1

Introduction

Felodipine is a calcium channel blocker from the class of dihydropyridines. It is widely used due to its selective vasodilator effect in cardiovascular disorders primarily arterial hypertension and it dilates vessels without effects on cardiac contractility.[1–3] It provides smooth plasma concentrations and stable blood pressure reduction with little or no effects on heart rate.[3] There was no indication that felodipine treatment increases the total mortality or the incidence of cardiovascular events. Thus felodipine is generally safe for treatment of hypertension and maintains the quality of life in the treated hypertensive patients[3,4] Felodipine was proposed as a candidate drug in emergency and treatment of hypertensive crisis.[5] It was found that intravenous felodipine infusion was equally effective as nefidipine infusion in cases of emergency and hypertensive crisis where they lowered the blood pressure in more than 90% of the patients. Felodipine is

superior to nefidipine since it does not suffer from light sensitivity. Therefore, orodispersible tablets (ODTs) of felodipine may provide the rapid onset of action required for emergency. However, Felodipine is a model drug of the Biopharmaceutical Classification System (BCS) class II, Which features poor solubility, high permeability. The rate of absorption of class II drugs such as felodipine is often controlled by its solubility and dissolution rate in the fluid present at the absorption site. Various techniques have been employed to enhance the dissolution rate and absorption efficiency of water-insoluble drug such as micronization, co-grinding, formulation of inclusion complexes, solubilization by surfactants, solid disper-sions, solid solutions, hydrotrophy and co solvency.[6–8]

The most promising technique for promoting dis-solution is the formation of liquisolid compact that promotes dissolution rate of water-insoluble drugs to a greater extent and also enhances the drug flow property.

ReseaRch aRtIcle

Rapidly absorbed orodispersible tablet containing molecularly dispersed felodipine for management of hypertensive crisis: Development, optimization and in vitro/in vivo studies

Emad B. Basalious, Wessam El-Sebaie, and Omaima El-Gazayerly

Faculty of Pharmacy, Cairo University, Department of Pharmaceutics and Industrial Pharmacy, Cairo, Egypt

abstractA liquisolid orodispersible tablet of felodipine, a BCS Class II drug, was developed to improve drug dissolution and absorption through the buccal mucosa for management of hypertensive crisis. A 24 full-factorial design was applied to optimize felodipine liquisolid systems (FLSs) having acceptable flow properties and possessing enhanced drug dissolution rates. Four formulation variables; The liquid type, X

1 (PG or PEG), drug concentration, X

2 (10% and 20%),

type of coat, X3 (Aerosil® and Aeroperl®) and excipients ratio, X

4 (10 and 20) were included in the design. The systems

were assessed for dissolution and flow properties. Following optimization, the formulation components (X1, X

2, X

3

and X4) were PEG, 10%, Aerosil® and 20, respectively. The optimized FLS was compressed into felodipine liquisolid

orodispersible tablet using Prosolv® as carrier material (FLODT-2). The in vitro and in vivo disintegration times of FLODT-2 were 9 and 7 s, respectively. The in vivo pharmacokinetic study using human volunteers showed a significant increase in dissolution and absorption rates of the formulation of FLODT-2 compared to soft gelatin capsules filled with felodipine solution in PEG under the same conditions. Our results proposed that the optimized FLODT formulation could be promising to manage hypertensive crisis.

Keywords: Felodipine, optimization, orodispersible tablet, full-factorial design, liquisolid

Address for Correspondence: Emad B. Basalious , Faculty of Pharmacy, Cairo University, Department of Pharmaceutics and Industrial Pharmacy, Cairo, 11562 Egypt. E-mail: dremadbasalious@gmail.com

(Received 08 November 2011; accepted 10 January 2012)

Pharmaceutical Development and Technology, 2012, 1–10, Early Online© 2012 Informa Healthcare USA, Inc.ISSN 1083-7450 print/ISSN 1097-9867 onlineDOI: 10.3109/10837450.2012.659258

Pharmaceutical Development and Technology

2012

00

00

00

00

08 November 2011

02 February 2012

10 January 2012

1083-7450

1097-9867

© 2012 Informa Healthcare USA, Inc.

10.3109/10837450.2012.659258

LPDT

659258

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

2 E.B. Basalious et al.

Pharmaceutical Development and Technology

Liquisolid compacts of poorly soluble drugs containing a drug molecularly dispersed in a solubilizing vehicle show enhanced drug dissolution due to an increased surface area of drug, an increased aqueous solubility of the drug, and an improved wettability of the drug par-ticles. Accordingly, this improved drug dissolution may result in higher drug absorption and thus, an improved oral bioavailability[9–13]

The concept of liquisolid compacts can be used to for-mulate liquid medications such as liquid drugs and solu-tions or suspensions of water-insoluble solid drugs carried in suitable nonvolatile solvent systems into acceptably flowing and compressible powders. Simple blending of such liquid medications with selected powder excipients referred as the carrier (cellulose) and coating materials (silicates), can yield dry-looking, non-adherent, free-flowing, and readily compressible powders.[14–17]

Literature lacks any data about the application of liquisolid technique for development of felodipine liquisolid orodispersible tablet (FLODT) useful for man-agement of hypertension crisis. The developed FLODT with enhanced solubility and dissolution hastens the absorption of felodipine and avoids its hepatic first pass metabolism through the partial absorption from buccal mucosa and esophagus. Thus, the aim of this study was the formulation and optimization of liquisolid systems that contain molecularly dispersed felodipine and pos-sess enhanced dissolution and absorption rates. The liqu-isolid systems that showed acceptable flowability were then compressed into FLODT. Furthermore felodipine pharmacokinetics was studied after buccal administra-tion of the optimized FLODT to human volunteers com-pared to a felodipine solution in PEG filled in soft capsule (felodipine soft capsule).

