医药学英文文献概要

AbstractMeloxicam- -cyclodextrin (ME- -CD) inclusion complex was prepared by a fluid-bed coating technique upon solvent removal and simultaneousdepositing onto the surface of nonpareil pellets and using PVP K30 as a binding agent to facilitate good coating. The resultant pellets werespherical and intact in shape with good flowability and friability. SEM analysis showed that the pellets were smooth and had a tightly coatedinclusion complex layer. In vitro dissolution of the inclusion complex pellets in pH 7.4 phosphate buffer was dramatically enhanced at an ME/CDratio of 1/1. DSC and powder X-ray diffractometry proved the absence of crystallinity in the ME/CD inclusion complexes. Moreover, Fouriertransform-infrared spectrometry together with Raman spectrometry indicated that the thiazole ring of ME was possibly included in the cavity of-CD. 2008 Chinese Society of Particuology and Institute of Process Engineering, Chinese Academy of Sciences. Published by Elsevier B.V. Allrights reserved.Keywords: Meloxicam; Inclusion complex; -Cyclodextrin; Fluid-bed; Pellets; Dissolution; Characterization1. Introduction Cyclodextrins (CDs) comprise a family of cyclic oligosaccha-rides, of which several members are used in many applicationsassociated with the pharmaceutical, agrochemical, fragrance,and food industries (Davis&Brewster, 2004). Basic CDs ofpharmaceutical interest contain six (a-CD), seven ((3-CD) andeight (y-CD) (a一1,4)-linked a-n-glucopyranose units (Brewster&Loftsson, 2007). Due to the chair configuration of theglucopyranose units, the CDs take the shape of a truncatedcone or torus with the hydroxyl groups oriented to the coneexterior, which makes the entire CD molecule water-soluble(Loftsson&Brewster, 1996; Stella&Rajewski, 1997). Thecentral cavity of the CD molecule is lined with skeletal car-bon and ethereal oxygen moieties of the glucose residue,which make it relatively apolar and creates a hydropho-bic microenvironment (Loftsson&Brewster, 1996; Stella&Rajewski, 1997). These properties endow the CDs with theability to host a variety of hydrophobic guest molecules toform inclusion complexes. The encapsulation of drug moleculesinto the hydrophobic cavities is aimed at improving theirsolubility, stability and other properties, and has been thebasis of many pharmaceutical applications (Figueiras, Car-valho, Ribeiro, Tomes-Labandeira,&Veiga, 2007; Jun et al.,2007). CD inclusion complexes are usually prepared as pow-ders before formulation by means of precipitation fromsaturated aqueous solution (Latrofa et al., 2001), kneading(Rajendrakumar, Madhusudan,&Pralhad, 2005), freeze-drying (Bouquet et al., 2007), and spray-drying (Lin&Kao,1989). However, each method has several limitations includingexcessive consumption of energy and time, and tedious pre-formulation treatment such as pulverization, sieving andmixing.The extra formulation processing inevitably brings about extracosts and variation in product quality as well as lower productiveefficiency. Fluid-bed coating is a "one-step" technique that is commonlyused to perform film coating based on the process of solventevaporation and simultaneous co-precipitation of the coatingmaterials onto a substrate. In previous study (Sun et al., 2008;Y. lu et al. / PartirZhang et al., 2008), this technique has been employed to pro-duce solid dispersion dosage forms in one step. The processinvolves spraying of the solution of drug/carrier and subse-quent deposition of the co-precipitate onto nonpareil pelletsin the drying airflow in a fluid-bed coater. Since preparationof inclusion complexes also involves the process of solventremoval, fluid-bed coating has been attempted to produce inclu-sion complexes in our earlier studies (Zhang et al., 2009). Forease of manipulation, we previously selected 2-hydroxypropyl-p-CD as the host material