Dual Activity of Hydroxypropyl-beta;-Cyclodextrin and Water-Soluble Carriers on CarvedilolIntroduction:Carvedilol (CAR) is a non-selective alpha; and beta; blocker categorized as class II drug with low water solubility. Several recent studies have investigated ways to overcome this problem. The aim of the present study was to combine two of these methods: the inclusion complex using hydroxypropyl-beta;-cyclodextrin (HPbeta;CD) with solid dispersion using two carriers: Poloxamer 188 (PLX) and Polyvinylpyrrolidone K-30 (PVP) to enhance the solubility, bioavailability, and the stability of CAR. Kneading method was used to prepare CAR-HPbeta;CD inclusion complex (KD). CAR-carrier and KD- carrier solid dispersions were prepared by solvent evaporation method. In vitro dissolution test was conducted in three different media: double-distilled water (DDW), simulative gastric fluid (SGF), and PBS pH 6.8 (PBS). The interactions between CAR, HPbeta;CD, and different carriers were explored by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (XRD), and differential scanning colorimetry (DSC). The results showed higher solubility of CAR in KD-PVP solid dispersions up to 70, 25, and 22 fold compared to pure CAR in DDW, SGF, and PBS, respectively. DSC and XRD analyses indicated an improved degree of transformation of CAR in KD-PVP solid dispersion from crystalline to amorphous state. This study provides a new successful combination of two polymers with the dual action of HPbeta;CD and PLX/PVP on water solubility and bioavailability of CAR.Literature review:(1) CAR, 1-(9H-Carbazol-4-yloxy)-3-{[2-(2- methoxyphenoxy) ethyl] amino} -2-propanol (Fig. 1a), is a beta;-blocker used to treat heart failure and hypertension (2) CAR, discovered by Fritz Wiedemann(3)is a white crystalline powder soluble in organic solvents and was classified, according to the Biopharmaceutical Classification System, as class II drug with low aqueous solubility (68 mu;g/ml)(4) Its water solubility is a fundamental property that affects drug absorption after oral administration. Moreover, its dissolution and gastrointestinal permeability are the parameters that control its bioavailability (5) The most frequent causes of low oral bioavailability are attributed to poor solubility and low permeability.Cyclodextrins are cyclic (alpha;-1,4)-linked oligosaccharides of alpha;-D-glucopyranose, containing a relatively hydrophobic central cavity and hydrophilic outer surfaceResearch problem: Dual Activity of Hydroxypropyl-beta;-Cyclodextrin and Water-Soluble Carriers on the Solubility of CarvedilolResearch objectives: It improves the solubility of carvedilol which is a poorly soluble compoundMethods:Preparation of CAR-HPbeta;CD Inclusion ComplexCAR and HPbeta;CD complex in the molar ratio (1:1) was prepared by kneading technique. A small volume of methanol/water (1:1 v/v) solution was added to the required quantity of HPbeta;CD to form a paste using a glass mortar.CAR equimolar was then added and triturated for 45 min until formation of a homogenous paste. The resultant mass was dried overnight at 40 2C in a hot air oven. The dried mass thus obtained was ground in a mortar, passed through sieve No. 80 (180 7.6 mu;m), and stored for further analysis.Preparation and Characterization of CAR-Carrier and KD- Carrier Solid DispersionsPreparation of CAR-Carrier Solid Dispersion. CAR solid dispersions in PLX and PVP were prepared, in the weightratio of 1:1 (PLX1, PVP1), 1:3 (PLX2, PVP2), and 1:5 (PLX3, PVP3), by solvent evaporation method (28,29). Accurately weighted amounts of PLX and PVP were dissolved in co- solvent of ethanol/methylene chloride 1:1 (v/v %) and methanol, respectively. Two hundred milligrams of CAR was dispersed in each solution and stirred for 60 min at room temperature using a magnetic stirrer to produce clear solutions. Organic solvents were then rapidly evaporated under vacuum using rotary evaporator