Materials

Felodipine was kindly obtained from Alkan Pharmaceutical Industries (Cairo, Egypt). Propylene gly-col, polyethylene glycol 400, Polysorbat 80 were obtained from El-Nasr pharmaceutical chemicals company (Cairo, Egypt). Prosolv® SMCC 90 and Vivapur® PH 102 (MCC PH 102) were kindly provided by RJS (Rosenberg, Germany). Aerosil® 200 pharma (amorphous silicon dioxide) and Aeroperl® 300 pharma (granulated silicon dioxide) were obtained from Degussa (Hanau-WoIfgang,

Germany). Crospovidone and Aspartame were pur-chased from Sigma, (St. Louis, USA). Lemon flavor was kindly supplied by chemical industry development (CID), (Egypt). The internal standard Solifenacin succinate was kindly supplied by DELTA Pharma (Egypt). Acetonitrile and methanol were from Sigma Aldrich (St. Louis, USA). All other chemicals were of analytical grade.

Methods

Preliminary screening of liquid vehicle and liquid load factor range appropriate for formulating felodipine liquisolid systems5 mg felodipine was dispersed in the liquid vehicles (propylene glycol (PG), polyethylene glycol 400 (PEG) and polysorbat 80) in glass vial. The mixture was heated to 60°C with constant stirring. The dispersion was then sonicated for 15 min until a homogenous mixture was formed. The liquid medication was then mixed with the calculated amount of the carrier material (MCC® PH 102) in a mortar using pestle. The coating material (Aeroperl®) was then added to the mixture with gentle mixing. The mixture of carrier and coating material (excipient ratio) was set at a ratio of 20:1. Finally, each liquisolid powder was blended with 10% w/w of a disintegrating agent (Crospovidone®). Depending on the concentration of drug dispersion and the amount of carrier material, dif-ferent liquid load factors (ranged from 0.125 to 0.23) were employed in the liquisolid systems. The composition of these liquisolid systems is shown in Table 1. The flow properties of the liquisolid systems were estimated by determining Carr’s index, and Hausner’s ratio. The Bulk density and Tap densities were determined for the calcu-lation of Hausner’s ratio and Carr’s Index.[18,19]

Formulation optimization of felodipine liquisolid systems (FLSs)In order to produce dry-looking, non-adherent, free-flowing and readily compressible liquisolid powders possessing optimum drug dissolution, a 24 full-factorial design was employed to evaluate the individual and combined effects of four formulation variables on felo-dipine dissolution rate. In this design, four factors are evaluated, each at two levels, and experimental trials were performed at all sixteen possible combinations. The liquid type, X

1 (PG or PEG), drug concentration, X

2 (10%

Table 1. Composition and flow properties of felodipine liquisolid systems prepared for screening the appropriate dispersing liquids and load factor range.Type dispersing liquid

Ratio of drug to dispersing liquid

% drug concentration in dispersing liquid

Weight of liquid medicationW (mg)a

Load Factor L

fb

Hausner’s ratio Carr’s Index

PG 1:6 14.29 35 0.23 1.26 25.24%Tween 80 1:6 14.29 35 0.23 1.43 30.20%PEG 400 1:6 14.29 35 0.23 1.23 21.80%PEG 400 1:6 14.29 35 0.175 1.17 14.90%PEG 400 1:4 20 25 0.125 1.16 15.60%aLiquid medication contains 5 mg felodipine.b152.17 mg, 200 mg and 200 mg MCC PH 102 was blended with the liquid medication to give 0.23, 0.175 and 0.125 liquid load factors.

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

Rapidly absorbed orodispersible tablet of felodipine for management of hypertensive crisis 3

© 2012 Informa Healthcare USA, Inc.

and 20%), type of coat, X3 (Aerosil® and Aeroperl®) and

excipients ratio, X4 (10 and 20) were selected as the inde-

pendent variables. The dependent variable (responses) was the cumulative amount dissolved in water in 30 min (Q

30). The composition of FLSs is presented in Table 2.

Constant weight of MCC PH 102 (210 mg) was used as a carrier. Two values of Lf (0.119 and 0.23) were obtained based on the weight of liquid medication (containing 5 mg felodipine). The statistical analysis was performed using Minitab computer software. Felodipine liquisolid systems (FLSs) were prepared as previously mentioned. The optimum liquisolid system of this study is selected to have optimum flow properties and the maximum felo-dipine dissolution (Q30).

The effect of various carrier types on the flow and dis-solution properties of the optimized liquisolid system of felodipine was also studied. FLSs using optimum liquid type, coat type, drug concentration and excipients ratio were prepared using different carrier types, namely, Prosolv®, MCC PH102 and a mixture of mannitol and MCC in a ratio of 1:1.

Evaluation of the felodipine liquisolid systems (FLSs)Determination of flow propertiesFLSs were evaluated by determining Car’s index, and Hausner’s ratio as previously mentioned.