because of its high solubility bothin aqueous and organic solvents. Preliminary results by SEMrevealed a loosely packed layer of inclusion complexes whichnecessitate improvement of the compactness and robustnessof the coating layer. Furthermore, sincep-CD is more eco-nomic and frequently used in oral formulations, it is mandatoryto prepare inclusion complex pellets using this less solubleCD. Meloxicam (ME) (Fig. 1) is a highly potent non-steroidalanti-inflammatory drug (NSAID) that is highly effective againstvarious arthritic conditions (Noble&Balfour, 1996). LikemanyNSAIDs, meloxicam is practically water-insoluble atphysiolog-ical pH, and the rate of absorption is relatively slow after oraladministration (Busch et al., 1998; Hanft, Turck, Scheuerer,&Sigmund, 2001; Tiirck, Roth,&Busch, 1996). Thus, as a ClassII compound according to the Biopharmaceutics ClassificationSystem (Lipka&Amidon, 1999), increasing the aqueous solu-bility of meloxicam is of therapeutic importance. Meloxicam CDinclusion complexes have been prepared by conventional knead-ing and co-evaporation methods (Naidu et al., 2004; Naidu,Chowdary, Murthy, Becket,&Crooks, 2007). In this study,meloxicam-(3-CD inclusion complex was prepared by the fluid-bed coating method using PVP K30 as binder to achieve acompact coating of the inclusion complex. Although physi-cal characterization of meloxicam-CD inclusion complexes hasbeen performed in previous work (Naidu et al., 2004, 2007), thephysical state of meloxicam-CD inclusion complexes preparedby the fluid-bed coating method has not been characterized.Herein, the resultant inclusion complex pellets were character-ized by dissolution study, DSC, powder X-ray diffractometry,FT-IR and Raman spectrometry to find evidence of inclu-sloe.2. Materials and methods2.1. Materials Meloxicam (ME) was purchased from Wanqing Pharma-ceutical Co. Ltd. (Suzhou, China).p-cyclodextrin(p-CD,Yingmei)) was purchased from Yongguang CyclodextrinCo. Ltd. (Guangdong, China). Nonpareil pellets (Suglets)PF101, 710-850 p,m) were provided by NP Pharm (Bazainville,France). Polyvinyl pyrrolidone (PVP) K30 was kindly giftedfrom China Division, ISP Chemicals Co. (Shanghai, China).Chromatographic methanol was a TEDIA product (USA).Deionized water was prepared by a Milli-Q water purifyingsystem (Millipore, USA). All other reagents were of analyticalgrade.2.2. Preparation of inclusion complex pellets ME-p-CD inclusion complex pellets were prepared in a Mini-Glatt fluid-bed coater (Wurster insert, Glatt GmbH, Binzen,Germany) (Sun et al., 2008; Zhang et al., 2009). Limited byits poor solubility in water at ambient temperature,p-CD wasfirst dissolved in hot water and kept at 80 0C. ME was dis-solved in 60% ethanol aqueous solution (adjusted to pH 11.0with NaOH) under continuous stirring until complete disso-lution. The ME solution was added gradually to thep-CDsolution with intensive agitation, after which the mixture wasallowed to cool down to about 40 0C under stirring. PVP K30was added to the resulting solution at a ratio of 1/3 to the totalsolid of ME-(3-CD. The final solution was then sprayed througha nozzle onto fluidized nonpareil cores. The detailed operat-ing conditions were as follows: inlet air temperature, 40 0C;product temperature, 35 0C; air flow rate, 98 m3/h; spray rate,1.0 ml/min; atomizing air pressure, 1.4-1.5 bar; spray nozzlediameter, 0.5 mm. After completion of complex layering, thepellets were dried for a further 15 min at 35 0C. The inclu-sion complexes were prepared at stoichiometric ME/CD ratioof 1/1 and other two ratios of 1/2 and 2/1. Recoveries werecalculated as: Recovery(%)=Wpellet/} Wnonpareil+WS) x 100%,where Wpellet} Wnonpareu and WS denote the weight of inclu-sion complex pellets collected after coating, the weight ofnonpareil pellets and the weight of total solid in sprayfluid. To