pH-independent controlled release tablets containing ...

Journal of Drug Delivery Science and Technology 46 (2018) 365–377

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Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst

pH-independent controlled release tablets containing nanonizing valsartan solid dispersions for less variable bioavailability in humans

T

Jun-Bom Parka,1, Chulhun Parkb,1, Zhong Zhu Piaob, Hardik H. Aminb, Nilesh M. Meghanib, Phuong H.L. Tranc, Thao T.D. Trand,e, Jing-Hao Cuif, Qing-Ri Caof, Euichaul Ohg, Beom-Jin Leeb,∗ a

College of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea College of Pharmacy and Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea c Deakin University, Geelong, School of Medicine, Australia d Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam e Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam f College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China g College of Pharmacy, The Catholic University, Bucheon 420-743, Republic of Korea b

A R T I C LE I N FO

A B S T R A C T

Keywords: Nanonizing solid dispersion Valsartan Adsorption Carrier Enhanced dissolution pH-independent controlled release Reliable human bioavailability

The aims of this work were to design pH-independent controlled release (CR) tablet containing nanonizing solid dispersion (SD) adsorbed on hydrophilic silica (Aeroperl® 300/30). Valsartan (VAL) was chosen to simultaneously modulate solubility and release rate due to its poor water solubility in low pH condition and short elimination half-life. Based on extensive equilibrium solubility and compatibility studies, poloxamer 407 was selected as a SD carrier. The melted mixtures of drug and poloxamer 407 were adsorbed onto hydrophilic fumed silica (Aeroperl® 300/30). Ternary SD system changed crystalline drug into an amorphous state and had intermolecular hydrogen bonding as confirmed by FT-IR with poloxamer 407. The dissolution rate of SD system was markedly enhanced as compared with pure VAL or commercial Diovan® tablet in simulated gastric fluid (pH 1.2). Interestingly, the particle size of SD system was gradually nanonized for 2 hr, ranging from 600 nm to 150 nm during dissolution process. The SD-loaded CR (SD-CR) tablets using hydroxypropylmethylcellulose (HPMC 4000) showed pH-independent zero-order release and good stability at accelerated conditions for six months. The SDCR tablet showed minimized inter-subject variation of maximum plasma concentration as compared with commercial Diovan® tablets in healthy human volunteers.

1. Introduction The development of oral solid dosage formulations containing poorly water-soluble drugs has been one of the most frequent challenges in pharmaceutical industry. Solid dispersion (SD) is one of the most successful strategies to modulate dissolution rate and bioavailability of poorly water-soluble drugs [1–4]. Depending on the physical state (crystalline or amorphousness) of the carrier, preparation method and formulation composition, the SD can also be classified into four generations by our research group [5]. Briefly, the first generation is crystalline solid dispersion; the second generation of SD contain amorphous carriers which are mostly polymers; In the third of SD, the surface active agents or self-emulsifiers are introduced as carriers; the fourth generation is a controlled release solid dispersion (CRSD) containing poorly water-soluble drugs [5].

∗

1

Corresponding author. E-mail address: [email protected] (B.-J. Lee). Equally contributed.

https://doi.org/10.1016/j.jddst.2018.05.031 Received 4 January 2018; Received in revised form 15 May 2018; Accepted 21 May 2018 Available online 22 May 2018 1773-2247/ © 2018 Elsevier B.V. All rights reserved.

In case of model drug with poor water solubility and short elimination half-life, it is interesting to design a proper dosage form to enhance solubility and modulate release rate at the same time. Furthermore, oral CR formulations containing SD can readily liberate an adequate amount of poorly water-soluble drug in a controlled manner, offering pharmaceutical and therapeutic benefits such as increased patient adherence, reduced dosing frequency, minimized side effects and prolonged effect by maintaining a constant blood concentration level [6,7]. However, there have been few SD reports to simultaneously consider solubility enhancement and controlled release for poorly water-soluble drugs with a short-half-life [8,9]. VAL was chosen as a model drug. VAL is used in the treatment of hypertension [10] but it has low bioavailability (AUC 23%), probably related to its poor water-solubility in low pH-conditions, i.e., 87 μg/ml at pH 1.2 but 5 mg/ml at pH 6.8 [11]. The drug is only minimally