In vitro dissolution of felodipine from the prepared liquisolid systems in distilled waterIn vitro dissolution of FLSs in distilled water were per-formed to study the extent of drug dissolution enhance-ment. The dissolution of felodipine from its liquisolid systems was performed in 500 mL distilled water main-tained at 37 ± 0.5°C using the USP Dissolution Tester Apparatus II (VK 700, Vankel, USA), at a rotation speed of

50 rpm. Aliquots from the dissolution medium were with-drawn at 5, 10, 15, 20, 30, 45 and 60 min time intervals. The withdrawn samples were then centrifuged at 5000 rpm for 10 min and analyzed for felodipine content by measuring the absorbance at λ

max 363.6 nm using distilled

water as blank. A similar volume of distilled water was added to the dissolution medium in order to maintain a constant volume in the dissolution vessel. The cumula-tive amount of felodipine dissolved from each liquisolid system after 30 min (Q

30) was used for assessment of drug

dissolution.

Compression of the optimized FLSs into orodispersible tabletsThe optimized FLSs were mixed with 6 mg lemon fla-vour and 3 mg aspartame and then compressed into 11 mm ODTs using a single punch machine. Batches of 200 biconvex tablets (310 mg each), containing 5 mg of felo-dipine per tablet, were prepared and exposed to further investigation.

Evaluation of the optimized felodipine liquisolid orodispersible tablets (FLODTs)Physical characterizationFLODTs were evaluated by carrying out tests for weight variation, friability, hardness, disintegration, dissolution, and content uniformity. All the tests were carried out in triplicate and according to the compendial specifica-tions. The in vitro disintegration test was carried out on six tablets in distilled water at 37 ± 2°C using the USP dis-integration apparatus (Logan instruments incorporation, NJ, USA).

Determination of wetting time and water absorption ratioWetting time and water absorption ratio of FLODTs was determined by placing five circular tissue papers in a

Table 2. Composition of felodipine liquisolid systems (FLSs) and their flow and dissolution properties.

FormulaLiquid

type (X1)

Drug Concentration in liquid vehicle (X

2)

Weight of liquid medicationa (mg)

Type of coat (X

3) L

fb

Excipients ratio (X

4) (carrier:coat) H.R. C.I. Q

30(%)

FLS-1 PEG 20% 25 Aeroperl® 0.119 20 1.20 16.80% 11.40

FLS-2 PEG 10% 50 Aeroperl® 0.238 20 1.19 20.10% 32.5

FLS-3 PG 20% 25 Aeroperl® 0.119 20 1.20 16.70% 9.82

FLS-4 PG 10% 50 Aeroperl® 0.238 20 1.22 18.10% 10.08

FLS-5 PEG 20% 25 Aerosil® 0.119 20 1.23 18.80% 12.56

FLS-6 PEG 10% 50 Aerosil® 0.238 20 1.18 15.50% 36.72

FLS-7 PG 20% 25 Aerosil® 0.119 20 1.24 19.90% 9.52

FLS-8 PG 10% 50 Aerosil® 0.238 20 1.27 21.30% 11.46

FLS-9 PEG 20% 25 Aeroperl® 0.119 10 1.15 13.50% 5.38

FLS-10 PEG 10% 50 Aeroperl® 0.238 10 1.23 19.20% 18.91

FLS-11 PG 20% 25 Aeroperl® 0.119 10 1.15 13.60% 11.04

FLS-12 PG 10% 50 Aeroperl® 0.238 10 1.15 13.60% 9.67

FLS-13 PEG 20% 25 Aerosil® 0.119 10 1.23 19.00% 10.35

FLS-14 PEG 10% 50 Aerosil® 0.238 10 1.25 20.00% 18.76

FLS-15 PG 20% 25 Aerosil® 0.119 10 1.24 19.80% 9.66

FLS-16 PG 10% 50 Aerosil® 0.238 10 1.21 17.90% 9.52aLiquid medication contains 5 mg felodipine.bConstant weight of MCC PH 102 (210 mg) was used as a carrier giving 2 values of Lf based on weight of liquid medication.

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

4 E.B. Basalious et al.

Pharmaceutical Development and Technology

petri dish of 10 cm diameter. Ten milliliters of water con-taining a water-soluble red dye (Amaranth), was added to the petri dish. The dye solution was used to identify complete wetting of the tablet surface. A FLODT was carefully placed on the surface of the tissue paper in the petri dish at 25°C. The time required for water to reach the upper surface of the tablets and to completely wet them was noted as the wetting time.[20–22] These measurements were carried out in replicates of three. Wetting time was recorded using a stopwatch.

The weight of the tablet prior to placement in the petri dish was noted (W

b) utilizing a Shimadzu digital balance

(Japan). The wetted tablet was removed and reweighed (W

a). Water absorption ratio, R, was then determined

according to the following equation.[20]

R = 100 * (Wa – W

b)/W

b

Where Wb

and Wa

were tablet weights before and after water absorption, respectively.

In vitro dissolutionThe in vitro dissolution of felodipine from FLODTs was performed in 500 mL 0.5% SLS solution maintained at 37 ± 0.5°C using the USP Dissolution Tester Apparatus II, at a rotation speed of 50 rpm as previously mentioned.

In vivo disintegration timeIn vivo disintegration time of FLODTs was determined by placing ODT into the mouth of two healthy males adult volunteers without water. The time until the volunteers felt that the tablet had disappeared in their mouths was recorded as in vivo disintegration time (n = 3).

