Beta-cyclodextrin Solid Dispersion

1. Curr Drug Deliv. 2011 Apr 1. [Epub ahead of print]

Enhancement of Solubility and Permeability of Candesartan Cilexetil by UsingDifferent Pharmaceutical Interventions.

Shaikh SM, Avachat AM.

Sinhgad College of Pharmacy, Vadgaon (Budruk), Pune-41, [email protected].

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 hencethe permeability of CAN by preparing solid dispersions/inclusion complexes. Soliddispersions 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-β-cyclodextrin (HP-β-CD) [complexing agent] by grinding andspray drying method. Saturation solubility method was used to evaluate the effectof various carriers on aqueous solubility of CAN. Based on the saturationsolubility data, two drug-carrier combinations, PEG 6000 (MA 1:5) and HP-β-CD(1:1 M grinding) were selected as optimized formulations. FTIR, DSC, and XRDstudies indicated no interaction of the drug with the carriers and providedvaluable insight on the possible reasons for enhanced solubility. Dissolutionstudies showed an increase in drug dissolution of about 22 fold over the puredrug for PEG 6000 (MA 1:5) and 12 fold for HP-β-CD (1:1 M grinding). Ex-vivopermeability studies revealed that the formulation having the greatestdissolution also had the best absorption through the chick ileum. Capsulescontaining solid dispersion/ complex exhibited better dissolution profile thanthe marketed product. Thus, the solid dispersion/inclusion complexation techniquecan 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 complexationand 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 inclusioncomplexation using hydroxy propyl beta-cyclodextrin (HP beta-CD) byco-evaporation technique and by, solid dispersion, prepared by the melt methodusing poloxamer 407 (L 127). Phase solubility studies showed AL type curves with both the carriers. Dissolution of LMN was significantly improved (p < 0.05) byinclusion complexation and solid dispersion preparation. Results of solid statecharacterization performed by Fourier Transform Infrared Spectroscopy,Differential Scanning Calorimetry and Powder X-ray Diffractrometry techniquesrevealed a decrease in the crystallinity of LMN that might be accounting forimprovement 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 solublenovel 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, andpharmacological assessment of a drug inclusion complex for a novel camptothecinanalog (CA) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). Camptothecins analogbelong to topoisomerase-I inhibitor class of compounds with proven anti-tumoractivity but exhibit poor solubility. To enhance solubility a drug inclusioncomplex with cyclodextrin was developed using a spray-drying process. The powder complex characterized using DSC, XRPD, FT-IR, and ¹H NMR techniques confirmedinteraction of cyclodextrin with the CA indicating formation of a true complexwherein the drug is encapsulated in the cyclodextrin cavity. The saturationsolubility and dissolution kinetics of drug complex evaluated in a discriminatingmedium 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 inthe rate and extent of absorption for the drug complex as compared to ananoparticulate dispersion that was used as the positive control. Pharmacologicalactivity following peroral administration of drug complex in athymic nude micewith implanted tumors revealed that the tumor inhibition activity was equivalent to commercially available intravenous (IV) formulation with comparable safetyprofile. These studies demonstrated for the first instance feasibility ofdeveloping a safe and efficacious peroral formulation for a sparingly solublecamptothecin 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.2042-7158.2010.01173.x.Epub 2010 Nov 16.

Fast-dissolving sublingual solid dispersion and cyclodextrin complex increase theabsorption of perphenazine in rabbits.

Turunen E, Mannila J, Laitinen R, Riikonen J, Lehto VP, Järvinen T, Ketolainen J,Järvinen K, Jarho P.

School of Pharmacy/Pharmaceutical Chemistry, University of Eastern Finland,Kuopio, Finland. [email protected]

OBJECTIVES: The sublingual administration route as well as solid dispersionformation with macrogol 8000 and complexation with β-cyclodextrin (β-CyD) wereinvestigated as ways for improving the absorption of perphenazine, a poorlywater-soluble drug subjected to substantial first-pass metabolism.METHODS: The absorption of perphenazine was studied in rabbits after sublingualadministration of perphenazine/macrogol solid dispersion, solidperphenazine/β-CyD complex and plain micronized perphenazine, as well as afterperoral administration of an aqueous perphenazine solution. Solid formulationswere prepared by freeze-drying (perphenazine/macrogol solid dispersion) orspray-drying (perphenazine/β-CyD complex).KEY FINDINGS: The value for area under the curve from 0 to 360 min (AUC(0-360min) ) of perphenazine after peroral administration was only 8% of the AUC(0-360 min) value obtained after intravenous administration, while the correspondingvalues for the sublingually administered formulations were 53%(perphenazine/macrogol solid dispersion), 41% (perphenazine/β-CyD complex) and64% (micronized perphenazine). There are three possible mechanisms to explainthese results: avoidance of the first-pass metabolism; good sublingual absorptionof perphenazine; and rapid dissolution rate of perphenazine from the studiedformulations.CONCLUSIONS: With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, thesolid 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 sublingualadministration of a solid dispersion in vivo.


5. AAPS PharmSciTech. 2010 Dec;11(4):1730-7. Epub 2010 Dec 7.

Polymeric surfactant based etodolac chewable tablets: formulation and in vivoevaluation.

Ibrahim MM, El-Nabarawi M, El-Setouhy DA, Fadlalla MA.

Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, CairoUniversity, Kasr El-Aini Street, Cairo, 11562, Egypt.

Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potentialantitumor and uric acid lowering effects. It shows dissolution rate-dependentbioavailability. This work was carried out to improve the dissolution rate ofetodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. Thepolymeric surfactant inutec, 2-hydroxypropyl-β-cyclodextrin, and tromethaminewere used at three different drug/carrier ratios. The dissolution rate of ET atpH 1.2 and 6.8 is improved in all of the solid dispersion systems compared tothat of the pure drug and physical mixtures. DSC of coevaporates at 1:5drug/carrier ratio providing the fastest dissolution rate suggested loss of ETcrystallinity which was further confirmed by X-ray diffraction. Inutec-basedcoevaporate was chosen for the formulation of ET chewable tablets. Chewabletablets (F3) that met the USP monograph specifications for ET tablets, with 86%dissolved amount within 15 min, was chosen for in vivo absorption study incomparison with pure ET-filled hard gelatin capsules. The results showedsignificantly 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 tabletscompared 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 ofdissolution profile.

Palanisamy M, Khanam J.

Department of Pharmaceutical Technology, Jadavpur University, Kolkata, WestBengal, India. [email protected]

BACKGROUND: Dissolution testing is an important test for judging theeffectiveness of a pharmaceutical dosage form. Many drugs create adverse effectbecause 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 variouswater-soluble carriers was studied to improve the dissolution of PRD. To obtainthe optimized formulation, solid dispersions were prepared employing differentmethods using different carriers with various drug:carrier ratios. Theirdissolution behaviors were also compared. Fourier transform infrared (FTIR)spectroscopy, powder X-ray diffraction, and thermal analysis were studied tocharacterize 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 vitrodissolution rate of PRD was remarkably improved in the solid dispersion of thedrug compared with physical mixture and drug alone. This can be attributed toimproved wettability, dispersibility, decrease in crystallinity, and increase in amorphous fraction of the drug. The results obtained from Fourier transforminfrared spectroscopy and powder X-ray diffraction showed good evidence ofdrug-carrier interaction while using carriers such ashydroxypropyl-β-cyclodextrin (HP-βCD) and polyethylene glycol (PEG).Crystallinity of the drug was reduced in the solid dispersions prepared withhydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone-co-vinyl acetate 64, and PEGas revealed from the differential scanning calorimetry thermograms.CONCLUSION: The results suggested that the solid dispersion with selectedexcipients is a powerful tool to accelerate the dissolution of poorlywater-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 formulationdesign 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 non-destructivetechniques in the evaluation of risperidone solid dispersions (SD) withmethyl-β-cyclodextrin (MBCD) and subsequent incorporation of the SD into orallydisintegrating tablets (ODT) for a faster release of risperidone. The SD wasprepared by a solvent evaporation method and evaluated by scanning electronmicroscopy (SEM), Fourier transform infrared (FTIR), near infrared spectroscopy(NIR), NIR-chemical imaging (NIR-CI), powder X-ray diffraction (PXRD) anddifferential scanning calorimetry (DSC). DSC and XRD analysis indicated that

crystallinity of SD has reduced significantly. FTIR showed no interaction betweenrisperidone 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 bycorrelation 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) andsuperdisintegrant (Kollidon(®) CL-SF, Ac-Di-Sol or sodium starch glycolate).Disintegration time, T(50) and T(90) were decreased in the formulationscontaining mannitol and Kollidon(®) CL-SF, but increased with galenIQ™-721 andsodium starch glycolate, respectively. NIR-CI images confirmed the homogeneity ofSD and ODT formulations.


8. Molecules. 2010 Jun 4;15(6):4067-84.

Pharmaceutical composition of valsartan: beta-cyclodextrin: physico-chemicalcharacterization and anti-hypertensive evaluation.

Jensen CE, dos Santos RA, Denadai AM, Santos CF, Braga AN, Sinisterra RD.

Departamento de Química, ICEx, Universidade Federal de Minas Gerais, AvenidaPres. Antônio Carlos 6627, 31270-901, Belo Horizonte, [email protected]

Valsartan, a water-insoluble drug, is mainly used in the treatment ofhypertension albeit with reduced oral bioavailability. The aim of work was todevelop a valsartan:beta-cyclodextrin (VAL:beta-CD) pharmaceutical composition inorder to improve its water solubility and bioavailability. The VAL:beta-CDcomplexes were prepared by the kneading, solid dispersion and freeze-dryingmethods, of which the freeze-drying method (FDY) was found to be the best toprepare 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 withbeta-cyclodextrin (beta-CD). Microcalorimetric titrations suggested the formationof 1:1 inclusion complex between VAL and beta-CD. The apparent stabilityconstants 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 showedthat reduction in arterial pressure for the FDY complex is better than withvalsartan used alone. The better activity of FDY can be attributed to the higher

solubility of valsartan after inclusion in the cyclodextrin cavity, as suggest bythe intrinsic dissolution studies.


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, SouthKorea.

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 amethylene chloride/ethanol mixture, the solvent-wetting method with ethanol andthe surface-attached method with water, respectively. The solubility anddissolution of the drug in the three solid dispersions were evaluated compared todrug powder. Furthermore, their physicochemical properties were investigatedusing SEM, DSC and powder X-ray diffraction. The solubility and dissolution ofthe drug were significantly improved in the order of the tacrolimus-loaded solid dispersion prepared by: solvent-evaporation method>solvent-wettingmethod>surface-attached method. The solid dispersions prepared by solventevaporation appeared as an aggregated form with the amorphous form. Inparticular, the solid dispersion prepared by the solvent-evaporation methodimproved solubility about 900-fold and dissolution of tacrolimus 15-fold because of its reduced particle size, increased surface area and close contact betweenthe hydrophilic carrier and the drug. In the solvent-wetting method, the drug,which was changed to an amorphous form, was attached onto the surface ofundissolved carriers. However, the solid dispersion prepared by thesurface-attached method gave an unchanged crystalline form. In this soliddispersion, the carriers were attached to the surface of the undissolved drug,resulting in changing the drug from being hydrophobic to hydrophilic. As thecrystal form of drug in this solid dispersion was not converted to the amorphous form unlike other solid dispersions, it gave relatively less solubility anddissolution of the drug than did the others. Thus, in the development of asolid-dispersion system containing poorly water-soluble drugs, the method ofpreparation plays an important role in the solubility and crystallinity of thedrugs.


