DSpace at VNU: Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine

Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine Thao Truong-Dinh Tran*, Phuong Ha-Lien Tran* International University, Vietnam National

Investigation of polyethylene oxide-based prolonged release

solid dispersion containing isradipine Thao Truong-Dinh Tran*, Phuong Ha-Lien Tran*

International University, Vietnam National University, Ho Chi Minh City, Vietnam

*Correspondence: ttdthao@hcmiu.edu.vn - thlphuong@hcmiu.edu.vn

The aim of the study was to press a synergistic act of a formulation: (1) enhancing the dissolution rate of a poorly water-soluble drug; (2) controlling the release rate of the drug There is still little published research on such a formulation The model drug used in the current study

is isradipine (IS), a calcium channel blocker of the dihydropyridine class To fulfill the expected target, solid dispersion containing IS was first prepared with the carrier polyethylene glycol 6000 (PEG 6000) with the melting method and then polyethylene oxide N-60K (PEO N-60K) was utilized to induce drug release in a controlled manner Physicochemical properties of the solid dispersion and physical mixture were character-ized by powder x-ray diffraction (PXRD) and Fourier transform infrared (FTIR) spectroscopy to investigate the structural behavior of drug and IS-PEG interactions, respectively Preparation of such a formulation not only enhanced but also controlled the drug dissolution rate in both simulated gastric (pH 1.2) and intestinal (pH 6.8) media This result should be a consideration for pharmaceutical scientists in maintaining the desired blood levels of drugs with narrow therapeutic fluctuation ranges for extended periods of time after a single administration.

Key words: Prolonged release – Solid dispersion – Poorly water-soluble drug – Enhanced drug release rate – Prolonged release manner – Phys-icochemical characterization.

Improving the solubilization of poorly water-soluble drugs is very

important because it determines the therapeutic efficacy of a drug

product Despite high permeability, many promising new chemical

entities (NCEs) are generally only absorbed in the upper small

intes-tine, so absorption is reduced significantly after the ileum i.e., there

is a small absorption window Therefore, to overcome dissolution rate

limiting absorption and low bioavailability of these drugs, various

solubilization strategies have been developed Nevertheless, solid

dispersion (SD) has been widely used and is considered a common

method enhancing the solubility, dissolution rate, and bioavailability

of poorly soluble drugs [1-5] Hydrophilic polymers, such as

poly-ethylene glycol, hydroxypropylcellulose, polyvinylpyrrolidone, etc.,

are commonly used in SD preparation However, the SD generally

tends to be immediate-release forms with the inherent drawbacks of

high peak drug concentrations in the blood, short times following

administration when drug concentrations in the blood reach their tmax

and relatively short durations of effective concentration levels in the

blood [6] To overcome such problems, an interest in a strategy for the

combined systems of improved solubilization and prolonged release

of poorly water-soluble drugs has been raised recently [7, 8] These

dosage forms provide an immediately available dose for an immediate

action followed by a gradual and continuous release of subsequent

doses to maintain the plasma concentration of poorly water-soluble

drugs over an extended period of time Moreover, prolonged release

dosage forms containing SDs have been considered effective systems

for treatment over a long period and could be prepared using

polymer-based systems [9] However, there have been few such studies reported

so far A prolonged release-solid dispersion (PR-SD) comprising both

functions of SD and prolonged release for poorly water-soluble drugs

has therefore been investigated in the current study Isradipine (IS),

a calcium antagonist for treating hypertension [10] and known to be

poorly water-soluble in aqueous solution (less than 10 µg/mL) [11], was

chosen as a model drug Moreover, IS has unfavorable properties that

make it a candidate for a research aiming to enhance its bioavailability

It is 90-95 % absorbed and is subject to extensive first-pass metabolism,

resulting in a relatively low bioavailability of about 15-24 % [12, 13]