Pharmacokinetic study in healthy human volunteersStudy design and subjectsThe study was carried out to compare the pharmacoki-netics of felodipine from the optimized FLODT-2 to a soft capsule filled with felodipine solution in PEG. A single-dose, two-period randomized cross-over design was adopted under fasting condition. Four healthy adult male volunteers participated in this comparative study (weight 65–80 kg, age between 25 and 35 years, and height from 167 to 185 cm), and all are nonsmokers. The biochemical examination of the volunteers revealed normal kidney and liver functions. The nature and the purpose of the study were fully explained to them. None of the volun-teers were on any drug treatment one week before the participation in the study. An informed written consent was obtained from each volunteer. The in vivo study pro-tocol was reviewed and approved by the research ethics committee at the Faculty of Pharmacy, Cairo University, Egypt. The protocol complies with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for humans.

The study was performed on two periods. Period I, half the number of volunteers (group 1) received the optimized FLODT-2 in their buccal cavities (treatment A) and the other half (group 2) swallowed one felodipine

soft capsule (treatment B). Both treatments were admin-istered after 12-h overnight fasting. Food and drink (other than water, which was allowed after 2 h) were not allowed until 4 h after dosing, and then a standard breakfast and lunch were given to all volunteers according to a time schedule. A washout period of 1 week separated the peri-ods. In period II, group 1 received treatment B and group 2 received treatment A.

Sample collectionThe study was supervised by a physician who was also responsible for the volunteers’ safety and collection of samples during the study. Blood samples (~5 mL), for felodipine analysis were drawn into evacuated heparin-ized glass tubes through an indwelling cannula at the following sampling times: 0 min (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 8 and 24 h after administration of each treatment. Blood samples were centrifuged at 3500 rpm for 10 min at 4°C; plasma was transferred directly into 5 mL plastic tubes and stored frozen at −20°C pending drug analysis.

Sample preparationAll frozen human plasma samples were thawed at ambi-ent temperature. Human plasma samples (1 mL) were placed in 7 mL glass tubes, and 50 μL of IS solution was added to each and vortexed for 30 s. Two mL Methyl-t-butyl-ether was then added, and samples were then vortexed for 1 min. The tubes were then centrifuged for 15 min at 3000 rpm. The upper organic phases were then transferred to clean glass tubes, filtered through 0.45 µm Millipore filter and evaporated to dryness using centrifugal vacuum concentrator (Eppendorf, Germany) at 40°C. Dry residues were then reconstituted with 100 μL of mobile phase and 20 μL was injected using the autosampler.

LC–MS/MS assay of felodipineThe quantitative determination of felodipine in human plasma was performed by a sensitive and selective liq-uid chromatographic method coupled with electrospray ionization tandem mass spectrometry (LC–MS/MS) pro-cedure described by Kim et al.[23] The mobile phase was composed of a mixture of acetonitrile and ammonium acetate (80:20, v/v). Solifenacin succinate was used as internal standard (IS).

Pharmacokinetic and statistical analysisPlasma concentration-time data of felodipine was ana-lyzed for each subject by non-compartmental pharma-cokinetic models using computer program, Kinetica® (version 5, Thermo Fischer Scientific, NY, USA). The t

1/2

(h) was calculated as 0.693/K. The maximum drug con-centration (C

max, ng/mL) and the time to reach C

max (T

max,

h) were obtained from the individual plasma concentra-tion-time curves. The area under the curve AUC

0–24 (ng h/

mL) was determined as the area under the plasma con-centration-time curve up to the last measured sampling

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

Rapidly absorbed orodispersible tablet of felodipine for management of hypertensive crisis 5

© 2012 Informa Healthcare USA, Inc.

time and calculated by the linear trapezoidal rule. The area under the curve from zero to infinity AUC

0−∞ (ng h/

mL) was calculated as AUC0−∞

= AUC0–24

+ Ct/K where Ct is the last measured concentration at the time t.

The pharmacokinetic parameters, Cmax

, t1/2

, AUC0–24

, and AUC

0−∞ were compared between treatments A and

B with ANOVA test for the untransformed data The non-parametric Signed Rank Test (Mann–Whitney’s test) was used to compare the medians of t

max for treatments A and

B using the software Minitab®. The level of significance was α = 0.05. A p value of ≤ 0.05 was considered statisti-cally significant.

Results and discussions

Preliminary screening of liquid vehicle and liquid load factor range appropriate for formulating felodipine liquisolid systemsSeveral liquisolid systems were preliminary prepared to select the type of liquid vehicle, drug concentration and the range of load factors (L

f) to be used in optimization of

liquisolid systems. These preliminary liquisolid systems were evaluated by determination of their flow properties through measurement of Carr’s index and Hausner’s ratio (Table 1). Liquisolid systems prepared by polysorbate 80 were characterized by poor flow as indicated by the higher values of HR and CI (1.43 and 30.2, respectively)(Table 1). Thus, it was excluded from further studies. An acceptably flowing and compressible liquisolid system can be prepared only if a maximum liquid load on the carrier material is not exceeded; such a characteristic amount of liquid is termed the liquid load factor (L

f)

and defined as the ratio of the weight of liquid medica-tion (W) over the weight of the carrier powder (Q) in the system.[24] It is obvious that decreasing the liquid load factors (L

f), enhanced the powder flow. A reasonable

flow was achieved within the whole range of liquid load factors (L

f) between 0.125 and 0.23, this is in agreement

with what was stated in literature that it is hard to prepare formulation with good flowability and compactability when loading factor is above 0.25.[14,15,25] Therfore, PEG and PG were used as liquid vehicles with a load factor less than 0.25.

