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Maintaining Supersaturation of Nimodipine by PVP with or without the Presence of Sodium Lauryl Sulfate and Sodium Taurocholate Yipshu Pui, Yuejie Chen, Huijun Chen, Shan Wang, Chengyu Liu, Wouter Tonnis, Linc Chen, Peter Serno, Stefan Bracht, and Feng Qian Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00253 • Publication Date (Web): 21 May 2018 Downloaded from http://pubs.acs.org on May 22, 2018

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Molecular Pharmaceutics

Maintaining Supersaturation of Nimodipine by PVP with or without the Presence of Sodium Lauryl Sulfate and Sodium Taurocholate

Yipshu Pui1, Yuejie Chen1, Huijun Chen1, Shan Wang1, Chengyu Liu1, Wouter Tonnis2, Linc Chen3, Peter Serno4, Stefan Bracht2, Feng Qian*1

1

School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, and MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, P.R. China. 2

Chemical and Pharmaceutical Development, Research and Development, Bayer AG, 13342 Berlin, Germany.

3

4

Chemical and Pharmaceutical Development, Research and Development, Bayer AG, Beijing 100020, China.

Chemical and Pharmaceutical Development, Research and Development, Bayer AG, 42096 Elberfeld, Germany

* To whom correspondence should be addressed: Prof. Feng Qian: [email protected], Tel: 86-10-62794733

Manuscript for Molecular Pharmaceutics

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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract figure.

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Abstract

Amorphous solid dispersion (ASD) is one of the most versatile supersaturating drug delivery systems to improve the dissolution rate and oral bioavailability of poorly water soluble drugs. PVP based ASD formulation of nimodipine (NMD) has been marketed and effectively used in clinic for nearly 30 years, yet the mechanism by which PVP maintains the supersaturation and subsequently improves the bioavailability of NMD was rarely investigated. In this research, we first studied the molecular interactions between NMD and PVP by solution NMR using CDCl3 as the solvent, and drug-polymer Flory-Huggins interaction parameter. No strong specific interaction between PVP and NMD was detected in the non-aqueous state. However, we observed that aqueous supersaturation of NMD could be significantly maintained by PVP, presumably due to the hydrophobic interactions between the hydrophobic moieties of PVP and NMD in aqueous medium. This hypothesis was supported by dynamic light scattering (DLS) and supersaturation experiments in the presence of different surfactants. DLS revealed the formation of NMD/PVP aggregates when NMD was supersaturated, suggesting the formation of hydrophobic interactions between the drug and polymer. The addition of surfactants, sodium lauryl sulfate (SLS) or sodium taurocholate (NaTC), into PVP maintained NMD supersaturation demonstrated different effects: SLS could only improve NMD supersaturation with concentration above its critical aggregation concentration (CAC) value, while not with lower concentration. Nevertheless, NaTC could prolong NMD supersaturation independent of concentration, with lower concentration outperformed higher concentration. We attribute these observations to PVP-surfactant interactions and the formation of PVP/surfactant complexes. In summary, despite of the lack of specific interactions in the non-aqueous state, NMD aqueous supersaturation in the presence of PVP was attained by hydrophobic interactions between the hydrophobic moieties of NMD and PVP. This hydrophobic interaction could be disrupted by surfactants, which interact with PVP competitively, thus hinder the capability of PVP to maintain NMD supersaturation. Therefore, caution is needed when evaluating such ASDs in vitro and in vivo when various surfactants are present either in the formulation or in the surrounding medium.

Keywords

Nimodipine; amorphous solid dispersion; surfactant; sodium lauryl sulfate; sodium taurocholate; supersaturation;

