Carvedilol Research Articles

Co-rotating twin screw process for continuous manufacturing of solid crystal suspension: A promising strategy to enhance the solubility, permeation and oral bioavailability of Carvedilol.

In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier. In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months. Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content. TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.

Functionalized calcium carbonate (FCC) as a novel carrier to solidify supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS)

Functionalized calcium carbonate (FCC), a novel pharmaceutical excipient, has shown promising properties in the field of oral drug delivery. The current study aimed at evaluating the feasibility of FCC as a carrier for the solidification of self-nanoemulsifying drug delivery systems (SNEDDS) containing the poorly water-soluble model drug carvedilol (CRV). Conventional, subsaturated SNEDDS (80 %-SNEDDSliquid) and supersaturated SNEDDS (200 %-SNEDDSliquid) were loaded onto FCC via physical adsorption at three ratios; 2.5:1, 3.0:1 and 3.5:1 (w/w) of FCC:SNEDDSliquid, respectively, generating free-flowing powders (SNEDDSFCC) with drug loading ranging from 0.8 % to 2.6 % (w/w) CRV. The emulsification of SNEDDSFCC in a USP II dissolution setup (in purified water) was characterized using dynamic light scattering, resulting in similar droplet sizes and PDIs as observed for their liquid counterparts. The morphology and physical state of the obtained SNEDDSFCC were characterized using scanning electron microscopy and differential scanning calorimetry. The physical stability and drug release upon dispersion were assessed as a function of storage time. The 200 %-SNEDDSliquid were physically stable for 6 days, however, solidification using FCC stabilized the supersaturated concentrations of CRV for a test period of up to 10 weeks (solidification ratios 3.0:1 and 3.5:1 (FCC:SNEDDSliquid)). SNEDDSFCC achieved an improved rate and extent of drug release upon dispersion compared to the crystalline CRV in tap water (pH 7.5), however, to a lesser extent than their liquid counterparts. After 8 weeks of storage (25 °C at dry conditions), FCC was still able to rapidly release the SNEDDSliquid and demonstrated the same rate and extent of drug release as freshly prepared samples. The solidification of 200 %-SNEDDSliquid in presence of FCC greatly improved the drug loading and showed an enhanced drug release profile compared to the conventional systems. In conclusion, FCC showed potential as a carrier for solidification of SNEDDS and for the development of novel supersaturated solid SNEDDS for the oral delivery of poorly water-soluble drugs.

Ultrasound-assisted continuous crystallization of metastable polymorphic pharmaceutical in a slug-flow tubular crystallizer

Metastable polymorphic pharmaceuticals have garnered significant attention in recent years due to their enhanced physicochemical properties, including solubility, bioavailability, and intellectual property considerations. However, the manufacturing of metastable form pharmaceuticals remains a formidable challenge. The stable preparation of metastable carvedilol (CVD) form Ⅱ crystals during CVD production is elusive, leading to substantial inconsistencies in product quality and regulatory compliance. In this study, we successfully prepared metastable CVD Form Ⅱ crystals using a continuous tubular crystallizer. Our findings demonstrate that the tubular crystallizer exhibits high efficiency and robustness for generating metastable crystal Form Ⅱ. We optimized the crystallization process by incorporating air bubble segments and employing ultrasonic irradiation strategies to overcome blockages and wall sticking issues encountered during operation. Ultimately, we developed an ultrasound-assisted continuous slug-flow tubular crystallization method and evaluated its performance. The results indicate that the CVD crystals produced through this process are resilient, sustainable, and uninterrupted products with promising potential for producing metastable polymorphic pharmaceuticals while effectively addressing encrustation problems associated with continuous tubular crystallization.

Investigating Carvedilol's Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of β-Adrenergic Agonists.

Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). β-adrenoceptor antagonist drugs (β-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of β-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind β-blockers' anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed β-blockers' cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC50 of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with β-agonists, in comparison to the control. This effect might be attributed to β-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR's multifaceted anticancer properties, implying that combining CAR with β-agonists could be a useful strategy for lung cancer treatment.

Development of a Carvedilol Oral Liquid Formulation for Paediatric Use.

