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1. Curr Drug Deliv. 2011 Apr 1.

[Epub ahead of print] Enhancement of Solubility and Permeability of Candesartan Cilexetil by Using Different Pharmaceutical Interventions. Shaikh SM, Avachat AM. Sinhgad College of Pharmacy, Vadgaon (Budruk), Pune-41, India. prof_avachat@yahoo.com. The poor solubility and wettability of Candesartan cilexetil (CAN) leads to poor dissolution and hence, low bioavailability after oral administration. The aim of the present study was to improve the solubility and dissolution rate and hence the permeability of CAN by preparing solid dispersions/inclusion complexes. Solid dispersions were prepared using PEG 6000 [hydrophilic polymer] and Gelucire 50/13 [amphiphilic surfactant] by melt agglomeration (MA) and solvent evaporation (SE) methods in different drug-to-carrier ratios, while inclusion complexes were made with hydroxypropyl- -cyclodextrin (HP- -CD) [complexing agent] by grinding and spray drying method. Saturation solubility method was used to evaluate the effect of various carriers on aqueous solubility of CAN. Based on the saturation solubility data, two drug-carrier combinations, PEG 6000 (MA 1:5) and HP- -CD (1:1 M grinding) were selected as optimized formulations. FTIR, DSC, and XRD studies indicated no interaction of the drug with the carriers and provided valuable insight on the possible reasons for enhanced solubility. Dissolution studies showed an increase in drug dissolution of about 22 fold over the pure drug for PEG 6000 (MA 1:5) and 12 fold for HP- -CD (1:1 M grinding). Ex-vivo permeability studies revealed that the formulation having the greatest dissolution also had the best absorption through the chick ileum. Capsules containing solid dispersion/ complex exhibited better dissolution profile than the marketed product. Thus, the solid dispersion/inclusion complexation technique can be successfully used for enhancement of solubility and permeability of CAN. PMID: 21453263 [PubMed - as supplied by publisher]

2. Pharmazie. 2011 Feb;66(2):119-23. Improvement of dissolution properties of lamotrigine by inclusion complexation and solid dispersion technique. Parmar Komal R, Satapara Vijay P, Shah Sunny R, Sheth Navin R.

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot, Gujarat, India. The aim of the present work was to improve the dissolution characteristics of the poorly water soluble antiepileptic drug lamotrigine (LMN) by inclusion complexation using hydroxy propyl beta-cyclodextrin (HP beta-CD) by co-evaporation technique and by, solid dispersion, prepared by the melt method using poloxamer 407 (L 127). Phase solubility studies showed AL type curves with both the carriers. Dissolution of LMN was significantly improved (p < 0.05) by inclusion complexation and solid dispersion preparation. Results of solid state characterization performed by Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry and Powder X-ray Diffractrometry techniques revealed a decrease in the crystallinity of LMN that might be accounting for improvement in the dissolution properties as seen from dissolution studies. PMID: 21434574 [PubMed - indexed for MEDLINE]

3. Drug Deliv. 2011 May;18(4):294-303. Epub 2011 Jan 10. Drug product development and pharmacological evaluation of a sparingly soluble novel camptothecin analog for peroral administration. Nekkanti V, Karatgi P, Paruchuri S, Pillai R. CPS Product Development, Dr Reddy's Laboratories Limited, Hyderabad-500090, India. This work focused on the developmental aspects, pharmacokinetic evaluation, and pharmacological assessment of a drug inclusion complex for a novel camptothecin analog (CA) and 2-hydroxypropyl- -cyclodextrin (HP- -CD). Camptothecins analog belong to topoisomerase-I inhibitor class of compounds with proven anti-tumor activity but exhibit poor solubility. To enhance solubility a drug inclusion complex with cyclodextrin was developed using a spray-drying process. The powder complex characterized using DSC, XRPD, FT-IR, and H NMR techniques confirmed interaction of cyclodextrin with the CA indicating formation of a true complex wherein the drug is encapsulated in the cyclodextrin cavity. The saturation solubility and dissolution kinetics of drug complex evaluated in a discriminating medium showed significantly higher solubility and faster dissolution as compared to a physical mixture or powder blend comprising of drug and cyclodextrin. Pharmacokinetic (PK) studies in Wistar rats indicated a significant increase in

the rate and extent of absorption for the drug complex as compared to a nanoparticulate dispersion that was used as the positive control. Pharmacological activity following peroral administration of drug complex in athymic nude mice with implanted tumors revealed that the tumor inhibition activity was equivalent to commercially available intravenous (IV) formulation with comparable safety profile. These studies demonstrated for the first instance feasibility of developing a safe and efficacious peroral formulation for a sparingly soluble camptothecin analog that may provide another viable, patient compliant, and cost effective option for the treatment of solid tumors. PMID: 21214430 [PubMed - in process]

4. J Pharm Pharmacol. 2011 Jan;63(1):19-25. doi: 10.1111/j.20427158.2010.01173.x. Epub 2010 Nov 16. Fast-dissolving sublingual solid dispersion and cyclodextrin complex increase the absorption of perphenazine in rabbits. Turunen E, Mannila J, Laitinen R, Riikonen J, Lehto VP, Jrvinen T, Ketolainen J, Jrvinen K, Jarho P. School of Pharmacy/Pharmaceutical Chemistry, University of Eastern Finland, Kuopio, Finland. elina.turunen@uef.fi OBJECTIVES: The sublingual administration route as well as solid dispersion formation with macrogol 8000 and complexation with -cyclodextrin ( -CyD) were investigated as ways for improving the absorption of perphenazine, a poorly water-soluble drug subjected to substantial first-pass metabolism. METHODS: The absorption of perphenazine was studied in rabbits after sublingual administration of perphenazine/macrogol solid dispersion, solid perphenazine/ -CyD complex and plain micronized perphenazine, as well as after peroral administration of an aqueous perphenazine solution. Solid formulations were prepared by freeze-drying (perphenazine/macrogol solid dispersion) or spray-drying (perphenazine/ -CyD complex). KEY FINDINGS: The value for area under the curve from 0 to 360 min (AUC(0-360 min) ) of perphenazine after peroral administration was only 8% of the AUC(0360 min) value obtained after intravenous administration, while the corresponding values for the sublingually administered formulations were 53% (perphenazine/macrogol solid dispersion), 41% (perphenazine/ -CyD complex) and 64% (micronized perphenazine). There are three possible mechanisms to explain these results: avoidance of the first-pass metabolism; good sublingual absorption

of perphenazine; and rapid dissolution rate of perphenazine from the studied formulations. CONCLUSIONS: With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, the solid dispersion preparation and cyclodextrin complexation were postulated to be useful ways to attain successful sublingual administration of perphenazine. Good sublingual absorption was also achieved by micronization of perphenazine. As far as we are aware, this paper is one of the first to evaluate the sublingual administration of a solid dispersion in vivo. PMID: 21155811 [PubMed - indexed for MEDLINE]

5. AAPS PharmSciTech. 2010 Dec;11(4):1730-7. Epub 2010 Dec 7. Polymeric surfactant based etodolac chewable tablets: formulation and in vivo evaluation. Ibrahim MM, El-Nabarawi M, El-Setouhy DA, Fadlalla MA. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt. Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potential antitumor and uric acid lowering effects. It shows dissolution rate-dependent bioavailability. This work was carried out to improve the dissolution rate of etodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl- -cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The dissolution rate of ET at pH 1.2 and 6.8 is improved in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. DSC of coevaporates at 1:5 drug/carrier ratio providing the fastest dissolution rate suggested loss of ET crystallinity which was further confirmed by X-ray diffraction. Inutec-based coevaporate was chosen for the formulation of ET chewable tablets. Chewable tablets (F3) that met the USP monograph specifications for ET tablets, with 86% dissolved amount within 15 min, was chosen for in vivo absorption study in comparison with pure ET-filled hard gelatin capsules. The results showed significantly higher mean C (max) and shorter mean T (max) (about 2 h earlier) and about 1.32-fold higher mean AUC(0-24) values for the F3 chewable tablets compared to ET-filled capsules. PMCID: PMC3011074 [Available on 2011/12/7] PMID: 21136309 [PubMed - in process]