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Introduction

The common use of combinatory chemistry and high-throughput screening strategies in drug discovery process facilitated the selection and nomination of numerous poorly water soluble drugs with increasing molecular weight and hydrophobicity1, 2. The clinical use of poorly water-soluble pharmaceutical candidates is limited due to the low aqueous solubility, low dissolution rate, as well as the consequently poor and unstable bioavailability3. Various of formulation strategies have been developed to overcome the challenges of low solubility, such as amorphous solid dispersion (ASD), nanosizing, salt formation, cocrystal and self-emulsification drug delivery systems, enabling better bioavailability of these APIs4, 5. The fast dissolution of API in these formulation approaches would generally induce the supersaturation state of API. To improve the oral bioavailability of API, it is necessary to maintain the supersaturation state for a sufficient period of time to achieve an adequate amount of absorption4-6. However, it is challenging to prolong the supersaturation state of API since the supersaturated API tends to precipitate out or recrystallize thermodynamically5, 7. ASD, a formulation where the drug molecules are dispersed in polymer matrix in amorphous state, is a very promising oral solid formulation strategy to improve API bioavailability by overcoming the poor solubility and dissolution rate8-10. In ASD, drug molecules disperse in polymer matrix in amorphous state8, 9. The hydrophilic polymer plays an important role in the dissolution of ASD by increasing the initial dissolution rate and maintaining the supersaturation state of API. The previous work found that the interaction between API and polymer was a decisive factor controlling faster initial dissolution rate and higher supersaturation degree for longer time to enhance the dissolution performance of ASD 6, 11. Surfactants are also widely used excipients in ASD, which increase the wettability and the apparent aqueous solubility of poorly-water soluble compounds, resulting in better release of drug from the tablets12-15, or to improve the processability when used as plasticizers during hot melt extrusion16. Although addition of surfactants often improves the dissolution rate of ASDs 12, 17, the role of surfactants on drug supersaturation varies depending on the drugs and polymers involved6, 16, 18-21. Nimodipine (NMD), a BCS II drug with very low aqueous solubility22, was used as a model drug in this study to investigate the mechanism of PVP maintained supersaturation, as well as the role of surfactants during the PVP mediated supersaturation process. The marketed product of NMD is formulated into ASD with PVP23. In our research, we observed 4


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that despite the absence of strong specific interaction between NMD and PVP in the solid or non-aqueous state, PVP could still effectively maintain the aqueous supersaturation of NMD. To identify the mechanism, sodium lauryl sulfate (SLS) and sodium taurocholate (NaTC), two anionic surfactants were introduced as probes, to assess their impact on the supersaturation of NMD. SLS is used in many marketed formulations, such as Kalydeco, a spray dried ASD formulation9, 24

. NaTC is one of the commonly used bile salts, a class of biological surfactants crucial for in vivo digestion and

absorption, as well as for solubilization of lipophilic drugs25-30. We demonstrated that hydrophobic interactions between NMD and PVP appeared to be the key mechanism for PVP mediated NMD supersaturation in aqueous medium, which could be sensitively affected by the presence and types of surfactants.

Materials and Methods Materials Nimodipine (NMD) was kindly provided by Bayer AG. Sodium lauryl sulfate (SLS) (Kolliphor SLS Fine) was provided by BASF Chemical Company Ltd. (Ludwigshafen, Germany). All buffer salts used for dissolution media, as well as DMSO used for solvent in the supersaturation experiment were obtained from Beijing Chemical Works (Beijing, China). Sodium taurocholate (NaTC) was obtained from Sigma-aldrich (USA). The chemical structure and key physiochemical properties of NMD, PVP, SLS, and NaTC are summarized in Figure 1.

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Figure 1. Chemical structure of nimodipine (NMD), PVP, SLS, and NaTC

Characterization of the drug-polymer interactions in non-aqueous state 1.

Drug-polymer Flory-Huggins interaction parameter Crystalline NMD and PVP (40/60, w/w) mixtures were cryomilled at 10 Hz for 10 min before annealing at different

temperatures for 4 h to achieve equilibrium. The mixture was then scanned at 10°C/min to detect any residual crystals. The solubilization temperature was determined as the lowest temperature where no crystalline NMD was detected. The Flory-Huggins interaction parameter between PVP and NMD, i.e., the χ value, was then obtained by a previously reported Flory-Huggins data fitting method 31. 2.

Solution Nuclear Magnetic Resonance (NMR) Solution NMR using CDCl3 as the solvent was used to reveal the molecular mechanism of drug-polymer

interactions. Different amounts of NMD, and NMD/PVP mixtures (100/0, 50/50, 33.3/66.7, 25/75 and 20/80, w/w) were dissolved in in CDCl3, and the

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C NMR and 1H NMR spectra were obtained at room temperature (Bruker AV-400,

Bruker BioSpin GmbH, Rheinstetten, Germany). Aqueous solubility of crystalline NMD in different dissolution media Aqueous solubility of crystalline NMD in PBS solution in the presence of either PVP, SLS or NaTC was determined by the addition of excess amount of crystalline NMD in the dissolution media, followed by sonication for 30 min, and then shaking using an orbital shaker (37 °C, Burrell wrist action shaker, model 75) for 24h. The suspension was then centrifuged twice at 13,000 rpm for 3 min, and the drug concentration in the clear supernatant was determined by HPLC/UV−vis. The concentration of PVP was 0.2 mg/mL, the concentration of SLS was 0.2 mM, 1.0 mM, or 1.5 mM, and the concentration of NaTC was 0.5 mM and 3 mM. Supersaturation of NMD in presence of excipients The effect of different excipients and their combination on the supersaturation of NMD was investigated. In all the experiments, the polymer or/and the surfactant were dissolved in PBS solution (pH=6.5) first. The concentrations of the excipients, including PVP, SLS and NaTC, were maintained the same as the solubility measurement described in the previous section. A 20 mg/mL NMD solution was prepared in DMSO. In each 20 mL of various dissolution media, 50 µL 6