Due to the short half-life of 8 h [14, 15], IS is also a good candidate for prolonged release dosage form in 24 h So far, isradipine has been reportedly used as the model drug in previous research into buccal tablets [12], osmotic system [16-18] and transdermal delivery system [19] Still, the drug has never been introduced into the formulation of prolonged release solid dispersion The polymer family of ethylene oxide i.e., polyethylene glycol 6000 (PEG 6000) and polyethylene oxide N-60K (PEO N-60K) were chosen as a hydrophilic carrier for SD preparation and polymer for prolonged release dosage form, respectively, due to some advantages such as flexibility, low toxicity, unlikelihood of specific interactions with biological chemicals, etc The SDs of drugs with PEG 6000 may be useful to solve various problems such as enhancement of stability, solubility and dissolution rate [20, 21] Although PEG 6000 can be used in both solvent and melting method for SD preparation, the melting method was chosen in this study due to the preferable environmental and cost aspects Drug dissolution studies were performed in both simulated gastric (pH 1.2) and intestinal (pH 6.8) media to figure out if the drug release behaviors satisfied the enhanced release rate in controlled manner as compared

to the pure drug The possible interaction between the drug and PEG was investigated through Fourier transform infrared spectroscopy (FTIR) Moreover, the change of drug structure, especially for the drug crystallinity, if any, was also studied through powder x-ray diffraction (PXRD) analysis

I MATERIALS AND METHODS

1 Materials

Lactose was obtained from Meggle (Wasserburg, Germany) Magnesium stearate was purchased from Katayama Chemical Co (Osaka, Japan) Polyethylene glycol 6000 (PEG 6000) was purchased from Yakuri Pure Chemicals Co., Ltd (Osaka, Japan) Polyethylene oxide N-60K (PEO N-60K) was provided by the Dow Chemical Company (United States) The solvents used were high performance liquid chromatography (HPLC) grade All other chemicals were of analytical grade and were used without further purification

2 Methods

2.1 HPLC analysis

IS concentration was determined by HPLC system with a Luna

5 µ C18 analytical column (150 × 4.6 mm) The mixture of methanol,

deionized water and acetonitrile (7:3:5) was used as a mobile phase

The UV detector was set at 325 nm to analyze the column effluent

The entire solution was filtered through a 0.45 µM membrane filter

(MilliporeCorp., Bedford) and was degassed prior to use

Twenty-microliter samples were injected into HPLC system for analysis

2.2 Preparation of SD containing isradipine

The SD was prepared by the melting method First, PEG 6000

was melted at 160 °C by stirring hot plate IS was then incorporated

in melted PEG 6000 The resulting binary mixtures were constantly

stirred for 15 min to dissolve and mix IS with PEG 6000 When a

clear solution was obtained, the mixture was immediately frozen at

-20 °C in a deep freezer for 30 min The SD sample was cooled down

to room temperature in 30 min The drug crystallinity of this sample

was then investigated via DSC and PXRD In order to prepare tablets,

the SD sample was ground and passed through a 60-mesh sieve The

SDs consisting of IS and PEG 6000 were prepared in weight ratios

1:3, 1:6 and 1:9 The detailed formulations are described in Table I To

ensure the absence of degradation, IS concentration of the SD sample

was determined by HPLC before tableting

2.3 Preparation of prolonged release solid dispersion tablet

The SD sample was blended with PEO N-60K, lactose and finally

with magnesium stearate The blend homogeneity was confirmed by

quantification of the IS amount in the mixture This sample was

di-rectly compressed into a 200 mg tablet equivalent to 5 mg IS by round

punches and dies with a 6-mm diameter The hardness was controlled

at 25 ± 2 N and a dwell time of 10 s The detailed formulations were

also described in Table I.