6. Drug Dev Ind Pharm. 2011 Apr;37(4):373-86. Epub 2010 Sep 14. Solid dispersion of prednisolone: solid state characterization and improvement of dissolution profile. Palanisamy M, Khanam J. Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India. krpmohanraj@gmail.com BACKGROUND: Dissolution testing is an important test for judging the effectiveness of a pharmaceutical dosage form. Many drugs create adverse effect because of insufficient solubility at the physiological pH. This study is aimed to improve the dissolution properties of prednisolone (PRD) that falls under the category of class II biopharmaceutics system. METHODS: In this study, preparation of solid dispersions with various water-soluble carriers was studied to improve the dissolution of PRD. To obtain the optimized formulation, solid dispersions were prepared employing different methods using different carriers with various drug:carrier ratios. Their dissolution behaviors were also compared. Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction, and thermal analysis were studied to characterize the prepared solid dispersion. RESULTS: PRD formed stable complexes with carriers as indicated by the stability constants (K(a)) of 9.5-597.2 M(-1). The results indicated that in vitro dissolution rate of PRD was remarkably improved in the solid dispersion of the drug compared with physical mixture and drug alone. This can be attributed to improved wettability, dispersibility, decrease in crystallinity, and increase in amorphous fraction of the drug. The results obtained from Fourier transform infrared spectroscopy and powder X-ray diffraction showed good evidence of drug-carrier interaction while using carriers such as hydroxypropyl- -cyclodextrin (HP- CD) and polyethylene glycol (PEG). Crystallinity of the drug was reduced in the solid dispersions prepared with hydroxypropyl- -cyclodextrin, polyvinylpyrrolidone-co-vinyl acetate 64, and PEG as revealed from the differential scanning calorimetry thermograms. CONCLUSION: The results suggested that the solid dispersion with selected excipients is a powerful tool to accelerate the dissolution of poorly water-soluble drugs. PMID: 20839923 [PubMed - in process]

7. Int J Pharm. 2010 Nov 15;400(1-2):49-58. Epub 2010 Aug 27.

Risperidone solid dispersion for orally disintegrating tablet: its formulation design and non-destructive methods of evaluation. Rahman Z, Zidan AS, Khan MA. Division of Product Quality and Research, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. The focus of present investigation was to assess the utility of nondestructive techniques in the evaluation of risperidone solid dispersions (SD) with methyl- -cyclodextrin (MBCD) and subsequent incorporation of the SD into orally disintegrating tablets (ODT) for a faster release of risperidone. The SD was prepared by a solvent evaporation method and evaluated by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), near infrared spectroscopy (NIR), NIR-chemical imaging (NIR-CI), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). DSC and XRD analysis indicated that crystallinity of SD has reduced significantly. FTIR showed no interaction between risperidone and MBCD. Partial least square (PLS) was applied to the NIR data for the construction of chemometric models to determine both components of the SD. Good correlations were obtained for calibration and prediction as indicated by correlation coefficients >0.9965. The model was more accurate and less biased in predicting the MBCD than risperidone as indicated by its lower mean accuracy and mean bias values. SD-3 (risperidone:MBCD, 1:3) was incorporated into ODT tablets containing diluent (D-mannitol, FlowLac() 100 or galenIQ-721) and superdisintegrant (Kollidon() CL-SF, Ac-Di-Sol or sodium starch glycolate). Disintegration time, T(50) and T(90) were decreased in the formulations containing mannitol and Kollidon() CL-SF, but increased with galenIQ-721 and sodium starch glycolate, respectively. NIR-CI images confirmed the homogeneity of SD and ODT formulations. PMID: 20801200 [PubMed - indexed for MEDLINE]

8. Molecules. 2010 Jun 4;15(6):4067-84. Pharmaceutical composition of valsartan: beta-cyclodextrin: physico-chemical characterization and anti-hypertensive evaluation. Jensen CE, dos Santos RA, Denadai AM, Santos CF, Braga AN, Sinisterra RD. Departamento de Qumica, ICEx, Universidade Federal de Minas Gerais, Avenida Pres. Antnio Carlos 6627, 31270-901, Belo Horizonte, Brazil.

cej.jensen@gmail.com Valsartan, a water-insoluble drug, is mainly used in the treatment of hypertension albeit with reduced oral bioavailability. The aim of work was to develop a valsartan:beta-cyclodextrin (VAL:beta-CD) pharmaceutical composition in order to improve its water solubility and bioavailability. The VAL:beta-CD complexes were prepared by the kneading, solid dispersion and freeze-drying methods, of which the freeze-drying method (FDY) was found to be the best to prepare an inclusion complex. A physical mixture PM was also prepared. Complexes were characterized by thermal analysis, Fourier transformed-infrared (FTIR) spectroscopy, Powder X-ray diffractometry, intrinsic dissolution and NMR (2D-ROESY). Phase-solubility analysis showed A(L)-type diagrams with beta-cyclodextrin (beta-CD). Microcalorimetric titrations suggested the formation of 1:1 inclusion complex between VAL and beta-CD. The apparent stability constants K(1:1) calculated from phase-solubility plots were 165.4 M(-1) (298 K), 145.0 M(-1) (303 K) and 111.3 M(-1) (310 K). In vivo experiments in rats showed that reduction in arterial pressure for the FDY complex is better than with valsartan used alone. The better activity of FDY can be attributed to the higher solubility of valsartan after inclusion in the cyclodextrin cavity, as suggest by the intrinsic dissolution studies. PMID: 20657427 [PubMed - indexed for MEDLINE]

9. Int J Pharm. 2010 Aug 16;395(1-2):161-6. Epub 2010 May 24. Effect of the solid-dispersion method on the solubility and crystalline property of tacrolimus. Joe JH, Lee WM, Park YJ, Joe KH, Oh DH, Seo YG, Woo JS, Yong CS, Choi HG. College of Pharmacy, Yeungnam University, 214-1 Dae-Dong, Gyongsan 712-749, South Korea. Three solid dispersions containing poorly water-soluble tacrolimus were prepared with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and dioctyl sulfosuccinate (DOSS) using a spray-drying technique via the solvent-evaporation method with a methylene chloride/ethanol mixture, the solvent-wetting method with ethanol and the surface-attached method with water, respectively. The solubility and dissolution of the drug in the three solid dispersions were evaluated compared to drug powder. Furthermore, their physicochemical properties were investigated using SEM, DSC and powder X-ray diffraction. The solubility and dissolution of

the drug were significantly improved in the order of the tacrolimus-loaded solid dispersion prepared by: solvent-evaporation method>solvent-wetting method>surface-attached method. The solid dispersions prepared by solvent evaporation appeared as an aggregated form with the amorphous form. In particular, the solid dispersion prepared by the solvent-evaporation method improved solubility about 900-fold and dissolution of tacrolimus 15-fold because of its reduced particle size, increased surface area and close contact between the hydrophilic carrier and the drug. In the solvent-wetting method, the drug, which was changed to an amorphous form, was attached onto the surface of undissolved carriers. However, the solid dispersion prepared by the surface-attached method gave an unchanged crystalline form. In this solid dispersion, the carriers were attached to the surface of the undissolved drug, resulting in changing the drug from being hydrophobic to hydrophilic. As the crystal form of drug in this solid dispersion was not converted to the amorphous form unlike other solid dispersions, it gave relatively less solubility and dissolution of the drug than did the others. Thus, in the development of a solid-dispersion system containing poorly water-soluble drugs, the method of preparation plays an important role in the solubility and crystallinity of the drugs. PMID: 20580799 [PubMed - indexed for MEDLINE]

