http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–6 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2015.1055763

RESEARCH ARTICLE

Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Nyu Medical Center on 07/13/15 For personal use only.

Ying Zhao, Chao Wu, Zongzhe Zhao, Yanna Hao, Jie Xu, Tong Yu, Yang Qiu, and Jie Jiang Pharmacy School, Liaoning Medical University, Linghe District, Jinzhou, Liaoning Province, P.R. China

Abstract

Keywords

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs.

Biodegradability, biological safety, nitrendipine, poorly water-soluble drugs, starch macrocellular foam

Introduction At present, about 40% of the active drugs obtained from highthroughput drug screening are poorly water-soluble1. It is very important for researchers to study biopharmaceutical classification system (BCS) type II drugs which have a high permeability and low water solubility2. During the drug absorption process, the dissolution rate of poor water-soluble drugs is the rate-limiting step. A low drug solubility, low dissolution rate and incomplete absorption after oral administration in the gastrointestinal fluids affect the therapeutic effect of poorly water-soluble drugs3 and seriously limit their application. There are many traditional pharmaceutical solubilization methods to increase their dissolution rate, such as forming inclusion complexes with cyclodextrins4–6, solid dispersion technology7–9, ultra-fine grinding10–12, adding solubilizers and co-solvents13,14, and salt formation15,16. The development of nanotechnology provides a new way to solve the problem of the slow dissolution rate of poorly water-soluble drugs. At present, inorganic porous materials are widely used to improve the solubility of poorly water-soluble drugs, such as mesoporous silicon materials17–19, mesoporous carbon material20,21 and porous hydroxyapatite22,23. The nano-pore structure of these materials has a large specific surface area, controllable pore size and high pore volume, which is suitable for loading drug molecules. Due to the space limitations of the nano-pores, drugs cannot recrystallize and a reduction in crystallinity results in drug being present in an amorphous state or a microcrystalline state24. According to the Ostwald–Freundlich and Noyes–Whitney

Address for correspondence: Chao Wu, Pharmacy School, Liaoning Medical University, 40 Songpo Road, Linghe District, Jinzhou, Liaoning Province 121001, P.R. China. Tel: +86 04164673439. E-mail: [email protected]

History Received 1 April 2015 Revised 13 May 2015 Accepted 15 May 2015 Published online 13 July 2015

equations25, a reduction in drug particle size and the increase in specific surface area not only improves the dissolution rate of drugs, but also promotes the contact between nanoscale drug particles and biological membranes. Nevertheless, the biological safety and biodegradability of inorganic porous materials are unpredictable, which limits their applications. In this study, we examined one kind of new material, starch macrocellular foam (SMF). It not only has the advantages of inorganic porous materials, but also possesses good biological safety and biodegradability. The most important thing is that starch, as a natural product, is widely available and inexpensive. In the last few decades, there have been relatively few studies of starch foam. Initially, Glenn and Irving26 developed a microcellular starch-based foam from semirigid aqueous gels which had heterogeneous pores with a continuous cell–wall structure. Shortly afterwards, Buttery et al.27 proved that starch microcellular foam could effectively adsorb a variety of volatile compounds, similar to other microcellular foams, such as activated charcoal. In recent years, Glenn and Irving prepared food-grade macrocellular foam based on starch to supplement the diet of useful insects such as honeybees28. Wu et al. also developed a biodegradable porous starch foam as a carrier in order to improve the dissolution and enhance the oral bioavailability of water-insoluble drugs29. In this study, we used a new technology to prepare SMF. Silicon nanospheres, as hard templates, were added to starch solution to form a gel. After lyophilization, the templates were removed and the sample was lyophilized again. If the solvent exchange method is used for drying, the structure of the starch may collapse and this results in a low porosity biopolymer material. However, lyophilization would be an ideal method of solving these problems. The advantage of SMF is that the pore size can be controlled and is homogeneous. Moreover, if the template is removed, this leaves a great deal of interconnected spherical pores which are suitable as a drug reservoir for increasing the drug loading.

