Embed Size (px)
Citation preview
This article was downloaded by: [ZAINAB EASSA]On: 06 May 2013, At: 09:14Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UK
International Journal of Green Nanotechnology:BiomedicinePublication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/ugnb20
Development and Dissolution Velocity Studies of anOral Albendazole Nanocrystal Solid FormulationR. Ravichandran aa Regional Institute of Education (NCERT), Bhopal, IndiaPublished online: 10 Dec 2010.
To cite this article: R. Ravichandran (2010): Development and Dissolution Velocity Studies of an Oral Albendazole NanocrystalSolid Formulation, International Journal of Green Nanotechnology: Biomedicine, 2:2, B55-B66
To link to this article: http://dx.doi.org/10.1080/1943085x.2010.532066
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematicreproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form toanyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contentswill be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses shouldbe independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims,proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly inconnection with or arising out of the use of this material.
International Journal of Green Nanotechnology: Biomedicine, 2:B55–B66, 2010Copyright c© Taylor & Francis Group, LLCISSN: 1943-085x print / 1943-0906 onlineDOI: 10.1080/1943085x.2010.532066
Development and Dissolution Velocity Studies of an OralAlbendazole Nanocrystal Solid Formulation
R. Ravichandran
ABSTRACT. During the last 10 years, the formulation of drugs as nanocrystals has rapidly evolved intoa mature drug delivery strategy, with currently five products on the market. The major characteristicof these systems is the rapid dissolution velocity, enabling bioavailability enhancement after oraladministration. This study describes the preparation of a solid dosage tablet form of spray-driedalbendazole nanocrystal and compares its dissolution behavior with a market tablet in different media.The aim was to obtain a stable nanocrystal loaded drug tablet with an increased drug saturation solubilityand dissolution velocity. Solubility and dissolution experiments were performed to verify the obviousimprovement of the dissolution behavior compared with the commercial product. Improved dissolutionbehavior in drug nanocrystal-loaded solid dosage forms should lead to better bioavailability of poorlysoluble drugs in the body.
KEYWORDS. albendazole, nanocrystal, tablet, dissolution evaluation
INTRODUCTION
Albendazole (ABZ), methyl [5-(propylthio)-1 H-benzimidazol-2yl] carbamate (Figure 1) isan effective broad-spectrum anthelmintic used inthe treatment of intestinal helminth infections.[1]
Systemic absorption of ABZ is warranted for thetreatment of inoperable or disseminated casesof hydatidosis, other systemic helminthiases,AIDS-related microspordia, and giardiasis.[2–7]
It is the drug of choice in the; treatment ofechinococcosis.[1] Albendazole therapy is espe-cially important in systemic cestode infections,particularly in neurocysticercosis.[8] Though al-bendazole is effective for treatment of these dis-eases, the therapeutic response is unpredictable
Received 9 July 2010; accepted 8 October 2010.Facilities were obtained from Torrent Research Center, Ahmedabad, High Security Animal Disease Lab-
oratory, Bhopal and Central Food Technological Research Institute, Mysore.R. Ravichandran is affiliated with the Regional Institute of Education (NCERT), Bhopal, India.Address correspondence to R. Ravichandran, Regional Institute of Education (NCERT), Bhopal 462 013,
India. E-mail: [email protected]
due to its low and erratic bioavailability as a re-sult of its low aqueous solubility.[9−11] ABZ be-longs to biopharmaceutical classification systemtype II (low aqueous solubility with high perme-ability), thus showing dissolution rate–limitedabsorption.[12,13] Thus, it has poor solubilityand poor oral bioavailability.[10] Improvementof oral bioavailability is of clinical importancein the treatment of systemic helminthiasis suchas echinococcosis because it is an alternativeto surgery.[11] Researchers followed differentapproaches in an attempt to improve oralbioavailability. For example, albendazole solu-tion was formulated by use of surfactants suchas polysorbates and bile salts or cosolvents liketranscutol.[14] Some of these excipients may also
B55
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
B56 INTERNATIONAL JOURNAL OF GREEN NANOTECHNOLOGY: BIOMEDICINE
FIGURE 1. Chemical structure of albendazole: methyl [5-(propylthio)-1 H-benzimidazol-2yl] carba-mate; formula C12H15N3O2S; mol. mass 265.333 g/mol. (Figure provided in color online.)
