Elsevier

Journal of Controlled Release

Volume 305, 10 July 2019, Pages 18-28
Journal of Controlled Release

Co-delivery of latanoprost and timolol from micelles-laden contact lenses for the treatment of glaucoma

https://doi.org/10.1016/j.jconrel.2019.05.025Get rights and content

Abstract

Glaucoma is a group of irreversible ocular diseases which result in damage to the optic nerve and vision loss. The objective of the present work was to develop micelles-laden contact lenses (CLs-M) that could achieve the sustained release of timolol and latanoprost simultaneously for the treatment of glaucoma. CLs-M were obtained by free radical polymerization of HEMA monomer with timolol and latanoprost loaded mPEG-PLA micelles. The prepared CLs-M had a minimal impact on critical CLs properties, and could release timolol and latanoprost in simulated tear fluid for 144 h and 120 h individually, which is promising for extended drugs release applications. The in vivo PK study on rabbit eyes showed sustained timolol and latanoprost release for up to 120 h and 96 h in tear fluid, respectively. There was significant improvement of the mean residence time (79.6-fold and 122.2-fold) and bioavailability (2.2-fold and 7.3-fold) for both timolol and latanoprost delivered by CLs-M compared with eye drops. An in vivo PD study in a rabbit model with high IOP showed sustained reduction in the IOP for over 168 h. The relative pharmacological availability (PA) of CLs-M was 9.8 times as high as the eye drops. The protein adsorption, ocular irritation study and histological examination study indicated the safety of CLs-M. Therefore, this work has demonstrated the promising potential of micelles-laden CLs to co-deliver timolol and latanoprost for an extended period of time to treat glaucoma.

Introduction

Glaucoma is the second leading cause of irreversible blindness after cataracts, and is projected to affect over 100 million people by 2040 [[1], [2], [3]]. It is characterized by an increase in intraocular pressure (IOP) and eventual damage of the optic nerve, fiber layer and ganglion cells. Although the pathogenesis of the disease is not fully understood, high IOP is still recognized as the major risk factor for the development of the condition [4]. Thus, ophthalmic drugs that lower the IOP to a safe level play a key role in treating glaucoma, and can reduce risk of visual field progression from 13% to 19% per lowering 1 mmHg IOP [5,6]. For ocular diseases, systemic administration is often ineffective, mainly due to the blood–ocular barrier, and therefore ophthalmic drug delivery by the topical route is considered to be the most appropriate treatment route [7]. Eye drops are the most common dosage forms for topical administration, accounting for over 90% of the marketed ophthalmic formulations [8]. However, eye drops only have 1–5% corneal bioavailability due to rapid tear turnover, non-productive absorption in conjunctiva and the nasal cavity, a rapid clearance mechanism and low permeability of corneal epithelium [9,10]. Thus, to attain the desired therapeutic drug concentrations, eye drops must be administered with high-frequency dosing regimens, which exacerbate side effects and reduce patient compliance [11].

In recent years, contact lenses (CLs) have been shown to be promising as ocular drug delivery systems for improving bioavailability and patient compliance. In 1965, CLs soaked in a 1% homatropine aqueous solution were first used as a vehicle for ocular drug delivery by Sedlacek [12]. Following this, ophthalmic drugs such as timolol [13], dexamethasone [14], pilocarpine [15], pirfinedone [16], aminoglycosides and fluoroquinolones [17] have been successfully loaded into CLs by the soaking method. It has been shown that drugs soaked into CLs could reach a higher drug bioavailability compared to eye drop therapy [18]. Unfortunately, most of the loaded drugs are released in only a few hours by the traditional soaking method, which hampers the application of CLs for prolonged drug delivery. Recent advances in nanotechnology and materials science offer a great opportunity for increasing the duration of drug release from CLs [19]. Nanoparticles can be embedded in CLs matrix to form a composite drug delivery system, and the drug release duration of the composition system is longer than the CLs matrix alone. The release of Prednisolone from PLGA nanoparticles-laden CLs prepared by Elshaer et al. was >24 h [20]. Maulvi et al. prepared novel cyclosporine-loaded Eudragit S100 nanoparticles-laden CLs which achieved sustained release of cyclosporine, without no leaching of the drug during the storage period. However, the main limitations of the nanoparticle-laden CLs mentioned above are low transparency, which restrict the application of this type of CLs. To maintain transparency, micelles are more suitable to be loaded into CLs because of their smaller particle sizes. As demonstrated by Chauhan et al, HEMA (hydroxyethyl methacrylate) hydrogels containing cyclosporine A micelles achieved sustained drug release, and didn't compromise optical properties [21]. Additionally, the hydrophilic groups on the surface of the micelles have an improved compatibility with CLs matrix than the hydrophobic surface of polymer nanoparticles.

