2 g-1). The composites make the drug dissolution independent of the environmental conditions of the gastrointestinal tract and its absorption less variable, more predictable, and independent from the pH of the medium.

Unique Positive Cooperativity Between the ß-Arrestin-Biased ß-Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the ß2-Adrenergic Receptor.

Among ß-blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other ß-blockers in its ability to elicit ß-arrestin-biased agonism, which has been suggested to underlie its cardioprotective effects. Augmenting the pharmacologic properties of carvedilol thus holds the promise of developing more efficacious and/or biased ß-blockers. We recently identified compound-6 (cmpd-6), the first small molecule positive allosteric modulator of the ß2-adrenergic receptor (ß2AR). Cmpd-6 is positively cooperative with orthosteric agonists at the ß2AR and enhances agonist-mediated transducer (G-protein and ß-arrestin) signaling in an unbiased manner. Here, we report that cmpd-6, quite unexpectedly, displays strong positive cooperativity only with carvedilol among a panel of structurally diverse ß-blockers. Cmpd-6 enhances the binding affinity of carvedilol for the ß2AR and augments its ability to competitively antagonize agonist-induced cAMP generation. Cmpd-6 potentiates ß-arrestin1- but not Gs-protein-mediated high-affinity binding of carvedilol at the ß2AR and ß-arrestin-mediated cellular functions in response to carvedilol including extracellular signal-regulated kinase phosphorylation, receptor endocytosis, and trafficking into lysosomes. Importantly, an analog of cmpd-6 that selectively retains positive cooperativity with carvedilol acts as a negative modulator of agonist-stimulated ß2AR signaling. These unprecedented cooperative properties of carvedilol and cmpd-6 have implications for fundamental understanding of G-protein-coupled receptor (GPCR) allosteric modulation, as well as for the development of more effective biased beta blockers and other GPCR therapeutics. SIGNIFICANCE STATEMENT: This study reports on the small molecule-mediated allosteric modulation of the ß-arrestin-biased ß-blocker, carvedilol. The small molecule, compound-6 (cmpd-6), displays an exclusive positive cooperativity with carvedilol among other ß-blockers and enhances the binding affinity of carvedilol for the ß2-adrenergic receptor. Cooperative effects of cmpd-6 augment the ß-blockade property of carvedilol while potentiating its ß-arrestin-mediated signaling functions. These findings have potential implications in advancing G-protein-coupled receptor allostery, developing biased therapeutics and remedying cardiovascular ailments.

Preparation, Characterization, and Selection of Optimal Forms of (S)-Carvedilol Salts for the Development of Extended-Release Formulation.

(S)-carvedilol (S-CAR) is the dominant pharmacodynamic conformation of carvedilol, but its further development for extended-release formulation is restricted by its poor solubility. This study aimed to prepare and screen S-CAR salts that could be used to improve solubility and allow extended release. Five salts of S-CAR with well-known acid counterions (i.e., phosphate, hydrochloride, sulfate, fumarate, and tartrate) were produced using similar processes. However, these salts were obtained with water contents of 1.60-12.28%, and their physicochemical properties differed. The melting points of phosphate, hydrochloride, and tartrate were 1.1-1.5 times higher than that of the free base. The solubility of S-CAR salts was promoted to approximately 3-32 times higher than that of the free base at pH 5.0-8.0. Typical pH-dependent solubilities were evidently observed in S-CAR salts, but considerable differences in solubility properties among these salts were observed. S-CAR phosphate and hydrochloride possessed high melting points, considerable solubility, and excellent chemical and crystallographic stabilities. Accordingly, S-CAR phosphate and hydrochloride were chosen for further pharmacokinetic experiments and pharmaceutical study. S-CAR phosphate and hydrochloride extended-release capsules were prepared using HPMC K15 as the matrix and presented extended release in in vitro and in vivo evaluations. Results implied that water molecules in the hydrated salt were a potential threat to the achievement of crystal stability and thermostability. S-CAR phosphate and hydrochloride are suitable for further development of the extended-release formulation.

Central composite design for the development of carvedilol-loaded transdermal ethosomal hydrogel for extended and enhanced anti-hypertensive effect.