Carvedilol (CARV) is an 'off-label' β-blocker drug to treat cardiovascular diseases in children. Since CARV is nearly insoluble in water, only CARV solid forms are commercialized. Usually, CARV tablets are manipulated to prepare an extemporaneous liquid formulation for children in hospitals. We studied CARV to improve its aqueous solubility and develop an oral solution. In this study, we assessed the solubility and preliminary stability of CARV in different pH media. Using malic acid as a solubility enhancer had satisfactory results. We studied the chemical, physical, and microbiological stability of 1 mg/mL CARV-malic acid solution. A design of experiment (DoE) was used to optimize the CARV solution's preparation parameters. A 1 mg/mL CARV solution containing malic acid was stable for up to 12 months at 25 °C and 30 °C and 6 months at 40 °C. An equation associating malic acid with CARV concentrations was obtained using DoE. Microbiological data showed that the use of methylparaben was not necessary for this period of time. We successfully developed an aqueous CARV solution suitable for paediatrics and proven to be stable over a 12-month period.

3D Printing of Personalised Carvedilol Tablets Using Selective Laser Sintering.

Selective laser sintering (SLS) has drawn attention for the fabrication of three-dimensional oral dosage forms due to the plurality of drug formulations that can be processed. The aim of this work was to employ SLS with a CO2 laser for the manufacturing of carvedilol personalised dosage forms of various strengths. Carvedilol (CVD) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) blends of various ratios were sintered to produce CVD tablets of 3.125, 6.25, and 12.5 mg. The tuning of the SLS processing laser intensity parameter improved printability and impacted the tablet hardness, friability, CVD dissolution rate, and the total amount of drug released. Physicochemical characterization showed the presence of CVD in the amorphous state. X-ray micro-CT analysis demonstrated that the applied CO2 intensity affected the total tablet porosity, which was reduced with increased laser intensity. The study demonstrated that SLS is a suitable technology for the development of personalised medicines that meet the required specifications and patient needs.

Supercritical fluid (SCF)-assisted preparation of cyclodextrin-based poly(pseudo)rotaxanes for transdermal purposes

This study aims to investigate the effect of the preparation of solid dispersions using supercritical CO2 (scCO2) on the physicochemical properties and the performance of supramolecular gels based on polymer-cyclodextrin (CD) interactions (named poly(pseudo)rotaxanes, PPR) envisaging a transdermal administration. Solid dispersions containing Soluplus®, the antihypertensive drug carvedilol (CAR), and CD (αCD or HPβCD) were prepared and characterized by HPLC, XRPD, FTIR, and DSC. PPRs prepared from solid dispersions (SCF gels) and the corresponding physical mixtures (PM gels) were analyzed regarding rheology, morphology, in vitro drug diffusion, and ex vivo drug skin permeation. The application of scCO2 led to the loss of the crystalline lattice of CAR while preserving its chemical identity. On the contrary, αCD crystals were still present in the SCF solid dispersions. SCF gels were more uniform than their corresponding PM, and the supercritical treatment resulted in changes in the rheological behavior, reducing the viscosity. CAR in vitro diffusion was significantly higher (p < 0.05) for the αCD-based SCF gel than its corresponding PM gel. Drug skin permeation showed a significant increase in drug flux from CD-based SCF gels (containing αCD or HPβCD) compared to corresponding PM gels. Additionally, the pretreatment of the skin with αCD exhibited increased CAR permeation, suggesting an interaction between αCD and the skin membrane. Results evidenced that SCF processing decisively modified the properties of the supramolecular gels, particularly those prepared with αCD.Graphical