circumvent the interference of nonpareil cores on physi-cal characterization, the ME-p-CD inclusion complex was alsoprepared by spraying into the drying chamber without nonpareilcores under the same coating conditions and collected at thebottom..Characterization of inclusion complex pelletsThe coating weight gain (CWG)(%，w/w) was used to defineweight percent of the inclusion complex layer, and was cal-勺Je2.thculated as: CWG(%)=( Wtot一Wsub)/Wsub X 100%, where Wtotand Wsub denote the weight of the final inclusion complex pel-lets and the weight of the original nonpareil cores, respectively(Zhang et al., 2009). The flowability of the inclusion complex pellets wasdetermined using angle of repose (B) measurements. The mea-surement assembly was composed of a funnel hanging directlyover the center of a receiving culture dish with a diameter of8 cm. The pellets were allowed to fall through the nozzle of thefunnel and heap into a cone in the culture dish. The radius andheight of the heap were measured and the angle of repose wascalculated as: B=arctg (hlr), where h and r were the height andradius of the cone. The friability of the inclusion complex pellets was determinedusing a Chinese Pharmacopoeia appendix method originatedfor tablets. The pellets were weighed and run in a CJY-300Bfriabilator (Shanghai Huanghai Pharmaceutical Control Equip-ment Co. Ltd., China) for 4 min at 25 rpm. The pellets werethen dusted and reweighed. The friability was subsequently cal-culated as percentage of weight lost. A limiting value of 1%for friability tests has been suggested by the Chinese Pharma-copoeia. The size distribution of the pellets was determined using aset of standard industrial sieves of 18, 20, 24 and 26 meshes,respectively, and a sieve shaker (Octagon Digital, Endecotts,England) operated for 5 min at a frequency of 50 Hz andan amplitude of 1 mm. The weight retained in each frac-tion was determined by analytical balance (model BS210S,Sartorius, German) and the percentage of each fraction wascal cul ated.2.4. Determination of ME by HPLC ME in pellets and dissolution medium was determined byHPLC, a Chinese Pharmacopoeia monograph method. The Agi-lent 1100 series HPLC system (Agilent, USA) was composedof a quaternary pump, a degasser, an autosampler, a columnheater, and a tunable ultraviolet detector. ME was separatedby a C 18 column (Venusil XBP, 5 p,m, 4.6 mm x 150 mm,Agela, China) guarded with a refillable precolumn (C18,1.0 mm x 20 mm, Alltech, USA) at 30 0C and detected at270 nm. The mobile phase consisted of 55% methanol and 45%ammonium acetate aqueous solution (0.1 mol/L) pumped at aflow rate of 1.0 ml/min.2.5. Dissolution studies The dissolution studies were performed using a ZRS-8Gdissolution tester (Tianda Tianfa Technology Co. Ltd., Tian-jin, China) based on the Chinese Pharmacopoeia Method III(the small beaker-method). Inclusion complex pellets contain-ing 7.5 mg of ME were sealed in hard gelatin capsules andimmersed in 100 ml of pH 7.4 phosphate buffer thermostati-cally maintained at 37士0.5 0C at a rotation speed of 100 rpm.Aliquots of 5 ml sample were withdrawn at pre-determinedtime intervals and immediately filtered (Millex) AP, Milli-pore, 0.4 p,m). The filtrate was analyzed by HPLC for ME asdescribed above. In the meantime, an equal volume of the blankmedium of the same temperature was added to keep constantvolume.2.6. Scanning electron microscopy (SEM) Both surface and cross-section morphology of the inclu-sion complex pellets were observed under a scanning electronmicroscope (Philips XL30 Series, Holland). Prior to the exam-ination, samples were fixed on a brass stub using double-sidedtape and then gold coated in vacuum by a sputter coater.The pictures were then taken at an excitation voltage of10 k V.2.7. Differential scanning calorimetry (DSC) Thermal analysis of the samples (ME,p-CD, physical mix-ture and inclusion complex powder) were carried out with aDSC 204A/G Phoenix) Instrument (Netzsch, Germany). About5 mg of sample was weighed into a non-hermetically sealed alu-minum pan. The samples were heated from 20 to 320 0C at aheating rate of 5 0C/min. All the DSC measurements were madein nitrogen atmosphere and the flow rate was 100 ml/min.2.8. Powder X-ray diJ为}actome抑(PXRD少 PXRD of the samples (ME,p-CD, physical mixture andinclusion complex powder) was performed with an X"pert PROX-ray diffractometer (Panalytical, Holland) over the 2.5-500 2Brange at a scan rate of 40/min, where the tube anode was Cuwith Ka=0.154 nm monochromatized with a graphite crystal.The pattern was collected with 40 kV of tube voltage and 40 mAof tube current in step scan mode (step size 0.02, counting time1 s/step).2.9. Fourier transform-infrared spectrometry (FT-IR) FT-IR spectra of the samples (ME,p-CD, physical mixtureand inclusion complex powder) were obtained on a NicoletAvatar 360 spectrometer (U.S.). The samples were first groundand mixed thoroughly with KBr, an infrared transparent matrix.The KBr disks were prepared by compressing the powder. Thescans were obtained from 4000 to 400 cm一1 at resolution of1 c,”一1.2.10. Raman spectrometry The Raman spectra of the samples (ME,p-CD, physical mix-ture and inclusion complex powder) were collected utilizing a1800 back scattering geometry and a LabRAM FT-Raman spec-trometer (Horiba Jobin Yvon, France). Radiation of 785 nm froma He:Ne laser was applied for excitation, and the signals wererecorded by CCD detector with a resolution of 1 cm一1.3. Results and discussion3.1. Preparation of inclusion complex pellets The synthesized ME-p-CD inclusion complex, in differentratios and various CWGs, were successfully deposited ontopellet substrates with recoveries of over 90%. The resultingpellets were spherical and intact in shape. The inclusion com-plex pellets showed a smooth surface with only minor crevicesas observed by SEM (Fig. 2A and B), highly in contrast tothe rough surface found for piroxicam-hydroxypropyl-p-CDinclusion complex pellets as described in our previous stud-ies (Zhang et al., 2009). The cross-section view confirmed alayer of tightly coated inclusion complexes around the non-pared core (Fig. 2C) again in contrast to the loosely natureof the piroxicam-hydroxypropyl-p-CD inclusion complex pel-lets (Zhang et al., 2009). As CDs are weak binders, inclusioncomplexes can only be coated at a lower density, which ren-ders them sensitive to pressure damage (Zhang et al., 2009).In this study, PVP K30, a good binder extensively used as acoating material, was employed to bind the ME-p-CD inclusioncomplex. The resulting coating layer showed a smooth surface,high density, reduced thickness androbustness as compared withthe piroxicam-hydroxypropyl-p-CD coating layer without anybinder (Zhang et al., 2009). With the aid of PVP K30, the diameter of the final pelletsshowed only a slight increase in size as compared to piroxicam-hydroxypropyl-p-CD inclusion complex pellets (Zhang et al.,2009). At a CWG of about 100% and ME-(3-CD ratio of 1/1, thediameter of 43.78% of the pellets increased from 0.71-0.85 mm(nonpareil cores) to 0.80-0.90 mm, while the diameter of theremaining 56.22% increased to 0.90-1.00 mm. The angle ofrepose was (22.27士5.620), indicating good flowability, and theweight loss was well below 0.5%, indicating a good friabil-ity. To perform uniform coating, the inclusion complex wassprayed into the drying chamber in solution form. However, thisis difficult forp-CD because its solubility in water is rather low(18.5 mg/ml, 20 0C) (Brewster&Loftsson, 2007). In prelimi-nary studies,p-CD was heated to 80 0C to dissolve completelybefore coating, but precipitation ofp-CD in the spray supplyingtube occurred as a result of temperature