BACKGROUND: Carvedilol, the anti-hypertensive drug, has poor bioavailability when administered orally. Ethosomes-mediated transdermal delivery is considered a potential route of administration to increase the bioavailability of carvedilol. The central composite design could be used as a tool to optimize ethosomal formulation. Thus, this study aims to optimize carvedilol-loaded ethosomes using central composite design, followed by incorporation of synthesized ethosomes into hydrogels for transdermal delivery of carvedilol. RESULTS: The optimized carvedilol-loaded ethosomes were spherical in shape. The optimized ethosomes had mean particle size of 130 ± 1.72 nm, entrapment efficiency of 99.12 ± 2.96%, cumulative drug release of 97.89 ± 3.7%, zeta potential of - 31 ± 1.8 mV, and polydispersity index of 0.230 ± 0.03. The in-vitro drug release showed sustained release of carvedilol from ethosomes and ethosomal hydrogel. Compared to free carvedilol-loaded hydrogel, the ethosomal gel showed increased penetration of carvedilol through the skin. Moreover, ethosomal hydrogels showed a gradual reduction in blood pressure for 24 h in rats. CONCLUSIONS: Taken together, central composite design can be used for successful optimization of carvedilol-loaded ethosomes formulation, which can serve as the promising transdermal delivery system for carvedilol. Moreover the carvedilol-loaded ethosomal gel can extend the anti-hypertensive effect of carvedilol for a longer time, as compared to free carvedilol, suggesting its therapeutic potential in future clinics.

A Multivariate Approach for the Determination of the Optimal Mixing Ratio of the Non-Strong Interacting Co-Amorphous System Carvedilol-Tryptophan.

Converting crystalline compounds into co-amorphous systems is an effective way to improve the solubility of poorly water-soluble drugs. It is, however, of critical importance for the physical stability of co-amorphous systems to find the optimal mixing ratio of the drug with the co-former. In this study, a novel approach for this challenge is presented, exemplified with the co-amorphous system carvedilol-tryptophan (CAR-TRP). Following X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) of the ball-milled samples to confirm their amorphous form, Fourier-transform infrared spectroscopy (FTIR) and principal component analysis (PCA) were applied to investigate intermolecular interactions. A clear deviation from a purely additive spectrum of CAR and TRP was visualized in the PCA score plot, with a maximum at around 30% drug (mol/mol). This deviation was attributed to hydrogen bonds of CAR with TRP ether groups. The sample containing 30% drug (mol/mol) was also the most stable sample during a stability test. Using the combination of FTIR with PCA is an effective approach to investigate the optimal mixing ratio of non-strong interacting co-amorphous systems.

Determination and Comparison of the Solubility, Oil-Water Partition Coefficient, Intestinal Absorption, and Biliary Excretion of Carvedilol Enantiomers.

Carvedilol is administered as a racemic mixture for the therapy of hypertension and heart failure. S-enantiomer is the dominant conformation of pharmacodynamics, but its further development was obstructed by its poor bioavailability. In this study, carvedilol and its enantiomers were compared in terms of solubility, permeability, and biliary excretion, and reasons for the poor bioavailability were discussed. Equilibrium solubility and log P were measured by a shake flask method at a wide pH range (1.2-8.0), and intestinal absorption and biliary excretion were evaluated using a single-pass rat intestinal perfusion model. According to BCS guidance, carvedilol and its R/S enantiomers are considered highly soluble at pH value less than 5.0 and low soluble at neutral or weak alkaline conditions. RS-carvedilol showed significantly lower solubilities at pH 1.2-5.0 and higher solubilities at pH 6.0-8.0 than its enantiomers. In addition, carvedilol and its enantiomers possessed similar log P values at pH 1.2-8.0. High intestinal permeabilities of carvedilol and its enantiomers were observed, and S-carvedilol showed higher absorption than R-carvedilol and RS-carvedilol. The biliary excretion about two major metabolites, 1-hydroxycarvedilol O-glucuronide and 8-hydroxycarvedilol O-glucuronide, of RS-carvedilol, S-carvedilol, and R-carvedilol were 66.4%, 73.5%, and 54.3%, respectively. In conclusion, there are significant differences amongst carvedilol and its R/S enantiomers in terms of solubility, intestine absorption, and biliary excretion abilities. The first pass effect is the primary reasons for the low bioavailability of S-carvedilol. Therefore, pharmaceutical strategies or parenteral routes should be considered to avoid the first pass metabolism.