10. Eur J Pharm Sci. 2010 Mar 18;39(5):336-47. Epub 2010 Jan 20. In vitro characterization and pharmacokinetics in mice following pulmonary delivery of itraconazole as cyclodextrin solubilized solution. Yang W, Chow KT, Lang B, Wiederhold NP, Johnston KP, Williams RO 3rd. Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA. This study aims to make a 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) solubilized itraconazole (ITZ) solution (i.e., HPbetaCD-ITZ) suitable for pulmonary delivery by nebulization, and compare pharmacokinetics of inhaled nebulized aerosols of HPbetaCD-ITZ versus a colloidal dispersion of ITZ nanoparticulate formulation (i.e., URF-ITZ). Solid state characterizations of lyophilized HPbetaCD-ITZ by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) indicated the formation of dynamic inclusion complexes between ITZ and HPbetaCD. Nebulized aerosols of both HPbetaCD-ITZ and colloidal dispersion of URF-ITZ were confirmed suitable for deep lung delivery. Single doses of the nebulized aerosols (equivalent to 5.3mg ITZ/mL in 5 mL) in mice produced similar ITZ lung

depositions and pharmacokinetic profiles, with ITZ lung levels of approximately 4 microg/g wet lung weight upon completion of nebulization and remained above 0.5 microg/g at 24h. HPbetaCD-ITZ demonstrated faster systemic absorption of ITZ across lung epithelium than URF-ITZ, with t(max) values of 1.5 and 3.0 h, and AUC(0-infinity) of 2513 and 3717 ng h/mL, respectively. The fast absorption of solubilized ITZ across lung mucosal surface may be due in part to the elimination of the phase-to-phase transition. PMID: 20093186 [PubMed - indexed for MEDLINE]

11. Eur J Pharm Biopharm. 2009 Sep;73(1):154-61. Epub 2009 May 22. Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of superdisintegrants. Srinarong P, Faber JH, Visser MR, Hinrichs WL, Frijlink HW. Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands. P.srinarong@rug.nl In this study, it was shown that the incorporation of superdisintegrants in solid dispersion tablets containing a high drug load can strongly enhance the dissolution rate of the highly lipophilic drug fenofibrate. In addition, the dissolution rate was more increased when the superdisintegrant was incorporated in the drug containing solid dispersions than when it was physically mixed with the solid dispersions. The dissolution rate enhancement strongly depended on the type of superdisintegrants and increased in the order Polyplasdone XL-10<Polyplasdone XL<<Ac-Di-Sol approximately Primojel. The dissolution behavior also depended on the type of hydrophilic carriers. Solid dispersion tablets based on inulin 4 kDa, polyethylene glycol 20K and polyvinylpyrrolidone K30 showed a much faster dissolution than those based on mannitol and hydroxypropyl-beta-cyclodextrin. Finally, inulin 4 kDa-based solid dispersion tablets showed excellent storage stability, while polyethylene glycol 20K-and polyvinylpyrrolidone K30-based solid dispersion tablets did not. PMID: 19465121 [PubMed - indexed for MEDLINE]

12. J Pharm Pharmacol. 2008 Sep;60(9):1121-9. Enhanced solubility and dissolution rate of lamotrigine by inclusion complexation

and solid dispersion technique. Shinde VR, Shelake MR, Shetty SS, Chavan-Patil AB, Pore YV, Late SG. Department of Pharmaceutical Chemistry, Government College of Pharmacy, Karad, Maharashtra, 415124, India. The solid-state properties and dissolution behaviour of lamotrigine in its inclusion complex with beta-cyclodextrin (betaCD) and solid dispersions with polyvinylpyrrolidone K30 (PVP K30) and polyethyleneglycol 6000 were investigated. The phase solubility profile of lamotrigine with betaCD was classified as AL-type, indicating formation of a 1:1 stoichiometry inclusion complex, with a stability constant of 369.96+/-2.26 M(-1). Solvent evaporation and kneading methods were used to prepare solid dispersions and inclusion complexes, respectively. The interaction of lamotrigine with these hydrophilic carriers was evaluated by powder X-ray diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry. These studies revealed that the drug was no longer present in crystalline state but was converted to an amorphous form. Among the binary systems tested, PVP K30 (1:5) showed greatest enhancement of the solubility and dissolution of lamotrigine. PMID: 18718114 [PubMed - indexed for MEDLINE]

13. Eur J Pharm Biopharm. 2008 Sep;70(1):187-98. Epub 2008 Mar 20. Effect of formulation parameters on 2-methoxyestradiol release from injectable cylindrical poly(DL-lactide-co-glycolide) implants. Desai KG, Mallery SR, Schwendeman SP. Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA. The objective of this study was to investigate the potential of various formulation strategies to achieve 1-month continuous (improved) release of the novel anti-cancer drug, 2-methoxyestradiol (2-ME), from injectable cylindrical poly(DL-lactide-co-glycolide) (PLGA) implants. PLGA implants were prepared by a solvent extrusion method. PLGA 50:50 (M(w)=51 kDa, end group=lauryl ester) (PLGA-lauryl ester) implants loaded with 3-30 wt% 2-ME exhibited a pronounced lag phase (i.e., corresponding to induction time to polymer mass loss) and triphasic

release profile. Incorporation of 5 wt% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) (approximately 57% release after 28 days) or Pluronic F127 (approximately 42% release after 28 days) in PLGA-lauryl ester implants reduced the lag-phase and improved the drug release moderately over a period of 28 days. The formation and the incorporation of a 2-ME/polyethylene glycol (PEG) 8000 solid dispersion in PLGA-lauryl ester implants further increased drug release (approximately 21% and 73% release after 1 and 28 days, respectively), attributable to improved drug solubility/dissolution, higher matrix porosity, and accelerated polymer degradation. Blending of PLGA 50:50 (M(w)=24 kDa, end group=COOH) (PLGA-COOH) with the PLGA-lauryl ester also provided moderate enhancement of 2-ME release over a period of 28 days. PLGA-COOH (M(w)=24 kDa) implants with 3-5% w/w pore-forming MgCO(3) exhibited the most desirable drug release among all the formulations tested, and, demonstrated 1-month slow and continuous in vitro release of approximately 80% 2-ME after a minimal initial burst. Hence, these formulation approaches provide several possible avenues to improve release rates of the hydrophobic drug, 2-ME, from PLGA for future application in regional anti-cancer therapy. PMCID: PMC2884995 PMID: 18472254 [PubMed - indexed for MEDLINE] 14. Pharmazie. 2007 Aug;62(8):604-7. Enhancement of bioavailability and anthelmintic efficacy of albendazole by solid dispersion and cyclodextrin complexation techniques. Kalaiselvan R, Mohanta GP, Madhusudan S, Manna PK, Manavalan R. Department of Pharmacy, Annamalai University, Annamalai Nagar, Tamil Nadu, India. kalaipharmacy@yahoo.com The objective of this study was to improve the oral bioavailability and therapeutic efficacy of albendazole (ABZ) employing solid dispersion and cyclodextrin complexation techniques. Solid dispersion (dispersion) was prepared using ABZ and polyvinylpyrrolidone (PVP) polymer (1:1 weight ratio). Ternary inclusion complex (ternary complex) was prepared using ABZ, hydroxypropyl beta-cyclodextrin (HPbetaCD) and L-tartaric acid (1:1:1 molar ratio). In rabbits with high gastric acidity (gastric pH approximately 1), ternary complex and solid dispersion showed a bioavailability enhancement of 3.2 and 2.4 fold respectively, compared to a commercial suspension (p < 0.05). The rise in gastric pH (pH > 5) caused a 62% reduction in AUC (area under the plasma level curve) for the commercial suspension, whereas the reduction in case of PVP dispersion and ternary complex was only 43% and 37% respectively. The rapid absorption of the

drug from solid dispersion and ternary complex was reflected in improved anthelmintic efficacy against the systemic phases of Trichinella spiralis. The ternary complex was significantly more efficient than solid dispersion and exhibited the highest larvicidal activity (90%) at a dose of 50 mg x kg(-1) (p < 0.05). These results suggest that the bioavailability and therapeutic efficacy of the ternary complex might be high even if there is a great variation in the gastric pH. PMID: 17867556 [PubMed - indexed for MEDLINE]