10. Eur J Pharm Sci. 2010 Mar 18;39(5):336-47. Epub 2010 Jan 20.

In vitro characterization and pharmacokinetics in mice following pulmonarydelivery 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 forpulmonary delivery by nebulization, and compare pharmacokinetics of inhalednebulized aerosols of HPbetaCD-ITZ versus a colloidal dispersion of ITZnanoparticulate formulation (i.e., URF-ITZ). Solid state characterizations oflyophilized HPbetaCD-ITZ by differential scanning calorimetry (DSC), Fouriertransform 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 lungdepositions and pharmacokinetic profiles, with ITZ lung levels of approximately 4microg/g wet lung weight upon completion of nebulization and remained above 0.5microg/g at 24h. HPbetaCD-ITZ demonstrated faster systemic absorption of ITZacross lung epithelium than URF-ITZ, with t(max) values of 1.5 and 3.0 h, andAUC(0-infinity) of 2513 and 3717 ng h/mL, respectively. The fast absorption ofsolubilized ITZ across lung mucosal surface may be due in part to the eliminationof the phase-to-phase transition.


11. Eur J Pharm Biopharm. 2009 Sep;73(1):154-61. Epub 2009 May 22.

Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets byincorporation of superdisintegrants.

Srinarong P, Faber JH, Visser MR, Hinrichs WL, Frijlink HW.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen,Groningen, The Netherlands. [email protected]

In this study, it was shown that the incorporation of superdisintegrants in soliddispersion tablets containing a high drug load can strongly enhance thedissolution rate of the highly lipophilic drug fenofibrate. In addition, the

dissolution rate was more increased when the superdisintegrant was incorporatedin the drug containing solid dispersions than when it was physically mixed withthe solid dispersions. The dissolution rate enhancement strongly depended on the type of superdisintegrants and increased in the order PolyplasdoneXL-10<Polyplasdone XL<<Ac-Di-Sol approximately Primojel. The dissolution behavioralso depended on the type of hydrophilic carriers. Solid dispersion tablets basedon inulin 4 kDa, polyethylene glycol 20K and polyvinylpyrrolidone K30 showed amuch faster dissolution than those based on mannitol andhydroxypropyl-beta-cyclodextrin. Finally, inulin 4 kDa-based solid dispersiontablets showed excellent storage stability, while polyethylene glycol 20K-andpolyvinylpyrrolidone K30-based solid dispersion tablets did not.


12. J Pharm Pharmacol. 2008 Sep;60(9):1121-9.

Enhanced solubility and dissolution rate of lamotrigine by inclusion complexationand 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 itsinclusion complex with beta-cyclodextrin (betaCD) and solid dispersions withpolyvinylpyrrolidone K30 (PVP K30) and polyethyleneglycol 6000 were investigated.The phase solubility profile of lamotrigine with betaCD was classified asAL-type, indicating formation of a 1:1 stoichiometry inclusion complex, with astability constant of 369.96+/-2.26 M(-1). Solvent evaporation and kneadingmethods 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 spectroscopyand differential scanning calorimetry. These studies revealed that the drug wasno 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 thesolubility and dissolution of lamotrigine.


13. Eur J Pharm Biopharm. 2008 Sep;70(1):187-98. Epub 2008 Mar 20.

Effect of formulation parameters on 2-methoxyestradiol release from injectablecylindrical 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 variousformulation strategies to achieve 1-month continuous (improved) release of thenovel anti-cancer drug, 2-methoxyestradiol (2-ME), from injectable cylindricalpoly(DL-lactide-co-glycolide) (PLGA) implants. PLGA implants were prepared by asolvent 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 lagphase (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 reducedthe 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) 8000solid 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, andaccelerated polymer degradation. Blending of PLGA 50:50 (M(w)=24 kDa, endgroup=COOH) (PLGA-COOH) with the PLGA-lauryl ester also provided moderateenhancement 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 drugrelease among all the formulations tested, and, demonstrated 1-month slow andcontinuous in vitro release of approximately 80% 2-ME after a minimal initialburst. Hence, these formulation approaches provide several possible avenues toimprove release rates of the hydrophobic drug, 2-ME, from PLGA for futureapplication in regional anti-cancer therapy.

PMCID: PMC2884995PMID: 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, [email protected]

The objective of this study was to improve the oral bioavailability andtherapeutic efficacy of albendazole (ABZ) employing solid dispersion andcyclodextrin complexation techniques. Solid dispersion (dispersion) was prepared using ABZ and polyvinylpyrrolidone (PVP) polymer (1:1 weight ratio). Ternaryinclusion complex (ternary complex) was prepared using ABZ, hydroxypropylbeta-cyclodextrin (HPbetaCD) and L-tartaric acid (1:1:1 molar ratio). In rabbits with high gastric acidity (gastric pH approximately 1), ternary complex and soliddispersion 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 thecommercial suspension, whereas the reduction in case of PVP dispersion andternary complex was only 43% and 37% respectively. The rapid absorption of thedrug from solid dispersion and ternary complex was reflected in improvedanthelmintic efficacy against the systemic phases of Trichinella spiralis. Theternary complex was significantly more efficient than solid dispersion andexhibited 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 ofthe ternary complex might be high even if there is a great variation in thegastric pH.