have some absorption-enhancing effects, whichcan be useful for increasing the oral bioavail-ability of ABZ formulations. Unfortunately,many of these agents can be irritants to digestivesystem linings, so their use must be restrictedwhenever possible. Alternatively, the ABZsolubility can be improved by elaboration ofsolid dispersions with polyvinylpyrrolidone,[15]
although use of organic cosolvents and thehigh quantity of the complexing agent incomplexation techniques are the limiting factorsfor these products. Another possible way ofovercoming this problem is to improve wettingand increase the surface area of the drug byformulating as drug nanoparticles. This may re-sult in improved solubility and dissolution rate,thereby enhancing oral bioavailability.[16,17]
In the last decade the area of oral nanopar-ticulate drug delivery systems has receivedconsiderable attention.[18,19] Nanoparticulatesystems studied include polymeric, solid lipid,liposomes, niosomes, micelles, microemulsions,submicron emulsions, and drug nanoparti-cles. Nanonization is gaining commercial im-portance, with more products seen in themarket.[20–24] Sirolimus (Rapamune, Wyeth)and fenofibrate (Emend, Merck) are commer-cially available on the market with the drug asnanocrystals. Many other products are in thepipeline at different phases of clinical trials.[25]
Drug nanoparticles or drug nanosuspensionsconsist of drug particles between 200 and 500nm stabilized with/without additives.[25] Nan-onization helps in significant improvement ofpharmacokinetic parameters of poorly bioavail-able drugs.[26–28] Unlike other nanosystems,this dosage form contains surfactants at verylow concentrations. Albendazole has disso-lution rate–limited bioavailability and there-fore formulating as a nanosuspension mightimprove its dissolution rate, thereby enhanc-
ing oral bioavailability.[29,30] The ultimate goalof our research was to produce a greaterimprovement in the dissolution and bioavail-ability of ABZ through nanoparticulate formu-lations. Recently we have prepared albendazolenanosuspensions by high-pressure homogeniza-tion and characterized them for their physico-chemical properties.[31] A solid oral formulationwas tested for improved bioavailability in vivoin rats by pharmacokinetic studies.[32] In thisarticle we report the preparation and formula-tion of an oral solid dosage form of albendazolenanocrystals in the form of a tablet along withits dissolution characteristics compared to com-mercial tablets.
MATERIALS AND METHODS
Materials
Albendazole was gift sample from Jug-gat Pharma, Bangalore, India. Albendazolenanosuspensions were stabilized by the blockcopolymer Poloxamer 188 (Sigma-Aldrich) andsodium dodecyl sulfate (Fluka, Switzerland).Milli-Q Plus water, double-distilled water (Mil-lipore), was used as dispersion medium. Theother chemicals were of analytical reagent grade(SRL, Mumbai, India).
Preparation of AlbendazoleNanosuspensions
The albendazole nanosuspension (ABZ-NS)was produced via high-pressure homogeniza-tion (HPH) in pure water using a Micron Lab40 (APV Homogenizer, Germany) at room tem-perature, applying 20 homogenization cycles at1500 bar (equal to 150,000 kPa and 21,756 psi).
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
R. Ravichandran B57
Spray Drying
Spray drying was employed to obtain freelyflowable albendazole nanocrystal powder. Al-bendazole nanosuspensions, having a drug con-centration of 10% (w/w), were dried with aMini Spray-dryer B-190 (Buchi Lab, Switzer-land). The Mini Spray-dryer B-190 was set withregard to temperature inlet (110–100◦C), out-let (74–76◦C), and air volume (600 L/h). Thespray-dried albendazole nanocrystals were di-rectly collected after the process.
Particle Size Analyses
Photon correlation spectroscopy (PCS; Zeta-sizer Nano ZS, Malvern Instruments, UK) andlaser diffraction (LD; Coulter LS230, Beckman-Coulter, Germany) were employed to determinethe particle size. PCS measurements were per-formed at 20◦C and each sample was analyzedthree times. PCS yields the intensity weightedmean diameter of the bulk population (z-average,measuring range: 3 nm–3 µm) and the polydis-persity index (PI) as measures for the width ofthe size distribution. The PI ranges from zero(monodisperse particles) to 0.500 (broad distri-bution); values above 0.5 do not allow allocationof a logarithmic normal distribution to the PI. LDwas repeated three times and the results werecalculated as volume size distribution using Mietheory with the optical parameters 1.593 for thereal refractive index and 0.01 for the imaginaryrefractive index. As characterization parametersthe diameters 10%, 50%, 90%, and 99% wereused. For example, diameter 99% means that99% of the particles are below the given sizevalue.
Preparation of the Tablets and DrugRelease
Albendazole is a white to off-white powder. Itis soluble in dimethylsulfoxide, strong acids, andstrong bases. It is slightly soluble in methanol,chloroform, ethyl acetate, and acetonitrile. Al-bendazole is practically insoluble in water. Eachwhite to off-white, film-coated tablet contains200 mg of albendazole. The formulations of thealbendazole tablets are shown in Table 1. Themass of each tablet prepared was calculated to
TABLE 1. Composition of albendazole tabletformulations
Excipients (mg)
Formulation NC (mg) MC (mg) AV AC Ex Mg T
A 200 — 594 35 — 14 7B 200 — 594 — 35 14 7C — 200 594 35 — 14 7Market — 200 ∗ ∗ ∗ ∗ ∗
NC = albendazole nanocrystal (ABZNC-E); MC = albendazole mi-crocrystal; AV = Avicel PH 101; AC = AcDiSol; Ex = Explotab; Mg= Mg stearate; T = talc; Market = marketed tablet; * not known.
have the same content of albendazole (200 mg)and a total mass equal to the marketed tablet(850 mg). The tablet mass was prepared for 200tablets by adding the spray-dried albendazolenanocrystals (ABZNC-E) to the tablet excipients(Table 1) in a tumbler (Turbula, Switzerland).The tablets were prepared using direct compres-sion by a single punch tablet machine (KorschPressen, Germany).