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of the NMD DMSO solution was added, thus the initial concentration of NMD in the dissolution medium was 50 µg/mL. The solution was then vibrated at 100 rpm with a shaker (37 °C, Burrell wrist action shaker, Model 75), and 0.3 mL of each dissolution media was obtained at 15, 30, 60, 120, 240 min and centrifuged at 13,000 rpm for 3 min (n=3). The obtained clear supernatant was analyzed by HPLC/UV−vis (Shimadzu LC-20AT; Kyoto, Japan) for the determination of drug concentration. During this supersaturation study, the precipitates were also investigated by polarizing microscope. Supersaturation parameter, a dimensionless parameter defined earlier to describe the extent of drug supersaturation

32

,

was determined to compare the NMD supersaturation behavior in different media. Another parameter, the supersaturation ratio was used to quantify the degree of supersaturation was defined below:

=

(1)

where S is the supersaturation ratio, C is drug concentration in the dissolution medium, and Ceq is the equilibrium solubility of the crystalline drug in the dissolution medium. Particle size measurement in the supersaturated solution by dynamic light scattering Dynamic Light Scattering (DLS) was employed to measure the particle size of the sub-visible aggregates in the supersaturated solution. The supersaturated NMD PBS solution in the presence or absence of PVP were compared. Samples were obtained at 30 min during the supersaturation study, centrifuged at 13,000rpm for 10 min, and the clear supernatant was analyzed by DLS (DynaPro Plate Reader III, Wyatt Technology Corporation, U.S.A., radius range: 0.2-2500 nm) to measure the particle size of any sub-visible aggregates. Characterization of the surfactant-polymer interactions in aqueous solution 1.

Fluorescence spectroscopy method to study the CMC/CAC of surfactant/polymer solution. The critical micelle concentration (CMC) of surfactant solution and the critical aggregation concentration (CAC) of

the surfactant/PVP solution were determined by a fluorescence spectroscopy method using a FS5 Spectrofluorometer (Edinburgh Instruments Ltd, UK) spectrometer33. Pyrene, a commonly used hydrophobic fluorescent probe, was used at 1.0 µM in the media to detect the environmental change because of its two sensitive characteristic excitation peaks. The excitation wavelength was 334 nm and the intensity ratio between 372 and 383 nm emission peaks was used to characterize the polarity change in solution33. The intensity ratio was measured as a function of the SLS concentration in 7



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PBS (pH=6.5) for CMC determination. For CAC determination, a fixed PVP concentration of 200µg/mL was presence. 2.

Solution Nuclear Magnetic Resonance (NMR) Molecular interactions between PVP and SLS or PVP and NaTC in aqueous environment were characterized by

solution NMR (Bruker AV-400, Bruker BioSpin GmbH, Rheinstetten, Germany). Surfactant, polymer and surfactant/polymer mixtures were dissolved in deuterium water. The concentration of SLS, NaTC and PVP was 20 mg/mL, 40 mg/ mL and 80 mg/mL, respectively, for NMR analysis. Their

13

C NMR spectra were obtained at room

temperature with an operating frequency of 400 MHz.

Results and Discussion Molecular interaction between NMD and PVP in non-aqueous state 1.

Drug-polymer interaction parameter Drug-polymer interaction was proved to be crucial for supersaturation maintenance during the dissolution of ASDs.

Flory-Huggins interaction parameter (χ) and solution NMR were used in this study to qualitatively determine the interaction between NMD and PVP in ASDs. The Flory-Huggins interaction parameter is a constant thermodynamic value determined by the chemical structures of the drug and the polymer

8, 34

. A negative χ indicates that drug-polymer

interaction is stronger than the drug-drug, or polymer-polymer interaction, thus the system is completely miscible8, 34. The melting onset of NMD was 396.15K and the solubilization temperature of NMD in presence of 60wt% PVP was measured to be 388.15 K (DSC traces not shown), the χ value between PVP and NMD was then calculated to be 0.21. This positive χ value indicates that there is no strong attractive interaction between NMD and PVP in non-aqueous state, consistent with our earlier finding35. The later NMR spectra also demonstrated that no specific interaction between NMD and PVP could be observed in the non-aqueous state. 2.