15. Acta Pharm. 2005 Sep;55(3):223-36. Influence of cyclodextrin complexation on piroxicam gel formulations. Jug M, Be irevi -La an M, Kwokal A, Cetina-Cizmek B. Department of Pharmaceutics Faculty of Pharmacy and Biochemistry University of Zagreb, Zagreb, Croatia. mjug@pharma.hr The aim of this work was to evaluate the role of cyclodextrins in topical drug formulations. Solid piroxicam (PX) complexes with beta-cyclodextrin (beta-CD) and randomly methylated beta-cyclodextrin (RAMEB) were prepared by freeze-drying and characterized using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and near infrared spectroscopy (NIR). A physical mixture of PX and cyclodextrins was characterized by enhanced dissolution properties compared to the dissolution profile of the pure drug due to in situ complex formation. Formation of the PX-cyclodextrin inclusion complex additionally improved the drug dissolution properties. Influence of CDs on drug permeation from the water dispersion and the prepared hydroxypropyl methylcellulose (HPMC) gels was investigated. Permeation of the drug involved three consecutive processes: dissolution of the solid phase, diffusion across the swollen polymer matrix and drug permeation through the membrane. Complexation increased PX diffusion by increasing the amount of diffusible species in the donor phase. Slower drug diffusion through the HPMC matrix was the rate limiting step in the overall diffusion process. Possible interaction between the hydrophilic polymer and cyclodextrin may result in physicochemical changes, especially in a change of rheological parameters. PMID: 16375834 [PubMed - indexed for MEDLINE]

16. Pharm Dev Technol. 2005;10(1):105-14.

Formulation studies and in vivo evaluation of a flurbiprofen-hydroxypropyl beta-cyclodextrin system. Govindarajan R, Nagarsenker MS. Bombay College of Pharmacy, Mumbai, India. The purpose of this study was 1) to investigate in vivo advantages of a flurbiprofen (FPN)-hydroxypropyl beta-cyclodextrin (HPbetaCD) solid dispersion (SD) in rats, 2) to study factors affecting the drug release from SD formulations, and 3) to evaluate the pharmacokinetic profile of the drug when administered as SD, in humans. The solubility of FPN in water and dissolution media was evaluated as a function of HPbetaCD concentration. The SD was prepared by coevaporation from dilute aqueous NH3 and evaluated in rats. The release of the drug from tablet formulations and capsules of SD was studied in simulated gastric fluid and phosphate buffer, pH 7.2. The bioavailability of drug when administered as SD was evaluated in humans. HPbetaCD enhanced the solubility of the drug, and SD improved bioavailability and reduced ulcerogenicity of the drug in rats. The type of excipient used affected drug release from tablets. Presence of microcrystalline cellulose, a hydrophilic polymeric excipient, resulted in uptake of water and stabilization of the resulting gels-like structure of HPbetaCD-containing tablets. This adversely affected drug release. The release from capsules filled with SD was comparable to that obtained from plain SD powder. The drug-HPbetaCD association constant in water was much lower than the values reported in literature. The bioavailability (which could suffer in case of higher association constant) was enhanced on administration of SD-filled capsules to humans. PMID: 15776818 [PubMed - indexed for MEDLINE]

17. Drug Dev Ind Pharm. 2005 Jan;31(2):169-78. Celecoxib-cyclodextrin systems: characterization and evaluation of in vitro and in vivo advantage. Nagarsenker MS, Joshi MS. Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Mumbai 400098, India. mangal_nagar@vsnl.net Solid dispersions of Celecoxib were prepared with hydroxypropyl beta cyclodextrin by various methods such as physical mixture, cogrinding, kneading, and

coevaporation. The dispersions were characterized by differential scanning calorimetry (DSC), X-ray diffraction patterns, infrared spectroscopy, and nuclear magnetic resonance studies. The DSC thermograms of the dispersions indicated potential of heat-induced interaction between Celecoxib and cyclodextrin that could influence in vitro drug dissolution. The dispersions exhibited faster rates of dissolution compared to that of Celecoxib. The kneaded dispersion with the fastest in vitro dissolution rate when compressed into tablets showed a better release profile compared to the tablets of pure Celecoxib. In vivo studies revealed that the kneaded dispersion provided for quicker response and was more effective in inhibiting rat paw edema as compared to Celecoxib alone, thus confirming the advantage of improved pharmacological activity of Celecoxib when administered as a solid dispersion with cyclodextrin. PMID: 15773284 [PubMed - indexed for MEDLINE]

18. Indian J Exp Biol. 2005 Jan;43(1):46-52. Chronobiological and chronopharmacological studies of ketoprofen and its solid dispersion form using adjuvant arthritis model in rats. Solankar AK, Jagtap AG. Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098, India. aksolankar@yahoo.com Chronobiology of rheumatoid arthritis (RA) was studied using a standard adjuvant arthritis animal model. Chronopharmacology of ketoprofen, and its solid dispersion forms was also studied. Temporal variations in the degree of articular inflammation (paw volume) and progression of articular destruction were studied by injecting Freund's Complete Adjuvant (FCA) at 0800 and 2000 hrs. Temporal variations in anti-inflammatory effects and ulcerogenic effect were also studied by administration of plain ketoprofen (20 mg/kg) and its solid dispersion with hydroxypropyl beta-cyclodextrin (equivalent to 20 mg/kg of ketoprofen) at the same time points (0800 and 2000 hrs) twice weekly for 22 days. Solid dispersion of ketoprofen was found to be more effective in inhibiting progression of RA. The incidence and severity of ulcers was found to be less with the solid dispersion. The protective effect of ketoprofen and its solid dispersion was significantly higher when these were administered at 0800 hrs. The incidence of ulceration was

more in 2000 hrs group. Thus, it was observed that in the adjuvant induced arthritis model, inflammation and articular damage was significantly greater in the rest period of diurnally active rats than in the activity phase. KPF and its solid dispersion showed better protection from inflammation in the morning than in the evening. PMID: 15691065 [PubMed - indexed for MEDLINE]

19. Acta Pol Pharm. 2004 Jan-Feb;61(1):21-30. Dissolution behaviour of nalidixic acid solid dispersions using water soluble dispersion carriers. Mallick S, Sahu A, Pal K. Division of Formulation Development and Drug Delivery Systems, Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, Mayurbhanj-757 086. Orissa, India. smallickin@yahoo.co.in The oral bioavailability of nalidixic acid (NA) is low due to its poor solubility and slow dissolution. Solid dispersions of NA containing varying concentrations of polyvinylpyrrolidone (PVP), beta-cyclodextrin (BCD) and sodium starch glycolate (SSG) were prepared by solvent evaporation technique in an attempt to improve dissolution rate of NA. Physical characterization of NA, physical mixtures (PM) and solid dispersions were investigated by a variety of analytical methods including scanning electron microscopy (SEM), infrared (IR) spectroscopy and powder X-ray diffraction (XRD). SEM was useful in the verification of possible nalidixic acid inclusion in the dispersion system by studying its surface and shape characteristics of different samples. IR analysis demonstrated no strong interaction between the drug and the carrier exists in the solid dispersions. The degree of crystallinity of nalidixic acid decreased and also differed with the dispersion systems of different carriers. Disolution studies indicated that the dissolution rate and percent dissolution efficiency (DE) were significantly increased in the solid dispersions compared with drug alone. The relative potency of the carriers to enhance the dissolution rate of nalidixic acid was in the order: BCD > PVP > SSG. The dissolution rate of the drug in the solid dispersions was faster when the ration of the drug to carrier was smaller. F-test suggests that first order model may be used for explaining the kinetics of drug release from all the solid dispersion systems.