at 50C. The resultant solid masses were crashed, desiccated overnight in electric oven at 40C, ground using glass mortar, passed through sieve No. 80 (180 7.6 mu;m), and stored for further analysis.Preparation of KD-Carrier Solid Dispersions. The new solid dispersions KD-PLX (SDPLX1, SDPLX2, SDPLX3) and KD-PVP (SDPVP1, SDPVP2, SDPVP3) were prepared using the method described above, where an accurately weighted amount of KD (containing 200 mg of CAR) was added to the prepared carrier solutions.Determination of the Saturation SolubilitySaturation solubility of the inclusion complex and solid dispersions was performed in DDW. An excess amount of each of the preparations was added to 25-ml volumetric flasks containing 10-ml distilled water. The solutions were shaken, for at least 48 h until equilibrium, using thermostatically controlled shaker at 37C. The solutions were transferred to tubes and centrifuged at 4000 rmp for 10 min. The superna- tant was withdrawn and filtered through a 0.45-mu;m membrane filter. The samples were assayed for drug content using UV spectrophotometer at 242 nm.In Vitro Dissolution StudiesIn vitro dissolution tests were performed using Intelligent Dissolution Tester (type ZRS-4) with three different dissolu- tion media: DDW, SGF, and PBS. Pure CAR, KD, and solid dispersions (equivalent to 12.5 mg of CAR) were added to 900 ml of medium (n = 3) at 37 0.5C and stirring rate of 100 rmp. Five milliliter of samples were withdrawn at specific time intervals. The same volume of fresh solution was replaced after each withdrawal. The samples were analyzed for drug content using UV spectrophotometer 242 nm. Dissolution performance was evaluated by calculating the dissolution efficiency (DE)References:1. Goodman LS. Goodman and Gilmans the pharmacologicalbasis of therapeutics. New York: McGraw-Hill; 1996.2. Wiedemann F, Kampe W, Thiel M, Sponer G, Roesch E,Dietmann K. Hypotensive, angina pectoris. Google Patents.1985.3. Vieth M, Siegel MG, Higgs RE, Watson IA, Robertson DH,Savin KA, et al. Characteristic physical properties and structuralfragments of marketed oral drugs. J Med Chem. 2004;47(1):22432.4. Amidon GL, Lennerns H, Shah VP, Crison JR. A theoreticalbasis for a biopharmaceutic drug classification: the correlationof in vitro drug product dissolution and in vivo bioavailability.Pharm Res. 1995;12(3):41320.5. Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics:past, present and future. Nat Rev Drug Discov.2004;3(12):102335. Epub 2004/12/026. Archontaki H, Vertzoni M, Athanassiou-Malaki M. Study onthe inclusion complexes of bromazepam with beta;-and beta;-hydroxypropyl-cyclodextrins. J Pharm Biomed Anal. 2002;28(3):7619.7. Popescu C, Manda P, Juluri A, Janga KY, Cidda M, Murthy SN.Enhanced dissolution efficiency of zaleplon solid dispersions viamodified beta;-cyclodextrin molecular inclusion complexes. 2015;1.8. Dandawate PR, Vyas A, Ahmad A, Banerjee S, Deshpande J,Swamy KV, et al. Inclusion complex of novel curcumin analogueCDF and beta;-cyclodextrin (1: 2) and its enhanced in vivoanticancer activity against pancreatic cancer. Pharm Res.2012;29(7):177586.9. Wang J, Cao Y, Sun B, Wang C. Characterisation of inclusioncomplex of trans-ferulic acid and hydroxypropyl-beta;-cyclodextrin.Food Chem. 2011;124(3):106975.10. Nguyen TA, Liu B, Zhao J, Thomas DS, Hook JM. Aninvestigation into the supramolecular structure, solubility, stabilityand antioxidant activity of rutin/cyclodextrin inclusioncomplex. Food Chem. 2013;136(1):18692.11. Xu C, Tang Y, Hu W, Tian R, Jia Y, Deng P, et al. Investigationof inclusion complex of honokiol with sulfobutyl ether-beta;-cyclodextrin. Carbohydr Polym. 2014;113:915.12. Wang D, Chen G, Ren L. Preparation and characterization ofthe sulfobutylether-beta;-cyclodextrin inclusion complex of amiodaronehydrochloride with enhanced oral bioavailability infasted state. 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