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. 2022 Apr 7;14(4):816.
doi: 10.3390/pharmaceutics14040816.

Non-Effective Improvement of Absorption for Some Nanoparticle Formulations Explained by Permeability under Non-Sink Conditions

Kazuya Sugita  1   2 , Noriyuki Takata  2 , Etsuo Yonemochi  1
Affiliations

Non-Effective Improvement of Absorption for Some Nanoparticle Formulations Explained by Permeability under Non-Sink Conditions

Kazuya Sugita et al. Pharmaceutics. .

Abstract

We evaluated the in vitro permeability of nanoparticle formulations of high and low lipophilic compounds under non-sink conditions, wherein compounds are not completely dissolved. The permeability of the highly lipophilic compound, griseofulvin, was improved by about 30% due to nanonization under non-sink conditions. Moreover, this permeability was about 50% higher than that under sink conditions. On the other hand, for the low lipophilic compound, hydrocortisone, there was no difference in permeability between micro-and nano-sized compounds under non-sink conditions. The nanonization of highly lipophilic compounds improves the permeability of the unstirred water layer (UWL), which in turn improves overall permeability. On the other hand, because the rate-limiting step in permeation for the low lipophilic compounds is the diffusion of the compounds in the membrane, the improvement of UWL permeability by nanonization does not improve the overall permeability. Based on this mechanism, nanoparticle formulations are not effective for low lipophilic compounds. To accurately predict the absorption of nanoparticle formulations, it is necessary to consider their permeability under non-sink conditions which reflect in vivo conditions.

Keywords: absorption; lipophilicity; nanoparticle formulation; non-sink condition; permeability.

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Conflict of interest statement

K.S. and N.T. are the researchers currently employed by Chugai Pharmaceutical Co., Ltd. The funders/companies had no role: in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The molecular structure of: (a) griseofulvin; (b) hydrocortisone.
Figure 2
Figure 2
Particle size distribution (PSD) of: (a) griseofulvin samples; (b) hydrocortisone samples. The results were transformed to volume distribution. The PSD parameters for each sample are summarized in Table 1. The PSD of the nanosuspensions was measured by dynamic light scattering, where water was used as the solvent. The PSD of the microparticle samples was measured by laser diffraction size analyzer, where the saturated heptane solution of the compound containing 0.2% sorbitan monooleate was used as the solvent.
Figure 3
Figure 3
Scanning electron microscopy (SEM) image of griseofulvin samples (a–c) and hydrocortisone samples (d,e).
Figure 4
Figure 4
X-ray powder diffraction pattern of: (a) griseofulvin samples; (b) hydrocortisone samples.
Figure 5
Figure 5
Griseofulvin concentration–time profiles in: (a) the acceptor chamber; (b) the donor chamber. The results represent the average griseofulvin concentration ± SD (n = 3) for nanosuspension griseofulvin (◆), S-microparticle griseofulvin (▲) and L-microparticle griseofulvin (●).
Figure 6
Figure 6
Calculated apparent permeability (Papp) of griseofulvin. The results represent the average Papp ± SD (n = 3).
Figure 7
Figure 7
Hydrocortisone concentration–time profile in: (a) the acceptor chamber; (b) the donor chamber. The results represent the average hydrocortisone concentration ± SD (n = 3) for nanosuspension hydrocortisone (◇) and microparticle hydrocortisone (△).
Figure 8
Figure 8
Calculated Papp of hydrocortisone. The results represent the average Papp ± SD (n = 3).
Figure 9
Figure 9
Comparison of Papp of nanosuspension griseofulvin under non-sink conditions and sink conditions. The sink condition result is taken from our previous report [25]. The results represent the average Papp ± SD (n = 3). Adapted from [25], MDPI, 2021.
Figure 10
Figure 10
Calculated unstirred water layer (UWL) thickness under sink and non-sink conditions for microparticle samples and for nanosuspensions.
Figure 11
Figure 11
Calculated permeability improvement effect for microparticle and nanoparticle compounds under non-sink conditions. The permeability of model compounds ranges from Papp,sink = 0.00097 cm/min to Papp,sink = 0.029 cm/min. Papp,sink and Papp,non-sink represent the Papp under sink conditions and under non-sink conditions, respectively.
Figure 12
Figure 12
Proposed mechanism of permeability improvement by nanoparticle formulations.
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References

    1. Doak B.C., Over B., Giordanetto F., Kihlberg J. Oral druggable space beyond the rule of 5: Insights from drugs and clinical candidates. Chem. Biol. 2014;21:1115–1142. doi: 10.1016/j.chembiol.2014.08.013. - DOI - PubMed
    1. Abrahamsson B., McAllister M., Augustijns P., Zane P., Butler J., Holm R., Langguth P., Lindahl A., Müllertz A., Pepin X., et al. Six years of progress in the oral biopharmaceutics area—A summary from the IMI OrBiTo project. Eur. J. Pharm. Biopharm. 2020;152:236–247. doi: 10.1016/j.ejpb.2020.05.008. - DOI - PubMed
    1. Rosenberger J., Butler J., Muenster U., Dressman J. Application of a Refined Developability Classification System. J. Pharm. Sci. 2019;108:1090–1100. doi: 10.1016/j.xphs.2018.10.044. - DOI - PubMed
    1. Williams H.D., Trevaskis N.L., Charman S.A., Shanker R.M., Charman W.N., Pouton C.W., Porter C.J. Strategies to address low drug solubility in discovery and development. Pharmacol. Rev. 2013;65:315–499. doi: 10.1124/pr.112.005660. - DOI - PubMed
    1. Wais U., Jackson A.W., He T., Zhang H. Nanoformulation and encapsulation approaches for poorly water-soluble drug nanoparticles. Nanoscale. 2016;8:1746–1769. doi: 10.1039/C5NR07161E. - DOI - PubMed

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