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2.2. Methods

Table 1 Formulation composition of SDs (unit: mg). Code

VAL

PEG 6000

Gelucire 50/13

Poloxamer 407

Aeroperl 300/30

SD1 SD2 SD3 SD4 SD5

80 80 80 80 80

80 – – – –

– 80 – – –

– – 80 60 40

80 80 80 80 80

2.2.1. Determination of VAL solubility in various pharmaceutical excipients An excess amount of VAL was added to a 1.5 ml snap-cap Eppendorf tube (Hamburg, F.R.G) containing various additives. The resulting mixture was sufficiently mixed and then placed in a constant temperature water bath at 37 °C for three days. Aliquots were centrifuged at 13,000 rpm for 10 min (Hanil, Korea). The supernatant layer was carefully collected and then adjusted with a proper dilution. The concentration of VAL was quantified by HPLC from a standard calibration curve. Data are expressed as mean ± S.D. (n = 3).

Table 2 Formulation compositions of SD-loaded tablets (unit: mg). Code

SDa

Avicel PH102

HPMC 4000 cps

Magnesium stearate

F1 F2 F3 F4

220 220 220 220

176 156 146 136

– 20 30 40

4 4 4 4

a

2.2.2. Preparation of samples for compatibility studies The pure VAL was added to a 10 ml glass test tube containing various pharmaceutical excipients. The ratio of drug to excipients was 1:3 (w/w). The binary physical mixtures were prepared without adding solvent. The resulting mixtures were sufficiently mixed and then stored for four weeks under 40 °C/75% relative humidity (RH) conditions. The samples were observed for intactness and quantified for degradability using HPLC to verify drug content or peak shape.

SD contains 80 mg of VAL.

2.2.3. Preparation of ternary SD and physical mixture (PM) Three SD carriers such as poloxamer 407, gelucire 50/13 and PEG 6000 were chosen for the preparation of SD via hot melt method. The detailed formulation compositions of the ternary SDs are listed in Table 1. For each formulation, VAL and the carrier were first mixed, and then the resulting mixtures were heated in an oil bath (Heating mantle, Model-61HMR-BIL, Korea) at 70 °C and sufficiently stirred. Thereafter, the adsorbent (Aeroperl®300/30) was added into the melted carrier solution to adsorb melted solution. After sufficient mixing, the mixtures were solidified by cooling to −20 °C within 2 hr. The solidified mass was pulverized thoroughly with a pestle and mortar to pass through a 30-mesh sieve. For comparison, PM was prepared by blending a mixture of VAL: poloxamer 407: Aeroperl®300/30 at a ratio of 10:7.5:10 (w/w) in a mortar.

metabolized and excreted largely (about 80%) unchanged [12]. A high inter-subject variability of immediate release VAL resulting from poor water solubility was reported in previous bioequivalence studies [12]. Moreover, due to the short half-life (6–9 hrs) [13], VAL is a good candidate for use in developing CR dosage forms combined with SD technique. Valsartan SD powders with poloxamer 407 was previously prepared using solvent evaporation methods and oral pharmacokinetics of SDs was also evaluated in rats [14]. However, the pH independent controlled release tablet was not investigated in human volunteers. Furthermore, adsorption of SD prepared by hot-melting method onto hydrophilic fumed silica (Aeroperl® 300/30) to get free-flowing properties are very important to compress SD into tablet. The principal goals of this research, therefore, were: (i) to select proper pharmaceutical excipients for preparing ternary SD to improve solubility and dissolution rate of VAL, (ii) to design pH-independent SD-CR tablet, and (iii) finally to compare in vivo bioavailability of SD-CR tablets with commercial tablet (Diovan®) in healthy human volunteers.

2.2.4. Preparation of SD-CR tablets The formulations of SD-CR tablets are listed in Table 2. Matrix tablets were prepared using direct compression. SD, Avicel PH102, and HPMC were separately sieved using 30-mesh sieves. Then the components were mixed thoroughly with a pestle and mortar. Finally, magnesium stearate was added as a lubricant and the mixture was stirred for approximately 10 min. The resulting mixtures were directly compressed in a conventional tableting machine (Cube group, Gimpo, Korea). The cylindrical tablets containing ternary SD system showed the following characteristics: diameter 10 mm; hardness 70 ± 10 N.