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SMF, as a carrier material, was used to load nitrendipine (NDP) into the porous network structure with the solvent evaporation method. NDP, a typical BCS-drug, is widely used to treat cardiovascular disorders because of its good selectivity for vascular conduction and contractility as a dihydropyridine calcium channel blocker producing peripheral vasodilatation. Scanning electron microscopy (SEM) characterizes the structure of the SMF. The physical state of NDP in the NDP-SMF was investigated by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). In vitro and in vivo tests were carried out to compare the dissolution rate and oral bioavailability of the NDP-SMF tablets with those of commercial tablets.

Materials and methods Materials NDP with a purity499% was provided by Zhengzhou Debao Fine Chemical Co., Ltd. (Zhengzhou, China). Soluble starch was obtained from Tianjin Shengcheng Fine Chemical Co., Ltd. (Tianjin, China). Tetraethylorthosilicate (TEOS) was supplied by Tianjin Guangfu Fine Chemical Co., Ltd. (Tianjin, China). Ammonia, hydrofluoric acid and anhydrous ethanol were provided by Tianjin Yongsheng Fine Chemical Co., Ltd. (Tianjin, China). Acetonitrile of chromatographic grade was supplied by Shengyang Fine Chemical Co., Ltd. (Tianjin, China). Deionized water was used in all experiments. Preparation of SMF and drug loading Step 1: 180 mL anhydrous ethanol, 65 mL deionized water and 4.5 mL ammonia were placed in an Erlenmeyer flask and stirred until homogeneously mixed. Then, 15 mL TEOS was added to the mixture. After stirring for 4 h at room temperature, the mixture was centrifuged at 9500 rpm/min for 10 min and then the supernatant was removed. The remaining precipitate was washed twice with anhydrous ethanol and water and dried at 40  C for 12 h in a vacuum oven (DZF6050, Shanghaiboyuan, Shanghai, China). The obtained solid was composed of silicon nanospheres (SNS)30. Step 2: An aqueous slurry of starch (25% w/w) was heated to 100  C in a beaker under stirring until pellucid. SNS was added to the starch solution then, after 1 h, the starch solution was poured into a petri-dish and allowed to gel at 5  C for 24 h and the starch gel was dried by lyophilization. The sample was soaked in 10% hydrofluoric acid/anhydrous ethanol to remove the SNS and washed three times with anhydrous ethanol. Then, SMF was obtained by lyophilization and stored in a dryer. NDP was dissolved in acetone and mixed with SMF in mass ratios of 1/1, 1/3, 1/5, 1/10, 1/15 and stirred for 5 h at room temperature. The NDP-SMF was dried in a vacuum dryer for 24 h. The loading capacity was determined by ultraviolet spectrophotometry (UV) (UV-2000, Unico). Characterization of SMF and NDP-SMF The surface topography of SMF was observed under an SEM (JSM7001F, JEOL, Japan) operated at 20 kV. SMF and NDP-SMF were examined using DSC (DSC-60, Shimadzu, Japan (Beijing, China)) at a constant heating rate of 10  C/min over the range of 50 to 300  C under an inert nitrogen atmosphere at a flow rate of 150 mL/ min. XRPD (Rigaku Geigerflex XRD, Co., Japan, Cu Ka radiation, 30 kV and 30 mA Philips) was used to further investigate the physical state of NDP in the NDP-SMF. The step size was 0.02 and the scanning rate was 0.5 /min over the angular range of 5 (2) to 60 . An FT-IR spectrometer (Bruker IFS 55, Switzerland) was used to record the FT-IR spectra with the aid of KBr pellets over the range 400–4000 cm1 in a dry atmosphere.