A COMPARATIVE QUALITY STUDY OF SELECTED AUTHORIZED AND SMUGGLED MEDICINES IN ADEN, YEMEN

In Yemen, most of the medicines are imported. Drugs that enter the country by legal means undergo some tests by Supreme Board for Drugs and Medical Appliances (SBDMA) to evaluate the quality of the product. However, some medicines enter the country illegally (smuggling) and this makes them bypass the evaluation of their quality by the SBDMA. This work was carried out to determine the physical quality control parameters of authorized and smuggled drug products marketed in Aden pharmacies. The authorized and smuggled brands of cefuroxime (CEF), atorvastatin (ATR), and carvedilol (CAR) tablets available in Aden pharmacies were selected. The tablets were evaluated for their physical properties and quality control parameters including weight variation, hardness, friability, and disintegration test. The level of drug content also was evaluated using UV spectroscopy. The physical assessment showed that the authorized and smuggled brands of the same products were uniform in shape, color, packing, and labeling information except for the registration number and manufacture date which were present only on the authorized brands. The three authorized and smuggled brands of CEF, ATR, and CAR complied with the official specifications for weight version, diameter, thickness and hardness, friability, and disintegration tests except for the hardness value of ATR. All authorized brands agreed with the label claims whereas some smuggled brands contained the appropriate active ingredients but did not contain the right amounts.

The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy.

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study's objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity.

Synthesis, characterization, biological and theoretical studies of a new Pd(II) complex of drug carvedilol: Strong anticancer activity against several cell lines

In this study, a new Pd(II) complex of the drug carvedilol (CAR), [Pd(CAR)2Cl2] (PdCAR), was synthesized and characterized using X-ray crystal structure determination, CHN elemental analysis, and FT-IR, 1H NMR and UV–Vis spectroscopies. The crystal structure of the above complex shows that the Pd atom lies on a center of symmetry and is coordinated by two ligands (CAR) and by two chloride anions in a square planar arrangement. It means that each carvedilol ligand is coordinating to the Pd atom in a monodentate fashion, via the aliphatic nitrogen atom. Theoretical studies showed that the nature of the bond between PdCl2 and two carvedilol ligands, similar to that between PdCl2 and two dimethylamine (DMA) ligands, is mainly electrostatic. Interestingly, the CAR−PdCl2 bond is stronger than the DMA−PdCl2 bond. The UV–Vis and NMR studies indicate that the PdCAR complex is stable in solution. The DNA interaction studies were performed using the molecular docking simulation. The results indicated that the binding affinity of the PdCAR for B-DNA is higher than that of the CAR. Furthermore, the cytotoxicity effects of CAR, PdCAR and cisplatin (CIS) against MCF-7, HepG2, SW-480, CT-26 and HEK-293 cell lines were also evaluated and compared by MTT assay. The results showed that the cytotoxicity of both CAR and PdCAR on the above cell lines in all cases, except MCF-7, is higher than that of CIS.

Carvedilol solubility enhancement by multicomponent crystallization with coformers of benzoic acid, isonicotinamide, and saccharin

Multicomponent crystallization is a method that can modify the physicochemical properties of Carvedilol (CVD), thereby increasing its solubility. Based on in silico screening the coformers (Benzoic Acid, Isonicotinamide, and Saccharin) showed non-covalent interactions with CVD, so the multicomponent crystal preparation of CVD by solvent evaporation method used these coformers with mole ratios of 1:1, 1:2, and 2:1. Multicomponent CVD:Isonicotinamide (1:2) exhibits increased saturation solubility of up to 140 mg/L and increased dissolution of up to 99.48%. The infra-red (IR) spectrum showed a peak shift, a thermogram pattern that was different from the DSC results, and a new peak on the XRD multicomponent crystal diffractogram indicating the formation of a new solid phase compared to pure Carvedilol. Therefore, the formation of multicomponent crystals can increase the solubility and dissolution rate of CVD, and all characteristics indicate the presence of interaction between CVD and Isonicotinamide, and the formation of a new solid phase.