2. Materials and methods 2.1. Materials VAL (purity > 99.0%) was purchased from Du-Hope pharmaceutical Corp (NanJing, China). Polyethylene glycol (PEG 6000), Poloxamer 407, microcrystalline cellulose (Avicel® PH102), Gelucire 50/13, and magnesium stearate were received as gifts from Seoul Pharmaceutical Corp. (Seoul Korea). Hydroxypropylmethyl cellulose (HPMC, Methocel grade E4MP) was supplied from Sinyo Chemical Industries (Tokyo, Japan). Hydrophilic fumed silica (Aeroperl® 300/30) was purchased from Degussa (Korea). Spironolactone (purity > 99.5%), kindly obtained from Daewoong Pharmaceutical Corp. (Seoul, Korea), was used as the internal standard (I.S.). Methanol and acetonitrile (HPLC grade) were purchased from Fisher Scientific Ltd. (Seoul, Korea). Commercial Diovan® tablet (Novartis, Korea) was chosen as the reference for dissolution and human pharmacokinetics studies although the formulation and process are trade secret. All other reagents were of reagent grade and used without further purification.

2.2.5. HPLC analysis for in vitro dissolution test The HPLC system (Jasco, Tokyo, Japan) consisted of a pump (PU980), a UV–visible spectrophotometric detector (UV-975), an autosampler (Jasco, AS-950-10), a degasser (DG-980-50), a reverse phase column (Luna 5 μm C18 100A, 150 × 4.6 mm), and an integrator (Borwin 1.20 software). The concentration of VAL was determined at a wavelength of 234 nm. The mobile phase, consisting of a 55:45 (v/v) mixture of acetonitrile and 0.015 M potassium dihydrogen phosphate (pH 2.0), was degassed under vacuum for 5 min. The flow rate of the mobile phase was 1.2 ml/min. A 20-μL sample was injected into the HPLC system [15]. 2.2.6. In vitro dissolution studies The dissolution test was performed according to the USP dissolution II paddle method (50 rpm, 900 ml dissolution medium and

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Fig. 1. Phase equilibrium solubility of VAL in various pharmaceutical excipients at 37 °C. [S1, SGF; S2, water; S3, SIF; S4, Oleic acid; S5, Castor oil; S6, SLS; S7, Brij 98; S8, Brij 97; S9, Cremophor EL; S10, Cremophor RH 40; S11, Tween 80; S12, Tween 60; S13, Carbopol 934; S14, Poloxamer 407; S15, Poloxamer 188; S16, PEG 6000; S17, PEG 4000; S18, Gelucire 44/14; S19, Gelucire 50/13; S20, Mannitol; S21, HPMC 4000; S22, HPMC SR 100,000; S23, HPMC 100,000; S24, PVP K-30; S25, HP- β -CD; S26, HPC; S27, MC; S28, CMC-Na; S29, PG; S30, Glycerin; S31, Sorbitol; S32, Citric acid; S33, Polyvinyl alcohol; S34, Bentonite].

given time for tablets initially prepared and tablets under storage conditions.

37 ± 0.5 °C) using a DST-600A dissolution tester (Labfine, Seoul, Korea). SDs were tested in 900 ml of SGF. Dissolution samples of ternary SD were collected at 5, 15, 30, 60, 90, and 120 min with the replacement of an equivalent amount of fresh medium to maintain a constant dissolution volume after each collection. Matrix tablets were placed in 900 ml of SGF (simulated gastric fluid) for 2 hr, and then switched to 900 ml of SIF (simulated intestinal fluid). The concentration of samples was then determined by HPLC as described previously. All dissolution tests were performed in triplicate.

2.2.8. Thermal analysis (DSC) The thermal behaviors of VAL, Poloxamer 407, Aeroperl® 300/30, PM, and SD powder were investigated using Dupont DSC (USA). The sample (approximately 5 mg) was weighed in a standard open aluminum pan, while an empty pan of the same type was used as a reference. The heat running for each sample was increased from 20 °C to 200 °C at 5 °C/min, using nitrogen as the purge gas. Calibration of the temperature and heat flow was performed with indium.