15. Acta Pharm. 2005 Sep;55(3):223-36.

Influence of cyclodextrin complexation on piroxicam gel formulations.

Jug M, Bećirević-Laćan M, Kwokal A, Cetina-Cizmek B.

Department of Pharmaceutics Faculty of Pharmacy and Biochemistry University ofZagreb, Zagreb, Croatia. [email protected]

The aim of this work was to evaluate the role of cyclodextrins in topical drugformulations. Solid piroxicam (PX) complexes with beta-cyclodextrin (beta-CD) andrandomly methylated beta-cyclodextrin (RAMEB) were prepared by freeze-drying and characterized using differential scanning calorimetry (DSC), X-ray powderdiffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and nearinfrared spectroscopy (NIR). A physical mixture of PX and cyclodextrins wascharacterized by enhanced dissolution properties compared to the dissolutionprofile of the pure drug due to in situ complex formation. Formation of thePX-cyclodextrin inclusion complex additionally improved the drug dissolutionproperties. Influence of CDs on drug permeation from the water dispersion and theprepared hydroxypropyl methylcellulose (HPMC) gels was investigated. Permeationof the drug involved three consecutive processes: dissolution of the solid phase,

diffusion across the swollen polymer matrix and drug permeation through themembrane. Complexation increased PX diffusion by increasing the amount ofdiffusible species in the donor phase. Slower drug diffusion through the HPMCmatrix was the rate limiting step in the overall diffusion process. Possibleinteraction between the hydrophilic polymer and cyclodextrin may result inphysicochemical changes, especially in a change of rheological parameters.


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

Formulation studies and in vivo evaluation of a flurbiprofen-hydroxypropylbeta-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 aflurbiprofen (FPN)-hydroxypropyl beta-cyclodextrin (HPbetaCD) solid dispersion(SD) in rats, 2) to study factors affecting the drug release from SDformulations, and 3) to evaluate the pharmacokinetic profile of the drug whenadministered as SD, in humans. The solubility of FPN in water and dissolutionmedia was evaluated as a function of HPbetaCD concentration. The SD was prepared by coevaporation from dilute aqueous NH3 and evaluated in rats. The release ofthe drug from tablet formulations and capsules of SD was studied in simulatedgastric fluid and phosphate buffer, pH 7.2. The bioavailability of drug whenadministered as SD was evaluated in humans. HPbetaCD enhanced the solubility ofthe 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 inuptake of water and stabilization of the resulting gels-like structure ofHPbetaCD-containing tablets. This adversely affected drug release. The releasefrom capsules filled with SD was comparable to that obtained from plain SDpowder. The drug-HPbetaCD association constant in water was much lower than thevalues reported in literature. The bioavailability (which could suffer in case ofhigher association constant) was enhanced on administration of SD-filled capsulesto humans.


17. Drug Dev Ind Pharm. 2005 Jan;31(2):169-78.

Celecoxib-cyclodextrin systems: characterization and evaluation of in vitro andin vivo advantage.

Nagarsenker MS, Joshi MS.

Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Mumbai 400098,India. [email protected]

Solid dispersions of Celecoxib were prepared with hydroxypropyl beta cyclodextrinby various methods such as physical mixture, cogrinding, kneading, andcoevaporation. The dispersions were characterized by differential scanningcalorimetry (DSC), X-ray diffraction patterns, infrared spectroscopy, and nuclearmagnetic resonance studies. The DSC thermograms of the dispersions indicatedpotential of heat-induced interaction between Celecoxib and cyclodextrin thatcould influence in vitro drug dissolution. The dispersions exhibited faster ratesof dissolution compared to that of Celecoxib. The kneaded dispersion with thefastest in vitro dissolution rate when compressed into tablets showed a betterrelease profile compared to the tablets of pure Celecoxib. In vivo studiesrevealed that the kneaded dispersion provided for quicker response and was moreeffective in inhibiting rat paw edema as compared to Celecoxib alone, thusconfirming the advantage of improved pharmacological activity of Celecoxib whenadministered as a solid dispersion with cyclodextrin.


18. Indian J Exp Biol. 2005 Jan;43(1):46-52.

Chronobiological and chronopharmacological studies of ketoprofen and its soliddispersion 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. [email protected]

Chronobiology of rheumatoid arthritis (RA) was studied using a standard adjuvant arthritis animal model. Chronopharmacology of ketoprofen, and its soliddispersion forms was also studied. Temporal variations in the degree of articularinflammation (paw volume) and progression of articular destruction were studiedby injecting Freund's Complete Adjuvant (FCA) at 0800 and 2000 hrs. Temporalvariations in anti-inflammatory effects and ulcerogenic effect were also studied by administration of plain ketoprofen (20 mg/kg) and its solid dispersion withhydroxypropyl beta-cyclodextrin (equivalent to 20 mg/kg of ketoprofen) at thesame time points (0800 and 2000 hrs) twice weekly for 22 days. Solid dispersionof 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 significantlyhigher 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 inducedarthritis model, inflammation and articular damage was significantly greater inthe rest period of diurnally active rats than in the activity phase. KPF and its solid dispersion showed better protection from inflammation in the morning thanin the evening.


19. Acta Pol Pharm. 2004 Jan-Feb;61(1):21-30.

Dissolution behaviour of nalidixic acid solid dispersions using water solubledispersion carriers.

Mallick S, Sahu A, Pal K.