PMID: 15259854

[PubMed - indexed for MEDLINE]

20. J Pharm Pharmacol. 2004 Jun;56(6):725-33. Influence of preparation methodology on solid-state properties of an acidic drug-cyclodextrin system. Govindarajan R, Nagarsenker MS. Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400098, India. We have investigated the influence of processing variables on the solid-state of a model drug, flurbiprofen, in cyclodextrin-based systems and its effect on dissolution behaviour of the drug. The interaction between flurbiprofen and hydroxypropyl beta-cyclodextrin (HP-beta-CyD) was studied by NMR spectroscopy and phase solubility studies. Binary systems containing flurbiprofen and HP-betaCyD or povidone (polyvinylpyrrolidone) K30, prepared by various processes, were characterized by FTIR, DSC, XRD and dissolution studies. HP-beta-CyD enhanced the solubility of flurbiprofen and increased dissolution rates from binary systems. It was found to be superior to povidone K30 in producing higher dissolution rates. The method of preparation of the binary systems and the agents used were found to have a major influence on the final solid-state of flurbiprofen. Solvents and processing conditions favouring greater interaction between flurbiprofen and the cyclodextrin during the preparation process resulted in greater extent of drug-cyclodextrin association and/or greater amorphization of the drug. Use of ammonia during the preparation of binary systems yielded solids from which very rapid drug dissolution was achieved, due to a higher extent of molecular dispersion of the drug. Processing variables therefore could significantly influence the solid-state of a drug in cyclodextrin-based formulations and thereby affect its dissolution behaviour. This could lead to significant effects on the in-vivo performance of the formulation. PMID: 15231037 [PubMed - indexed for MEDLINE]

21. Drug Dev Ind Pharm. 2004 Jan;30(1):53-64. Valproic acid-hydrophilic cyclodextrin complexes and valproic acid-solid dispersions: evaluation of their potential pharmaceutical use. Trapani G, Cutrignelli A, Latrofa A, Franco M, Serra M, Pisu MG, Biggio G, Liso G. Dipartimento Farmaco-Chimico, Facolt di Farmacia, Universit degli Studi di

Bari, Bari, Italy. xtrapani@farmchim.uniba.it The purpose of this study was to evaluate the potential use of two novel solid formulations of valproic acid (VPA) prepared by complexation with hydrophilic cyclodextrins (CDs) as hydroxypropyl-beta- and sulfobutylether-betacyclodextrin and by solid dispersion (SD) in hydrophilic carriers as polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K-30 (PVP K-30). The corresponding cyclodextrin-based complexes were prepared by the freeze-drying method while the solid dispersions were obtained by the solvent method. Valproic acid solubility improved by CDs complexation and solid dispersion techniques. Comparison of dissolution profiles with that of VPA sodium salt (NaVP) was made by using release parameters such as dissolution efficiency, percent of drug dissolved after 60 min, and difference and similarity factors. Based on difference and similarity factors, it can be concluded that all the VPA formulations possess dissolution profiles essentially equivalent to those of NaVP at pH 6. However, this conclusion is not confirmed by using the analysis of variance (ANOVA) approach, indicating some significant differences between some SD-based formulations and NaVP at that pH value. Preliminary pharmacological studies in the pentylenetetrazole test in rats showed some important differences among the SD-based formulations, NaVP, and VPA as oil/water emulsion. Some implications and limitations of the investigated formulations are discussed. PMID: 15000430 [PubMed - indexed for MEDLINE]

22. Eur J Pharm Biopharm. 2003 Nov;56(3):453-9. Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitro and in vivo evaluation. Yksel N, Karata A, Ozkan Y, Sava er A, Ozkan SA, Baykara T.

Department of Pharmaceutical Technology, Ankara University, School of Pharmacy, Ankara, Turkey. nyuksel@pharmacy.ankara.edu.tr Piroxicam is a non-steroidal anti-inflammatory drug that is characterized by low solubility and high permeability. The purpose of the study was to investigate the in vitro and in vivo performance of the semi-solid dispersion prepared with Gelucire 44/14 and Labrasol into hard gelatin capsules (GL) for enhancing the dissolution rate of the drug. The results were evaluated by comparing with pure piroxicam filled into hard gelatin capsules (PP) and a commercially available

tablet dosage form containing a piroxicam:beta-cyclodextrin complex (CD). The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). Amongst the dosage forms, GL provided at least 85% piroxicam dissolution within 30 min in each of the media, behaving like a fast-dissolving immediate release drug product. Oral bioavailability of 20 mg piroxicam in GL, CD, and PP was compared after administration of a single dose to eight healthy volunteers. Three treatments were administered in crossover fashion, separated by a washout period of 2 weeks. Piroxicam was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of piroxicam from GL (Cmax=2.64 micrograms/ml, tmax=82.5 min) was significantly higher than that of the PP (Cmax=0.999 micrograms/ml, tmax=144 min) (P<0.05) and similar to that of CD (Cmax=2.44 micrograms/ml, tmax=120 min) (P>0.05). The relative bioavailability values as the ratios of mean total AUC for GL relative to PP and CD, were 221 and 98.6%. Piroxicam is characterized by a slow and gradual absorption via the oral route and this causes a delayed onset of therapeutic effect. Thus, plain piroxicam preparations are not indicated for analgesia. The results of the in vivo study revealed that the GL dosage form would be advantageous with regards to rapid onset of action, especially in various painful conditions where an acute analgesic effect is desired. PMID: 14602190 [PubMed - indexed for MEDLINE]

23. Drug Dev Ind Pharm. 2003 Jul;29(6):641-52. Itraconazole formulation studies of the melt-extrusion process with mixture design. Rambali B, Verreck G, Baert L, Massart DL. Farmaceutische Instituut, Vrije Universiteit Brussel, Brussels, Belgium. bisoen.rambali@rivm.nl Itraconazole is a poorly water soluble compound. One method to increase the aqueous solubility of itraconazole is through formation of a solid dispersion. The purpose of this study is to develop a 40% w/w itraconazole formulation through solid dispersion formation, using hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and hydroxypropylmethyl-cellulose (HPMC) as mixture components. The solid dispersion was obtained by melt-extrusion using a twin-screw corotating

melt extruder. A D-optimal mixture design was applied for the development of the optimal itraconazole formulation. The itraconazole fraction varied between 20% w/w and 50% w/w in the mixture design and the HPMC and HP-beta-CD fractions varied between 10% w/w and 60% w/w. The itraconazole formulation was optimized by producing clear extrudates, minimizing the torque, and maximizing the glass transition temperature and the apparent itraconazole solubility in 0.1 N HCl. Regression models were developed for the torque, glass transition temperature, and apparent solubility of itraconazole. High itraconazole fraction in the mixture promoted a better melt processing (minimizes torque). High HPMC fraction (>33% w/w) resulted in clear extrudates, indicating a solid dispersion and resulted in high glass transition temperature of the melt. High HP-beta-CD fraction resulted in increased apparent itraconazole solubility in 0.1 N HCl. The optimal itraconazole formulation consisted of 45% w/w HPMC and 15% HP-beta-CD w/w. PMID: 12889782 [PubMed - indexed for MEDLINE]