Solution NMR investigation of the specific interaction between drug and polymer Solution NMR was used to investigate the molecular interaction between NMD and PVP. 1H NMR spectra and 13C

NMR spectra of NMD and NMD/PVP in CDCl3 were obtained and shown in Figure 2. Chloroform has relatively similar permittivity as air (i.e., ~4.8 for chloroform, ~1 for air, ~80 for water) thus provides a non-aqueous environment similar as air for drug and polymer to interact with each other. The –NH group chemical peak shifts in the 1H NMR spectra of 8


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different concentration of NMD (Figure 2A and 2B) could either be attributed to a potential intermolecular H-bonding interaction between –NH and -C=O groups on NMD, or to any other non-specific interactions caused by volume effects. To further confirm, we collected the 13C NMR spectra of the same samples (Figure 2C and 2D), where no -C=O chemical peak shifts were observed. This finding indicated that specific intermolecular interaction between NMD molecules was unlikely to exist. Similarly in the PVP/NMD mixtures, while increasing the PVP/NMD ratio causes similar downfield shift on –NH group (Figure 2E and 2F), 13C NMR spectra of the same samples (Figure 2G and 2H) showed that no –C=O chemical peak shifts, again inferring that no H-bonding interaction exists between NMD and PVP. Based on the above NMR results, we conclude that no strong specific molecular interaction existed between NMD molecule themselves or between NMD and PVP in non-aqueous state. It worth noting that, this does not exclude the possibility of any non-specific interactions between these molecules, although such interaction between NMD and PVP is likely to be weak, due to the positive Flory-Huggins interaction parameter between them as determined by the melting depression method earlier.

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Figure 2. (A) 1H NMR spectra of NMD with different concentrations; (B) Range from 6.5 to 5. 5 of (A); (C) 13C NMR spectra of NMD with different concentrations; (D) Range from 180 to 165 of (C); (E) 1H NMR spectra of NMD/PVP dissolved in CDCl3 with different ratios; (F) Range from 6.5 to 5. 5 of (E). (G) 13C NMR spectra of NMD/PVP dissolved in CDCl3 with different ratios. (H) Range from 180 to 165 of (G).

Supersaturation of NMD in the presence of PVP The solubility of crystalline NMD in PBS with and without PVP (200 µg/mL) was determined to be 1.18±0.06 and 1.37±0.10 µg/mL, respectively, i.e., the presence of PVP hardly changed the solubility of crystalline NMD. However, PVP does help to prolong the supersaturation of solution NMD, as shown in Figure 3A. Without PVP, the concentration of NMD decreased sharply from the initial concentration of 50 µg/mL (~40 fold supersaturation) to about 10 µg/mL within 15 min. The concentration of NMD kept decreasing to its solubility in the next 4 h. However, in presence of PVP, the concentration of NMD remained above 20 µg/mL for the first 2 h, and the calculated supersaturation parameter in this case was 0.36. The supersaturation degree was maintained at ~10 even after 4 h.

Figure 3. (A) Supersaturation profile of NMD in the absence/presence of PVP (n=3); B. Supersaturation of NMD in the presence or absence of PVP observed under PLM.

PLM was used to detect any micron-sized particles formed in the supersaturation solution. Figure 3B shows that, without PVP, a small amount of crystalline NMD was observed at the beginning of the supersaturation experiment. Larger amount of crystalline NMD with growing size was observed within 1 h, which indicated the continuous precipitation and crystallization of NMD from the supersaturated solution. By contrast, with the existence of PVP, only trace amount of crystalline NMD was observed until 1 h. PLM did not detect any spherical/transparent oily droplets either, which might have indicated liquid-liquid phase separation. 11



Overall, the above results suggested that although there was no strong specific molecular interaction between PVP and NMD, PVP could still maintain the supersaturation of NMD by inhibiting the crystallization of NMD. Particle size measurement of the supersaturated solution Although no observable particles were detected by PLM in the PVP maintained NMD supersaturation, we hope to confirm if there were any sub-visible aggregates in the supersaturation state using dynamic light scattering (DLS). Figure 4 shows the particle size and polydispersity of a pure PVP solution (200 µg/mL), as well as those of the NMD/PVP aggregates in the supersaturated NMD solution in presence PVP. The pure PVP has a mean radius of 8.88 nm and a dispersed molecular weight distribution with a percentage of polydispersity of 46.4. While in the presence of NMD, two sub-visible particle populations with mean radius of 6.09 nm and 63.7 nm respectively, were detected. We attribute the 6.09 nm population to pure PVP, while the larger 63.7 nm population to NMD/PVP aggregates. It’s worth noting that, in supersaturated NMD solution without PVP, no sub-visible particles were detected after removing the NMD crystalline precipitates by centrifugation (data not shown).