2.4 Dissolution studies

The pure IS, SD powders and tablets equivalent to 5 mg IS were

exposed to 900 mL dissolution media Dissolution of SD powder

was performed in enzyme-free simulated gastric fluid (pH 1.2) and

enzyme-free simulated intestinal fluid (pH 6.8) for 120 min using a

USP apparatus II (50 rpm, 37 °C) Dissolution of tablet was performed

according to previous research [22] Firstly, a dissolution test was

per-formed in enzyme-free simulated gastric fluid (pH 1.2) for 2 h using a

USP apparatus I (100 rpm, 37 °C) At the end of 2 h, the gastric fluid

was discarded and replaced with enzyme-free simulated intestinal fluid

(pH 6.8) Dissolution testing was continued until 24 h Samples were

withdrawn at predetermined intervals and replaced with an equivalent

amount of fresh medium to maintain a constant dissolution volume

The concentrations of IS were finally analyzed by HPLC as described

above

2.5 Powder x-ray diffraction (PXRD)

A D5005 diffractometer (Bruker, Germany) using Cu-Kα

radia-tion at a voltage of 40 kV, 50 mA, was used to investigate PXRD

patterns of pure IS, PEG 6000 and all SD samples To understand the

clear functioning mechanism of dissolution enhancement, the plain

binary SD of pure IS was separately mixed with PEG 6000 to obtain physical mixtures (PM) The samples were scanned in increments of 0.02° from 5 to 60° (diffraction angle 2θ) at 1 s/step, using a zero background sample holder

2.6 Fourier transform infrared spectroscopy (FTIR)

A FTIR spectrophotometer (Model Excaliber Series UMA-500, Bio-Rad, United States) was used to investigate the spectra of pure IS, PEG 6000, PM, SD samples The wavelength was scanned from 500

to 4000 cm-1 with a resolution of 2 cm-1 KBr pellets were prepared

by gently mixing 1 mg of the sample with 200 mg KBr

2.7 Contact angle measurement

Pure IS and SD samples were dissolved in ethanol of a 5 % con-centration The solution was then spin-coated on to a silicon (100) wafer at a speed of 3000 rpm for 30 s using a Head-Way PM101DT-R485 spinner (Shinu MST Co Ltd.) and then dried in air to form a thin film Contact angles were measured by the sessile drop technique

on a contact angle gonimeter (DSA 100, Kruss GmbH, Germany) In each experiment, a drop of deionized water was placed on the surface

of the thin film at room temperature The measurements were taken five times by reading directly

2.8 Solubility study

An excess of IS (1 mg) was added to the tube containing either

1 mL of water, 1 mL of enzyme-free simulated gastric fluid (pH 1.2),

1 mL of enzyme-free simulated intestinal fluid (pH 6.8) or solution containing 5 % excipient in water and shaken in a water bath at 37 ˚C (100 rpm) for 72 h The aliquot was filtered through a 0.45 µm mem-brane filter (Millipore, United States) and immediately diluted with the mobile phase for determination of IS content by HPLC analysis

II RESULTS AND DISCUSSION

1 Solubility and dissolution study

Our preliminary study showed that IS has low solubility in water and intestinal fluid (6.98 ± 0.01 and 8.64 ± 0.05 µg/mL, respectively), but has a higher solubility in gastric fluid (114.01 ± 1.17 µg/mL) Interestingly, incorporating 5 % PEG 6000 in water (w/v) increased drug solubility (128.63 ± 2.72 µg/mL) These results suggested that molecular interaction between IS and PEG 6000 possibly occurred

to increasing the drug solubility

The formulation of poorly water-soluble drugs for oral delivery

is one of the most frequent and greatest challenges to formulation scientists in the pharmaceutical industry The most attractive option for increasing the release rate is through solid dispersion formulation approaches Therefore, the solid dispersion formulations of IS with carrier PEG 6000 at various ratios were screened for the selection of the most suitable incorporation Pure IS was compared with other

SD formulations for dissolution rate at pH 1.2 and pH 6.8 (Figures 1 and 2, respectively) The incorporation of PEG 6000 as the carrier in

the solid dispersion at three ratios in the study (F1, F2, F3) all showed the increase in the dissolution kinetics of IS from polyethylene glycol SDs in both media while drug release from the pure material was almost zero, indicating the poorly water-soluble property of the drug Among the SDs formulated with PEG 6000, the incorporation of PEG 6000 and

Table I - Formulation compositions of SD powder (F1, F2, F3) and prolonged release solid dispersion tablet (F4, F5).