Division of Formulation Development and Drug Delivery Systems, Department ofPharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia,Mayurbhanj-757 086. Orissa, India. [email protected]

The oral bioavailability of nalidixic acid (NA) is low due to its poor solubilityand slow dissolution. Solid dispersions of NA containing varying concentrationsof polyvinylpyrrolidone (PVP), beta-cyclodextrin (BCD) and sodium starchglycolate (SSG) were prepared by solvent evaporation technique in an attempt toimprove dissolution rate of NA. Physical characterization of NA, physicalmixtures (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 ofpossible nalidixic acid inclusion in the dispersion system by studying itssurface and shape characteristics of different samples. IR analysis demonstrated no strong interaction between the drug and the carrier exists in the soliddispersions. The degree of crystallinity of nalidixic acid decreased and alsodiffered with the dispersion systems of different carriers. Disolution studiesindicated that the dissolution rate and percent dissolution efficiency (DE) were significantly increased in the solid dispersions compared with drug alone. Therelative potency of the carriers to enhance the dissolution rate of nalidixicacid was in the order: BCD > PVP > SSG. The dissolution rate of the drug in thesolid 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 ofdrug release from all the solid dispersion systems.


20. J Pharm Pharmacol. 2004 Jun;56(6):725-33.

Influence of preparation methodology on solid-state properties of an acidicdrug-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 ondissolution behaviour of the drug. The interaction between flurbiprofen andhydroxypropyl beta-cyclodextrin (HP-beta-CyD) was studied by NMR spectroscopy andphase solubility studies. Binary systems containing flurbiprofen and HP-beta-CyD or povidone (polyvinylpyrrolidone) K30, prepared by various processes, werecharacterized by FTIR, DSC, XRD and dissolution studies. HP-beta-CyD enhanced thesolubility of flurbiprofen and increased dissolution rates from binary systems.It was found to be superior to povidone K30 in producing higher dissolutionrates. The method of preparation of the binary systems and the agents used werefound to have a major influence on the final solid-state of flurbiprofen.Solvents and processing conditions favouring greater interaction betweenflurbiprofen and the cyclodextrin during the preparation process resulted ingreater extent of drug-cyclodextrin association and/or greater amorphization ofthe 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 ofmolecular dispersion of the drug. Processing variables therefore couldsignificantly influence the solid-state of a drug in cyclodextrin-basedformulations and thereby affect its dissolution behaviour. This could lead tosignificant effects on the in-vivo performance of the formulation.


21. Drug Dev Ind Pharm. 2004 Jan;30(1):53-64.

Valproic acid-hydrophilic cyclodextrin complexes and valproic acid-soliddispersions: 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, Facoltà di Farmacia, Università degli Studi diBari, Bari, Italy. [email protected]

The purpose of this study was to evaluate the potential use of two novel solidformulations of valproic acid (VPA) prepared by complexation with hydrophiliccyclodextrins (CDs) as hydroxypropyl-beta- and sulfobutylether-beta-cyclodextrin and by solid dispersion (SD) in hydrophilic carriers as polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K-30 (PVP K-30). The correspondingcyclodextrin-based complexes were prepared by the freeze-drying method while the solid dispersions were obtained by the solvent method. Valproic acid solubilityimproved by CDs complexation and solid dispersion techniques. Comparison ofdissolution profiles with that of VPA sodium salt (NaVP) was made by usingrelease parameters such as dissolution efficiency, percent of drug dissolvedafter 60 min, and difference and similarity factors. Based on difference andsimilarity factors, it can be concluded that all the VPA formulations possessdissolution 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-basedformulations and NaVP at that pH value. Preliminary pharmacological studies inthe pentylenetetrazole test in rats showed some important differences among theSD-based formulations, NaVP, and VPA as oil/water emulsion. Some implications andlimitations of the investigated formulations are discussed.


22. Eur J Pharm Biopharm. 2003 Nov;56(3):453-9.

Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitroand in vivo evaluation.

Yüksel N, Karataş A, Ozkan Y, Savaşer A, Ozkan SA, Baykara T.

Department of Pharmaceutical Technology, Ankara University, School of Pharmacy,Ankara, Turkey. [email protected]

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 thein vitro and in vivo performance of the semi-solid dispersion prepared withGelucire 44/14 and Labrasol into hard gelatin capsules (GL) for enhancing thedissolution rate of the drug. The results were evaluated by comparing with purepiroxicam 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 within30 min in each of the media, behaving like a fast-dissolving immediate releasedrug product. Oral bioavailability of 20 mg piroxicam in GL, CD, and PP wascompared after administration of a single dose to eight healthy volunteers. Threetreatments were administered in crossover fashion, separated by a washout period of 2 weeks. Piroxicam was monitored in plasma by high-performance liquidchromatography. The apparent rate of absorption of piroxicam from GL (Cmax=2.64micrograms/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 bioavailabilityvalues as the ratios of mean total AUC for GL relative to PP and CD, were 221 and98.6%. Piroxicam is characterized by a slow and gradual absorption via the oralroute and this causes a delayed onset of therapeutic effect. Thus, plainpiroxicam preparations are not indicated for analgesia. The results of the invivo study revealed that the GL dosage form would be advantageous with regards torapid onset of action, especially in various painful conditions where an acuteanalgesic effect is desired.


23. Drug Dev Ind Pharm. 2003 Jul;29(6):641-52.

Itraconazole formulation studies of the melt-extrusion process with mixturedesign.

Rambali B, Verreck G, Baert L, Massart DL.

Farmaceutische Instituut, Vrije Universiteit Brussel, Brussels, [email protected]

Itraconazole is a poorly water soluble compound. One method to increase theaqueous solubility of itraconazole is through formation of a solid dispersion.The purpose of this study is to develop a 40% w/w itraconazole formulationthrough 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 corotatingmelt 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 fractionsvaried between 10% w/w and 60% w/w. The itraconazole formulation was optimized by

producing clear extrudates, minimizing the torque, and maximizing the glasstransition 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 themixture promoted a better melt processing (minimizes torque). High HPMC fraction (>33% w/w) resulted in clear extrudates, indicating a solid dispersion andresulted in high glass transition temperature of the melt. High HP-beta-CDfraction resulted in increased apparent itraconazole solubility in 0.1 N HCl. Theoptimal itraconazole formulation consisted of 45% w/w HPMC and 15% HP-beta-CDw/w.