Determination of the Optimal Molar Ratio in Amino Acid-Based Coamorphous Systems.

Coamorphous drug formulations are a promising approach to improve solubility and bioavailability of poorly water-soluble drugs. On the basis of theoretical assumptions involving molecular interactions, the 1:1 molar ratio of drug and coformer is frequently used as "the optimal ratio" for a homogeneous coamorphous system (i.e., the coamorphous system with the highest physical stability and, if strong interaction is possible between two molecules, the highest glass transition temperature (Tg)). In order to more closely investigate this assumption, l-aspartic acid (ASP) and l-glutamic acid (GLU) were investigated as coformers for the basic drug carvedilol (CAR) at varying molar ratios. Salt formation between CAR with ASP or GLU was expected to occur at the molar 1:1 ratio based on their chemical structures. Interestingly, the largest deviation between the experimental Tg and the theoretical Tg based on the Gordon-Taylor equation was observed at a molar ratio of around 1:1.5 in CAR-ASP and CAR-GLU systems. In order to determine the exact value of the ratio with the highest Tg, a data fitting approach was established on thermometric data of various CAR-ASP and CAR-GLU systems. The highest Tg was found to be at CAR-ASP 1:1.46 and CAR-GLU 1:1.43 mathematically. Spectroscopic investigations and physical stability measurements further confirmed that the optimal molar ratio for obtaining a homogeneous system and the highest stability can be found at a molar ratio around 1:1.5. Overall, this study developed a novel approach to determine the optimal ratio between drug and coformers and revealed the influence of varying molar ratios on molecular interactions and physical stability in coamorphous systems.

Preparation of a thiols ß-cyclodextrin/gold nanoparticles-coated open tubular column for capillary electrochromatography enantioseparations.

Inspired by the distinct chemical and physical properties of nanoparticles, here a novel open-tubular capillary electrochromatography column was prepared by electrostatic assembly of poly(diallydimethylammonium chloride) onto the inner surface of a fused-silica capillary, followed by self-adsorption of negatively charged SH-ß-cyclodextrin/gold nanoparticles. The formation of the SH-ß-cyclodextrin/gold nanoparticles coated capillary was confirmed and characterized by scanning electron microscopy and energy dispersive spectrometry. The results of scanning electron microscopy and energy dispersive spectrometry studies indicated that SH-ß-cyclodextrin/gold nanoparticles were successfully coated on the inner wall of the capillary column. The performance of the SH-ß-cyclodextrin/gold nanoparticles coated capillary was validated by the analysis of six pairs of chiral drugs, namely zopiclone, carvedilol, salbutamol, terbutaline sulfate, phenoxybenzamine hydrochloride, and ibuprofen. Satisfactory enantioseparation results were achieved, confirming the use of gold nanoparticles as the support could enhance the phase ratio of the open-tubular capillary column. Additionally, the stability and reproducibility of the SH-ß-cyclodextrin/gold nanoparticles coated capillary column were also investigated. Then, this proposed method was well validated with good linearity (≥0.999), recovery (90.0-93.5%) and repeatability, and was successfully used for enantioseparation of ibuprofen in spiked plasma samples, which indicated the new column's potential usage in biological analysis.

A Soluplus/Poloxamer 407-based self-nanoemulsifying drug delivery system for the weakly basic drug carvedilol to improve its bioavailability.

Carvedilol (CAR), a ß-adrenoceptor and α1-receptor blocker, has pH-dependent solubility, which greatly limits its oral bioavailability. In this work, a precipitation inhibitor-based self-nanoemulsifying drug delivery system (PI-SNEDDS) was developed by employing Soluplus and Poloxamer 407 to improve drug dissolution and to inhibit drug precipitation in the gastrointestinal tract. In vitro phase distribution and in vivo dissolution studies indicated that PI-SNEDDS significantly increased drug content in the oil phase of the nanoemulsions in the stomach and greatly inhibited the subsequent precipitation of CAR in the intestine compared with the carvedilol self-nanoemulsifying drug delivery system (CAR SNEDDS) and the carvedilol tablets. Moreover, a 1.56-fold increase in the relative bioavailability of CAR was observed for the CAR PI-SNEDDS (397.41%) compared to a CAR SNEDDS (254.09%) with commercial capsules as a reference. Therefore, our developed PI-SNEDDS is a promising vehicle for improving the dissolution and bioavailability of poorly soluble drugs with pH-dependent solubility.