Formulation IS (mg) PEG 6000 (mg) PEO N-60K

(mg) Lactose (mg) stearate (mg)Magnesium Total (mg) Comments F1

F2

F3

F4

F5

5 5 5 5 5

15 30 45 45

20 35 50 200 200

SD powder

SD powder

SD powder Tablet Tablet

drug at the ratio of 1:9 (F3) shows the highest dissolution rate in both

media (Figures 1 and 2) Specifically, percents of IS release are about

6, 55 and 73 % at pH 1.2 and 5, 50 and 74 % at pH 6.8 after 120 min

for F1, F2 and F3, respectively From the above result, it is clear that

the dissolution rate increases by increasing the carrier concentration

regardless of pH of the medium, indicating the pH-independence of

the SD formulations The formation of a polyethylene glycol film

around the drug particles reduces the hydrophobicity of their surfaces

(the values of the contact angles for pure IS, F1, F2 and F3 are 74.8,

40.1, 25.3 and 17.5θ, respectively), thus improving the wettability of

the drug Therefore, the more the polymer concentrates around the

drug particle, the more the wettability of drug leading to the increased

dissolution rate that can be reached Usually, the increased drug

dis-solution rate from a solid dispersion is due to the increased wettability

of the drug by the carrier, drug particle size reduction through the SD

preparation, absence of aggregation of drug crystals, polymorphic

transformation of drug crystals, i.e., the common phenomena in which

conversion of the drug from crystalline to amorphous/microcrystalline

state occurs and chemical interactions between drug and carrier [3,

23] The carrier PEG 6000 has been known as a favorable polymer

for solid dispersion preparation since it was found to not undergo

any chemical change during the preparation of solid dispersion [24]

However, the physical state of PEG 6000 sometimes changes

mark-edly during the preparation of SDs, especially the crystallinity of this

semicrystalline polymer and/or the proportion of crystal modifications

with different folds may change Hence, the structural behavior of the SD as well as the interaction between the drug and PEG 6000, if any, were investigated in the study and will be discussed at the next session Moreover, the IS concentration of the SD sample determined

by HPLC ensured that the analyzed dispersions had no degradation Since the solid dispersion F3 showed the highest drug release rate and the release profiles as an index of stability of F3 were also unchanged after 6 months of storage at 40 °C/75 % RH storage condi-tions (data not shown), it was selected to prepare the prolonged release formulations with PEO (F4, F5) This is a non-ionic, water-soluble polymer forming swelling hydrophilic matrices [8] extensively used as

a prolonged release excipient to modify drug release and dissolution Once in contact with a liquid, PEO will start to hydrate and swell, forming a hydrogel layer that regulates further penetration of the liquid into the matrix and diffusion of the drug molecules from the dosage form [25, 26] The hydrogel layer formation will slow down the rate of water intake whilst declining and prolonging that of drug release The formation generally occurs through three stages: (1) initial hydrogel increase due to polymer swelling; (2) maintenance of constant gel layer thickness between swelling and dissolution front; (3) reduction

in gel layer thickness due to depletion of the core [27-29] Figure 3

depicts the prolonged release behavior of F4 and F5 tablets for 24 h

in which the concentration of PEO increases in the formulation F5

As compared to the F3 solid dispersion formulation, the drug release from F4 and F5 tablets expressed the prolonged release behavior The increase in PEO proportion retarded water uptake by the matrix core, consequently prolonging drug diffusion and dissolution from the preparations Since the F4 and F5 tablets comprise both functions of

SD and PR, it provides a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time Lacking any of the two func-tions will not satisfy the expected release behavior For example, if the tablets contain the pure drug only with the prolonged release polymers, certainly the drug release rate from such formulation will be very low since the percentage of drug release from the pure IS is almost zero

In other words, a conventional controlled matrix tablet cannot induce the IS release rate From that point, it can be seen that drug solubility plays a very important role in modifying the rate and extent of drug release Thus, it is necessary to improve the drug solubility first and then the functioning of the prolonged release behavior for the formu-lation On the contrary, if the formulation is only the solid dispersion without modifying the drug prolonged release property, certainly the drug release rate cannot be well controlled during 24 h and, hence, cannot provide a uniform and prolonged therapeutic effect Therefore, formulations comprising both functions of SD and PR for poorly water-soluble drugs were prepared Such PR dosage forms containing