Formulation optimization of felodipine liquisolid systems (FLSs)Based on the results of preliminary screenings, the appropriate liquid vehicles (PG and PEG) and liquid load factor (L

f) lower than 0.25 were selected to formulate

FLSs having optimum flow as well as dissolution prop-erties. In order to rapidly obtain the optimal FLSs, a 24 factorial design was applied in this study. The liquid type (PG and PEG) (X

1), drug concentration in liquid vehicle

(10% and 20%) (X2)

, type of coat (Aerosil and Aeroperl)

(X3), and excipent ratio (10 and 20) (X

4) were chosen as

formulation variables. The cumulative amount of felo-dipine dissolved in water in 30 min (Q30) was selected as response variable. The flow properties and Q30 of

FLSs are summarized in Table 2. Constant weight of MCC PH 102 (210 mg) was used as a carrier giving L

f =

0.119 or 0.238 (lower than 0.25), based on weight of liq-uid medication. Two felodipine concentrations in liquid vehicles were used. The lower concentration (10%, w/w) gave a molecular solution of felodipine while a molecu-lar suspension was obtained by the higher felodipine concentration (20%, w/w). Aeroperl® is a granulated highly pure colloidal silicon dioxide prepared to be used in pharmaceutical products. Aeroperl® is advantageous over Aerosil® as it has higher specific surface area and tapped density. It can serve as a good candidate for liqui-solid tablets.

The optimum liquisolid system of this study is selected to have optimum flow properties and the maximum felodipine dissolution (Q30). Powder flow properties are crucial in handling and processing oper-ations such as flow from hoppers, mixing and com-pression. A uniform flow from the hoppers into the die cavity ensures uniform tablet weight and drug content. Poor flowing powders present many difficulties to the pharmaceutical industry.[17]

The powder flowability of FLSs was determined using Hausner’s ratio and Carr’s index (compressibility index, CI). Hausner’s ratio (HR) was related to the inter particle friction; powders with a low interparticle fric-tion had a ratio of approximately 1.25 indicating a good flow. All FLSs showed acceptable Hausner’s ratio except FLS-8 whose Hausner’s ratio was 1.27 i.e. above 1.25.[26] Generally powders with Carr’s index (CI) below 25% have acceptable flowability,[17] while powders with CI below 18% are considered very flowing. The sixteen liquisolid systems had CI between 13.5 % (FLS-9) to 21.3 % (FLS-8) which means that all liquisolid systems have acceptable flow.

The in vitro dissolution results (Q30) of felodipine from FLSs are shown in Figure 1 and Table 2. It is obvi-ous that FLS-6, FLS -2, FLS -10 and FLS −14 give the highest values of Q30, 36.72%, 32.50%, 18.91% and 18.765%, respectively. These liquisolid systems com-posed of 10% drug concentration in PEG as a liquid vehicle. The higher Q

30 values could be due to the lower

concentration of drug thus the majority of drug was found in a molecularly solubilized form. The Q30 val-ues of FLS-10 and FLS -14 are approximately half that of FLS -6, FLS -2. It is worthy to note that increasing the excipent ratio from 10 (in FLS -10 and FLS -14) to 20 (in FLS -6 and FLS -2) approximately doubled the val-ues of Q30. Other FLSs, containing 10% and 20% drug concentration in PG had significantly lower Q30 values. The limited increase of felodipine dissolution by these systems was probably due to the lower solubility of felodipine in PG.

Analysis of full-factorial experimental design24 full-factorial experimental design was designed to evaluate main effects and interactions of the four chosen variables that may affect the dissolution rate of FLSs. The

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

6 E.B. Basalious et al.

Pharmaceutical Development and Technology

standardized effect of the independent variables and their interaction on the dependent variable was inves-tigated by preparing Pareto charts (Figure 2). The chart includes a vertical reference line at the critical p value of 0.05. An effect that exceeds the vertical line is considered to be statistically significant.[27,28]

The fact that the bars for the variables X1, X

2 and X

4

extend after the reference line indicates that using PEG as a liquid vehicle, maximum value of excipient ratio[20] and lowest value of drug concentration (10%) significantly increased the values of Q

30 and consequently felodipine

dissolution rate. These observations conform to what was previously stated in literature that liquisolid systems with higher excipient ratio (contain high amount of cellulose and low amount of silica) show enhanced disintegra-tion and de-aggregation properties and the consequent enhancement of felodipine dissolution..[14] Liquisolid systems with lower drug concentration in the liquid vehicle contain higher fraction of drug that is solubilized and molecularly dispersed in the liquid vehicle leading to better dissolution.[9,12,15] The type of coat had a non sig-nificant effect on drug dissolution (Figure 2).

As shown in Figure 2, The extension of the bars of the interactions (X

1X

2) and (X

1X

4) and (X

2X

4) after the reference

line in the Pareto chart indicates that there were significant interactions (liquid type/drug concentration, liquid type/excipient ratio and drug concentration/ excipient ratio) on the mean Q

30 values of FLSs. It is obvious that the dissolu-

tion rate of FLSs containing PEG were positively affected by excipient ratio and negatively affected by drug concen-tration with greater extent than that of FLSs containing PG. Figure 3 shows the contour plots of Q

30 for FLSs contain-

ing a) PG/Aerosil®, b) PG/Aeroperl®, c) PEG/Aerosil®, and d) PEG/Aeroperl®. Rapid dissolution of felodipine from FLSs containing PG could be obtained by using high excipient ratio with low drug concentration or low excipi-ent ratio with high drug concentration (Figure 3a and 3b). However, in case of FLSs containing PEG, the maximum dissolution rate could be obtained only by using the high-est excipient ratio[20] with the smallest drug concentration (10%) with Aerosil® or Aeroperl® as coat material (Figure 3c and 3d). The enhancement of dissolution rate from FLSs

Figure 1. The cumulative amount of felodipine dissolved in water in 30 minutes (Q30) from felodipine liquisolid systems (FLSs). (See colour version of this figure online at www.informahealthcare.com/phd)

Figure 2. Standardized Pareto charts for (Q30) of felodipine liquisolid systems (FLSs). (See colour version of this figure online at www.informahealthcare.com/phd)Ph

arm

aceu

tical

Dev

elop

men

t and

Tec

hnol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Purd

ue U

nive

rsity

on

11/0

3/12

For

pers

onal

use

onl

y.