2.2.7. Stability study The SD-loaded matrix tablets were stored for up six months in a high-density polyethylene plastic bottle with silica gel at 40 °C/75% RH. The dissolution profiles and drug content were determined at the

2.2.9. Powder X-ray diffraction (PXRD) Powder X-ray diffraction of VAL, Poloxamer 407, Aeroperl® 300/30,

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Fig. 2. Compatibility between VAL and various excipients at 40 °C/75% RH. (left: control; center: after two weeks; right: after four weeks). [C1, Brij 98; C2, Brij 97; C3, Cremophor EL; C4, Cremophor RH 40; C5, Tween 80; C6, Tween 60; C7, Poloxamer 407; C8, SLS; C9, HPMC 4000; C10, HPMC-SR100000; C11, HPMC 100,000; C12, PVP k 30; C13, HPC; C14, PEG 6000; C15, PEG 4000; C16, CMC-Na; C17, methyl cellulose; C18, HP-β-CD; C19, Lactose; C20, Starch 1500; C21, Avicel PH102; C22, Primojel; C23, Ac-di-Sol; C24, Cros-povidone; C25, Aerosil 200; C26, Aeroperl 300; C27, talc; C28, magnesium stearate; C29, MgO; C30, bentonite] Data are expressed as mean ± S.D. (n = 3).

ground and thoroughly mixed with KBr at a ratio of 1:5 (sample: KBr). The KBr discs were prepared by compressing the powders at a pressure of 5 tons for 5 min in a hydraulic press.

PM, and SD powder was performed with a D5005 diffractometer (Bruker, Germany) using Cu-K radiation at a voltage of 40 kV and a current of 50 mA. The samples were scanned in increments of 0.02° from 3° to 60° (diffraction angle 2θ) with a rate of one second per step, using a zero background sample holder.

2.2.12. Distribution and particle size determination during dissolution process Adequate pure VAL as control and SD equivalent to 80 mg VAL were dispersed into the SGF (900 ml) with dissolution conditions. The samples were collected at 5, 15, 30, 60, 90, and 120 min for the determination of dissolving particle sizes. The particle size was determined by DLS (ELS-8000, Otsuka Electronics Co. Ltd., Osaka, Japan).

2.2.10. Scanning electron microscopy (SEM) Scanning electron microscopy (SEM) was used to examine VAL, Poloxamer 407, Aeroperl® 300/30, PM, and SD powder, using a Cambridge Stereo Scan 200 (London, UK) at an accelerating voltage of 15 kV. The samples were mounted onto brass stages using double-sided adhesive tape and coated with gold-palladium for 60 s under an argon atmosphere using a Jeol JFC-1100 sputter coater (Jeol, Japan).

2.2.13. Bioavailability studies in healthy human volunteers A validated method [15] was applied to determine the plasma concentration of VAL from a clinical trial in which eight healthy male volunteers were treated orally with one 80 mg commercial Diovan® tablet and one test tablet, which is the usual dose, with 240 ml of water. The eight volunteers were randomly divided into two groups for a balanced 2 × 2 two-way crossover design. The human volunteers fasted

2.2.11. Fourier transform infrared spectroscopy (FTIR) The Fourier transform infrared spectroscopy (FTIR) spectra (400–4000 cm−1) of VAL, Poloxamer 407, Aeroperl® 300/30, PM, and SD powders were recorded with a resolution of 2 cm−1 using FTIR spectrophotometer 430 (Jasco, Japan). The samples were previously

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Fig. 3. The effect of SD carrier types (A) and the content of poloxamer 407 (B) on the drug release rate in the SGF (pH 1.2).

biomedical research involving human subjects and the rules of Good Clinical Practice. The in vivo bioavailability was carried out under the bioequivalence guidelines (KFDA2007-23) of the Ministry of Food & Drug Safety after all participants signed a written informed consent. Non-compartmental pharmacokinetic analysis was performed. The maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) after oral administration were directly determined from concentration-

overnight. Blood samples were collected into heparinized glass tubes before administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h post-dose. Blood samples were separated immediately by centrifugation at 3000 × g for 10 min and the plasma stored at −40 °C until analysis. The protocol of this study was approved (BE002009-05) by the Ethics Committee, Kangwon National University (Chuncheon, Korea) according to the Declaration of Helsinki as amended in Seoul 2008 for

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Fig. 4. Solubility of pure VAL and its SD system in various pH media.

time curves. The area under the plasma concentration – time curve from 0 to 36 h (AUC0-36) was calculated using the linear trapezoidal rule. All data were expressed as mean ± standard deviation (S.D.). The pharmacokinetic parameters AUC0–36h, Cmax, and Tmax were used for statistical analysis using the BA Calc 2002 program (Korea). All statistical calculations were performed at 5% significance level.

