2-Hydroxypropyl-β-cyclodextrin

(2-Hydroxypropyl)-β-cyclodextrin is a widely used drug delivery vehicle to improve the stability and bioavailability.

In Vitro:Cell treatment with (2-Hydroxypropyl)-β-cyclodextrin results in the activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and in enhancement of the cellular autophagic clearance capacity[1]. (2-Hydroxypropyl)-β-cyclodextrin treatment reduces intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. The IC50 values for (2-Hydroxypropyl)-β-cyclodextrin after 72 hours exposure are in the range of 3.86–10.09 mM. (2-Hydroxypropyl)-β-cyclodextrin also shows anticancer effects against CML cells expressing a T315I BCR-ABL mutation (that confers resistance to most ABL tyrosine kinase inhibitors), and hypoxia-adapted CML cells that have characteristics of leukemic stem cells. In addition, colony forming ability of human primary AML and CML cells is inhibited by (2-Hydroxypropyl)-β-cyclodextrin[2].

In Vivo:(2-Hydroxypropyl)-β-cyclodextrin administration promotes transcription factor EB-mediated clearance of proteolipid aggregates that accumulate due to inefficient activity of the lysosome-autophagy system in cells derived from a patient with a lysosomal storage disorder[1]. Intraperitoneal injection of (2-Hydroxypropyl)-β-cyclodextrin significantly improves survival in leukemia mouse models. Systemic administration of (2-Hydroxypropyl)-β-cyclodextrin to mice has no significant adverse effects[2].

References:
[1]. Song W, et al. 2-Hydroxypropyl-β-cyclodextrin promotes transcription factor EB-mediated activation of autophagy: implications for therapy. J Biol Chem. 2014 Apr 4;289(14):10211-22. [2]. Yokoo M, et al. 2-Hydroxypropyl-β-Cyclodextrin Acts as a Novel Anticancer Agent. PLoS One. 2015 Nov 4;10(11):e0141946.

Exploring the interactions of irbesartan and irbesartan-2-hydroxypropyl-beta-cyclodextrin complex with model membranes.[Pubmed:28274845]

Biochim Biophys Acta Biomembr. 2017 Jun;1859(6):1089-1098.

The interactions of irbesartan (IRB) and irbesartan-2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) complex with dipalmitoyl phosphatidylcholine (DPPC) bilayers have been explored utilizing an array of biophysical techniques ranging from differential scanning calorimetry (DSC), small angle X-ray scattering (SAXS), ESI mass spectrometry (ESI-MS) and solid state nuclear magnetic resonance (ssNMR). Molecular dynamics (MD) calculations have been also conducted to complement the experimental results. Irbesartan was found to be embedded in the lipid membrane core and to affect the phase transition properties of the DPPC bilayers. SAXS studies revealed that irbesartan alone does not display perfect solvation since some coexisting irbesartan crystallites are present. In its complexed form IRB gets fully solvated in the membranes showing that encapsulation of IRB in HP-beta-CD may have beneficial effects in the ADME properties of this drug. MD experiments revealed the topological and orientational integration of irbesartan into the phospholipid bilayer being placed at about 1nm from the membrane centre.

Complexation of oxethazaine with 2-hydroxypropyl-beta-cyclodextrin: increased drug solubility, decreased cytotoxicity and analgesia at inflamed tissues.[Pubmed:28211640]

J Pharm Pharmacol. 2017 Jun;69(6):652-662.