Figure 4. Particle size and the polydispersity of (A) PVP particles in pure 200 µg/mL solution; B. PVP/NMD aggregates in the supersaturation solution (NMD with 200 µg/mL PVP) at 30 min. No sub-visible particles were detected after removing of the NMD crystalline precipitates in the supersaturation of NMD without PVP.

Surfactant-polymer interaction in aqueous solution If hydrophobic interaction contributed to the PVP mediated supersaturation, surfactants would be able to affect this process. Therefore, we employed SLS and NaTC to investigate the impact of surfactants on the supersaturation of NMD 12


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in the presence or absence of PVP. The interaction between surfactant and polymer was studied to determine the amount of surfactants needed in the supersaturation experiment. 1.

CMC/CAC value of surfactant and surfactant/PVP CAC is defined as the onset concentration of micelle formation on a certain concentration of polymer, indicating

the attachment of micelle-like aggregates of the surfactant to the polymer chain

13, 14, 18

. Below the CAC value, the

unstable association between surfactant and polymer occurs, while above the CAC value, the association between surfactant and polymer becomes stable, which leads the formation of polymer/surfactant micelle 36. As shown in Figure 5, the CMC/CAC values of the SLS and PVP (200 µg/mL)/SLS were 2.75 and 1.0 mM, respectively. SLS was reported to strongly interact with PVP through hydrophobic interaction18, 37. The hydrophobic interaction exists between the hydrophobic chain of SLS and the hydrophobic segments of polymers, which allows more SLS in the bulk solution rather than on the solution surface, leading to a lower CAC value compared with the CMC value38, 39. For NaTC, the CMC value was 11.75 mM and the CAC value of PVP (200 µg/mL)/NaTC remained the same, indicating the absence of strong PVP/NaTC interactions. This was also supported by the 13C NMR spectra of NaTC/PVP in deuterium water, as discussed later.

Figure 5. CMC/CAC values of surfactant and surfactant/PVP (200 µg/mL): (A) SLS; (B) NaTC.

2.

Solubility of crystalline NMD in solutions containing different surfactants and surfactant/PVP combinations We then measured the aqueous solubility of crystalline NMD in different solutions containing different surfactants,

or PVP/surfactant combinations as summarized in Table 1. The addition of SLS up to 1.5 mM into the PBS did not 13



improve the aqueous solubility of NMD. However, with the addition of NaTC, solubility of NMD was doubled. The combined use of PVP and SLS led to different results depending the concentration used: no enhancement in the solubility of crystalline NMD was observed below or at the CAC value (Figure 5A), while the combination of 1.5 mM SLS and PVP significantly promote the solubility of crystalline NMD due to the formation of PVP/SLS micelle above CAC, where the solubility increased ~ 3 times compared that in the PVP or SLS only solution. In contrast, the combination use of NaTC/PVP, regardless the ratio and concentrations, failed to improve the solubility of crystalline NMD. These observations are consistent with the different surfactant/PVP interaction behaviors as reported earlier.

Table 1. Aqueous solubility of crystalline NMD in PBS, at pH 6.5, with the presence of PVP and/or SLS or NaTC with different concentrations (n=3).

3.

Dissolution Medium

Solubility of NMD (µg/mL)

PBS

1.18±0.06

200 µg/mL PVP

1.37±0.10

0.2 mM SLS

1.16±0.13

1.0 mM SLS

1.58±0.05

1.5 mM SLS

1.58±0.12

0.2 mM SLS+200 µg/mL PVP

1.55±0.20


1.03±0.23


3.74±0.26

0.5 mM NaTC

2.27±0.10

0.5 mM NaTC+200 µg/mL PVP

2.49±0.07

3 mM NaTC

2.34±0.08

3 mM NaTC+200 µg/mL PVP

2.33±0.03

Solution NMR Furthermore, 13C NMR was employed to investigate the specific interaction in SLS/PVP and NaTC/PVP systems in

deuterium water. Table 2 and Table 3 listed the significant chemical peak shifts (>0.08 ppm) in the two 13C NMR spectra. No chemical peak shifts were observed in their 1H NMR spectra (data not shown here). For SLS/PVP system, significant 14


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chemical peak shifts on Cb of PVP and C12 of SLS were observed, which was attributed to the hydrophobic interaction, similarly as previous observations

39-41

. For NaTC/PVP system, the chemical peak shifts on the NaTC molecules were

negligible (generally

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