Time (min)

0

20

40

60

80

pure IDP F1 F2 F3

Figure 1 - Dissolution profiles of IS from SDs of F1, F2 and F3 compared

to the pure drug as a function of time in gastric fluid (pH 1.2)

Time (min)

0

20

40

60

80

pure IDP F1 F2 F3

Figure 2 - Dissolution profiles of IS from SDs of F1, F2 and F3

com-pared to the pure drug as a function of time in intestinal fluid (pH 6.8)

Time (hrs)

0 20 40 60 80

F4 F5

Figure 3 - Dissolution profiles of IS from PR-SDs of F4 and F5 in 24 h.

SD provide an immediately available dose for an immediate action

followed by a gradual and continuous release of subsequent doses to

maintain the plasma concentration of poorly water-soluble drugs over

an extended period of time

2 Physicochemical characterization

The possible alteration of the molecular interactions between the

functional groups of the drug and those of the polymer as well as

drug crystallinity were investigated by instrumental analysis Thus,

F1, F2, F3 formulations were introduced into this study Moreover, a

physical mixture was also prepared to clearly explain the interaction

and changes of the drug’s structural behaviors in those three

formula-tions, if any Structures of pure materials such as drug and polymer

were also compared in this analysis Two highly regarded methods

for characterizing drug crystallinity are PXRD and DSC analyses

Generally, when the structure of the drug is more amorphous, greater

increases in the drug dissolution rate from SD can be obtained A

simple method to decrease the drug crystallinity of SD is to increase

the ratio of carrier to drug [30, 31] However, the addition of carrier

cannot enhance drug release constantly until it reaches a particular

level In other words, the addition of carrier should be halted as the

crystal structure of drug changes into being totally amorphous, because

more carrier amount will not increase the effect or may even inhibit

drug release owing to harder diffusion or the growth of

semicrystal-line areas [32] It should also be noted that beyond the amorphization

composition, the addition of more carrier may help in maintaining

the degree of supersaturation attained during dissolution The

disap-pearance of a melting peak in the DSC or a distinctive peak for the

drug in the diffractogram in the SD systems indicates that the drug is

present in amorphous form or that a high concentration of the drug

is dissolved in the solid-state [7, 33-35] However, the DSC analysis

meets a limitation: if the percentage of crystallinity is below 2 %, it

generally cannot be detected with DSC Moreover, the model drug

can be dissolved in the melted polymer solution before it reaches to

its melting point during DSC measurement [36] This may explain

why the melting event in the thermograms of drug in the partially

amorphous form cannot be detected in some cases [32] Therefore, the

structural behaviors of the systems in this research were investigated

by PXRD only (Figure 4) The PXRD pattern of PEG 6000 had two

characteristic peaks of high intensity at 19.2 and 22.1° [30] or at 19.2

and 23.3° [37] All PXRD patterns of SDs, PM and pure PEG 6000

in our studies showed two similar characteristic peaks of PEG 6000

at 19.14 and 23.37°, meeting results of the previous reports The very

slight changes of the peak may be due to the source of the material

Besides, IS exhibits numerous characteristic peaks on PXRD

dif-fractograms, indicating that it is a naturally crystalline drug, a factor

that contributes to its poor water solubility It is known that the lack

of a distinctive peak of a drug in SD systems demonstrates that a

high concentration of the drug is dissolved in the solid state [37-39]

Moreover, a large reduction in characteristic peaks indicates an

amor-phous state [34, 37] All of the SD formulations showed a decreased

number of distinct peaks of the drug on the PXRD diffractograms

as compared to the PM, especially for those compared to that of the

pure drug The PM still shows some significant characteristic peaks of

the drug expressed by ovals on Figure 4 as compared to those of the

SDs In other words, it is evident that the enhanced dissolution rate

of drug from the SDs was attributable to the SD preparation whereby

it decreases the drug crystallinity Thus, PEG 6000 can play a role as

the SD carrier and change the crystalline structure of IS into a partially

crystalline structure, and hence, lead to the enhanced drug dissolution

rate It should be recognized that the PXRD diffractograms of F1, F2

and F3 are not quite different The difference in dissolution profiles

among SD can be favorably explained by the water adsorption level

and may additionally be due to the difference in the crystallite size

domains of drug in the presence of different amount of carrier

Structural alterations and a lack of a crystal structure can lead to changes in the molecular bonding energy between functional groups [7, 32] Therefore, FT-IR spectra of the SD systems were character-ized to investigate the molecular interactions among functional groups

