J DRUG DEL SCI TECH., 23 (3) 269-274 2013 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 characterized 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 – Physicochemical 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 intestine, 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 polyethylene 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 polymerbased 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 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 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 269 Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine Thao Truong-Dinh Tran, Phuong Ha-Lien Tran J DRUG DEL SCI TECH., 23 (3) 269-274 2013 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 to 60° (diffraction angle 2θ) at s/step, using a zero background sample holder Methods 2.1 HPLC analysis IS concentration was determined by HPLC system with a Luna 5à C18 analytical column (150 ì 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 Twentymicroliter samples were injected into HPLC system for analysis 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 cm-1 KBr pellets were prepared by gently mixing mg of the sample with 200 mg KBr 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 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 The SD sample was cooled down to room temperature in 30 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 2.7 Contact angle measurement Pure IS and SD samples were dissolved in ethanol of a 5 % concentration 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 PM101DTR485 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, mL of enzyme-free simulated gastric fluid (pH 1.2), 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 membrane filter (Millipore, United States) and immediately diluted with the mobile phase for determination of IS content by HPLC analysis 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 directly compressed into a 200 mg tablet equivalent to mg IS by round punches and dies with a 6-mm diameter The hardness was controlled at 25 ± N and a dwell time of 10 s The detailed formulations were also described in Table I II RESULTS AND DISCUSSION 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 2.4 Dissolution studies The pure IS, SD powders and tablets equivalent to 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 using a USP apparatus II (50 rpm, 37 °C) Dissolution of tablet was performed according to previous research [22] Firstly, a dissolution test was performed in enzyme-free simulated gastric fluid (pH 1.2) for h using a USP apparatus I (100 rpm, 37 °C) At the end of 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 radiation 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 Table I - Formulation compositions of SD powder (F1, F2, F3) and prolonged release solid dispersion tablet (F4, F5) Formulation IS (mg) PEG 6000 (mg) F1 F2 F3 F4 F5 5 5 15 30 45 45 45 PEO N-60K (mg) Lactose (mg) 40 60 108 88 270 Magnesium stearate (mg) 2 Total (mg) Comments 20 35 50 200 200 SD powder SD powder SD powder Tablet Tablet Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine Thao Truong-Dinh Tran, Phuong Ha-Lien Tran J DRUG DEL SCI TECH., 23 (3) 269-274 2013 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 months of storage at 40 °C/75 % RH storage conditions (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 functions 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 formulation 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 80 % drug release 60 40 pure IDP F1 F2 F3 20 0 20 40 60 80 100 120 Time (min) Figure - 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) 80 % drug release 60 40 pure IDP F1 F2 F3 20 0 20 40 60 80 100 120 Time (min) Figure - Dissolution profiles of IS from SDs of F1, F2 and F3 compared to the pure drug as a function of time in intestinal fluid (pH 6.8) 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 dissolution 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 markedly during the preparation of SDs, especially the crystallinity of this semicrystalline polymer and/or the proportion of crystal modifications 80 % drug release 60 40 F4 F5 20 0 10 15 20 Time (hrs) Figure - Dissolution profiles of IS from PR-SDs of F4 and F5 in 24 h 271 Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine Thao Truong-Dinh Tran, Phuong Ha-Lien Tran J DRUG DEL SCI TECH., 23 (3) 269-274 2013 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 F3 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 formulations, 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 semicrystalline 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 disappearance 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 diffractograms, 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 amorphous 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 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 F2 F1 PM IDP PEG 6000 10 20 30 40 50 60 theta Figure - PXRD patterns of IS, PEG 6000, PM and SDs 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 characterized 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 F3 F2 F1 PM IDP PEG 6000 4000 3500 3000 2500 2000 Wavelength (cm-1) Figure - FTIR spectra of IS, PEG 6000, PM and SDs 272 1500 Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine Thao Truong-Dinh Tran, Phuong Ha-Lien Tran J DRUG DEL SCI TECH., 23 (3) 269-274 2013 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 addition to the change of drug crystallinity discussed above in the PXRD diffractograms 12 13 14 15 16 * 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 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dispersion containing isradipine Thao Truong-Dinh... stearate (mg) 2 Total (mg) Comments 20 35 50 200 200 SD powder SD powder SD powder Tablet Tablet Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine. .. Wavelength (cm-1) Figure - FTIR spectra of IS, PEG 6000, PM and SDs 272 1500 Investigation of polyethylene oxide-based prolonged release solid dispersion containing isradipine Thao Truong-Dinh Tran,