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In vitro drug release studies of NDP-SMF and NDP-SMF tablets To evaluate the cumulative percentage dissolution of drug released from NDP-SMF, a USP dissolution apparatus type II (RC-8D, Tianjin Guoming Medical Equipment Co., Ltd., Tianjin, China) was used. The dissolution medium was water containing 0.1 M hydrochloric acid and 0.1% SDS. The temperature was kept at 37 ± 0.5  C and the paddle speed was 100 rpm. NDP-SMF containing an equivalent of 10 mg NDP was dissolved in 1000 mL dissolution medium31. Samples of the dissolution medium (5 mL) were taken at predetermined times (5, 10, 15, 20, 30, 45 and 60 min) and replaced with fresh release medium (5 mL) to keep the volume of the dissolution medium constant. The NDP content was measured at a wavelength of 238 nm using UV. Preparation of NDP-SMF tablets and in vivo pharmacokinetic (PK) studies Preparation of NDP-SMF tablets NDP-SMF tablets were prepared by powder direct compression technology. NDP-SMF powder and pharmaceutical adjuvants were ground in a mortar and then passed through an 80-mesh sieve. Finally, NDP-SMF tablets were obtained using a TDP single punch tabletting machine (TDP-1.5, Shanghai Wangqun, Shanghai, China). It was found that the hardness was 4–5 kg/cm2. Animals and dosing Rabbits (body weight 2.5 ± 0.5 kg) were supplied by the Experimental Animal Center of Liaoning Medical University (Jinzhou, China). The animal experiment protocol was approved by the Animal Ethics Committee, Liaoning Medical University. Twelve rabbits were randomly divided into two groups. Before the experiment, rabbits were fasted for at least 12 h. The two groups of rabbits were given oral doses of either commercial NDP tablets (Tianjin Yabao Pharmaceutical Technology Co., Ltd., Tianjin, China) or NDP-SMF tablets at a dose of 3 mg/kg. Blood samples (3 mL) were collected from the ear vein and placed in Eppendorf tubes containing heparin at the following times: 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h after dosing32. The plasma samples were collected by centrifugation at a speed of 4250g for 10 min using a high-speed centrifuge (TG22-WS, Shanghai Danding, Shanghai, China) and stored at 20  C until required for analysis. NDP in plasma and data analysis NDP was determined by HPLC (Hitachi L7110 pump equipped with L7420 UV–VIS detector, Japan). The chromatographic column was a Welch UltimateÕ XB-C18 column (5 mm, 200 mm  4.6 mm) and the mobile phase was a mixture of acetonitrile and water (60:40, v/v). The flow rate was 1.0 mL/min and the UV detection wavelength was set at 236 nm. For analysis, 20 mL internal standard (felodipine, 1 mg/mL) and 0.3 mL sodium hydroxide solution (1 mol/L) were added to 1 mL plasma samples. After shaking in a vortex mixer (WH-2, Shanghai, China) for 5 min, 5 mL ethyl acetate was added and shaking was continued for a further 5 min. After centrifugation at 4250g for 10 min, the organic layers were transferred to Eppendorf tubes and dried using a centrifugal drying machine (LNG-T120, Hualida, Zhejiang, China). Before analysis, residues were dissolved in 50 mL mobile phase. After shaking for 5 min, the samples were centrifuged at 12 750g for 10 min. Then, 20 mL samples of supernatant were subjected to HPLC analysis33,34. Standard PK parameters (±SD) of NDP were obtained from plasma concentration–time curves using a non-compartmental

DOI: 10.3109/10837450.2015.1055763

model with PKSolver (Department of Pharmaceutics, China Pharmaceutical University, China). The PK parameters were examined, including the maximum peak concentration of the drug in plasma (Cmax), the time to reach the maximum concentration (Tmax), the area under the curve (AUC0!24) and the half-life (t1/2).

