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Nimodipine Ophthalmic Formulations for Management of Glaucoma

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Abstract

Purpose

Preparation and evaluation of topical ophthalmic formulations containing nimodipine-CD complexes prepared using HP-β-CD, SBE-β-CD and M-β-CD for the management of glaucoma.

Methods

Nimodipine-CD complexes were prepared using a freeze-drying method. Two different molar ratios (NMD:CD) were used for each cyclodextrin. The inclusion complexes were characterized using DSC, FTIR, yield (%), drug content and in vitro release characteristics. NMD-CD complexes incorporated into chitosan eye drops and a temperature-triggered in situ gelling system were evaluated for their pH, viscosity and in vitro release characteristics. We determined the intraocular pressure (IOP) lowering effect of NMD-hydroxypropylmethylcellulose (HPMC) eye drops through a single dose response design using C57BL/6J mice. The minimum effective concentration (MEC) of nimodipine was further applied to mice that vary in the parental allele of Cacna1s, the drug target of nimodipine. Cytotoxicity was also evaluated.

Results

Our ophthalmic formulations possessed pH and viscosity values that are compatible with the eye. In vitro release of nimodipine was significantly increased from chitosan eye drops containing NMD-CD complexes compared to uncomplexed drug. Administration of nimodipine can lower IOP significantly after a single drop of drug HPMC suspension. The IOP-lowering response of the MEC (0.6%) was significantly influenced by the parental allele of Cacna1s.

Conclusions

Nimodipine can be used as a promising topical drug for management of glaucoma through ocular delivery.

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Abbreviations

AUCtotal :

Total area under the IOP reduction (%)-versus-time curve

B6:

C57BL/6J

Cacna1s :

Calcium voltage-gated channel subunit alpha1s

CCBs:

Calcium-channel blockers

CD:

Cyclodextrin

CE:

Complexation efficiency

DMSO:

Dimethyl sulfoxide

DSC:

Differential scanning calorimetry

EMEM:

Eagle’s minimal essential medium

FTIR:

Fourier transform infrared spectroscopy

HPMC:

Hydroxypropylmethylcellulose

HP-β-CD:

Hydroxypropyl-β-cyclodextrin

IOP:

Intraocular pressure

Kc :

Binding or stability constant

MEC:

Minimum effective concentration

MTT:

Methyl thiazol tetrazolium

M-β-CD:

Methyl-β-cyclodextrin

PBS:

Phosphate buffered saline

PEG 300:

Poly (ethylene glycol, Mn 300)

PM:

Physical mixture

R:

Universal gas constant

S0 :

Aqueous solubility of the drug in the absence of cyclodextrin

SBE-β-CD:

Sulfobutyl ether-β-cyclodextrin

SEM:

Scanning electron microscopy

SLS:

Sodium lauryl sulfate

T:

Experimental operating temperature (Kelvin)

Tend :

Time required for IOP to return again to its baseline

Tmax :

Time required to reach maximum decrease in IOP

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ACKNOWLEDGEMENTS AND DISCLOSURES

This study was supported by an unrestricted grant from Research to Prevent Blindness (New York, NY), a grant from the Knights Templar Eye Foundation, and a grant from the Egyptian Government Joint Supervision Program. We thank Dr. Soumyajit Majumdar (Department of Pharmaceutics and Drug Delivery, University of Mississippi) for his assistance in generating the DSC and FTIR data. We also thank Dr. Joel Bumgardner (Department of Biomedical Engineering, The University of Memphis) for the use of his viscometer.

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Authors and Affiliations

  1. Department of Ophthalmology, Hamilton Eye Institute, The University of Tennessee Health Science Center, 930 Madison Avenue, Suite 731, Memphis, Tennessee, 38163, USA

    Doaa Nabih Maria & Monica M. Jablonski

  2. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Doaa Nabih Maria & Monica M. Jablonski

  3. Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Doaa Nabih Maria, Abd-Elgawad Helmy Abd-Elgawad, Osama Abd-Elazeem Soliman & Marwa Salah El-dahan

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  1. Doaa Nabih Maria
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  2. Abd-Elgawad Helmy Abd-Elgawad
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  3. Osama Abd-Elazeem Soliman
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  5. Monica M. Jablonski
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Correspondence to Monica M. Jablonski.

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Maria, D.N., Abd-Elgawad, AE.H., Soliman, O.AE. et al. Nimodipine Ophthalmic Formulations for Management of Glaucoma. Pharm Res 34, 809–824 (2017). https://doi.org/10.1007/s11095-017-2110-x

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  • DOI: https://doi.org/10.1007/s11095-017-2110-x

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