Rapidly absorbed orodispersible tablet of felodipine for management of hypertensive crisis 7

© 2012 Informa Healthcare USA, Inc.

containing PEG was higher than that obtained from FLSs containing PG. This observation could be due to the higher solubility of felodipine in PEG.

The effect of different carriers on dissolution properties of the optimized FLSsThe relatively low Q30 values (36.7% or 32.5%) of the optimized FLSs, containing MCC PH 102, PEG, 10% drug concentration, an excipient ratio of 20 and Aerosil® or Aeroperl®, encouraged us to use other carrier materials to enhance dissolution rate and flow properties. Other FLSs were prepared using the same formulation vari-ables of the optimized system except the carrier type. Prosolv®and a mixture of mannitol and MCC in a ratio of 1:1 were used instead of MCC PH 102. The composition of these optimized liquisolid systems are shown in Table 3.

The flow and dissolution properties of the prepared FLSs were compared with that obtained from FLS containing MCC PH 102 (FLS-2 and FLS-6). As shown in Table 3, all the optimized FLSs show acceptable flow as indicated by the values of HR (below 1.25) and CI (below 25%).

It is obvious that the optimized FLSs containing Aerosil® gave higher dissolution rate than those FLSs containing Aeroperl®. Moreover, the optimized FLSs containing Mannitol/MCC and Prosolv® as carriers (58.5% and 41.1%, respectively) gave higher dissolution rate than that of the original one containing MCC PH 102 (36.72%).

Evaluation of the optimized FLODTsThe optimized FLSs were compressed into Liquisolid ODTs of felodipine using Prosolv® and MCC PH 102 as

Figure 3. The contour plots of Q30

of felodipine liquisolid systems (FLSs) containing a) PG/Aerosil®, b) PG/Aeroperl®, c) PEG/Aerosil®, and d) PEG/Aeroperl®. (See colour version of this figure online at www.informahealthcare.com/phd)

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

8 E.B. Basalious et al.

Pharmaceutical Development and Technology

carrier materials. However, MCC: Mannitol carrier pro-duced friable tablets so that it was excluded. The compo-sition of FLODTs is shown in Table 4.

Table 4 shows the results of the tests performed to evaluate FLODTs. It is clear that they conformed to the requirements that should be present in tablets as uni-formity of weight and drug content. FLODTs also pos-sessed acceptable hardness and friability. The in vitro disintegration times of FLODT-1 and FLODT-2 were 11 sec and 9 sec, respectively. The in vivo disintegration times of FLODT-1 and FLODT-2 were 8 sec and 7 sec, respectively. The rapid disintegration of FLODT-2 could be explained by its rapid wetting (wetting time 6 sec.) and its high water absorption capacity (147%).

Figure 4 demonstrates comparison of drug dissolution from FLODT-1 and FLODT-2 to that from conventional felodipine tablet (5 mg felodipine with 10.5 mg Aerosil, 30 mg Crospovidone and 264 mg MCC PH 102) and felodipine soft capsule (soft gelatin capsule filled with 5 mg felodipine dissolved in 0.5 gm PEG) in 500 mL 0.5% sodium lauryl sulphate solution. Dissolution profiles reveal that felodipine was rapidly dissolved from FLODT-2 and felodipine soft capsule where 80.4% and 62.3% were dissolved after 10 min. dissolution, respectively, followed by FLODT-1 (59.7%) and finally conventional felodipine tablet (29.4%).

FLODT-1, FLODT-2 and felodipine soft capsule showed enhanced dissolution as the drug particles in these formulations were molecularly solubilized in PEG. After these systems are disintegrated in dissolution medium, drug particles are in a state of molecular disper-sion. Thus, the higher dissolution rates observed in these systems may be attributed to significantly larger surface

area of the molecularly dispersed drug particles.[15] The conventional felodipine tablet has a limited surface exposed for dissolution due to the hydrophobicity of the drug particles.

Complete felodipine dissolution was obtained from FLODT-2 and felodipine soft capsules (approximately 100% dissolved after I h). Therefore, they were selected for the in vivo pharmacokinetic study.