Repurposing of carvedilol to alleviate bleomycin-induced lung fibrosis in rats: Repressing of TGF-β1/α-SMA/Smad2/3 and STAT3 gene expressions

Idiopathic pulmonary fibrosis (IPF) is the most widely studied interstitial lung disease. IPF eventually leads to respiratory insufficiency, lung cancer, and death. Carvedilol (CAR) is a third-generation β-adrenergic receptor antagonist with an α1-blocking effect. CAR demonstrates antifibrotic activities in various experimental models of organ fibrosis. Aims: This work is designed to explore the possible alleviating effects of CAR on bleomycin (BLM)-induced lung fibrosis in rats. Main methods: The BLM rat model of lung fibrosis was achieved by intratracheal delivery of a single dose of 5 mg/kg of BLM. Seven days following BLM injection, either prednisolone or CAR was orally administered at doses of 10 mg/kg once daily for 21 days to the rats. The actions of CAR were evaluated by lung oxidant/antioxidant parameters, protein concentration and total leucocyte count (TLC) in bronchoalveolar lavage fluid (BALF), fibrosis regulator-related genes along with the coexistent lung histological changes. Key findings: CAR effectively decreased lung malondialdehyde level, increased superoxide dismutase activity, declined both protein concentration and TLC in BALF, downregulated TGF-β1/α-SMA/Smad2/3 and STAT3 gene expressions, and repaired the damaged lung tissues. Significance: CAR conferred therapeutic potential against BLM-induced lung fibrosis in rats, at least in part, to its antioxidant, anti-inflammatory, and antifibrotic activities. CAR could be utilized as a prospective therapeutic option in patients with lung fibrosis in clinical practice.

Abstract 5250: Effect of the β-blocker carvedilol in preventing DMBA-induced mammary gland tumor growth

Abstract According to global cancer statistics, breast cancer has now become the most diagnosed cancer and has become the fifth leading cause of cancer-related deaths worldwide. A promising method of retarding cancer-related mortality is cancer chemoprevention. However, there is no drug available that can be used routinely as a breast cancer-preventative agent. As carvedilol (CAR), an FDA-approved beta-adrenergic receptor blocker, reduces breast cancer mortality, we hypothesized that CAR might act as a breast cancer preventative agent. Three protocols were utilized to evaluate the ability of CAR to prevent 7,12-Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats. In protocol 1, two doses of CAR (2 and 10 mg/kg) were administered in drinking water as a 7-day pretreatment and throughout the study. In protocol 2, 10 mg/kg tamoxifen and 10 mg/kg carvedilol were provided as a 7-day pretreatment, and treatment was halted after six weeks. In protocol 3, CAR and the non-β-blocking enantiomer R-carvedilol (10 mg/kg) were given as a 7-day pretreatment and throughout the study. In all studies, animals were palpated weekly beginning at week 5 to detect the presence and location of mammary tumors. Tumors were measured using a caliper, and the experiments terminated at week 13. In protocol 1, only 10 mg/kg CAR was effective in delaying DMBA-mediated tumor occurrence (p = 0.0002); the first appearance of tumors and median tumor appearance in CAR-treated rats were separated from rats receiving DMBA alone by 2 and 4 weeks, respectively. However, tumors that did form grew at the same rate in all groups. In protocol 2, tamoxifen served as a control to prevent DMBA-mediated tumors; only one tamoxifen-treated rat developed a tumor at the end of the study. The tamoxifen-treated rats tumor formation was not statistically different than negative controls; however, the CAR group was not statistically different from the DMBA group. In protocol 3, CAR and R-CAR treatment showed delayed tumor formation and growth compared to the DMBA-only group, although not statistically significant. Combining all DMBA and 1-week pretreatment CAR data (n = 58 and 40, respectively), CAR effectively prevents DMBA-induced tumor incidence (p = 0.001), with a 3-week differential in the median tumor formation between the two groups. Therefore, continuous CAR treatment is essential to achieve the observed chemopreventive effects. As carvedilol is a clinically used beta-blocker, the results provide significant implications in breast cancer chemoprevention. Citation Format: Pabitra Kumar Sardar, Steven Yeung, Ayaz Shahid, Bradley T. Andresen, Ying Huang. Effect of the β-blocker carvedilol in preventing DMBA-induced mammary gland tumor growth. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5250.