(Figure 5) The most important vibration detected in the spectrum of

PEG 6000 is the OH stretching at 2881 cm-1, which obviously appears

in the spectra of all of the PM and SDs, indicating the presence of PEG 6000 in the formulations IR spectrum of IS is characterized by the absorption of the amino group N-H located at 3346 cm-1 and the absorption of carbonyl group C=O at 1701 cm-1 In SDs’ spectra, the absorption of the amino group is shifted to the right at 3321 cm-1 and

2 theta

PEG 6000 IDP

PM F1

F2 F3

Figure 4 - PXRD patterns of IS, PEG 6000, PM and SDs.

Wavelength (cm -1 )

1500 2000

2500 3000

3500 4000

PEG 6000

IDP PM F1 F2 F3

Figure 5 - FTIR spectra of IS, PEG 6000, PM and SDs.

there is a new peak beside the peak of carbonyl group; whereas, those

changes didn’t occur in the PM’s spectrum The shift in the peaks

associated with the amino group indicates that there may have been

hydrogen bonding between the hydrogen atom of the NH group of

IS and a lone pair of electrons of oxygen atom in the PEG 6000 [40]

Meanwhile, the stabilizing interaction is intermolecular H-bonding as

red shift is observed in a fraction of the C=O vibration band (the new

peak beside the peak of carbonyl group) Thus, the changes evidenced

that there were some interactions of hydrogen bonding between the

IS and PEG 6000 in the SD formulations but not in the PM It could

be one reason elucidating the enhanced drug dissolution rate in

addi-tion to the change of drug crystallinity discussed above in the PXRD

diffractograms

* Investigation of the prolonged release-solid dispersion in the

research contributes a solution to the ongoing work of formulation

scientists in developing an active substance like IS with a short plasma

half-life and poor water solubility The enhanced drug dissolution

was attributed to the changes of drug crystallinity and interactions of

hydrogen bonding between the drug and the PEG 6000 Moreover, the

fact that utilizing PEO could preferably extend the optimum therapeutic

activity over a longer period of time provides an ideal drug delivery

system to deliver an adequate amount of drug in a controlled manner

Therefore, the current PR-SD technique provides a valuable foundation

to achieve optimal drug bioavailability and further investigate optimal

therapeutic delivery systems through a scientific understanding of

diverse polymeric carriers, preparation methods and characterization

of physicochemical properties

REFERENCES

1 Sekiguchi K., Obi N.- Studies on absorption of eutectic mixture I

A comparison of the behavior of eutectic mixture of sulfathiazole

and that of ordinary sulfathiazole in man.- Chem Pharm Bull.,

9, 866-872, 1961.

2 Goldberg A.H., Gibaldi M., Kanig J.L., Mayersohn M.- Increasing

dissolution rates and gastrointestinal absorption of drugs via

solid solutions and eutectic mixtures IV Chloramphenicol-urea

system.- J Pharm Sci., 55, 581-583, 1966.

3 Chiou W., Riegelman S.- Pharmaceutical applications of solid

dispersions.- J Pharm Sci., 60, 1281-1302, 1971.

4 Joe J.H., Lee W.M., Park Y.-J., Joe K.H., Oh D.H., Seo Y.G.,

Woo J.S., Yong C.S., Choi H.-G.- Effect of the solid-dispersion

method on the solubility and crystalline property of tacrolimus.-

Int J Pharm., 395, 161-166, 2010.

5 Han H.-K., Lee B.-J., Lee H.-K.- Enhanced dissolution and

bio-availability of biochanin A via the preparation of solid dispersion:

In vitro and in vivo evaluation.- Int J Pharm., 415, 89-94, 2011.