Pharmacokinetic Study in Healthy Human VolunteersThe mean plasma concentration-time profiles of felo-dipine following administration of single buccal dose of FLODT-2 and a single oral dose of felodipine soft capsule to four healthy human volunteers are shown in Figure 5. The mean pharmacokinetic characteristics are summarized in Table 5. After buccal administration of FLODT-2, felodipine was rapidly absorbed and reached a C

max of 15.69 ± 4.08 ng/mL at a T

max of 1 ± 0.25. After the

oral administration of felodipine soft capsule, felodipine reached a C

max of 13.44 ± 3.75 ng/mL at a T

max of 1.25 ±

0.29. Statistically insignificant differences (p > 0.05) were found between the pharmacokinetic parameters AUC

0–24,

AUC0−∞,

Cmax

, and t1/2

determined for both the optimized FLODT-2 and felodipine soft capsule which satisfied the bioequivalence criteria. The mean T

max estimated

from the optimized FLODT-2 was smaller and statisti-cally significantly different (p = 0.0218) relative to the mean T

max of felodipine soft capsule. This faster rate of

Table 3. Composition of the optimized FLSs using different carrier materials and their flow and dissolution properties.

Formula Carrier type Liquid vehicle Type of coatDrug

concentration %Excipients ratio

(carrier:coat) H.R. C.I. Q30

(%)

FLS-2 MCC PH 102 PEG Aeroperl® 10 20 1.19 20.10 32.5 ± 1.9

FLS-6 MCC PH 102 PEG Aerosil® 10 20 1.18 15.50 36.7 ± 2.4

FLS--17 Mannitol:MCC PEG Aeroperl® 10 20 1.19 16.48 51.6 ± 5.0

FLS--18 Mannitol:MCC PEG Aerosil® 10 20 1.16 14.13 58.5 ± 1.5

FLS--19 Prosolv® PEG Aeroperl® 10 20 1.14 12.70 40.3 ± 4.6

FLS--20 Prosolv® PEG Aerosil® 10 20 1.16 13.70 41.1 ± 2.7

Table 4. Characterization of FLODTs.

TestFLODT-1

(MCC PH 102)FLODT-2

(Prosolv®)Weight (mg) 312.12 ± 2.04 314.13 ± 0.94Drug content 98.23 ± 0.65 99.18 ± 0.27Friability 0.07% 0.02%Hardness (Kg) 3.5 ± 0.01 4 ± 0.12In vitro Disintegration time 11 ± 0.42 s 9 ± 0.25 sIn vivo Disintegration time 8 ± 0.14 s 7 ± 0.19 sWetting Time 6.5 ± 0.12 s 6 ± 0.08 sWater absorption percent 127% ± 3.14 145% ± 4.08Each FLODT contains 210 mg carrier, 10.5 mg Aerosil, 5 mg felodipine, 30 mg Crospovidone, 3 mg asparatam and 6 mg lemon flavor.

Figure 4. In vitro dissolution profiles of felodipine from FLODT-1 and FLODT-2 compared to that from conventional felodipine tablet and felodipine soft capsule (See colour version of this figure online at www.informahealthcare.com/phd)

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

Rapidly absorbed orodispersible tablet of felodipine for management of hypertensive crisis 9

© 2012 Informa Healthcare USA, Inc.

felodipine absorption obtained from FLODT-2 could be attributed to the partial absorption of drug through the membrane of buccal cavity and esophagus. Moreover, the rapid absorption of drug from FLODT correlates well with the results of in vitro dissolution which showed that felodipine was rapidly dissolved from FLODT-2 than that from the soft capsule.

Based on these findings, it could be concluded that a promising rabidly absorbed orodispersible tablet of felodipine was successfully designed for management of hypertensive crisis. However, because of the small num-ber of volunteers recruited in the study, the results can only be considered preliminary, and the efficacy of the optimized FLODT in emergency cases should be clini-cally studied with a larger number of volunteers to prove its clinical usability.

conclusion

In this study, FLs were prepared and in vitro evaluated. A 24 full-factorial experimental design was applied in

order to rapidly obtain the optimal FLS having accept-able flow and enhanced dissolution properties. The opti-mized FLODT formulation showed a significant increase in dissolution rate compared to felodipine solution in PEG filled in soft gelatin capsule in 0.5% SLS solution. The in vivo pharmacokinetic study suggests that the opti-mized FLODT developed in this work may be useful for management of hypertensive crisis due to the enhanced dissolution and rapid absorption of felodipine through the buccal mucosa. Further clinical studies with a larger number of subjects should be performed to prove the clinical usability of the optimized FLODT in emergency cases.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

References 1. Cardoza RM, Amin PD. A stability indicating LC method for

felodipine. J Pharm Biomed Anal 2002;27:711–718. 2. Migliorança LH, Barrientos-Astigarraga RE, Schug BS, Blume HH,

Pereira AS, De Nucci G. Felodipine quantification in human plasma by high-performance liquid chromatography coupled to tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2005;814:217–223.

3. Welin L, Elvelin L, Niklasson A, Olsson G, Elmfeldt D. Overview of the safety of felodipine based on clinical trials in patients with hypertension. Am J Cardiol 1997;79:996–999.

4. Wiklund I, Dimenas E, Partridge S. Effects of felodipine extended release on quality of life-an analysis of four clinical tials. Curr Ther Res. 1995;56:81–94.

5. Risler T, Bohm R, Wetzchewald D, Nast HP, Koch HH, Stein G et al. A comparison of the antihypertensive efficacy and safety of felodipine IV and nifedipine IV in patients with hypertensive crisis or emergency not responding to oral nifedipine. Eur J Clin Pharmacol 1998;54:295–298.

6. Al-Hamidi H, Edwards AA, Mohammad MA, Nokhodchi A. To enhance dissolution rate of poorly water-soluble drugs: glucosamine hydrochloride as a potential carrier in solid dispersion formulations. Colloids Surf B Biointerfaces 2010;76:170–178.