decrease. It was desir-able to increase the solubility ofp-CD to prevent precipitationduring the coating process. It is interesting to find that no pre-cipitation was observed during the whole coating process whensodium hydroxide was added to facilitate solubilization of ME.It seemed that sodium hydroxide functioned to increase the solu-bility ofp-CD in the final coating fluid after mixing both aqueousp-CD solution and ME ethanol solution and to prevent precipi-tation during the temperature decreasing process. Solubility ofp-CD in the mixed solution (20% aqueous ethanol solution withNaOH at pH of 10.8) was found to be 192.3士25.4 mg/g, whileit was only 22.6士0.9 mg/g (25 0C) in the same solution withoutsodium hydroxide. In a preliminary study, a weak base (ammo-nia water) was used as a solubilizer of ME. During the processof mixing the aqueousp-CD with the aqueous ethanol ME solu-tion and subsequent cooling, both ME andp-CD had a tendencyto precipitate. In contrast, when a stronger base like sodiumhydroxide was used to adjust the pH of the final spraying fluidto over 10.0, precipitation did not occur. Under such conditions,ME retained sufficient stability and no discernable alterationswere observed forp-CD and its products. On the whole, it is just all the above mentioned excellentfeatures, including gentle condition of the fluid-bed coatingmethod, stability of ME andp-CD in selected medium and quickprecipitation onto the surface of the pellet, as well as the robust-ness of the resulting coating layer, that contribute to the goodreproducibility of the produced pellets with difference amongdifferent batches of less than 5% both in content and dissolutionat 45 min (data not shown).3.2. Enhanced dissolution Dissolution of the inclusion complex pellets was studied atpH 7.4 in phosphate buffer. Since the solubility of ME at pH7.4 phosphate buffer was determined to be 1.09士0.01 mg/mlin preliminary studies (25 0C), a volume of 100 ml dissolutionmedium was considered sufficient to provide a sink condition forthe dissolution of as much as 7.5 mg of ME. Dissolution profilesof ME powder, ME/p-CD physical mixture (PM) at the ratioof 1/1, and inclusion complex pellets (IPs) at different ME/CDratios of 2/1, 1/1, and 1/2 andatafixed theoretical CWGof 100%were investigated and are shown in Fig. 3. As a water-insoluble drug, the dissolution of ME powderwas limited with a total of less than 15% dissolution at 45 min.For ME/p-CD physical mixture (1/1), about 6% and 60% dis-solution were observed at 15 min and 45 min, respectively. Theincrease in dissolution rate may be explained on the basis of thesolubilization of the drug in aqueousp-CD solutions (Corrigan&Stanley, 1982; Ghorab, Abdel-Salam, El-Sayad,&Mekhel,2004). However, after being formulated into inclusion complexpellets, the dissolution rate of ME increased significantly withover 90% dissolution within the initial 15 min. Since ME formedan inclusion complex withp-CD at a stoichiometric ratio of 1/1(Naidu et al., 2004), the enhancement of ME dissolution wasmore significant at ME/p-CD ratios of 1/1 and 1/2. As for theME/p-CD 2/1 system, there was "excess" amount of ME andan enhancement of dissolution was not as significant, indicatingincomplete inclusion.3.3. Differential scanning calorimetry The thermogram of ME showed a sharp endothermic peakat 264.6 0C corresponding to its melting point (Fig. 4A). TheDSC thermogram ofp-CD showed a broad endothermic effect,ranging from 70 to 170 0C (Fig. 4B), which may be attributableto the dehydration process. In the case of the ME/p-CD binarysystems, the characteristic thermal profile of ME was invariablypresent in the physical mixtures with a shift to a lower temper-ature (Fig. 4C). On the contrary, the binary systems preparedby the fluid-bed coating method showed the complete disap-pearance of the ME end。