Acetovanillone augmented the cardioprotective effect of carvedilol against cadmium-induced heart injury via suppression of oxidative stress and inflammation signaling pathways

Cardiac toxicity is a public health issue that can be caused by both environmental and occupational exposures. The current study aimed to investigate the effectiveness of carvedilol (CV), Acetovanillone (ACET), and their combination for ameliorating cadmium (Cd)-induced oxidative stress, inflammation, and necroptosis. Rats were assigned to; the normal group, Cd group (2 mg/kg; i.p., single dose), and the other three groups received orally CV (10 mg/kg), ACET (25 mg/kg), and CV plus ACET, respectively and a single dose of Cd. Oral administration of CV, ACET, and their combination significantly dampens cardiac oxidative injury by increasing antioxidants GSH and SOD levels, while it decreases MDA and NADPH oxidase levels mediated by decreasing cardiac abundance of Nrf2, HO-1, and SIRT1 and downregulating KEAP-1 and FOXO-3 levels. Also, they significantly attenuated inflammatory response as indicated by reducing MPO and NOx as well as proinflammatory cytokines TNF-α and IL-6 mediated by downregulating TLR4, iNOS, and NF-κB proteins expression as well as IκB upregulation. Moreover, they potently counteracted cardiac necroptosis by downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins expression. Of note, the combination of CV and ACET have marked protection that exceeded each drug alone. Conclusively, CV ad ACET potently mitigated Cd-induced cardiac intoxication by regulating NADPH oxidase, KEAP-1/Nrf2/HO-1, SIRT1/FOXO-3, TLR4/NF-κB/iNOS, and RIPK1/RIPK3/MLKL signals.

Characterization of co-amorphous carvedilol–maleic acid system prepared by solvent evaporation

The aim of this study was to enhance the solubility and stability of the water-insoluble drug carvedilol (CAR) with maleic acid (MLE) to create a co-amorphous system by a solvent evaporation method. Phase diagrams of co-amorphous CAR–MLE, constructed from peak height in the Fourier-transform infrared (FTIR) spectra and the glass transition temperature (Tg) from differential scanning calorimetry (DSC) measurements, revealed that the optimal molar ratio of CAR to MLE was 2:1. The FTIR spectra indicated that the secondary amine-derived peak of CAR and the carboxy group-derived peak of MLE disappeared in the CAR:MLE (2:1) co-amorphous system. DSC measurements showed that the endothermic peaks associated with the melting of CAR and MLE disappeared and a Tg at 43 °C was apparent. Furthermore, the solubility of CAR tested using the shaking flask method for 24 h at 37 °C was 1.2 μg/mL, whereas that of the co-amorphous system was approximately three times higher, at 3.5 μg/mL. Finally, the stability was evaluated by powder- X-ray diffraction at 40 °C; no clear diffraction peaks originating from crystals were observed in the amorphous state until after approximately three months of storage. These results indicate that co-amorphization of CAR with MLE improved the solubility of CAR while maintaining its stability in an amorphous form.

Supersaturation maintenance of carvedilol and chlorthalidone by cyclodextrin derivatives: Pronounced crystallization inhibition ability of methylated cyclodextrin

Cyclodextrin (CD) is used to solubilize poorly water-soluble drugs by inclusion complex formation. In this study, we investigated the effect of CD derivatives on stabilizing the supersaturation by inhibiting the crystallization of two poorly water-soluble drugs, carvedilol (CVD) and chlorthalidone (CLT). The phase solubility test showed that β-CD and γ-CD derivatives enhanced the solubility of CVD to a greater extent, whereas the solubility of CLT was enhanced more by β-CD derivatives. The solubilization efficacy of CD derivatives was dependent on the size fitness between the drug molecule and the CD cavity. In the drug crystallization induction time measurement, the same initial drug supersaturation ratio (S) was employed in all the CD solutions, and the methylated CD derivatives greatly outperformed unmethylated CD derivatives in stabilizing the supersaturation of both CVD and CLT. The crystallization inhibition strength of CD derivatives was strongly affected by the CD derivative substituent. Moreover, the calculated logarithm of octanol/water partition coefficients (log P) of CD derivatives showed a good correlation with drug crystallization inhibition ability. Thus, the high hydrophobicity of methylated CD plays an essential role in inhibiting crystallization. These findings can provide a valuable guide for selecting appropriate stabilizing agents for drug-supersaturation formulations.