3.2. Compatibility study of drug and pharmaceutical excipients A stable and effective solid dosage form can be achieved by using proper excipients. Although excipients have been conventionally thought to be inert, they have been shown to interact with the drug, preventing its absorption and bioavailability [20–22]. Drug-excipient interaction is an important and essential study in the development of a stable solid dosage form [23]. Quantitative assay after isothermal stress testing is a method commonly used for drug-excipient interaction studies. Traditional isothermal stress testing typically involves challenging drug-excipient mixtures with temperature and moisture [24]. Therefore, an accelerated condition (40 °C/75% RH) was selected in this compatibility study. Compatibility of binary blends between VAL and various pharmaceutical excipients at the 40 °C/75% RH condition for four weeks is shown in Fig. 2. The drug contents and physical appearance of all samples were almost unchanged. However, in the case of Tween 60, Tween 80, Cremophor EL, Cremophor RH 40, Brij 97, and Brij 98, the drug content was decreased after four weeks from 100% to 92.3, 83.1, 92.2, 84.9, 84.9, and 89.3%, respectively (Fig. 2A). These excipients or surfactants increased the solubility of VAL initially, but the degradation of VAL to a related substance during storage resulted in low drug stability. The impurity peaks were observed in HPLC examination; the retention times were from 1.5 to 2.5 min (data not shown). Thus, these could not be utilized for an optimal formulation.

3. Results and discussion 3.1. Solubility study Drug solubility is important in the selection process of a drug candidate because the drug needs to be absorbed across the intestinal walls to enter the portal vein after oral administration. Moreover, the solubility of a drug is generally mentioned as an important factor in the bioavailability of a pharmaceutical product and hence, many researchers have examined the relationship between solubility and gastrointestinal absorption [16–18]. A drug's solubility with various pharmaceutical excipients should be screened to select optimal dosage formulations [19]. Therefore, the effects of pH, solubilizers, oils, and fatty acids on drug solubility were evaluated in the study. The solubility of VAL in various pharmaceutical excipients at 37 °C is shown in Fig. 1. VAL is an acidic drug with highly pH-dependent solubility; under 87 μg/ml in the SGF, 152 μg/ml in water and approximately 5000 μg/ ml in the SIF. However, surfactants and co-surfactants have a tendency to enhance drug solubility. At 37 °C, the aqueous solubility of VAL was increased about 35-fold when the concentration of the polymer 407 in 1% aqueous solution was used. In the case of SLS and castor oil, drug solubility in water solutions of these agents improved about 33-fold and 58-fold, respectively. Based on these solubility studies, drug compatibility and aqueous dispersability, Poloxamer 407 was chosen as an appropriate carrier and solubilizer in the SD system and SD-loaded tablet formulations. The commonly used hydrophilic carriers such as PEG4000 and gelucire were also used for SD system as references.

3.3. Effect of formulation compositions in SDs The effect of carrier types on dissolution rate of SD in the SGF is shown in Fig. 3A. The percent release of pure VAL was very low (< 5%) due to its highly pH-dependent solubility. The dissolution rate of SDs at 120 min for SD1 (containing PEG 6000), SD2 (containing gelucire 50/ 13) and SD3 (containing poloxamer 407) were 59.1% (47.28 mg), 52.6% (42.08 mg), and 82.1% (65.68 mg), respectively. The dissolution of SD3 with poloxamer 407 was fastest and demonstrated an ideal drug release pattern. The effect of poloxamer 407 quantity on dissolution