24. Drug Dev Ind Pharm. 2003 Feb;29(2):139-44.

Carbamazepine/betaCD/HPMC solid dispersions. I. Influence of the spray-dryingprocess and betaCD/HPMC on the drug dissolution profile.

Koester LS, Mayorga P, Bassani VL.

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia,Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

The aim of this study was to compare carbamazepine (CBZ) solid dispersionsprepared by spray-drying of aqueous dispersions with the corresponding physicalmixtures. The influence of the association of beta-cyclodextrin (betaCD) andhydroxypropyl methylcellulose (HPMC) on the CBZ dissolution profile of thepreparations was investigated. Results demonstrated that CBZ release from soliddispersions is dependent on the ratio of betaCD and HPMC. The spray-dryingprocess confers better homogeneity to CBZ polymeric dispersions than the physicalmixture process. In summary, we demonstrated the feasibility of obtaining ahomogeneous polymeric solid dispersion of CBZ from an aqueous media byspray-drying and a clear influence of the betaCD:HPMC ratio on the releaseprofile of CBZ.


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

Comparative studies of the enhancing effects of cyclodextrins on the solubilityand 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 ratswere examined and compared with those after administration of a PROGRAF capsulecontaining the solid dispersion formulation of tacrolimus. Here we used naturalCyDs and the hydrophilic beta-CyD derivatives; that is, randomlymethylated-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 etherbeta-cyclodextrins (SBE-beta-CyDs). Of the natural CyDs, the solubility oftacrolimus increased in the addition of beta-CyD, indicating that the cavity ofbeta-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-ordercomplexes. The result of van't Hoff plot suggests that the enthalpy is dominantfor the complexation of tacrolimus with DM-beta-CyD. The dissolution rate oftacrolimus was markedly augmented by the complexation with DM-beta-CyD,reflecting its solubilizing activity. An in vivo study revealed that DM-beta-CyD increased the bioavailability of tacrolimus with low variability in theabsorption after oral administration of the tacrolimus suspension to rats. Thepresent results suggest that DM-beta-CyD is particularly useful in designing oralpreparations of tacrolimus with an enhanced bioavailability and a reducedvariability in absorption.


26. Drug Dev Ind Pharm. 2000 Nov;26(11):1141-50.

Effect of water-soluble carriers on dissolution characteristics of nifedipinesolid 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 andPEG6000), hydroxypropyl-beta-cyclodextrin (HP beta CD), and poloxamer 407 (PXM407) in four mixing ratios were prepared by melting, solvent, and kneadingmethods in order to improve the dissolution of NP. The enhancement of thedissolution 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% asshort as 15 min were obtained from PXM 407 solid dispersion prepared by themelting 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 thatNP existed in the amorphous state. The wettability and solubility were markedlyimproved in the PXM 407 system. The presence of intermolecular hydrogen bondingbetween NP and PEGs and between HP beta CD and PXM 407 was shown by infrared (IR)spectroscopy.


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. [email protected]

PURPOSE: The deformation behaviors of compressed freeze-dried and spray-driedtolbutamide/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 byfreeze-drying and spray-drying, and physical dispersions of TBM and HP-beta-CDwere blended. Deformation properties of the prepared materials were evaluated by using a compaction simulator and constants derived from Heckel plots. Moleculardynamics (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 overallparticle deformation than the spray-dried stable form I. Formation of moleculardispersions decreased the plastic and elastic behaviors of these materials. Also,the MD simulations showed a reduced molecular flexibility of the TBM-HP-beta-CDinclusion complex, as compared to HP-beta-CD.CONCLUSIONS: The formation of TBM and HP-beta-CD molecular dispersion resulted inmore rigid molecular arrangements, which were less prone to deformation thaneither HP-beta-CDs or physical dispersions. The results showed how differingmolecular, solid, particle, and powder state properties affect the deformationproperties of the materials studied.


28. J Pharm Pharmacol. 2000 Aug;52(8):949-56.

Solid dispersion of hydroxypropyl beta-cyclodextrin and ketorolac: enhancement ofin-vitro dissolution rates, improvement in anti-inflammatory activity andreduction 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 analgesicactivity. It is practically insoluble in water and has been implicated in causinggastrointestinal ulceration. This study describes the formulation of soliddispersions of ketorolac using hydroxypropyl beta-cyclodextrin (HPbeta-CyD) andbeta-cyclodextin (beta-CyD) as carriers, to improve the aqueous solubility of thedrug, thus enhancing its bioavailability. Also, reduction in ulcerogenicity wasanticipated. Differential scanning calorimetry and X-ray diffraction studiesindicated loss of crystalline nature of the drug, in the dispersions preparedwith HPbeta-CyD. NMR studies revealed a strong interaction between drug andHPbeta-CyD. Solid dispersions of drug with beta-CyD retained the crystallinenature of the drug. All the solid dispersions showed a remarkable improvement in the rate and extent of dissolution of ketorolac. The kneaded dispersion withHPbeta-CyD prepared using a 1:1 alcohol-water mixture showed promise in reducing the ulcer-inducing effect of ketorolac in rats. Oral administration of thisdispersion was found to inhibit carrageenan-induced paw oedema in rats to asignificantly greater extent compared with ketorolac or its trometamol salt.Though beta-CyD as a carrier for ketorolac gave faster release of the poorlysoluble drug, HPbeta-CyD proved to be superior to beta-CyD, as a carrier in thekneaded dispersion prepared using 1:1 alcohol-water mixture. These resultssuggest that solid dispersions of ketorolac with HPbeta-CyD aid in fasterdissolution and better bioavailability of the drug. The higher solubility of the drug in the presence of HPbeta-CyD also reduces local gastrointestinalside-effects of the drug.