24. Drug Dev Ind Pharm. 2003 Feb;29(2):139-44. Carbamazepine/betaCD/HPMC solid dispersions. I. Influence of the spray-drying process and betaCD/HPMC on the drug dissolution profile. Koester LS, Mayorga P, Bassani VL. Programa de Ps-Graduao em Cincias Farmacuticas, Faculdade de Farmcia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. The aim of this study was to compare carbamazepine (CBZ) solid dispersions prepared by spray-drying of aqueous dispersions with the corresponding physical mixtures. The influence of the association of beta-cyclodextrin (betaCD) and hydroxypropyl methylcellulose (HPMC) on the CBZ dissolution profile of the preparations was investigated. Results demonstrated that CBZ release from solid dispersions is dependent on the ratio of betaCD and HPMC. The spray-drying process confers better homogeneity to CBZ polymeric dispersions than the physical mixture process. In summary, we demonstrated the feasibility of obtaining a homogeneous polymeric solid dispersion of CBZ from an aqueous media by spray-drying and a clear influence of the betaCD:HPMC ratio on the release profile of CBZ. PMID: 12648010 [PubMed - indexed for MEDLINE]

25. J Pharm Sci. 2001 Jun;90(6):690-701.

Comparative studies of the enhancing effects of cyclodextrins on the solubility and oral bioavailability of tacrolimus in rats. Arima H, Yunomae K, Miyake K, Irie T, Hirayama F, Uekama K. Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. The enhancing effects of cyclodextrins (CyDs) on the solubility, the dissolution rate, and the bioavailability of tacrolimus after oral administration to rats were examined and compared with those after administration of a PROGRAF capsule containing the solid dispersion formulation of tacrolimus. Here we used natural CyDs and the hydrophilic beta-CyD derivatives; that is, randomly methylated-beta-cyclodextrin (RM-beta-CyD), heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and sulfobutyl ether beta-cyclodextrins (SBE-beta-CyDs). Of the natural CyDs, the solubility of tacrolimus increased in the addition of beta-CyD, indicating that the cavity of beta-CyD comfortably fits the drug. Of the beta-CyD derivatives, DM-beta-CyD had the greatest solubilizing activity and gave the A(p) type phase solubility curve as defined by Higuchi and Connors, suggesting the formation of higher-order complexes. The result of van't Hoff plot suggests that the enthalpy is dominant for the complexation of tacrolimus with DM-beta-CyD. The dissolution rate of tacrolimus was markedly augmented by the complexation with DM-beta-CyD, reflecting its solubilizing activity. An in vivo study revealed that DM-betaCyD increased the bioavailability of tacrolimus with low variability in the absorption after oral administration of the tacrolimus suspension to rats. The present results suggest that DM-beta-CyD is particularly useful in designing oral preparations of tacrolimus with an enhanced bioavailability and a reduced variability in absorption. PMID: 11357172 [PubMed - indexed for MEDLINE]

26. Drug Dev Ind Pharm. 2000 Nov;26(11):1141-50. Effect of water-soluble carriers on dissolution characteristics of nifedipine solid dispersions. Chutimaworapan S, Ritthidej GC, Yonemochi E, Oguchi T, Yamamoto K. Faculty of Pharmaceutical Sciences, Chulalongkom University, Bangkok, Thailand. Solid dispersions of nifedipine (NP) with polyethylene glycols (PEG4000 and

PEG6000), hydroxypropyl-beta-cyclodextrin (HP beta CD), and poloxamer 407 (PXM 407) in four mixing ratios were prepared by melting, solvent, and kneading methods in order to improve the dissolution of NP. The enhancement of the dissolution rate and the time for 80% NP dissolution T80% depended on the mixing ratio and the preparation method. The highest dissolution rate and the T80% as short as 15 min were obtained from PXM 407 solid dispersion prepared by the melting method at the mixing ratio of 1:10. The X-ray diffraction (XRD) patterns of solid dispersions at higher proportions of carriers demonstrated consistent with the results from differential scanning calorimetric (DSC) thermograms that NP existed in the amorphous state. The wettability and solubility were markedly improved in the PXM 407 system. The presence of intermolecular hydrogen bonding between NP and PEGs and between HP beta CD and PXM 407 was shown by infrared (IR) spectroscopy. PMID: 11068687 [PubMed - indexed for MEDLINE]

27. Pharm Res. 2000 Aug;17(8):942-8. Deformation behaviors of tolbutamide, hydroxypropyl-beta-cyclodextrin, and their dispersions. Suihko E, Poso A, Korhonen O, Gynther J, Ketolainen J, Paronen P. Department of Pharmaceutics, University of Kuopio, Finland. Eero.Suihko@uku.fi PURPOSE: The deformation behaviors of compressed freeze-dried and spray-dried tolbutamide/hydroxypropyl-beta-cyclodextrin molecular dispersions were evaluated and compared with similarly prepared tolbutamides (TBM), hydroxypropyl-beta-cyclodextrins (HP-beta-CD) and as their physical dispersions. METHODS: TBM, HP-beta-CD, and their 1:1 molecular dispersions were prepared by freeze-drying and spray-drying, and physical dispersions of TBM and HP-betaCD were blended. Deformation properties of the prepared materials were evaluated by using a compaction simulator and constants derived from Heckel plots. Molecular dynamics (MD) simulations were performed in order to gain a molecular-level view on the deformation behavior of TBM-HP-beta-CD inclusion complex. RESULTS: The freeze-dried TBM polymorphic form II was less prone to overall

particle deformation than the spray-dried stable form I. Formation of molecular dispersions decreased the plastic and elastic behaviors of these materials. Also, the MD simulations showed a reduced molecular flexibility of the TBM-HP-betaCD inclusion complex, as compared to HP-beta-CD. CONCLUSIONS: The formation of TBM and HP-beta-CD molecular dispersion resulted in more rigid molecular arrangements, which were less prone to deformation than either HP-beta-CDs or physical dispersions. The results showed how differing molecular, solid, particle, and powder state properties affect the deformation properties of the materials studied. PMID: 11028939 [PubMed - indexed for MEDLINE]

28. J Pharm Pharmacol. 2000 Aug;52(8):949-56. Solid dispersion of hydroxypropyl beta-cyclodextrin and ketorolac: enhancement of in-vitro dissolution rates, improvement in anti-inflammatory activity and reduction in ulcerogenicity in rats. Nagarsenker MS, Meshram RN, Ramprakash G. Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (East), Mumbai, India. Ketorolac, is a non-steroidal anti-inflammatory drug, with strong analgesic activity. It is practically insoluble in water and has been implicated in causing gastrointestinal ulceration. This study describes the formulation of solid dispersions of ketorolac using hydroxypropyl beta-cyclodextrin (HPbeta-CyD) and beta-cyclodextin (beta-CyD) as carriers, to improve the aqueous solubility of the drug, thus enhancing its bioavailability. Also, reduction in ulcerogenicity was anticipated. Differential scanning calorimetry and X-ray diffraction studies indicated loss of crystalline nature of the drug, in the dispersions prepared with HPbeta-CyD. NMR studies revealed a strong interaction between drug and HPbeta-CyD. Solid dispersions of drug with beta-CyD retained the crystalline nature of the drug. All the solid dispersions showed a remarkable improvement in the rate and extent of dissolution of ketorolac. The kneaded dispersion with HPbeta-CyD prepared using a 1:1 alcohol-water mixture showed promise in reducing the ulcer-inducing effect of ketorolac in rats. Oral administration of this dispersion was found to inhibit carrageenan-induced paw oedema in rats to a significantly greater extent compared with ketorolac or its trometamol salt. Though beta-CyD as a carrier for ketorolac gave faster release of the poorly soluble drug, HPbeta-CyD proved to be superior to beta-CyD, as a carrier in the kneaded dispersion prepared using 1:1 alcohol-water mixture. These results

suggest that solid dispersions of ketorolac with HPbeta-CyD aid in faster dissolution and better bioavailability of the drug. The higher solubility of the drug in the presence of HPbeta-CyD also reduces local gastrointestinal side-effects of the drug. PMID: 11007065 [PubMed - indexed for MEDLINE]