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significantly, about 200–fold, compared with that of pure VAL at pH 1.2. SD consistently maintained higher solubility over different pH condition while the solubility of VAL alone had high pH dependency. Poloxamers are block copolymers consisting of polyoxyethylene (POE) and polyoxypropylene (POP) units, representing hydrophilic and hydrophobic parts, respectively, and have been widely used in the pharmaceutical industry for numerous applications including the roles of carrier and surfactant in SD technology to improve the solubility and bioavailability of several poorly soluble drugs [26,27]. Based on these results, poloxamer 407 was used as SD carrier for further investigation. One manufacturing method to get free-flowing SD powders for further preparation of matrix tablet is to utilize adsorbents. Aeroperl® 300/30, an adsorption or thermal-stable agent, was selected for the formulation because it provides satisfactory powder fluidity and its large surface area protects against drug instability. SD 3 (VAL: Poloxamer: Aeroperl = 1: 1: 1) was finally chosen as a formulation for the preparation of tablets. 3.4. Physicochemical characterization of SDs To elucidate the enhanced dissolution rate of ternary SDs, the physical states of the drug crystals in the poloxamer-based SD were investigated using instrumental analysis, such as DSC, PXRD, SEM and FT-IR. The DSC thermograms of SDs are shown in Fig. 5A. The DSC analysis of pure VAL and poloxamer 407 showed sharp endothermal peaks at 90 °C and 54 °C, respectively, corresponding to their melting points. However, the endothermal peak of a drug melting point was not visible in the DSC curves of the PM and the SD, suggesting that VAL was molecularly well-dispersed and changed into an amorphous form [3,28]. PXRD was also used to ensure the change of crystallinity of VAL in the SD and the PM (Fig. 5B). The diffraction pattern of the pure drug showed its polymorphic form, as indicated by the distinctive broad peaks. The poloxamer alone exhibited two high-intensity peaks at 19 °C and 23 °C. The lack of distinctive broad peaks in the SD diffraction pattern indicated that a high concentration of the drug was dissolved in the solid state carrier matrix in an amorphous structure [28]. In ternary SD system, a drug may exist in an amorphous form in polymeric carriers, resulting in increased solubility and dissolution rates [29a]. In the FT-IR analysis (Fig. 6), the pure VAL showed two carbonyl absorption bands at 1734 and 1595 cm−1, assigned to the carboxyl carbonyl and amide-carbonyl stretching, respectively. Meanwhile, the poloxamer showed characteristic peaks at around 2900 and 1100 cm−1 and the major spectrum of Aeroperl® 300/30 was observed at around 1100 cm−1. The two absorption bands of pure VAL appeared unchanged in the PM, but the intensity of the 1595 cm−1 band decreased substantially and shifted to 1650 cm−1 in the SD. Based on the FT-IR analysis, the SD was compatible and had no intermolecular interaction with Aeroperl® 300/30, which was added to solidify the mixture. However, the drug demonstrated intermolecular hydrogen bonding with poloxamer 407. The hydrogen bond formation should work synergistically with poloxamer 407 to enhance the solubility and stability of the formulations [29]. The surface morphology of pure VAL, poloxamer 407, Aeroperl® 300/30, the PM, and the SD are shown in Fig. 7. VAL crystals had an acicular form, whereas poloxamer 407 and Aeroperl® 300/30 showed very smooth, round granular shapes. The acicular form of the drug was maintained in the PM but disappeared in the SD. In addition, it was also confirmed that the melted mixtures were adsorbed onto Aeroperl and the drug was attached to Aeroperl surface. According to the physical properties of Aeroperl from Evonik, “Aeroperl® 300/30 is a specifically

Fig. 5. DSC thermograms and PXRD patterns of VAL, Poloxamer 407, Aeroperl® 300/30, PM, and SD.

rate of the SD in the SGF is showed in Fig. 3B. The dissolution rates at 120 min were 4.7% (3.76 mg) (pure VAL), 82.1% (65.68 mg) (SD3), 81.2% (64.96 mg) (SD4), and 53.2% (42.56 mg) (SD5). The dissolution rate of the SD was significantly increased as the amount of poloxamer 407 increased due to its highly solubilizing capability [25]. It is known that the poloxamer's hydrophobic core forms a micelle-like structure in water [25]. It is also known that the enhanced dissolution rate of drugs from these SDs is based primarily on four different mechanisms [25]: (a) wetting of the drug is improved by direct contact of the drug with the hydrophilic matrix, (b) the saturation concentration around small particles is higher than around large particles, (c) the surface area is increased, and (d) the drug has higher energy in the amorphous state than in the crystalline state, through which the saturation concentration is increased. Fig. 4 clearly shows the solubility of pure VAL and its SD under different pH conditions. The drug solubility of the SD increased