For glaucoma therapy, several different classes of drugs are currently prescribed for IOP reduction, which inhibiting the aqueous humor production or improve its outflow, including prostaglandin F2α analogues, β-blockers, carbonic anhydrase inhibitors, and α2-adrenergic agonists. Latanoprost, a prostaglandin F2α analogue, is considered the first-line medication in drug therapy for glaucoma, and provides powerful IOP reduction by increasing the outflow of the aqueous humor [22]. β-blockers are the most commonly prescribed glaucoma medicines in a number of countries including the United Kingdom and the United States [23]. Timolol is one of most used β-blockers, which decreases the IOP by inhibiting the production of aqueous humor [24]. The simultaneous application of two drugs with different IOP lowering mechanisms can synergistically reduce intraocular pressure. For example, Xalacom® eye drops including 0.5% timolol and 0.005% latanoprost are available in the market, and have shown that combination therapy can be more beneficial than monotherapy [25].

In the present study, CLs-M were designed to sustain delivery of a beta blocker (timolol) and a prostaglandin F2α analogue (latanoprost) simultaneously in order to increase patient compliance and achieve the desired IOP-lowering effect. Both latanoprost and timolol loaded mPEG-PLA micelles were prepared by thin film hydration, and then embedded into CLs matrix by photopolymerization of HEMA. The critical properties of CLs such as transparency, water content, oxygen permeability and ion permeability were primarily characterized and the in vitro release, in vivo PK and PD and safety of CLs-M were systematically assessed. To our knowledge, this is the first study of simultaneous delivery of latanoprost and timolol from micelles-laden CLs for the treatment of glaucoma.

Section snippets

Materials

Timolol maleate and latanoprost were purchased from Meilun Biotechnology Co., Ltd. (Catalog No.:MB1248 and MB1135, Dalian, China). mPEG2000-PLA2400 was kindly supplied by Changchun Institute of Applied Chemistry. HEMA (2-Hydroxyethyl methacrylate) was purchased from Sigma-Aldrich Chemicals (Catalog No.:128635, St Louis, MO, USA). EGDMA (ethylene glycol dimethacrylate) was purchased from TCI (Catalog No.:E0102, Tokyo, Japan). Photoinitiator 1173 was purchased from Aladdin Bio-Chem Technology

Characterization of nanoparticles

The critical aggregation concentration (CAC) of mPEG–PLA was determined by the pyrene fluorescence probe method [30]. The CAC value of mPEG2000–PLA2400 is approximately 0.0012 mg/mL, which is able to self-assemble into aggregates in aqueous solution.

In order to load timolol into mPEG–PLA micelles efficiently, the timolol maleate salt was converted to timolol by neutralized with NaOH solution and the final conversion rate was 82.6%. The micelles loaded with both timolol and latanoprost were

Conclusions

mPEG-PLA micelles were prepared by a thin film hydration method to load both timolol and latanoprost, followed by mixing into HEMA monomer to obtain CLs-M after free radical polymerization. The resultant micelles exhibited an ultra-small particle size with a narrow particle size distribution, which ensured the transmittance of CLs-M. In addition, the hydrophilic shell of the micelles guaranteed good compatibility with the matrix of hydrogel CLs. The timolol and latanoprost were released from

Acknowledgement

The work was support by the Liaoning Province Natural Science Fund Project (No. 20180551031), Liaoning Province Doctoral Start-up Fund Program and Overseas Returnees Start-up Fund from Shenyang Pharmaceutical University (No. GGJJ2018102).

Declaration of competing interests

The authors declare no competing financial interest.

References (34)

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