The dissolution tests were performed usinga USP XXIII rotating paddle apparatus with aPharmatest PTW SIII (Pharma Test, Germany)at 37◦C and a rotating speed of 100 rpm. Tabletswere placed in the dissolution chamber contain-ing the dissolution media (900 mL). At certaintimes, samples were drawn from each dissolu-tion chamber. The samples were filtered throughSartorius R© 0.1 µm filters (Sartorius, Germany).From each vial an aliquot was withdrawn with a1-mL glass syringe (Poulten & Graf, Germany)and assayed by high-performance liquid chro-matography (HPLC) to evaluate the amount ofalbendazole dissolved. Any dilution of the sam-ples was intentionally avoided, to prevent anypossible interference with the chemical equilib-rium, particularly by considering the presence ofcolloidal particles.
HPLC Analysis of Albendazole
A sensitive and selective HPLC chromatog-raphy method using ultraviolet (UV) detectionwas developed for the determination of albenda-zole with oxibendazole as the internal standard.The HPLC system consisted of a Shimadzu LC6A HPLC instrument equipped with a solvent
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
B58 INTERNATIONAL JOURNAL OF GREEN NANOTECHNOLOGY: BIOMEDICINE
FIGURE 2. (A) PCS and (B) LD particles size distribution of albendazole formulations. (Figureprovided in color online.)
0
200
400
600
800
1000
1200
Raw ABZNS-E After 1 Year Spray dried
Formulation
PC
S (
nm
)
0.1
1
10
100
Raw ABZNS-E After 1 Year Spray dried
Formulation
LD
(µ
m) < d10% µm
< d50% µm
< d90% µm
< d99% µm
delivery pump, a Rheodyne injector valve, anda variable-wavelength UV detector. The columnused was C18 Gemini RS (Phenomenex) ana-lytical column (5 µm particle size; 25 cm ×4.6 mm ID) with mobile phase of methanol–water (60:40). The flow rate was maintained at0.8 mL/min. The eluate was monitored at 308nm. Retention time for ABZ and internal stan-dard are 18.8 and 8.2 min, respectively. The datawere recorded and calculated using Winchromesoftware.
RESULTS AND DISCUSSION
The albendazole nanosuspension on a labscale is typically produced by premilling fol-lowed by HPH in pure water using a continuousMicron Lab 40 at room temperature, applying 20homogenization cycles at 1500 bar. The formu-lation of albendazole nanosuspension was pre-pared using albendazole 10%, Poloxamer 1881%, sodium dodecyl sulfate (SDS) 0.2%, andwater 88%. Figure 2 shows the particle size dis-tribution of albendazole formulations by PCSand LD. The ABZNS had LD particle size dis-tribution of 0.1 (<d10%), 0.2 (<d50%), 0.8(<d90%), and 2 µm (<d99%). PCS size was 289nm, with zeta potential (mV) of −30.4 in waterand −21.6 in original medium. Visual examina-tion of crystals in nanosuspensions from imagesof the nanosuspensions from light microscopyand scanning electron microscopy showed fine,stable homogeneous distribution. It showed verygood physical and chemical stability over a one-year period. A spray-drying process was em-ployed to obtain dried albendazole nanocrystalshaving good redispersability, saturation solubil-
ity, and dissolution velocity. LD values were0.33 (<d10%), 0.15 (<d50%), 1.12 (<d90%),and 2.38 µm (<d99%). PCS size was 312 nmwith a PI of 0.37. In general, the saturation solu-bility of the nanocrystals was distinctly fivefoldhigher than for microparticles. The result alsoshowed the superiority of albendazole nanocrys-tals in dissolution behavior and was in agreementwith the Noyes-Whitney equation. According tothese results, albendazole nanocrystals are suit-able for incorporation into solid dosage form,such as tablets, capsules, pellets, etc. The finalproduct of a solid dosage form containing al-bendazole nanocrystals is evaluated in this workwith respect to dissolution testing and comparedto marketed dosage forms.