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granulated hydrophilic fumed silica with an average particle size of 20–60 μm. The high specific surface area (BET) of 270–330 m2/g, coupled with the mesoporous volume of approx. 1.5–1.9 ml/g means that Aeroperl® 300/30 is a versatile and highly absorptive carrier that may be used to incorporate liquids into solid pharmaceutical dosage forms.” These results were in accordance with the previous PXRD and DSC results, confirming that VAL was transformed from a crystal to an amorphous form upon dispersion by the melting method. The dissolution and particle size distribution of SD system in SGF (pH 1.2) are shown in Fig. 8, The mean particle size of VAL sharply decreased as follows: 580 nm, 165 nm, and 150 nm at three different times (5 min, 30 min, and 120 min), respectively. This reduced particle size enhanced the drug release rate due to increased surface area and better wettability of drugs [30]. 3.5. Release characteristics of controlled release matrix tablets Controlled release products have become popular for oral administration because they result in more consistent blood levels. Controlled release with zero-order release kinetics maintains drug plasma concentration at a constant level for a better therapeutic effect. Matrixbased controlled release tablets are the most popular and easiest formulations to manufacture on a commercial scale [31]. HPMC has been frequently used in the formulation of matrix-based CR drug delivery

Fig. 6. FT-IR spectra of pure VAL, Poloxamer 407, Aeroperl® 300/30, PM and SD. The arrow indicate the potential hydrogen bonding of SD.

Fig. 7. SEM photomicrographs of VAL, Poloxamer 407, Aeroperl® 300/30, PM, and SD. 372


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Fig. 8. The dissolution and nanonization phenomena of SD system in SGF (pH 1.2). A, B and C depict particle size distributions of dissolution media at three different times (5min, 30min, 120min). D describes particle size as a function of time during dissolution.

and gelled. On the other hand, SD system was well dispersed and dissolved into the polymeric network of HPMC I a controlled manner to form nanonized particles (See the changes of particle size in Fig. 8). The matrix tablet containing HPMC 30 mg (F3) showed an ideal controlled release profile with zero-order and pH-independent behavior, compared to the characteristics shown by the marketed Diovan® tablet in gastrointestinal fluid. Consequently, formulation F3 was selected as the optimal formulation for further investigation of stability and in vivo study using human subjects. Stability of the optimal formulation was studied for six months at 40 °C/75% RH storage conditions. The content of VAL in the tablets was very similar to starting values and recrystallization was not observed by DSC and PXRD during accelerated conditions over the six months (data not shown). Release of VAL from SD-loaded matrix tablets as a function of time is shown in Fig. 10. A dissolution test was also performed on the

systems. HPMC, a semisynthetic derivative of cellulose, is a swellable and hydrophilic polymer and very suitable as a retardant material in controlled release matrix tablets as it is nontoxic and easy to handle [32,33]. HPMC is also well known as a sustained release material in pharmaceutical industry. For this reason, HPMC was selected in the study to easily control the drug release rate from the SD-loaded tablets. The effect of HPMC on dissolution rate of SD-loaded tablets in the SGF is shown in Fig. 9. The dissolution rate of HPMC matrix tablets showed the controlled drug release pattern. The release rate of matrix tablets was decreased as the HPMC amount increased from 0 mg to 40 mg (F1, F2, F3, and F4) due to the high viscosity and swellable properties of HPMC. The release mechanism of HPMC is well known because of its ability to form a viscous gel and swellability to govern drug release via diffusion process. In this study, the SD containing API was physically dispersed into HPMC polymers. As water penetrates, HPMC is swelled

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Fig. 9. Effect of HPMC contents on the dissolution rate of VAL from SD-CR tablets.

Fig. 10. Dissolution profiles of SD-CR tablets after stability test at three and six months under accelerated condition.

accelerated conditions for six months.

900 ml of SGF for 2 hr, and then pH jumped into the 900 ml of SIF for 5 hr. There were no differences in release profiles as a function of time. Compared with values in the initial drug release profile, similarity factor (f2) values [34] were 91.5 and 77.4 for three months and six months, respectively. Based on the above results, the HPMC matrix tablet containing VALSD demonstrated good controlled-release behavior and stability at

3.6. In vivo pharmacokinetic studies A pharmacokinetic profile of VAL in human plasma after administration of a Diovan® tablet and a test tablet (each containing 80 mg of VAL) to a healthy volunteer is shown in Table 3 and Fig. 11.