29. Pharmazie. 2000 Jul;55(7):513-7.

In vitro and in vivo evaluation of anamylobarbitone/hydroxypropyl-beta-cyclodextrin complex prepared by afreeze-drying method.

Fathy M, Sheha M.

Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, [email protected]

The complex formation of amylobarbitone (AMB) with2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated in aqueoussolution and in the solid state. The apparent stability constant for complexformation (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 3fold. The solid dispersion system of AMB/HP-beta-CD in 1:1 molar ratio wasprepared by a freeze-drying method. Differential scanning calorimetry (DSC),x-ray diffractometry, (IR) and 1H NMR spectroscopy were used to confirm thatinclusion between the drug and HP-beta-CD occurred. The dissolution behavior ofthe drug as a physical mixture as well as the prepared complex, showed enhanceddrug dissolution properties of the prepared complex compared to the physicalmixture or the drug alone. The dissolution rate appeared in the first 2 min, 25times greater for the complex than for the drug alone. Furthermore, in-vivo studyrevealed that the duration and hypnotic activity of AMB after its oraladministration to mice were improved by inclusion.


30. Chem Pharm Bull (Tokyo). 2000 May;48(5):646-50.

Effects of aging on crystallization, dissolution and absorption characteristicsof 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 oftolbutamide from amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin(HP-beta-CyD) complex were investigated, in comparison with those ofpolyvinylpyrrolidone (PVP) solid dispersion. The amorphous solid complex oftolbutamide with HP-beta-CyD and the solid dispersion of tolbutamide with PVPwere prepared by a spray-drying method. During storage, a stable form oftolbutamide (form I) was crystallized from the amorphous PVP dispersion, whereas a metastable form of tolbutamide (form II) was crystallized from the HP-beta-CyD complex. The dissolution rate of tolbutamide from both HP-beta-CyD complex andPVP 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 dueto the formation of fast dissolving formII crystals. These in vitro dissolutioncharacteristics were clearly reflected in the in vivo absorption of tolbutamideand the glucose plasma level after oral administration in dogs. The resultssuggested that HP-beta-CyD is useful not only for converting crystallinetolbutamide to an amorphous substance, but also for maintaining the fastdissolution rate of the drug over a long period. Furthermore, the crystallizationof drugs from CyD complexes, with storage, seemed to be different from thatinvolving polymer excipients such as PVP.


31. Chemistry. 2000 Mar 17;6(6):999-1006.

Highly organized spherical hosts that bind organic guests in aqueous solutionwith 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 Adiameter that are soluble in aqueous solution were constructed. The binding ofxylenes, aryl ethers, polyaromatic compounds, ferrocene derivatives, and bicyclicaliphatic compounds were examined by NMR spectroscopy and microcalorimetry. NMRbinding studies indicated that binding depended upon guest hydrophobicity andshape. No binding was detected for guests in which a charge must be desolvated aspart 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 andfound to be indefinitely stable in the solid phase and in aqueous solution. Thebinding 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 thosefrom previous work with beta-cyclodextrin and cyclophane hosts, along withanalysis of the entropy-enthalpy compensation data, indicate that there is ahigher degree of guest desolvation with this host structure than with open-shell hosts. This accounts at least partially for the increase in affinity observedwith 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 thataromatic guests are bound with higher affinity than aliphatic ones in agreementwith results that point to the importance of London dispersion forces in theassociation of aromatic components in face-to-edge orientations. The correlation of changes in NMR chemical shift with microcalorimetry data supports a model inwhich increased CH-pi interactions strengthen association between host and guest due to the dominant role of van der Waals dispersion forces. Remarkably, thebinding constant for the 1,4 isomer of dimethoxybenzene is 32 times higher thanfor the 1,2 isomer, and even greater discrimination is observed between thexylene guests since the binding constant for p-xylene is 80 times greater thanthat for o-xylene. This discrimination between isomeric guests by a rigid hostindicates that changes in specific hydrophobic interactions have substantialeffects 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 ofhydrophilic 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-beta-CyD)form 1:1 solid complexes with an orally active angiotensin-converting enzymeinhibitor, captopril, while hydrophobic perbutanoyl-beta-CyD (TB-beta-CyD) forms a solid dispersion or solid solution with the drug. The binary system ofcaptopril/HP-beta-CyD or captopril/TB-beta-CyD and the ternary system ofcaptopril/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. Therelease 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, theretarding 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 themolar ratio of HP-beta-CyD further increased (>.25 molar ratio). Both waterpenetration studies and microscopic observation suggested that the retardingeffect is attributable to a gel formation of HP-beta-CyD in the TB-beta-CyDhydrophobic matrix. It was difficult to prolong plasma levels of captopril byadministering 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 (molarratio of 1:0.5:0.5) gave a plasma profile comparable to that of a commerciallyavailable sustained release preparation (Captoril R). Therefore, a combination ofHP-beta-CyD and TB-beta-CyD is useful for the controlled release of water-solubledrugs such as captopril.