Preparation of Solid Dosage Forms
Nanosizing refers to the reduction of drug par-ticle size down to the submicron range. Thoughreduction of particle size has been employed inthe pharmaceutical industry for several decades,recent advances in milling technology and ourunderstanding of such colloidal systems haveenabled the production of drug particles of50 to 200 nm size in a reproducible manner. Thesubmicron particles are stabilized with surfac-tants or polymers in nanosuspensions, which canbe further processed into standard dosage formssuitable for oral administration. These nanosus-pensions offer increased dissolution rates fordrug compounds and complement other tech-nologies used to enhance the bioavailability ofinsoluble compounds (BCS classes II and IV),such as solubility enhancers (i.e., surfactants),liquid-filled capsules, or solid dispersions ofdrugs in their amorphous state. Based on theNoyes-Whitney principle, reduction in particle
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
R. Ravichandran B59
FIGURE 3. Albendazole nanocrystal-loaded tablets (a) and marketed tablets (b). (Figure providedin color online.)
size will increase the dissolution rate due to in-creased effective particle surface area. This sizedependency comes only into effect for particlesof a size below approximately 1 µm (submicronparticulate), a phenomenon observed in tablet-ing that leads to an increase of the dissolutionrate of such fine drug particles.[21]
Formulation
On the market, no oral albendazole tabletis found in single dose form. Albendazole isnormally not combined with any other drugs.ZENTEL©R and Albenza©R tablets contain 200 mgalbendazole. The complete albendazole tabletformulations are presented in Table 1. Micro-crystal cellulose (Avicel PH 101) was used astablet filler due to good compressibility prop-erties. AcDiSol and Explotab were used asdry disintegrants. Magnesium stearate and talcwere incorporated as lubricant, glidant, and anti-adherent. Dried albendazole nanocrystals wereadmixed gently to the other tablet excipients. Atumbler was used to mix albendazole nanocrys-tals with the excipients. The tablet mass was fi-nally compressed using a single punch tablet ma-chine. Albendazole nanocrystal-loaded tabletswere produced using direct compression.
Direct Compression of the Tablet
The direct compression method was em-ployed to produce albendazole nanocrystal-loaded tablets. Direct compression was chosento minimize agglomeration of the nanocrystals
during longer processing by granulation. Thismethod is evidently more effective in avoidingparticle agglomerates and aggregates in tablet-ing. Avicel PH 101, AcDiSol, and Explotab aregood excipients for direct compression tablets.They offer suitable properties such as goodflowability and compressibility for the directcompression method. AcDiSol and Explotabare superdisintegrants designed to improve dis-solution behavior and are normally used forthe direct compression method.[33] To ensuresuccessful tablet production using direct com-pression, spray-dried albendazole nanocrystalswere selected because spray-dried albendazolenanocrystals offer better properties for the directcompression compared to lyophilized nanocrys-tals. Albendazole nanocrystals were admixed toother tablet excipients (Table 1) in a tumbler. Theprocess continued with compressing in a sin-gle punch tablet machine. Finally, the albenda-zole nanocrystal-loaded tablets were producedin simple form. Albendazole microcrystal tabletswere also produced using the same method. Thesame procedure was employed, with albendazolenanocrystals substituted for albendazole micro-crystals in the tablets. The final product of thealbendazole nanocrystal-loaded tablets can beseen in Figure 3.
Dissolution Study of Solid Dosage Forms
A dissolution test of drug tablets was per-formed using a USP XXIV rotating paddle ap-paratus. This method is known as method 2 in
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
B60 INTERNATIONAL JOURNAL OF GREEN NANOTECHNOLOGY: BIOMEDICINE
FIGURE 4. Percentage dissolved albendazole in water from nanocrystal formulations A and Bversus microcrystal formulation C. (Figure provided in color online.)
0
5
10
15
20
25
30
0 5 10 15 20 25 30Time (min)
% d
isso
lved
dru
g
Formulation A
Formulation B
Formulation C
United States Pharmacopoeia.[34] Given the drugcontents in the tablets, the dissolution test wasnot performed in sink conditions (drug amountin tablets above 30% of saturation solubility).Therefore, at a certain time the percentage ofdissolved drugs will be constant or change littlebecause the saturation solubility in the dissolu-tion media is going to be approached.
In Water
Three formulations of albendazole tabletswere prepared successfully. The dissolution be-havior of these tablets was evaluated and com-pared with each other. The dissolution profilesof the three albendazole tablets in water mediumare presented in Figure 4. In water medium, for-mulation A could release albendazole faster thanthe other formulations. Formulation A containedalbendazole nanocrystals with AcDiSol used asdry disintegrant. Compared to the microcrystaltablets (formulation C), the nanocrystal tabletshowed superior dissolution velocity. Within30 min, nanocrystal tablets of formulation Adissolved 24% of their albendazole content. Incontrast, microcrystal tablets let to the dissolu-tion of only 11% of albendazole over the sametime. The rate of dissolution was very high inthe first 15 min with almost 22% dissolutionand further increase was only an additional 2%with a stagnation effect. This shows the superi-ority of albendazole nanocrystal-loaded tablets(formulations A and B), which were fastest indissolution of albendazole.