29. Pharmazie. 2000 Jul;55(7):513-7. In vitro and in vivo evaluation of an amylobarbitone/hydroxypropyl-beta-cyclodextrin complex prepared by a freeze-drying method. Fathy M, Sheha M. Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Egypt. Fathy@mailcity.com The complex formation of amylobarbitone (AMB) with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated in aqueous solution and in the solid state. The apparent stability constant for complex formation (Kc) calculated by phase solubility and spectral shift methods was 524 M-1 and 568 M-1, respectively. The stoichiometric molar ratio of the complex was estimated to be 1:1 and the solubility of AMB in water was increased about 3 fold. The solid dispersion system of AMB/HP-beta-CD in 1:1 molar ratio was prepared by a freeze-drying method. Differential scanning calorimetry (DSC), x-ray diffractometry, (IR) and 1H NMR spectroscopy were used to confirm that inclusion between the drug and HP-beta-CD occurred. The dissolution behavior of the drug as a physical mixture as well as the prepared complex, showed enhanced drug dissolution properties of the prepared complex compared to the physical mixture or the drug alone. The dissolution rate appeared in the first 2 min, 25 times greater for the complex than for the drug alone. Furthermore, in-vivo study revealed that the duration and hypnotic activity of AMB after its oral administration to mice were improved by inclusion. PMID: 10944779 [PubMed - indexed for MEDLINE]

30. Chem Pharm Bull (Tokyo). 2000 May;48(5):646-50. Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex. Kimura K, Hirayama F, Arima H, Uekama K. Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.

The effects of storage on the crystallization, dissolution and absorption of tolbutamide from amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex were investigated, in comparison with those of polyvinylpyrrolidone (PVP) solid dispersion. The amorphous solid complex of tolbutamide with HP-beta-CyD and the solid dispersion of tolbutamide with PVP were prepared by a spray-drying method. During storage, a stable form of tolbutamide (form I) was crystallized from the amorphous PVP dispersion, whereas a metastable form of tolbutamide (form II) was crystallized from the HP-betaCyD complex. The dissolution rate of tolbutamide from both HP-beta-CyD complex and PVP dispersion was significantly faster than that of tolbutamide alone. However, the dissolution rate from the PVP dispersion markedly decreased with storage, because of the formation of slow dissolving form I crystals. On the other hand, the dissolution rate from the HP-beta-CyD complex was only slightly decreased due to the formation of fast dissolving formII crystals. These in vitro dissolution characteristics were clearly reflected in the in vivo absorption of tolbutamide and the glucose plasma level after oral administration in dogs. The results suggested that HP-beta-CyD is useful not only for converting crystalline tolbutamide to an amorphous substance, but also for maintaining the fast dissolution rate of the drug over a long period. Furthermore, the crystallization of drugs from CyD complexes, with storage, seemed to be different from that involving polymer excipients such as PVP. PMID: 10823700 [PubMed - indexed for MEDLINE]

31. Chemistry. 2000 Mar 17;6(6):999-1006. Highly organized spherical hosts that bind organic guests in aqueous solution with micromolar affinity: microcalorimetry studies Piatnitski EL, Flowers RA 2nd, Deshayes K. Center for Photochemical Sciences, Bowling Green State University, OH 43403, USA. Two novel closed-shell hemicarcerand-like hosts with spherical cavities of 11 A diameter that are soluble in aqueous solution were constructed. The binding of xylenes, aryl ethers, polyaromatic compounds, ferrocene derivatives, and bicyclic aliphatic compounds were examined by NMR spectroscopy and microcalorimetry. NMR binding studies indicated that binding depended upon guest hydrophobicity and shape. No binding was detected for guests in which a charge must be desolvated as

part of inclusion or for guests that can not fit within the cavity of the host. Three complexes 2.naphthalene, 2.p-xylene, and 2.ferrocene were isolated and found to be indefinitely stable in the solid phase and in aqueous solution. The binding constants for these complexes are estimated to be greater than 10(8) M-1. Thirteen guests were examined by microcalorimetry with binding constants ranging between 10(7) and 10(3) M-1. A comparison of results obtained here with those from previous work with beta-cyclodextrin and cyclophane hosts, along with analysis of the entropy-enthalpy compensation data, indicate that there is a higher degree of guest desolvation with this host structure than with openshell hosts. This accounts at least partially for the increase in affinity observed with these closed-shell hosts. Replacing a hydroxy group in the host portal with a hydrogen atom does not affect the binding constant, a finding consistent with the guest residing deeply buried within the host cavity. It was observed that aromatic guests are bound with higher affinity than aliphatic ones in agreement with results that point to the importance of London dispersion forces in the association of aromatic components in face-to-edge orientations. The correlation of changes in NMR chemical shift with microcalorimetry data supports a model in which increased CH-pi interactions strengthen association between host and guest due to the dominant role of van der Waals dispersion forces. Remarkably, the binding constant for the 1,4 isomer of dimethoxybenzene is 32 times higher than for the 1,2 isomer, and even greater discrimination is observed between the xylene guests since the binding constant for p-xylene is 80 times greater than that for o-xylene. This discrimination between isomeric guests by a rigid host indicates that changes in specific hydrophobic interactions have substantial effects upon binding affinity. PMID: 10785820 [PubMed - as supplied by publisher]

32. J Control Release. 2000 May 15;66(2-3):271-80. Controlled release of a water-soluble drug, captopril, by a combination of hydrophilic and hydrophobic cyclodextrin derivatives. Ikeda Y, Kimura K, Hirayama F, Arima H, Uekama K. Wakunaga Pharmaceutical Co., 1624 Shimokotachi, Kodacho, Takata-gun, Hiroshima, Japan. Parent beta-cyclodextrin (beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-betaCyD)

form 1:1 solid complexes with an orally active angiotensin-converting enzyme inhibitor, captopril, while hydrophobic perbutanoyl-beta-CyD (TB-beta-CyD) forms a solid dispersion or solid solution with the drug. The binary system of captopril/HP-beta-CyD or captopril/TB-beta-CyD and the ternary system of captopril/TB-beta-CyD/HP-beta-CyD in different molar ratios were prepared by the kneading method, and the release behavior of the drug was investigated. The release rate of captopril from the binary HP-beta-CyD system was rather fast, whereas that from the binary TB-beta-CyD system was comparatively slower, the retarding effect being dependent on the amounts of TB-beta-CyD. The release rate from the ternary captopril/TB-beta-CyD/HP-beta-CyD system was slowed down by the addition of small amounts of HP-beta-CyD, whereas the rate became faster as the molar ratio of HP-beta-CyD further increased (>.25 molar ratio). Both water penetration studies and microscopic observation suggested that the retarding effect is attributable to a gel formation of HP-beta-CyD in the TB-beta-CyD hydrophobic matrix. It was difficult to prolong plasma levels of captopril by administering orally either the binary HP-beta-CyD or TB-beta-CyD system in dogs. On the other hand, the ternary captopril/TB-beta-CyD/HP-beta-CyD system (molar ratio of 1:0.5:0.5) gave a plasma profile comparable to that of a commercially available sustained release preparation (Captoril R). Therefore, a combination of HP-beta-CyD and TB-beta-CyD is useful for the controlled release of watersoluble drugs such as captopril. PMID: 10742586 [PubMed - indexed for MEDLINE]