6 Sansom L.N.- Oral extended-release products.- Aust Prescr.,

22, 88-90, 1999.

7 Tran P.H.L., Tran T.T.-D., Lee K.H., Kim D.J., Lee B.J.-

Dissolu-tion-modulating mechanism of pH modifiers in solid dispersion

containing weakly acidic or basic drugs with poor water

solubil-ity.- Expert Opin Drug Deliv., 7, 647-661, 2010.

8 Tran P.H.L., Tran T.T.D., Park J.B., Lee B.-J.- Controlled release

systems containing solid dispersions: strategies and

mecha-nisms.- Pharm Res., 28, 2353-2378, 2011.

9 Wang Z., Horikawa T., Hirayama F., Uekama K.- Design and

in vitro evaluation of a modified-release oral dosage form of

nifedipine by hybridization of hydroxypropyl-β-cyclodextrin and

hydroxypropylcellulose.- J Pharm Pharmacol., 45, 942-946,

1993

10 Chrysant S.G., Cohen M.- Long-term antihypertensive effects

with chronic administration of isradipine controlled release.- Curr

Ther Res Clin Exp., 58, 1-9, 1997.

11 Leroueil-Le Verger M., Fluckiger L., Kim Y.-I., Hoffman M.,

Maincent P.- Preparation and characterization of nanoparticles containing an antihypertensive agent.- Eur J Pharm Biopharm.,

46, 137-143, 1998.

12 Bontha V.K., Pabbu B.B., Prasad G., Rudrangi S.R.S., Chilukala S., Rudrangi S.- Formulation and evaluation of isradipine buccal

tablets.- Res J Pharm Tech., 5, 1187-1196 2012.

13 Walton T., Symes L.- Felodipine and isradipine: new calcium-channel-blocking agents for the treatment of hypertension.- Clin

Pharm., 12, 261-275, 1993.

14 Keller D.L.- Parkinson disease.- Cleve Clin J Med., 79,

242-243 2012

15 Hafizullah M., Zaidi E., Abbas F.- Comparative efficacy of amlodipine and slow release isradipine as a monotherapy in

hypertensive patients.- J Postgrad Med Inst., 14, 22-27, 2000.

16 Patel A., Mehta T., Patel M., Patel K., Patel N.- Design porosity osmotic tablet for delivering low and pH-dependent soluble drug

using an artificial neural network.- Curr Drug Deliv., 9, 459-467,

2012

17 Ayer A.D., Swanson D.R., Kuczynski A.L.- Dosage form for treating cardiovascular diseases comprising isradipine.- Patent

US 4816263, 1989

18 Prisant L.M., Elliott W.J.- Drug delivery systems for treatment

of systemic hypertension.- Clin Pharmacokinet., 42, 931-940,

2003

19 Tirunagari M., Jangala V.R., Khagga M., Gannu R.- Transder-mal therapeutic system of isradipine: effect of hydrophilic and

hydrophobic matrix on in vitro and ex vivo characteristics.- Arch

Pharm Res., 33, 1025-1033 2010.

20 Desai K.G.H., Park H.J.- Solubility studies on valdecoxib in the presence of carriers, cosolvents, and surfactants.- Drug Dev

Res., 62, 41-48, 2004.

21 Law D., Krill S.L., Schmitt E.A., Fort J.J., Qiu Y., Wang W., Porter W.R.- Physicochemical considerations in the prepara-tion of amorphous ritonavir-poly(ethylene glycol) 8000 solid

dispersions.- J Pharm Sci., 90, 1015-1025, 2001.

22 Villanova J.C., Ayres E., Orefice R.L.- Design of prolonged release tablets using new solid acrylic excipients for direct

compression.- Eur J Pharm Biopharm., 79, 664-673, 2011.

23 Yang C., Xu X., Wang J., An Z.- Use of the co-grinding method

to enhance the dissolution behavior of a poorly water-soluble drug: generation of solvent-free drug-polymer solid dispersions.-

Chem Pharm Bull., 60, 837-845, 2012.

24 Akiladevi D., Shanmugapandiyan P., Jebasingh D., Basak S.- Preparation and evaluation of paracetamol by solid dispersion

technique.- Int J Pharm Pharm Sci., 3, 188-191, 2011.