In Buffer at pH 1.2
Albendazole dissolution from albendazoletablets was evaluated in buffer solution havinga pH of 1.2. Albendazole was dissolved fasterfrom nanocrystal tablets compared to microcrys-tal tablets, resembling the dissolution behaviorin water. Within 5 min, the nanocrystal tablets(formulation A) could dissolve almost 36% ofthe drug. By comparison, only 9% of the al-bendazole in the microcrystal tablets (formu-lation C) dissolved in the same time. Dissolu-tion of albendazole from nanocrystal tablets dis-tinctly increased over time. In a period of 30min, almost 43% to 52% of albendazole wasdissolved from the nanocrystal tablets. This wasmore than twice as fast as the dissolution of al-bendazole from microcrystal tablets (Figure 5).It was also noticed that in acidic medium thedrug dissolution was considerably greater thanin water.
In Buffer at pH 6.8
Nanocrystal tablets were again superior indissolving albendazole in buffer at pH 6.8.In this media, 22% of albendazole was dis-solved from the nanocrystal tablet (formula-tion A) within 10 min. In contrast, microcrys-tal tablets dissolved only 7% of the drug underthe same conditions. This means that nanocrys-tal tablets could dissolve drugs at triple the rateof the microcrystal tablets over a 10-min period(Figure 6).
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
R. Ravichandran B61
FIGURE 5. Percentage dissolved albendazole in buffer at pH 1.2 from nanocrystal formulations Aand B versus microcrystal formulation C. (Figure provided in color online.)
0
10
20
30
40
50
60
0 5 10 15 20 25 30
Time (min)
% d
isso
lved
dru
g
Formulation A
Formulation B
Formulation C
FIGURE 6. Percentage dissolved albendazole in buffer at pH 6.8 from nanocrystal formulations Aand B versus microcrystal formulation C. (Figure provided in color online.)
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Time (min)
% d
isso
lved
dru
g
Formulation A
Formulation B
Formulation C
FIGURE 7. Percentage of dissolved albendazole from nanocrystal tablets A and B versus marketedtablet in water. (Figure provided in color online.)
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Time (min)
% d
isso
lved
dru
g
Formulation A
Formulation B
Market Tablet
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
B62 INTERNATIONAL JOURNAL OF GREEN NANOTECHNOLOGY: BIOMEDICINE
FIGURE 8. Percentage dissolved albendazole from nanocrystal tablets A and B versus marketedtablet in buffer having a pH of 1.2. (Figure provided in color online.)
0
10
20
30
40
50
60
0 5 10 15 20 25 30
Time (min)
% d
isso
lved
dru
g
Formulation A
Formulation B
Market Tablet
Comparison of Nanocrystal-LoadedTablets and Marketed Tablets
Albendazole nanocrystal-loaded tablets (for-mulations A and B) were also compared to themarketed albendazole tablets. Figures 7, 8, and9 show dissolved albendazole from formulationsA and B and the marketed tablets. The nanocrys-tal tablets were distinctly superior in all disso-lution media. In water, the nanocrystal tablets(formulation A) dissolved about 22% of the drugwithin 15 min. Within the same time, the mar-keted tablets dissolved only 1.4% of their alben-
dazole. The nanocrystal tablets (formulation A)thus dissolved albendazole 16 times faster thanmarketed tablets in the first 15 min. In other me-dia, the dissolution behavior was also distinctlyimproved. After 5 and 10 min, the nanocrys-tal tablets (formulation A) dissolved 36% and22% of the drugs in buffer having a pH of 1.2and 6.8. Meanwhile in the same time, only 3%and 1.8% of albendazole was dissolved from themarketed tablets in buffer having a pH of 1.2 and6.8. This suggests that albendazole nanocrystal-loaded tablets have a high potential for oral ad-ministration and can improve the bioavailability
FIGURE 9. Percentage of dissolved albendazole from nanocrystal tablets A and B versus marketedtablet in buffer having a pH of 6.8. (Figure provided in color online.)
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Time (min)
% d
isso
lved
dru
g
Formulation A
Formulation B
Market Tablet
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
R. Ravichandran B63
of drugs in cases in which dissolution perfor-mance restricts bioavailability of drugs in thebody.