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Table 3 Pharmacokinetic parameters of VAL following oral administration of Diovan® tablet and SD-CR tablet (each containing 80 mg VAL) in human volunteers (n = 8). Volunteer

1 2 3 4 5 6 7 8 Mean ± SD

Diovan® tablet

Test tablet (F3)

Cmax (μg/ml)

Tmax (h)

AUC (μg·h/ml)

Cmax (μg/ml)

Tmax (h)

AUC (μg·h/ml)

3.658 0.586 0.386 2.119 1.634 1.332 0.999 0.943 1.46 ± 1.05 (72.02)a

3 3 3 4 4 3 3 3 3.25 ± 0.46 (14.24)a

25.624 7.079 5.145 19.906 12.368 13.858 8.978 9.795 12.84 ± 6.88 (53.55)a

2.314 1.748 0.890 2.042 2.107 0.624 0.840 2.116 1.59 ± 0.68 (43.20)a

4 4 2 2 4 4 6 3 3.63 ± 1.30 (35.93)a

17.936 14.26 5.842 32.608 16.476 5.697 6.792 25.457 15.63 ± 9.75 (62.36)a

Each value represents the mean ± standard deviation (SDw). a The number in parenthesis indicates relative standard deviation.

Fig. 11. Plasma concentration time curves of VAL after oral administration of Diovan® tablet and Test tablet (each containing 80 mg of VAL) to a healthy volunteer (n = 8). A; mean value with deviation, B and C; individual value of each volunteer.

Pharmacokinetic parameters of the reference Diovan® tablet were 1.457 ± 1.049 μg/ml (Cmax), 3.250 ± 0.426 h (Tmax), and 12.844 ± 6.878 μg h/ml (AUC0-36). These parameters agree with those reported previously [35]. Pharmacokinetic parameters of pH-independent SD-CR tablets (test) were given 1.585 ± 0.684 μg/ml (Cmax), 3.625 ± 1.302 h (Tmax), and 15.633 ± 9.749 μg h/ml (AUC036). Examination of results indicated that Cmax and AUC0-36 increased and Tmax was extended for the SD-CR tablets as compared with commercial Diovan® tablet but these differences were not statistically significant in a small number of human population. However, it is important to consider the inter-subject variability of pharmacokinetic parameters for determining the number of subjects for minimizing the adverse effects [36]. In the case of Diovan® tablet, a large intersubject variability of Cmax was noted due to outlying subject. In contrast, the inter-subject variability of Cmax in the SD-CR tablet was relatively lower and did not show any burst release as compared with Diovan® tablet as

a result of pH-independent release in a controlled manner. It was reported that maximum plasma concentrations of 2–4 μg/ml are reached after a single oral dose of 160 mg Diovan® 160 coated tablets [37]. Based on EMA documentation regarding Diovan, non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. However, the recommendation dose is generally 40 or 80 mg twice daily. EMA says that your doctor can increase the dose gradually over several weeks to a maximum of 160 mg twice daily. In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring. These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient) [38].

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Fig. 12. Schemetic diagram describing advanced performances of SD-CR VAL tablet via nanonization and pH-independent release.

References

It would be explained that the controlled release matrix tablets have the advantage of more consistent blood levels, avoiding potential side effects because VAL has been known to cause large individual differences in blood level due to the poor water solubility [39]. These properties may lead to many adverse effects such as regular heartbeat because of a narrow therapeutic window of VAL [40]. Fig. 12 shows a schematic diagram describing advanced performances of SD-CR tablet via nanonization process for pH-independent controlled release and reliable human bioavailability. The pH-independent controlled release tablet could provide a solubilized environment via nanonization process throughout the gastrointestinal tract, resulting in enhanced bioavailability of VAL with reduced Cmax deviation for better clinical therapy to modulate blood pressure more efficiently.

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4. Conclusions The SD was prepared using the hot melt method. The results of DSC, PXRD, SEM, and FT-IR studies showed the existence of VAL in the SD in an amorphous state. The dissolution rate of VAL from the SD was markedly enhanced in SGF compared to that of pure VAL. The amorphous state and reduction of VAL particle size were factors contributing to the enhanced release rate of VAL. The controlled release matrix tablet containing SD showed a pH-independent release profile. Although the optimal formulation tablets showed highly improved solubility and release rate in the SGF, these parameters were not significantly different from those of commercial Diovan® tablets. However, the controlled release matrix tablet with SD has the advantages of more consistent blood levels and fewer side effects. Conflicts of interest The authors declare that there is no conflict of interests. Acknowledgements This research was supported by a grant from the Ministry of Science, ICT and Future Planning (2013M3A9B5075841). We would like to thank Ajou University-Central Laboratory for the use of instruments. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx. doi.org/10.1016/j.jddst.2018.05.031. 376


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