33. Eur J Pharm Biopharm. 2000 Mar;49(2):119-27. Improvement of availability of allopurinol from pharmaceutical dosage forms I suppositories. Samy EM, Hassan MA, Tous SS, Rhodes CT. Deptartment of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, Egypt. Solid dispersion and crystallization of a very slightly water-soluble drug, allopurinol, were prepared using urea, sodium salicylate and betacyclodextrin (beta-CD) as carriers. The spectroscopic infra-red (IR), differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) data indicate a role of these carriers in decreasing the crystallinity of allopurinol and complexing abilities. Solid dispersion and crystallization of the drug with these carriers

were used in suppository formulations to investigate their role in enhancement of drug release through the membrane barrier. The bases used included Suppocire AM and the mixture of polyethylene glycols (PEGs). The release rates of allopurinol from lipophilic and hydrophilic suppository bases were examined and compared with those obtained for their inclusion compounds incorporated in the same bases. The prepared suppositories were evaluated for in-vitro drug release, when fresh and on storage. The release of pure allopurinol from the lipophilic base was remarkably higher than that from the hydrophilic one. The release of allopurinol from lipophilic as well as hydrophilic bases was significantly enhanced by crystallization of the drug from 5% w/v of sodium salicylate. Allopurinol crystallized from sodium salicylate, showed enhanced release reaching about 100% in 1 h from the Suppocire AM base. The obtained data from these experiments proved the superiority of the PEG formulations containing coevaporates of the drug to sodium salicylate, ratio 1:1, or of the drug to beta-CD, ratio 1:2; T(90%),12 and 36 min, respectively. A significant decrease of uric acid excretion in rabbits was observed after rectal administration of suppositories containing allopurinol crystallized from sodium salicylate. PMID: 10704894 [PubMed - indexed for MEDLINE]

34. Biol Pharm Bull. 1999 Mar;22(3):298-304. Effect of sugar-modified beta-cyclodextrins on dissolution and absorption characteristics of phenytoin. Tanino T, Ogiso T, Iwaki M. Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Osaka, Japan. Inclusion complexes of phenytoin (DPH) with 6-O-alpha-D-glucosyl (G1)- and 6-O-alpha-D-maltosyl (G2)-beta-cyclodextrins (beta-CyDs) were prepared in a molecular mixing ratio of 1:1. The advantages of these preparations in terms of dissolution characteristics and the oral absorbency of DPH were evaluated in comparison with the known solid dispersions of polyvinylpyrrolidone K-30 and sodium deoxycholate (DC-Na). The results of a phase-solubility study indicated that G1- and G2-beta-CyDs provided higher solubility for DPH than 2hydroxypropyl (HP)-beta-CyD. Irrespective of inclusion ability, the DPH/beta-CyD complexes allowed faster dissolution rates than those of the known dispersions in JP 1st and 2nd mediums. The dissolution behavior of the DPH/DC-Na dispersion was

considerably different between the 1st and 2nd mediums. The complexation by the sugar-modified derivatives yielded a higher stability of dissolved DPH in the JP 2nd medium than that yielded by K-30 or DC-Na. The safe estimation of carriers themselves indicated that G1- and G2-bet-CyDs did not damage the small intestine, while 10 mM DC-Na showed some damage. Compared with the DPH/K-30 dispersion, the preparations with the sugar-modified beta-CyDs were more effective in enhancing the absorbability of DPH after oral administration. These results clearly suggest that complexation with G1- and G2-beta-CyDs are useful forms for the oral delivery of DPH. The advantage of these complexes is that they produce an increased level of DPH available for gastrointestinal absorption. Additionally, G2-beta-CyD is recommended as a safe and potent additive for DPH. PMID: 10220288 [PubMed - indexed for MEDLINE]

35. Drug Dev Ind Pharm. 1998 Jul;24(7):653-60. Interactions between lonidamine and beta- or hydroxypropyl-beta-cyclodextrin. Palmieri GF, Wehrl P, Martelli S. Dipartimento di Scienze Chimiche, Universit di Camerino, Italy. The possibility of obtaining inclusion complexes between lonidamine and betaor hydroxypropyl-beta-cyclodextrin have been evaluated by phase solubility diagram, differential scanning calorimetry (DSC), and x-ray diffractometry. The applied complexation methods were spray-drying, kneading, and solid dispersion. DSC and x-ray analyses of the powders revealed an external interaction between lonidamine and cyclodextrins. Dissolution profiles of the obtained powders were also studied to define the most appropriate preparation method and molar ratio to use in attempts to increase lonidamine water solubility. PMID: 9876510 [PubMed - indexed for MEDLINE]

36. J Pharm Pharmacol. 1992 Jan;44(1):52-5. The influence of beta-cyclodextrin on the solubility and dissolution rate of paracetamol solid dispersions. Tasi LM, Jovanovi MD, Djuri ZR.

Faculty of Pharmacy, Belgrade University, Yugoslavia. The effect of cyclodextrin (beta-CD) on the solubility and dissolution rate of various paracetamol dispersion powders (1:1 w/w), and tablets was studied. Lower solubility was exhibited by a spray dried solid dispersion made from paracetamol-Ethocel-Macrogol 6000 (95:2:3). The improvement in solubility was influenced by complexation with beta-CD and the crystalline nature of the powder products made by different procedures. The difference in crystallinity was confirmed by X-ray powder diffraction patterns. The dissolution rate of paracetamol from tablets made from the solid dispersions was satisfactory compared with paracetamol alone. The differences between the dissolution rate from the examined paracetamol tablets resulted from the different solubility of each powder and from the structural changes of particles which influenced the consolidation of the tablet mass. PMID: 1350629 [PubMed - indexed for MEDLINE]

37. Chem Pharm Bull (Tokyo). 1990 Mar;38(3):728-32. Study of the interaction of clobazam with cyclodextrins in solution and in the solid state. Nakai Y, el-Said Aboutaleb A, Yamamoto K, Saleh SI, Ahmed MO. Faculty of Pharmaceutical Sciences, Chiba University, Japan. Inclusion complexes of clobazam with alpha-, beta-, gamma-cyclodextrins (CyDs) and heptakis(2.6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in aqueous solution and in the solid phase were studied by the solubility method, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry. In addition, inclusion complex of clobazam with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and the solid dispersion of clobazam with methyl cellulose (MC) in a ground mixture were investigated by IR, DSC and X-ray diffractometry. It was observed that DM-beta-CyD had the highest stability constant among the four CyDs in solution. Thermal and X-ray diffraction analyses showed that clobazam molecules existed in a molecularly dispersed state in the ground mixture of CyDs. Infrared spectra showed lower frequency shifts in the case of the ground mixtures of clobazam with natural CyDs, which can be attributed to the formation of hydrogen bonds between the two carbonyl groups of clobazam and hydroxyl groups of natural CyDs. In contrast, higher frequency

shifts were observed in the case of the ground mixtures of clobazam with methylated CyDs and MC and these were considered to be due to the monomolecular dispersion of clobazam in a hydrophobic environment. The mode of interaction of clobazam with DM-beta-CyD was different from that with natural CyDs in the ground mixtures. Furthermore, the crystalline inclusion complex of clobazam with DM-beta-CyD was obtained by heating of the coprecipitate in vacuo at 120 degrees C for 1 h. PMID: 2347015 [PubMed - indexed for MEDLINE]

38. Chem Pharm Bull (Tokyo). 1983 Apr;31(4):1350-6. Dissolution behavior and gastrointestinal absorption of dicumarol from solid dispersion systems of dicumarol-polyvinylpyrrolidone and dicumarol-beta-cyclodextrin. Sekikawa H, Fukuda N, Takada M, Ohtani K, Arita T, Nakano M. PMID: 6194905 [PubMed - indexed for MEDLINE]