Dissolution Performance
Compared to microcrystal tablets and mar-keted tablets, the nanocrystal tablets definitivelyshowed higher levels of percentage dissolvedalbendazole. In all three dissolution media,nanocrystal tablets dissolved albendazole atdistinctly faster rates compared to microcrystalsand marketed tablets. Therefore, nanocrystaltablets have superior characteristics to micro-crystals and marketed tablets, indicating a majoropportunity to enhance the bioavailability ofdrugs by nanosuspensions for oral administra-tion, in cases when dissolution is a rate-limitingfactor in bioavailability in the body like thatof albendazole. It is easy to understand that abio-relevant medium will need a similar surfaceactivity as biofluids and hence a study on invivo pharmacokinetic evaluation of albendazolenanoformulation with improved bioavailabilitywas also carried out and is found to yield asimilar positive result.[32]
Dissolution Velocity
An outstanding feature of nanocrystals isthe increase in saturation solubility and conse-quently an increase in the dissolution velocityof the compound. Based on the Noyes-Whitneyequation,[35] this increase in dissolution velocitytakes place in addition to the increase caused bythe enlargement of the surface area, for exam-ple, exploited in micronized products.[36] By de-creasing the particle size (e.g., to the nanometerrange), the surface area of the particulate is fur-ther increased. In addition, the Noyes-Whitneyequation describes that the dissolution veloc-ity dc/dtdepends on the concentration gradient(cs − cx)/h(cs is the saturation solubility; cx isthe equilibrium concentration in the bulk phase,and his the diffusional distance) and the Prandtlequation describes that the diffusional distancehis reduced for small particles. Thus, the simul-taneous increase in the saturation solubility cs
and the decrease in hlead to an increased con-centration gradient (cs − cx)/h, enhancing the
dissolution velocity in addition to the surfaceeffect.[37] Figure 10 summarizes these effects.
An increase in dissolution velocity and anincrease in saturation solubility can also beachieved by changing the crystalline state ofthe material (e.g., from crystalline to amorphousor partially amorphous). Due to thermodynamicreasons, the preservation of the amorphous stateis critical; therefore, the production of nanocrys-tals should lead to crystalline particles. Thecrystalline state of the albendazole nanocrystalsinvestigated in our study remained unchanged(100% crystalline) upon both HPH and drying.
Perspectives on Drug Nanocrystalsfor Oral Application
Recently, the particle size reduction effec-tiveness of drug substance–loaded tablets onoral bioavailability has been intensively inves-tigated. It has been proven that particle size re-duction leads to improved oral bioavailability inthe body. Takano et al. have specified that par-ticle size reduction leads to improved dissolu-tion rate and bioavailability.[38] In addition, therate-limiting steps of oral absorption were simu-lated. An increase in the dissolution rate and ad-ministered dose showed a shift from dissolutionrate–limited to solubility-limited absorption. Inthe study in dogs, the particle size reduction ofthe drugs improved the oral absorption.[38] Suchstudies provide a powerful tool to predict doselinearity and will aid in the development of for-mulating poorly soluble drugs (Biopharmaceuti-cal Classification System [BCS] class II [as wellas IV] drugs).
According to Hintz and Johnson,[39] a com-puter method has been developed to describethe theoretical dissolution rate of a polydispersepowder under non-sink conditions based on itsweight percentage particle size distribution. Itwas shown that finer particles in the size dis-tribution showed an improved dissolution be-havior. Moreover, the particle size distributionswere used to simulate their effect on the amountof drug absorbed orally.[39] Similarly, we sug-gest this promising albendazole tablet dosageform for oral administration. It leads to supe-rior physicochemical properties and should over-come the in vivo absorption problem of the
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
B64 INTERNATIONAL JOURNAL OF GREEN NANOTECHNOLOGY: BIOMEDICINE
FIGURE 10. Transfer of microcrystals to nanocrystals leads to an increase in surface area (upper).Increase in saturation solubility cs, decrease in diffusional distance h, and increase in the concen-tration gradient cs − cx/h. All effects increase the dissolution velocity dc/dt. (Figure provided in coloronline.)
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
R. Ravichandran B65
FIGURE 11. Mechanism of action: finelydispersed nanocrystals versus aggregatednanocrystals (similar to micrometer crystals).(Figure provided in color online.)
poorly soluble albendazole as class II BCS drug.Figure 11 summarizes the effects on bioavail-ability enhancement in the gut. It is importantthat the nanocrystals are released from the tabletor capsule as fine nanocrystals. It could be shownthat a slight aggregation does not yet impairthe dissolution velocity,[40] but pronounced ag-gregation will decrease the dissolution velocitystrongly.[41]
CONCLUSION
Nanosuspensions were formulated by high-pressure homogenization to overcome problemscaused by poor aqueous solubility. Increasein surface area enhances the dissolution rate.Spray-dried albendazole nanocrystals preparedby a high-pressure homogenization techniquecan be employed to produce solid dosage formsof the drug like tablets. Dried drug nanocrys-tals offer superior physicochemical properties.Albendazole nanocrystal-loaded tablets can beproduced using direct compression. From theNoyes-Whitney equation, the increased surfacearea and saturation solubility due to the de-creased radius result in increased dissolutionvelocity. This phenomenon was clearly demon-strated by the albendazole nanocrystals. Thedissolution velocity of nanocrystal-loaded soliddosage forms was evaluated. Drug nanocrystalswere released from the nanocrystal tablets at afaster rate compared to microcrystal tablets or
marketed tablets. Dissolution velocity of drugnanocrystals from solid dosage forms was su-perior compared to microcrystal-loaded soliddosage forms and the marketed solid dosageforms (tablet). Improved dissolution behaviorin drug nanocrystal-loaded solid dosage formsshould lead to better bioavailability of poorlysoluble drugs in the body.