Optimization of lipid materials in the formulation of S-carvedilol self-microemulsifying drug-delivery systems.

OBJECTIVES: The blocking effect of S-carvedilol (S-CAR) on the beta-adrenoceptor is about 100 times stronger than that of the right-handed conformation. However, further development is restricted because of its poor bioavailability caused by its low solubility and high first-pass effect. In the study, S-CAR self-microemulsifying drug-delivery systems (SMEDDSs) were established, and the effects of different lipid materials on the absorption and metabolism of S-CAR were investigated. METHODS: Six kinds of lipid materials with different chemical structures including oleic acid, glycerol monooleate, glycerol trioleate, oleoyl macrogol-6 glycerides, soybean lecithin, and α-tocopherol were selected to be the oil phase. The S-CAR SMEDDSs were prepared by the same ratio. In vitro characteristics, in vitro release, in situ intestine absorption, and bile excretion, as well as the in vivo characteristic of relative bioavailability, were determined. KEY FINDINGS: The lipid structure significantly affected physical characteristics, the absorption and excretion rates of S-CAR SMEDDSs. The findings of rat-intestine perfusion experiments showed that the S-CAR SMEDDSs decreased the bile-excretion rate of S-CAR. Compared with the S-CAR group, the oleic acid and soybean lecithin groups decreased the bile excretion to 32% and 45%, respectively. Pharmacokinetic studies showed that the AUCs of these two groups were about 1.9 and 1.7 times more than that of the S-CAR group, and the mean retention time was extended. CONCLUSION: The SMEDDS using ionic lipids (oleic acid or soybean lecithin) as oil phase can increase the oral bioavailability of S-CAR by increasing the solubility and reducing the first-pass effect.

Sublingual tablets containing spray-dried carvedilol-loaded nanocapsules: development of an innovative nanomedicine.

The aim of this study was to propose the use of spray-dried mucoadhesive carvedilol-loaded nanocapsules in the formulation of sublingual tablets. There is no previous report describing the preparation of tablets containing spray-dried nanocapsules or tablets containing nanocapsules, neither prepared by direct compression nor for sublingual administration. Tablets of 6 mm of diameter and 2.7 ± 0.2 mm of height were obtained with a mean weight of 44 ± 4 mg, carvedilol content of 0.164 ± 0.017 mg, and a disintegration time less than 25 min. They were produced using a force of 4.7 ± 1.6 kgf. The release profile of carvedilol from the tablets was evaluated using the dialysis bag method. In parallel, the release of nanocapsules from the tablet structure into the release medium was evaluated using dynamic light scattering. Nanocapsules that were released from the tablets into the release medium exhibited similar particle size distributions after recovery as in their original liquid suspension, without losing their original ability to control drug release. Therefore, sublingual tablets may be produced from spray-dried drug-loaded nanocapsules using a direct compression technique, providing a useful pharmaceutical approach for drugs that undergo first pass metabolism, such as carvedilol.

The Effect of Enzymes and Sodium Lauryl Sulfate on the Surface Tension of Dissolution Media: Toward Understanding the Solubility and Dissolution of Carvedilol.

The objective of this work was to study the effect of the physiologically relevant enzymes pepsin, pancreatin, and the synthetic surfactant sodium lauryl sulfate (SLS) on the surface tension of the dissolution media and the solubility and dissolution of the weakly basic drug carvedilol. Compendial dissolution media and buffer solutions that simulate the gastrointestinal fluid, prepared with and without the addition of SLS, were used in this study. The surface tension of the dissolution media; critical micelle concentration (CMC) of SLS in buffer solutions; and size, polydispersity index, and zeta potential of SLS micelles loading carvedilol were determined. The solubility and dissolution of carvedilol were investigated and compared with those of the corresponding media prepared without the addition of pepsin, pancreatin, and SLS. Results showed that the addition of pepsin, pancreatin, and SLS lowered the surface tension of the dissolution media to 54.8, 55.7, and ~ 30 mN/m, respectively. The solubility of carvedilol was significantly enhanced with pepsin and SLS; however, no significant difference was found with pancreatin. The dissolution rate of carvedilol was fast in simulated gastric fluid with and without pepsin. The dissolution was further enhanced in media with pancreatin and SLS. The dissolution data were corroborated with the molar micellar solubilization (X) of SLS, ranging between 0.02 and 3.09. Understanding the effect of pepsin, pancreatin, and SLS on the surface tension of the dissolution media and the solubility and dissolution of poorly soluble drugs can improve our knowledge of the performance of these drugs in vivo.