Results and discussion

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Morphology and structure We used lyophilization and natural drying for prepare SMF. The morphological and structural features of SMF and NDP-SMF were examined by SEM. Figure 1(A) shows that the diameter of the monodispersed silica nanospheres as hard templates was 100 nm. The microstructure of SMF obtained by lyophilization is shown in Figure 1(B). Its cross-section had spherical cavities caused by the removal of the template. The structure was highly suitable as a drug reservoir. Also, a porous network was formed due to water molecules leaving the starch gel, and this made all the spherical pores interconnected thereby reducing the diffusion resistance and increasing the drug dissolution rate. This unique

SMF for increasing the water insoluble drugs’ dissolution rate

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structure not only could increase the loading capacity but also improve the dissolution rate. Figure 1(C) shows the structure of SMF obtained by natural drying. Compared with Figure 1(B), it is clear that the removal of the template resulted in the formation of closed pores and there was no porous network to interconnect them. This was not beneficial for drug adsorption and release. Therefore, SMF obtained by air drying is not suitable as a drug carrier. Before and after drug loading, changes of in the state of NDP are shown in Figure 1(E) and (F). The crude NDP had irregular large crystals (greater than 100 mm). Pores of SMF after drug loading were filled with NDP. And all the features examined indicated that the porous network structure of SMF could adsorb drug and control the particle size by using the space restriction effect of the nanometer pores. DSC characterization DSC was performed to analyze the physical state of NDP in pores. As seen in Figure 2, the melting point of crude NDP was 160.42  C. Compared with the same ratio of the physical mixture, the melting peak of the NDP-SMF sample was wider and weaker.

Figure 1. The SEM images of SNS (A), SMF (B), natural drying SMF (C), lyophilization SMF (D), crude NDP (E) and the NDP-SMF sample (F).

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This showed that the porous network structure of SMF significantly increased the dispersion of NDP and inhibited crystallization of NDP. NDP adsorbed in the porous network structure of SMF was present in a microcrystalline state. With an increase in the proportion of SMF, the melting peak became wider and weaker. When the NDP/SMF ratio was 1/15, the melting peak disappeared. This indicated that NDP dispersed in the SMF pores was in an amorphous state. This led to the conclusion that the dispersion of the drug was proportional to the carrier ratio.

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of SMF significantly reduced the crystallinity of NDP and then NDP remained in a microcrystalline state in the porous network structure of SMF. With an increase in the SMF proportion, the number of the NDP diffraction peaks was greatly reduced and the diffraction intensity also significantly reduced. When the NDP/SMF ratio was 1/15, the diffraction peaks of NDP disappeared. These results proved that NDP was dispersed in the porous network structure of SMF in an amorphous state. The results of XRPD were consistent with the conclusions obtained by DSC.

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XRPD characterization The XRPD patterns were used to evaluate the crystal change in NDP in the porous network structure of SMF. As shown in Figure 3, compared with the patterns of crude NDP and SMF, the characteristic peaks of the physical mixture were the accumulated characteristic peaks of NDP and SMF. The characteristic peaks of NDP in the loaded sample were distinctly lower than that of the physical mixture in the same proportion. The reason for this was that the spatial confinement effect of the porous network structure

FT-IR characterization The FT-IR patterns were recorded to analyze the interaction of the chemical groups on the surface of NDP and SMF. As seen in Figure 4, crude NDP showed its characteristic peak at 3414 cm1. Compared the physical mixture with the same ratio of NDP-SMF, the FT-IR patterns had consistent characteristic peaks, which indicated that NDP and SMF did not interact. Furthermore, the FT-IR spectrum of SMF exhibited a hydroxyl stretching peak at 3000–3700 cm1, which showed that SMF had a hydrophilic surface with lots of hydrophilic groups. This promoted diffusion of the dissolution medium and accelerated the NDP release35. In vitro drug release studies

Figure 2. DSC patterns of SMF, crude NDP, physical mixtures and the NDP-SMF samples.

Figure 3. The XRPD powder patterns of SMF, crude NDP, physical mixtures and the NDP-SMF samples.