REFERENCES
1. Cook, G. C. Use of benzimidazole chemotherapy inhuman helminthiases: Indications and efficacy. Parasitol.Today 1990, 6(4), 133–136.
2. Wen, H.; New, R. R. C.; Craig, P. S. Diagnosis andtreatment of human hydatidosis. Br. J. Clin. Pharmacol.1993, 35, 565–574.
3. WHO Informal Working Group on Echinococcosis.Guidelines for treatment of cystic alveolar echinococcosisin humans. Bull. World Health Organ. 1996, 74, 231–242.
4. Misra, P. K.; Kumar, A.; Agarwal, U.; Jagota, S. C. Acomparative clinical trial of albendazole vs. metronidazolein giardiasis. Indian Pediatr. 1995, 32, 291–294.
5. Lecuit, N.; Oksenhendler, E.; Sarfati, C. The use ofalbendazole for disseminated microsporidian infection inpatients with AIDS. Clin. Infect. Dis. 1994, 19, 332–333.
6. Lopez-Garcia, M. L.; Torrado-Duran S.; Torrado-Duran, J.; Martinez, A. R.; Bolas, F. Albendazole ver-sus ricobendazole against enteral and parenteral stages ofTrichinella spiralis in mice. Int. J. Parasitol. 1997, 27, 781–785.
7. Keramidas, D.; Mavridis, G.; Soutis, M.; Passalidis,A. Medical treatment of pulmonary hydatidosis: Compli-cations and surgical management. Pediatr. Surg. Int. 2004,19, 774–776.
8. Del Brutto, O. H.; Sotelo, I.; Raman, G. C. Ther-apy for neurocysticercosis: A reappraisal. Clin. Infect. Dis.1993, 17, 730–733.
9. Gil Grande, L. A.; Rodriguez-Caabeiro, F.; Prieto, J.G.; Sanchez-Ruano, J. J.; Brasa, C. Randomised controlledtrial of efficacy of albendazole in intra-abdominal hydatiddisease. Lancet 1993, 342, 1269–1272.
10. Van Nieuwkerk, K. M. J.; Veenstra, J.; Wassenaar,R. P.; Blaauwgeers, H. L.; Geraedts, A. A.; Kroes, H. Pan-creatitis causes by rupture of liver hydatid cyst. Eur. J.Gastroenterol. Hepatol. 1993, 5, 563–565.
11. Yasawy, M. I.; ALKarawi, M. A.; Are, M. Combi-nation of praziquantel and albendazole in the treatment ofhydatid disease. Trop. Med. Parasitol. 1993, 44, 192–195.
12. Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J.R. A theoretical basis for a biopharmaceutic drug classifi-cation: The correlation of in vitro drug product dissolutionand in vivo bioavailability. Pharm. Res. 1995, 12, 413–420.
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
B66 INTERNATIONAL JOURNAL OF GREEN NANOTECHNOLOGY: BIOMEDICINE
13. Jung, H.; Medina, L.; Garcia, L.; Fuentes, I.; Es-parza, R. M. Absorption studies of albendazole and somephysicochemical properties of the drug and its metabolite,albendazole sulphoxide. J. Pharm. Pharmacol. 1998, 50,43–48.
14. Torrado, S. S.; Lopez, M. L.; Torrado, G.; Bolas, G.;Torrado, S.; Cadorniga, R. A novel formulation of albenda-zole solution: Oral bioavailability and efficacy evaluation.Int. J. Pharm. 1997, 156, 181–187.
15. Torrado, S.; Torrado, S.; Torrado, J. J.; Cadorniga,R. Preparation, dissolution and characterization of alben-dazole solid dispersions. Int. J. Pharm. 1996, 140, 247–250.
16. Jacobs, C.; Kayser, O.; Muller, R. H. Nanosuspen-sions as a new approach for the formulation for the poorlysoluble drug tarazepide. Int. J. Pharm. 2000, 196, 161–164.
17. Kayser, O.; Olbrich, C.; Yardley, V.; Kiderlen, A.F.; Croft, S. L. Formulation of amphotericin B as nanosus-pension for oral administration. Int. J. Pharm. 2003, 254,73–75.
18. Ravichandran, R. Nanoparticles in drug delivery:Potential green nanobiomedicine applications. Interna-tional Journal of Green Nanotechnology: Biomedicine2009, 1(2), B108–B130.
19. Ravichandran, R. Nanotechnology-based drug de-livery systems. NanoBiotechnology 2009, 5(1), 17–33.
20. Chen, X.; Young, T. J.; Sarkari, M.; Williams, R. O.;Johnston, K. P. Preparation of cyclosporine A nanoparticlesby evaporative precipitation into aqueous solution. Int. J.Pharm. 2002, 242, 3–14.