OBJECTIVES: Oxethazaine (OXZ) is one of the few local anaesthetics that provides analgesia at low pH, but presents poor solubility, cytotoxicity and no parenteral formulations. To address these issues, we aimed to prepare OXZ host-guest inclusion complex with hydroxypropyl-beta-cyclodextrin (HP-beta-CD). METHODS: The inclusion complex was formed by co-solubilization, followed by a job plot analysis to determine stoichiometry of complexation and dialysis equilibrium analysis (based on UV/VIS absorption and fluorescence profiles of OXZ). Complex formation was confirmed by phase-solubility data, X-ray, Scanning Electron Microscopy and DOSY-(1) H-NMR experiments. In vitro cytotoxicity was analysed by MTT test in 3T3 fibroblasts. In vivo analgesia was tested by Von Frey test (inflammatory wounds - rats). KEY FINDINGS: Oxethazaine complexed (1 : 1 molar ratio) with HP-beta-CD, as indicated by loss of OZX crystalline structure (X-ray) and strong host: guest interaction (NMR, K = 198/M), besides increased solubility. In vitro cell survival improved with the complex (IC50 OXZ = 28.9 mum, OXZ : HP-beta-CD = 57.8 mum). In addition, the complex (0.1% OXZ) promoted in vivo analgesia for the same time that 2% lidocaine/epinephrine did. CONCLUSION: Our results show that complexation improved physicochemical and biological properties of OXZ, allowing its application to inflamed tissues by parenteral routes.

Early experience with compassionate use of 2 hydroxypropyl-beta-cyclodextrin for Niemann-Pick type C disease: review of initial published cases.[Pubmed:28155026]

Neurol Sci. 2017 May;38(5):727-743.

Niemann-Pick type C (NP-C) is a rare neurodegenerative disorder. Management is mainly supportive and symptomatic. The investigational use of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) showed a promising role in treating NP-C, although efficacy and safety have not been established. We conducted searches of MEDLINE, Cochrane, EMBASE, and other databases of reported cases of HP-beta-CD compassionate use in NP-C disease. Sixteen reported cases were eligible, including evaluable information of 17 patients. The median onset age of HP-beta-CD was 14 years (range 2-49 years). Intrathecal route was employed in 16 patients, in 3 patients simultaneously to IV infusions. Intracerebroventricular route was used in two patients. An objective improvement of clinical outcomes was measured in 14 patients, mainly by the NIH NP-C Clinical Severity Score and brainstem auditory evoked potential. Besides, an increase in metabolism and activities of the brain were observed in image tests and cholesterol biomarkers. Most patients showed some clinical benefit or a stabilization of NP-C progression. There were 17 adverse events (AEs) reported in 11 patients, 11 of them related to the drug and 6 to the route of administration. Loss of hearing was reported in four patients. The most severe AE were fever and chemical meningitis. Results suggest that efficacy may be partial and dependent on the early administration of the drug, the severity of the disease, and interpersonal variability. HP-beta-CD could help stabilize NP-C with low toxicity potential, although some AEs have been reported. Moreover, controlled clinical trials would be necessary to evaluate the role of HP-beta-CD in NP-C.

Nano-precipitated curcumin loaded particles: effect of carrier size and drug complexation with (2-hydroxypropyl)-beta-cyclodextrin on their biological performances.[Pubmed:28130197]

Int J Pharm. 2017 Mar 30;520(1-2):21-28.

In this work, curcumin (CURC)-encapsulating nanoparticles (NPs), made up of an amphiphilic blend of poloxamers and PLGA (PPC NPs) at different polymer concentrations, were prepared by nanoprecipitation. CURC was preliminarily complexed with (2-hydroxypropyl)-beta-cyclodextrin (HPbetaCD) to improve its loading efficiency. The formation of host-guest complexes of CURC with HPbetaCD (CD-CURC) was confirmed by means of (1)HNMR studies and differential scanning calorimetry (DSC). Nanoprecipitation allowed to obtain NPs with a small size (90-120nm depending on the polymer concentration), a narrow size distribution and stable in water for 30days at 4 degrees C and in RPMI-1640 cell culture medium up to 72h at 37 degrees C. The in vitro release of CD-CURC, sustained up to 5days, was governed mainly by a diffusive mechanism. It was also found that the produced NPs were efficiently internalized by mesothelioma cells (MSTO-211H) in the cytoplasmic space, at an extent strongly dependent on NP size and polydispesity index, therefore pointing at the importance of NP preparation method in improving their uptake.

The effects of cyclodextrins on the disposition of intravenously injected drugs in the rat.[Pubmed:2052529]

Pharm Res. 1991 Mar;8(3):380-4.

Naproxen and flurbiprofen form complexes with hydroxypropyl-beta-cyclodextrin; with stability constants of 2207 and 12515 M-1, respectively. However, only small fractions of the drug remain complexed when the drug-cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-beta-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.