Topography of Simulated Intestinal Equilibrium Solubility.

Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques. In this article, we have measured equilibrium solubility utilizing a novel four component mixture design (4CMD) with biorelevant amphiphiles (bile salt, phospholipid, oleate, and monoglyceride) within a matrix of three pH values (5, 6, and 7) and total amphiphile concentrations (11.7, 30.6, and 77.5 mM) to provide a topographical and statistical overview. Three poorly soluble drugs representing acidic (indomethacin), basic (carvedilol), and neutral (fenofibrate) categories have been studied. The macroscopic solubility behavior agrees with literature and exhibits an overall increasing solubility from low pH and total amphiphile concentration to high pH and total amphiphile concentration. Within the matrix, all three drugs display different topographies, which can be related to the statistical effect levels of the individual amphiphiles or amphiphile interactions on solubility. The study also identifies previously unreported three and four way factor interactions notably between bile salt, phospholipid, pH, and total amphiphile concentration. In addition, the results also reveal that solubility variability is linked to the number of amphiphiles and the respective ratios in the measurement fluid, with the minimum variation present in systems containing all four amphiphiles. The individual 4CMD experiments within the matrix can be linked to provide a possible intestinal solubility window for each drug that could be applied in PBPK modeling systems. Overall the approach provides a novel overview of intestinal solubility topography along with greater detail on the impact of the various factors studied; however, each matrix requires 351 individual solubility measurements. Further studies will be required to refine the experimental protocol in order the maximize information garnered while minimizing the number of measurements required.

The Effect of Promiscuous Aggregation on in Vitro Drug Metabolism Assays.

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.

Characterising glass transition temperatures and glass dynamics in mesoporous silica-based amorphous drugs.

In this study the glass transition temperatures (Tgα and Tgß) in mesoporous silica-based amorphous drugs were characterized. For this purpose, mesoporous silica Parteck SLC (MPS) was loaded with the drugs ibuprofen and carvedilol, either below, at, or above the monomolecular drug loading capacities, i.e. the concentration at which the entire MPS surface is covered with a monolayer of drug molecules. The resulting amorphous forms were analysed using X-ray powder diffraction and the thermal behaviour was characterised with differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). The drug monolayer did not contribute to the thermal signal in DSC. Using DMA however, it could be shown that the monolayer indeed exhibited a very weak Tgα, and that the temperature range of this transition did not differ from that of the quench cooled amorphous drugs. Theoretical ab initio molecular dynamics simulations revealed that the nature of hydrogen bonding geometry of the functional groups interacting with the MPS surface were similar to that of the respective crystalline drugs, which results in restricted molecular motions for those functional groups. On the other hand, the non-interacting parts of the molecules exhibited molecular motions similar to what is observed in pure amorphous drugs. As a result of the interactions of the monolayer with the MPS surface, the monomolecular drug layer did not reveal a Tgß. However, a Tgß was found at any drug-MPS ratios above the monomolecular drug loading capacity as a result of the excess drug which forms a "true" amorphous phase. Overall, this study demonstrated that drug molecules forming an amorphous monolayer on the surfaces of a mesoporous silica particle, even though they are restricted in their mobility, exhibit a Tgα, but lack a Tgß, whereas any excess drug confined in the MPS pores showed similar properties as the pure amorphous drug. These findings will help to increase the overall understanding of drug loaded MS systems, including their physical stability as well as release properties.

Prediction of Hepatic Clearance of Stereoselective Metabolism of Carvedilol in Liver Microsomes and Hepatocytes of Sprague-Dawley and Cytochrome P450 2D-Deficient Dark Agouti Rats.