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 beta-cyclodextrin(beta-CD) as carriers. The spectroscopic infra-red (IR), differential scanningcalorimetry (DSC) and powder X-ray diffractometry (PXRD) data indicate a role of these carriers in decreasing the crystallinity of allopurinol and complexingabilities. Solid dispersion and crystallization of the drug with these carrierswere used in suppository formulations to investigate their role in enhancement ofdrug release through the membrane barrier. The bases used included Suppocire AMand the mixture of polyethylene glycols (PEGs). The release rates of allopurinol from lipophilic and hydrophilic suppository bases were examined and compared withthose obtained for their inclusion compounds incorporated in the same bases. The prepared suppositories were evaluated for in-vitro drug release, when fresh andon storage. The release of pure allopurinol from the lipophilic base wasremarkably higher than that from the hydrophilic one. The release of allopurinol from lipophilic as well as hydrophilic bases was significantly enhanced bycrystallization of the drug from 5% w/v of sodium salicylate. Allopurinolcrystallized from sodium salicylate, showed enhanced release reaching about 100% in 1 h from the Suppocire AM base. The obtained data from these experimentsproved the superiority of the PEG formulations containing coevaporates of thedrug 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 excretionin rabbits was observed after rectal administration of suppositories containing

allopurinol crystallized from sodium salicylate.


34. Biol Pharm Bull. 1999 Mar;22(3):298-304.

Effect of sugar-modified beta-cyclodextrins on dissolution and absorptioncharacteristics 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)- and6-O-alpha-D-maltosyl (G2)-beta-cyclodextrins (beta-CyDs) were prepared in amolecular mixing ratio of 1:1. The advantages of these preparations in terms ofdissolution characteristics and the oral absorbency of DPH were evaluated incomparison with the known solid dispersions of polyvinylpyrrolidone K-30 andsodium deoxycholate (DC-Na). The results of a phase-solubility study indicatedthat G1- and G2-beta-CyDs provided higher solubility for DPH than 2-hydroxypropyl(HP)-beta-CyD. Irrespective of inclusion ability, the DPH/beta-CyD complexesallowed faster dissolution rates than those of the known dispersions in JP 1stand 2nd mediums. The dissolution behavior of the DPH/DC-Na dispersion wasconsiderably different between the 1st and 2nd mediums. The complexation by thesugar-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 carriersthemselves 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 enhancingthe absorbability of DPH after oral administration. These results clearly suggestthat complexation with G1- and G2-beta-CyDs are useful forms for the oraldelivery of DPH. The advantage of these complexes is that they produce anincreased level of DPH available for gastrointestinal absorption. Additionally,G2-beta-CyD is recommended as a safe and potent additive for DPH.


35. Drug Dev Ind Pharm. 1998 Jul;24(7):653-60.

Interactions between lonidamine and beta- or hydroxypropyl-beta-cyclodextrin.

Palmieri GF, Wehrlé P, Martelli S.

Dipartimento di Scienze Chimiche, Università di Camerino, Italy.

The possibility of obtaining inclusion complexes between lonidamine and beta- or hydroxypropyl-beta-cyclodextrin have been evaluated by phase solubility diagram, differential scanning calorimetry (DSC), and x-ray diffractometry. The appliedcomplexation methods were spray-drying, kneading, and solid dispersion. DSC andx-ray analyses of the powders revealed an external interaction between lonidamineand cyclodextrins. Dissolution profiles of the obtained powders were also studiedto define the most appropriate preparation method and molar ratio to use inattempts to increase lonidamine water solubility.


36. J Pharm Pharmacol. 1992 Jan;44(1):52-5.

The influence of beta-cyclodextrin on the solubility and dissolution rate ofparacetamol solid dispersions.

Tasić LM, Jovanović MD, Djurić ZR.

Faculty of Pharmacy, Belgrade University, Yugoslavia.

The effect of cyclodextrin (beta-CD) on the solubility and dissolution rate ofvarious paracetamol dispersion powders (1:1 w/w), and tablets was studied. Lower solubility was exhibited by a spray dried solid dispersion made fromparacetamol-Ethocel-Macrogol 6000 (95:2:3). The improvement in solubility wasinfluenced by complexation with beta-CD and the crystalline nature of the powder products made by different procedures. The difference in crystallinity wasconfirmed by X-ray powder diffraction patterns. The dissolution rate ofparacetamol from tablets made from the solid dispersions was satisfactorycompared with paracetamol alone. The differences between the dissolution ratefrom the examined paracetamol tablets resulted from the different solubility ofeach powder and from the structural changes of particles which influenced theconsolidation of the tablet mass.


37. Chem Pharm Bull (Tokyo). 1990 Mar;38(3):728-32.

Study of the interaction of clobazam with cyclodextrins in solution and in thesolid 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 solutionand 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 withheptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and the solid dispersion ofclobazam 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 higheststability constant among the four CyDs in solution. Thermal and X-ray diffractionanalyses 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 beattributed to the formation of hydrogen bonds between the two carbonyl groups of clobazam and hydroxyl groups of natural CyDs. In contrast, higher frequencyshifts were observed in the case of the ground mixtures of clobazam withmethylated CyDs and MC and these were considered to be due to the monomoleculardispersion of clobazam in a hydrophobic environment. The mode of interaction ofclobazam with DM-beta-CyD was different from that with natural CyDs in the groundmixtures. Furthermore, the crystalline inclusion complex of clobazam withDM-beta-CyD was obtained by heating of the coprecipitate in vacuo at 120 degrees C for 1 h.


38. Chem Pharm Bull (Tokyo). 1983 Apr;31(4):1350-6.

Dissolution behavior and gastrointestinal absorption of dicumarol from soliddispersion systems of dicumarol-polyvinylpyrrolidone anddicumarol-beta-cyclodextrin.

Sekikawa H, Fukuda N, Takada M, Ohtani K, Arita T, Nakano M.


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