As shown in Figure 5, SMF could significantly improve the dissolution rate of NDP in comparison with crude NDP. The cumulative dissolution of crude drug was only 30% in 1 h. However, when the NDP/SMF ratio was 1:15, the cumulative dissolution after 10 min was as high as 60%. The main reason for this was that the space limitation effect of SMF nanopores inhibited the crystallinity of NDP and, accordingly, reduced the size of the NDP particles so that NDP was present in an amorphous or microcrystalline state in the porous network structure of SMF. According to the Noyes–Whitney equation36, the dissolution rate is proportional to the specific surface area of the drug particles. The role of the porous network structure of SMF in improving the dissolution rate of NDP fits the above theory. Furthermore, the hydrophilic surface of SMF also helped the dissolution medium reach and diffused into the porous network structure, which was beneficial for drug dissolution.

Figure 4. The FT-IR spectra obtained for SMF, crude NDP, physical mixture and the NDP-SMF samples.

SMF for increasing the water insoluble drugs’ dissolution rate

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DOI: 10.3109/10837450.2015.1055763

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Figure 5. In vitro drug cumulative dissolution percentage patterns of crude NDP and the NDP-SMF samples.

Figure 7. The concentration versus time profiles of referential commercial tablet and NDP-SMF tablet.

Table 1. Compositions of NDP-SMF tablet.

Table 2. PK parameters of NDP after oral administration of referential commercial tablet and NDP-SMF tablet.

Ingredients Carrier NDP-SMF Adjuvant Lactose PVP CMC-Na Magnesium stearate

Formulation 160 mg 66 mg 2 mg 20 mg 2 mg

Commercial tablet NDP-PSMF tablet

Tmax (h)

Cmax (ng/ml)

AUC0–24 (ng/ml h)

t1/2 (h)

2.00 1.00

104.79 383.06

793.26 1394.33

6.76 4.54

comparison with commercial tablets. The cumulative dissolution of NDP-SMF tablets was approximately 94% within 1 h while that of commercial tablets was only 73%. From the experimental results obtained, we found that NDP-SMF tablets were in line with market standards and could be used in PK experiments. In vivo pharmacokinetics Figure 7 shows the plasma concentration versus time profiles of NDP-SMF tablets and the reference commercial tablets. The PK parameters which obtained by non-compartmental analysis after oral administration are listed in Table 2. The Cmax value (p50.05) of NDP-SMF tablets was much higher than that of the reference commercial tablets, and the Tmax value (p50.05) of NDP-SMF tablets was approximately 67% longer than that of the reference commercial tablets. The relative bioavailability of NDP-SMF tablets was 175.7%. These results confirm that NDP-SMF tablets improve the oral bioavailability of NDP in comparison with the reference commercial tablets.

Conclusions Figure 6. In vitro drug cumulative dissolution percentage patterns of commercial tablet and NDP-SMF tablet.

Evaluation of NDP-SMF tablets First, we determined magnesium stearate as a lubricant. Adhesives, disintegrants and fillers were the remaining factors which mainly affect the drug release from NDP-SMF tablets. Thence, a three-factor orthogonal experiment was carried out to compare the effects of these factors on the drug release and obtained the optimum formulation (Table 1). As seen in Figure 6, NDP-SMF tablets exhibited a faster dissolution rate in

SMF was successfully prepared in this study and shown to possess a porous network structure suitable for improving the dissolution and oral bioavailability of insoluble drugs. SEM, XRPD and DSC characterization showed that NDP was adsorbed into the porous network structure of SMF and was present in an amorphous or microcrystalline state. In vitro drug release studies indicated that SMF markedly improved the dissolution rate of NDP. In the in vivo PK study, NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. These conclusions confirm the excellent application potential of SMF as a novel carrier for poorly water-soluble drugs. The application of organic nanometer porous material in pharmaceutics is clearly very useful.

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Declaration of interest This work was supported by the National Natural Science Foundation of China (no. 81302707), Natural Science Foundation of Liaoning Province (no. 2013022052), Dr. Start-up Foundation of Liaoning Province (no. 20141195), the Construction of Clinical Cardiovascular System Drug Evaluation Research Technology platform (no. 2012ZX09303016-002) and Supported by Quanmin Oral Graduate Sci-tech Innovation Foundation, the President Fund of Liaoning Medical University (no. QM2014012).

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Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs.

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rat...
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