21. Muller, R. H.; Jacobs, C.; Kayser, O. Nanosuspen-sions as particulate drug formulations in therapy. Rationalefor development and what we can expect for the future.Adv. Drug Deliv. Rev. 2001, 47, 3–19.
22. Weder, H. G.; van Hoogevest, P. Nanosuspensionsfor Intravenous Administration; U.S. Patent No. 5726164,1998.
23. Muller, R. H.; Jacobs, C. Buparvaquone mucoadhe-sive nanosuspensions: Preparation, optimisation and long-term stability. Int. J. Pharm. 2002, 237, 151–161.
24. Rabinow, B. E. Nanosuspensions in drug delivery.Nat. Rev. Drug. Discov. 2004, 3, 785–796.
25. Keck, C. M.; Muller, R. H. Drug nanocrystals ofpoorly soluble drugs produced by high pressure homoge-nization. Eur. J. Pharm. Biopharm. 2006, 62(1), 3–16.
26. Liversidge, G. G.; Cundy, K. C. Particle size reduc-tion for improvement of oral bioavailability of hydrophobicdrugs: I. Absolute oral bioavailability of nanocrystallinedanazol in beagle dogs. Int. J. Pharm. 1995, 125, 91–97.
27. Jinno, J.; Naoki, K.; Miyake, M.; Yamada, K.;Mukia, T.; Odomi, M.; Togu-chi, H.; Liversidge, G. G.;Higaki, K.; Kimura, T. Effect of particle size reduction ondissolution and oral absorption of a poorly water-solubledrug, cilostazol, in beagle dogs. J. Contr. Release 2006,111, 56–64.
28. Liversidge, G. G.; Conzentino, P. Drug particle sizereduction for decreasing gastric irritancy and enhancingabsorption of naproxen in rats. Int. J. Pharm. 1995, 125,309–313.
29. Yamasani, M. R.; Mittapalli, P. K.; Shashank,A. Formulation of nanosuspensions of albendazole fororal administration. Current Nanoscience 2008, 4(1), 53–58.
30. Mittapalli, P. K.; Yamasani, M. R.; Shashank, A. Im-proved bioavailability of albendazole following oral admin-istration of nanosuspension in rats. Current Nanoscience2007, 3(2), 191–194.
31. Ravichandran, R. Preparation and characterizationof albendazole nanosuspensions for oral delivery. Inter-national Journal of Green Nanotechnology: Biomedicine2010, 2(1), B1–B24.
32. Ravichandran, R. In vivo pharmacokinetic studies ofalbendazole nanoparticulate oral formulations for improvedbioavailability. International Journal of Green Nanotech-nology: Biomedicine 2010, 2(1), B46–B53.
33. Balasubramaniam, J.; et al. Effect of superdisinte-grants on dissolution of cationic drugs. Dissolution Tech-nologies 2008, 12, 18–25.
34. United States Pharmacopoeia Conventional. TheUnited States Pharmacopoeia, 24th rev. ed.; The UnitedStates Pharmacopoeia Conventional Inc.: Rockville,MD.
35. Noyes, A. A.; Whitney, W. R. The rate of solution ofsolid substances in their own solutions. J. Am. Chem. Soc.1987, 19, 930–934.
36. Muller, R. H.; Jacobs, C.; Kayser, O. Nanosus-pensions for the formulation of poorly soluble drugs. InPharmaceutical Emulsions and Suspensions; Nielloud, F.;Marti-Mestres, G., Eds.; Marcel Dekker: New York 2000;pp. 383–407.
37. Muller, R. H.; Akkar, A. Drug nanocrystals of poorlysoluble drugs. In Encyclopedia of Nanoscience and Nan-otechnology; Nalwa, H. S., Ed.; American Scientific Pub-lishers: Los Angeles, 2004; pp. 627–638.
38. Takano, R., et al. Rate-limiting steps of oral absorp-tion for poorly water soluble drugs in dogs; prediction froma miniscale dissolution test and a physiologically-basedcomputer simulation. Pharm. Res. 2008, 25(10), 2334–2344.
39. Hintz, R. J.; Johnson, K. C. The effect of particle sizedistribution on dissolution rate and oral absorption. Int. J.Pharm. 1989, 51, 9–17.
40. Keck, C., Fichtinger, A.; Viernstein, H.; Muller, R.Oral drug nanocrystals—Effect of potential aggregation onbioavailability. AAPS: Baltimore, 2004. Available onlineat: http://www.aapsj.org/abstracts/AM 2004/AAPS2004-002746.pdf
41. Nakarani, M.; Patel, P.; Patel, J.; Patel, P.; Murthy,R.S.R., Vaghani, S.S. Cyclosporin A-nanosuspension: For-mulation. Characterization and in vivo comparison with amarketed formulation. SciPharm. 2010, 78, 345–361.
Dow
nloa
ded
by [
ZA
INA
B E
ASS
A]
at 0
9:14
06
May
201
3