7. Valizadeh H, Zakeri-Milani P, Barzegar-Jalali M, Mohammadi G, Danesh-Bahreini MA, Adibkia K et al. Preparation and characterization of solid dispersions of piroxicam with hydrophilic carriers. Drug Dev Ind Pharm 2007;33:45–56.

8. Basalious EB, El-Sebaie W, El-Gazayerly O. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AAPS PharmSciTech 2011;12:799–810.

9. Nokhodchi A, Javadzadeh Y, Siahi-Shadbad MR, Barzegar-Jalali M. The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug (indomethacin) from liquisolid compacts. J Pharm Pharm Sci 2005;8:18–25.

10. Khaled KA, Asiri YA, El-Sayed YM. In vivo evaluation of hydrochlorothiazide liquisolid tablets in beagle dogs. Int J Pharm 2001;222:1–6.

11. Spireas S. Liquisolid systems and methods of preparing same. US patent 6423339 B1. 2002.

12. Spireas S, Sadu S. Enhancement of prednisolone dissolution properties using liquisolid compacts. Int J Pharm. 1998;166: 177–188.

Figure 5. The mean plasma concentration-time profiles of felodipine following administration of single buccal dose of FLODT-2 and a single oral dose of felodipine soft capsule to four healthy human volunteers. (See colour version of this figure online at www.informahealthcare.com/phd)

Table 5. Mean Pharmacokinetic parameters of felodipine following the buccal administration of FLODT-2 and oral administration of felodpine soft capsule to four human volunteers.

PK Parameter FLODT-2Felodipine

soft capsule Statistical testC

max (ng/mL) 15.69 ± 4.08 13.44 ± 3.75 p = 0.5062

Tmax

(h)a 1 ± 0.25 1.25 ± 0.29 p = 0.0218

AUC0–24

(ng.h/mL)

46.78 ± 9.37 51.31 ± 30.23 p = 0.8085

AUC0-∞

(ng.h/mL)

56.6 ± 14.87 60.9 ± 35.44 p = 0.7752

t½

(h) 8.64 ± 3.36 9.91 ± 3.56 p = 0.4649

aMedian.

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.

10 E.B. Basalious et al.

Pharmaceutical Development and Technology

13. Spireas S, Sadu S, Grover R. In vitro release evaluation of hydrocortisone liquisolid tablets. J Pharm Sci 1998;87: 867–872.

14. Javadzadeh Y, Jafari-Navimipour B, Nokhodchi A. Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine). Int J Pharm 2007;341: 26–34.

15. Javadzadeh Y, Siahi-Shadbad MR, Barzegar-Jalali M, Nokhodchi A. Enhancement of dissolution rate of piroxicam using liquisolid compacts. Farmaco 2005;60:361–365.

16. Tayel SA, Soliman II, Louis D. Improvement of dissolution properties of Carbamazepine through application of the liquisolid tablet technique. Eur J Pharm Biopharm 2008;69:342–347.

17. Tiong N, Elkordy AA. Effects of liquisolid formulations on dissolution of naproxen. Eur J Pharm Biopharm 2009;73: 373–384.

18. Nazzal S, Nutan M, Palamakula A, Shah R, Zaghloul AA, Khan MA. Optimization of a self-nanoemulsified tablet dosage form of Ubiquinone using response surface methodology: effect of formulation ingredients. Int J Pharm 2002;240:103–114.

19. Reddy KR, Mutalik S, Reddy S. Once-daily sustained-release matrix tablets of nicorandil: formulation and in vitro evaluation. AAPS PharmSciTech 2003;4:E61.

20. Battu SK, Repka MA, Majumdar S, Madhusudan RY. Formulation and evaluation of rapidly disintegrating fenoverine tablets: effect of superdisintegrants. Drug Dev Ind Pharm 2007;33:1225–1232.

21. Sammour OA, Hammad MA, Megrab NA, Zidan AS. Formulation and optimization of mouth dissolve tablets containing rofecoxib solid dispersion. AAPS PharmSciTech 2006;7:E55.

22. Setty CM, Prasad DV, Gupta VR, Sa B. Development of fast dispersible aceclofenac tablets: effect of functionality of superdisintegrants. Indian J Pharm Sci 2008;70:180–185.

23. Kim H, Roh H, Yeom S, Lee HJ, Han SB. Sensitive Determination of Felodipine in Human and Dog Plasma by Use of Liquid–Liquid Extraction and LC–ESI–MS–MS. Chromatographia. 2003;58: 235–240.

24. Spireas S, Wang T, Grover R. Effect of powder substrate on the dissolution properties of methyclothiazide liquisolid compacts. Drug Dev Ind Pharm 1999;25:163–168.

25. Akinlade B, Elkordy AA, Essa EA, Elhagar S. Liquisolid systems to improve the dissolution of furosemide. Sci Pharm 2010;78:325–344.

26. Schüssele A, Bauer-Brandl A. Note on the measurement of flowability according to the European Pharmacopoeia. Int J Pharm 2003;257:301–304.

27. Aboelwafa AA, Basalious EB. Optimization and in vivo pharmacokinetic study of a novel controlled release venlafaxine hydrochloride three-layer tablet. AAPS PharmSciTech 2010;11:1026–1037.

28. Shamma RN, Basalious EB, Shoukri RA. Development and optimization of a multiple-unit controlled release formulation of a freely water soluble drug for once-daily administration. Int J Pharm 2011;405:102–112.

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Pu

rdue

Uni

vers

ity o

n 11

/03/

12Fo

r pe

rson

al u

se o

nly.