Hydroxypropyl Methylcellulose Mediated Precipitation Inhibition of Sirolimus: From a Screening Campaign to a Proof-of-Concept Human Study

Abstract

The aim of this study was to develop a sirolimus (BCS class II drug substance) solid oral dosage form containing a precipitation inhibitor, which would result in an improved sirolimus absorption in humans compared to the formulation containing nanosized sirolimus without a precipitation inhibitor, i.e., Rapamune. The selection of the precipitation inhibitor was based on the results of a screening campaign that identified two "hit" excipients: HPMC 603 (i.e., Pharmacoat 603) and Poloxamer 407. However, in a confirmatory precipitation inhibitor study using biorelevant media (Fa/FeSSIF) HPMC 603 more effectively inhibited sirolimus precipitation than Poloxamer 407. In the PAMPA assay, HPMC 603, but not Poloxamer 407, significantly increased the flux of the sirolimus across the membrane lipid layer. Additionally, a differential scanning calorimetry (DSC) and an infrared (IR) spectroscopy study revealed that interactions between the sirolimus and HPMC 603 were developed that could lead to the observed precipitation inhibition effect. Based on the above data, two formulations with HPMC 603-coated sirolimus particles were developed, namely, formulation A (d (0.5) = 0.21 μm) and formulation B (d (0.5) = 1.7 μm). A human pharmacokinetic study outlined that significantly higher AUC and Cmax were obtained for formulations A and B in comparison to Rapamune. This result could be attributed to the HPMC 603 (Pharmacoat 603) mediated sirolimus precipitation inhibition resulting in improved sirolimus absorption from the gastrointestinal tract in humans.

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

“…Solid dispersions of HPMC and sirolimus demonstrated significant variation from the neat samples as well as a physical blend. Specifically, the sirolimus peaks at 1680–1640 cm −1 (C=C) and 1760–1670 cm −1 (C=O) in the solid dispersion were far broader than those from the pure drug, which the authors concluded was a result of interaction between the two species . This interaction was suggested to be partly responsible for the two‐fold increase in supersaturation and dissolution in the sirolimus‐HPMC solid dispersion vs the commercially available Rapamune ® nanoparticles.…”

“…Petrusevska and colleagues also employed FTIR spectroscopy to investigate the mechanism of interactions between a successful API‐PI formulation: sirolimus and HPMC . Solid dispersions of HPMC and sirolimus demonstrated significant variation from the neat samples as well as a physical blend.…”

“…In a subsequent human pharmacokinetic study, the novel formulation significantly outperformed the commercial formulation. This effect was attributed to the enhanced precipitation inhibition properties of HPMC in the novel formulation …”

Self-Emulsifying Granules and Pellets: Composition and Formation Mechanisms for Instant or Controlled Release

“… Abbreviations: n.c.: Non classified; n.a. : Non applicable; MCC: Microcrystalline Celullose; CSD: Colloidal Silicon Dioxide; HPMC: Hydroxypropyl-methylcellulose; PVP: Polivinylpyrrolidone; BCS classification was taken from literature as follows: Progesterone, Tuleu et al 2004 [ 3 ]; Gentamicin, Ito et al 2005 [ 12 ]; Nimesulide, Mudie et al 2012 [ 73 ]; Diazepam, Wu and Bennet 2005 [ 74 ]; Ezetimibe, Taupitz et al 2013 [ 75 ]; Griseofulvin, Lindenberg et al 2010 [ 76 ]; Candesartan Cilexetil, Nekkanti et al 2009 [ 67 ]; Nitrendipine, Takano et al 2006 [ 77 ]; Tetrahydrocurcumin, Wahlang et al 2011 [ 78 ]; Piroxicam, Shohin et al 2014 [ 79 ]; Paliperidone, Pandey et al 2013 [ 80 ]; Sirolimus, Petruševska et al 2013 [ 81 ]; Carbamazepine, Wu and Bennet 2005 [ 74 ]; Puerarin, Li et al 2015 [ 82 ]; Cilostazol, Jinno et al 2006 [ 83 ]; Lercaniditine, Non-classified; Repaglinide, Gao et al 2013 [ 84 ]; Ondansetron, Beg et al 2013 [ 53 ]; Atorvastatin calcium, Wu and Bennet 2005 [ 74 ]; Olmesartan medoxomil, Patel et al 2014 [ 34 ]; Ibuprofen, Cristofoletti and Dressman 2017 [ 85 ]; Furosemide, Vogelpoel et al, 2010 [ 86 ]; Propranolol, Granero et al 2010 [ 87 ]; Oleanolic acid, Tong et al 2011 [ 88 ]; Simvastatin, Jiang et al 2012 [ 60 ]; Glipizide, Zur et al 2015 [ 89 ]; Celecoxib, Yazdanian et al 2005 [ 90 ]; Lercanidipine, Suthar et al 2016 [ 54 ]; LogP values were taken from ref. [ 91 ].…”

Enhanced Supersaturation and Oral Absorption of Sirolimus Using an Amorphous Solid Dispersion Based on Eudragit® E

“…reported that HPMC effectively created a desired microenviroment that both maintained a supersaturated solution and prevented sirolimus precipitation [10]. In addition, it was observed that in vitro supersaturated dissolution data strongly correlated with in vivo pharmacokinetic parameters [9,10]. In fact, the oral bioavailability of sirolimus can be improved by enhancing in vitro supersaturation via an amorphous solid dispersion.…”