Potential cardioprotective and anticancer effects of carvedilol either free or as loaded nanoparticles with or without doxorubicin in solid Ehrlich carcinoma-bearing mice

AimThe aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. MethodsCAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. ResultsThere was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. ConclusionCAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.

Solubility Enhancement of Carvedilol by Solid Dispersion Technique Using Sodium Alginate, Guar Gum, Xanthan Gum, and Locust Bean Gum as Polymers

Carvedilol (CVD) is a non-selective β-blocker. CVD is included in BCS class II. It has low water solubility. In this research, solid dispersion was used to increase the solubility and dissolution profile of CVD. In silico study using the ligand-ligand docking method. The preparation of solid dispersion using the kneading method with a weight ratio of 1:1, 1:2, 1:3, and 1:4, evaluation of solid dispersion includes solubility and dissolution. The best solid dispersion was characterized using FTIR, DSC, and PXRD. In silico study showed complexes CVD-SA, CVD-GG, CVD-XG and CVD-LBG have a hydrogen interaction. SA and XG were chosen as carriers in solid dispersion. CVD solid dispersion showed increased solubility in all samples, with the highest increase at 90.63 times at CVD: XG (1:4). The results of the dissolution profile obtained at 60 min are 64.95 ± 0.45% at pure CVD, 83.32 ± 1.19% at CVD:SA (1:4), and 72.56 ± 3.62% at CVD: XG (1:4). The FTIR spectrum indicates an interaction between CVD and SA. The thermogram indicated the amorphous drug, and the diffractogram showed a decrease in crystallinity. Solid dispersion is proven to increase the solubility and dissolution profile of CVD. Solid dispersion CVD: SA (1:4) showed the highest solubility and dissolution profile.

Formulation and evaluation of mucoadhesive chitosan microspheres of carvedilol for nasal administration

The aim of this study was to develop and characterize chitosan microspheres of Carvedilol (CRV) for nasal delivery to improve bioavailability for treatment of hypertension and angina pectoris. Carvedilol comes under BCS class II, is poorly water soluble drug and highly permeable. Solubility of drug is determined by shaking flask method and lipophilicity of drug is determined by separating funnel method. The nasal route is very convenient for achieving high bioavailability and reduce hepatic first pass metabolism. Chitosan is obtained from chitin of fish, is biodegradable and nontoxic that is suitable for nasal administration. The microspheres were prepared by cross- linking method using glutaraldehyde as cross linking agent and this preparation is evaluated for size, entrapment efficiency (EE), in vitro mucoadhesion, in vitro drug release. The mucoadhesive property was also evaluated by in vitro wash off test. The microspheres were spherical with size of 15-40 micron, which is favorable for intranasal absorption. The EE was observed from 40% to 88% while percentage of mucoadhesion was from 74%to 88%. A strong interaction between mucin and chitosan microspheres was detected explaining absorption with electrostatic interaction. The microspheres released around 80% of drug in 6h. It was concluded that chitosan microspheres could be used to deliver CRV following nasal administration for improving the bioavailability.

Considerations on the Kinetic Processes in the Preparation of Ternary Co-Amorphous Systems by Milling

In non-strongly interacting co-amorphous systems, addition of a polymer, to further stabilize the co-amorphous systems, may influence the phase behavior between the components. In this study, the evolution of the composition of the amorphous phase in the ternary system carvedilol (CAR)-tryptophan (TRP)-hydroxypropylmethyl cellulose (HPMC) was investigated, based upon previously formed and characterized binary systems to which the third component was added (CAR - TRP + HPMC, CAR - HPMC + TRP and TRP - HPMC + CAR). Ball milling was used as the preparation method for all binary and ternary systems. The influence of the milling time on the co-amorphous systems was monitored by DSC and XRPD. Addition of HPMC reduced the miscibility of CAR with TRP due to hydrogen bond formation between CAR and polymer. These bonds became dominant for the interaction pattern. In addition, when CAR or TRP exceeded the miscibility limit in HPMC, phase separation and eventually crystallization of CAR and TRP was observed. All ternary co-amorphous systems eventually reached the same composition, albeit following different paths depending on the initially used binary system.