25 Colombo P., Bettini R., Santi P., Peppas N.A.- Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms

and optimal performance.- Pharm Sci Tech Today, 3, 198-204,

2000

26 Li H., Hardy R.J., Gu X.- Effect of drug solubility on polymer hydration and drug dissolution from polyethylene oxide (PEO)

matrix tablets.- AAPS PharmSciTech, 9, 437-443, 2008.

27 Colombo P., Bettini R., Massimo G., Catellani P.L., Santi P., Peppas N.A.- Drug diffusion front movement is important in drug release control from swellable matrix tablets.- J Pharm

Sci., 84, 991-997, 1995.

28 Bussemer T., Peppas N.A., Bodmeier R.- Evaluation of the swelling, hydration and rupturing properties of the swelling layer

of a rupturable pulsatile drug delivery system.- Eur J Pharm

Biopharm., 56, 261-270, 2003.

29 Tran T.T.-D., Tran P.H.L., Lim J., Park J.B., Choi S.K., Lee B.J.- Physicochemical principles of controlled release solid dispersion

containing a poorly water-soluble drug.- Ther Deliv., 1, 51-62,

2010

30 Mohanta G., Manna P., Kalaiselvan R., Manavalan R.- Studies

on mechanism of enhanced dissolution of albendazole solid

dispersions with crystalline carriers.- Indian J Pharm Sci., 68,

599-607, 2006

31 Okonogi S., Puttipipatkhachorn S.- Dissolution improvement

of high drug-loaded solid dispersion.- AAPS PharmSciTech,

7, E1-E6, 2006.

32 Leuner C., Dressman J.- Improving drug solubility for oral

de-livery using solid dispersions.- Eur J Pharm Biopharm., 50,

47-60, 2000.

33 Damian F., Blaton N., Naesens L., Balzarini J., Kinget R.,

Augustijns P., Van den Mooter G.- Physicochemical

characteri-zation of solid dispersions of the antiviral agent UC-781 with

polyethylene glycol 6000 and Gelucire 44/14.- Eur J Pharm

Sci., 10, 311-322, 2000.

34 Hu J.- Spray freezing into liquid (SFL) particle engineering

technology to enhance dissolution of poorly water soluble drugs:

organic solvent versus organic/aqueous co-solvent systems.-

Eur J Pharm Sci., 20, 295-303, 2003.

35 Liu C., Desai K.G.H., Liu C., Park H.J.- Enhancement of

dissolu-tion rate of rofecoxib using solid dispersions with urea.- Drug

Dev Res., 63, 181-189, 2004.

36 Tran T.T.-D., Ha N.S., Tran P.H.-L., Park J.-B., Lee B.-J.-

Disso-lution-enhancing mechanism of alkalizers in poloxamer-based

solid dispersions and physical mixtures containing poorly

water-soluble valsartan.- Chem Pharm Bull., 59, 844-850, 2011.

37 Tran P.H.L., Tran H.T.T., Lee B.-J.- Modulation of

microenvi-ronmental pH and crystallinity of ionizable telmisartan using

alkalizers in solid dispersions for controlled release.- J Control

Release, 129, 59-65, 2008.

38 Sheen P.-C., Khetarpal V.K., Cariola C.M., Rowlings C.E.- For-mulation studies of a poorly water-soluble drug in solid

disper-sions to improve bioavailability.- Int J Pharm., 118, 221-227,

1995

39 Tran T.T.-D., Tran P.H.-L., Lee B.-J.- Dissolution-modulating mechanism of alkalizers and polymers in a nanoemulsifying solid dispersion containing ionizable and poorly water-soluble

drug.- Eur J Pharm Biopharm., 72, 83-90, 2009.

40 Biswal S., Sahoo J., Murthy P., Giradkar R., Avari J.- Enhance-ment of dissolution rate of gliclazide using solid dispersions with

polyethylene glycol 6000.- AAPS PharmSciTech, 9, 563-570,

2008

MANUSCRIPT

Received 23 October 2012, accepted for publication 4 December 2012