Hepatic clearance (CLh) of carvedilol (CAR), which is eliminated via stereoselective metabolism by the CYP2D subfamily of cytochromes P450 (CYPs), was predicted using liver microsomes and hepatocytes from Sprague-Dawley (SD) rats and CYP2D-deficient Dark Agouti (DA) rats to determine the usefulness of prediction method. Plasma concentrations of CAR following intravenous injection to DA rats were higher than those in SD rats. The volume of distribution at steady state and total clearance (CLtot) of S-CAR were approximately two times greater than those of R-CAR in both strains. CLh predicted from in vitro studies using DA rat liver microsomes was different from that obtained from in vivo studies. In contrast, in vitro CLh prediction using DA rat hepatocytes was nearly identical to the CLh observed in DA rats in vivo, and was lower than that in SD rats. The predicted CLh in vitro using hepatocytes correlated well with the observed CLtot in vivo, which is expected to be nearly the same as CLh. These results suggest that in vitro metabolic studies using hepatocytes are more relevant with regard to stereoselectively predicting CLh of CAR than those using liver microsomes.

Transdermal ethosomal gel nanocarriers; a promising strategy for enhancement of anti-hypertensive effect of carvedilol.

The current study was conducted to develop vesicular ethosomal gel (ethogel) systems for upgrading the transdermal delivery of anti-hypertensive carvedilol. Ethosomes composed of Phospholipon 100 H, cholesterol, ethanol, and Transcutol P at different ratios, were prepared by thin-film hydration method with sonication. Carvedilol-loaded ethosomes were characterized by microscopic examinations followed by other in-vitro assessments. Selected ethosomal formulation (E10) was incorporated into different concentrations of gelling agents to prepare the ethogel formulations. Ethogels were subjected to physicochemical characterization, compatibility, and in-vitro drug release studies. Ex-vivo skin permeation and retention studies were performed followed by in-vivo studies in induced hypertensive rats. The smooth ethosomes demonstrated vesicular size of 201.55-398.55 nm, entrapment efficiency of 30.00-90.66% and loading capacity of 7.64-43.04% with zeta potential range of -30.30 to -44.90 mV. The homogeneous ethogels exhibited appropriate results of pH and drug content measurements. Spreadability was observed as a function of viscosity as the latter increased, the former decreased. The ethogel formulation (G2) manifested satisfactory physical appearance, spreadability, viscosity, and in-vitro release. In comparison to pure carvedilol gel, tested formulations (E10 and G2) developed high ex-vivo permeation, steady-state flux and drug retention through skin layers. The in-vivo study of G2 formulation revealed a significant gradual decline (p < 0.01) in the mean arterial pressure of rats at the second hour of experiment (146.11 mmHg) with continuous significant decrease (p < 0.001) after 6 h (98.88 mmHg). In conclusion, ethogels as promising lipid carriers proved their potential to enhance skin permeation with extended anti-hypertensive action of carvedilol.

A Comparative Study of the Use of Mesoporous Carbon and Mesoporous Silica as Drug Carriers for Oral Delivery of the Water-Insoluble Drug Carvedilol.

Mesoporous carriers have been extensively applied to improve the dissolution velocity and bioavailability of insoluble drugs. The goal of this work was to compare the drug-loading efficiency (LE) and drug-dissolution properties of mesoporous silica nanoparticles (MSN) and mesoporous carbon nanoparticles (MCN) as drug vectors oral delivery of water-insoluble drugs. For this purpose, MSN and MCN with similar particle size, surface area, and mesoporous diameter were prepared to precisely evaluate the effects of different textures on the drug-loading and dissolution behavior of insoluble drugs. Carvedilol (CAR), a Bio-pharmaceutic Classification System (BCS) class II drug, was loaded in the MSN and MCN by the solvent adsorption method and solvent evaporation method with different carrier-drug ratios. The carboxylated MCN (MCN-COOH) had a higher LE for CAR than MSN for both the two loading methods due to the strong adsorption effect and π-π stacking force with CAR. In vitro drug dissolution study showed that both MSN and MCN-COOH could improve the dissolution rate of CAR compared with the micronized CAR. In comparison to MSN, MCN-COOH displayed a slightly slower dissolution profile, which may be ascribed to the strong interaction between MCN-COOH and CAR. Observation of cell cytotoxicity and gastrointestinal mucosa irritation demonstrated the good biocompatibility of both MSN and MCN-COOH. The present study encourages further research of different carriers to determine their potential application in oral administration.