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Purpose: To report the development and therapeutic evaluation of a liposomal nanocarrier for sustained release of latanoprost, in the rabbit eye. Methods: We fabricated latanoprost-loaded egg-phosphatidylcholine (EggPC) liposomes using the film hydration technique. The delivery vehicles were nano-sized (Z avg = 109 ± 18 nm), had a narrow poly dispersity index (PDI = 0.19 ± 0.04), and a very high loading efficiency (94% ± 5%). Based on in vitro data, we evaluated this formulation for lowering intraocular pressure (IOP) in rabbit eyes. Following a single subconjunctival injection of the latanoprost loaded formulation, the eyes were clinically monitored and the IOP recorded. Results: Latanoprost-loaded EggPC liposomes demonstrated a high drug/lipid mole ratio of 0.181, remained stable for at least 6 months on storage (4°C), and at least 1 month at 25°C. A slow and sustained release of 60% of latanoprost was achieved by 14 days in the in vitro release study. The same formulation demonstrated a greater sustained IOP lowering effect compared with daily administration of topical latanoprost beyond 90 days (4.8 ± 1.5 vs 2.5 ± 0.9 mmHg; P < 0.001). No signs of inflammation were evident in the eyes from slit-lamp examination analysis. Conclusion: The loading required for a long-term sustained delivery of latanoprost for up to 90 days in the rabbit eyes was achieved with EggPC liposomes. A single injection of latanoprost-loaded EggPC liposomes can lower the IOP for up to 90 days, with a greater IOP lowering effect than daily topical administration of latanoprost.

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Therapeutic nanomedicine has concentrated mostly on anticancer therapy by making use of the nanosize for targeted therapy. Such nanocarriers are not expected to have sustained release of the bioactive molecule beyond a few days. There are other conditions where patients can benefit from sustained duration of action following a single instillation, but achieving this has been difficult in nanosized carriers. An important prerequisite for sustained delivery over several months is to have sufficiently high drug loading, without disruption or changes to the shape of the nanocarriers. Here we report on successful development of a drug-encapsulated nanocarrier for reducing intraocular pressure in a diseased nonhuman primate model and explain why it has been possible to achieve sustained action in vivo. The drug is a prostaglandin derivative, latanoprost, while the carrier is a nanosized unilamellar vesicle. The mechanistic details of this unique drug-nanocarrier combination were elucidated by isothermal titration calorimetry. We show, using Cryo-TEM and dynamic light scattering, that the spherical shape of the liposomes is conserved even at the highest loading of latanoprost and that specific molecular interactions between the drug and the lipid are the reasons behind improved stability and sustained release. The in vivo results clearly attest to sustained efficacy of lowering the intraocular pressure for 120 days, making this an excellent candidate to be the first truly sustained-release nanomedicine product. The mechanistic details we have uncovered should enable development of similar systems for other conditions where sustained release from nanocarriers is desired.

Topical medication remains the first line treatment of glaucoma; however, sustained ocular drug delivery via topical administration is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Currently, daily topical administration for lowering the intra-ocular pressure (IOP), has many limitations, such as poor patient compliance and ocular allergy from repeated drug administration. Poor compliance leads to suboptimal control of IOP and disease progression with eventual blindness. The delivery of drugs in a sustained manner could provide the patient with a more attractive alternative by providing optimal therapeutic dosing, with minimal local toxicity and inconvenience. To investigate this, we incorporated latanoprost into LUVs (large unilamellar vesicles) derived from the liposome of DPPC (di-palmitoyl-phosphatidyl-choline) by the film hydration technique. Relatively high amounts of drug could be incorporated into this vesicle, and the drug resides predominantly in the bilayer. Vesicle stability monitored by size measurement and DSC (differential scanning calorimetry) analysis showed that formulations with a drug/lipid mole ratio of about 10% have good physical stability during storage and release. This formulation demonstrated sustained release of latanoprost in vitro, and then tested for efficacy in 23 rabbits. Subconjunctival injection and topical eye drop administration of the latanoprost/liposomal formulation were compared with conventional daily administration of latanoprost eye drops. The IOP lowering effect with a single subconjunctival injection was shown to be sustained for up to 50 days, and the extent of IOP lowering was comparable to daily eye drop administration. Toxicity and localized inflammation were not observed in any treatment groups. We believe that this is the first demonstration, in vivo, of sustained delivery to the anterior segment of the eye that is safe and efficacious for 50 days.

Glaucoma is a chronic progressive optic neuropathy that is characterized by optic nerve changes and visual field loss. Elevated intraocular pressure (IOP) is the main modifiable risk factor. Chronic instillation of daily eyedrops to lower IOP is the primary treatment of choice, although it requires patient adherence and correct performance. We have developed a nanoliposome drug delivery system for the longer term delivery of latanoprost. In the present open-label, pilot study, the safety and efficacy of a single subconjunctival injection of liposomal latanoprost was evaluated in six subjects with a diagnosis of either ocular hypertension (OHT) or primary open-angle glaucoma (POAG). Subconjunctival injection of liposomal latanoprost was well tolerated by all six subjects. From a baseline IOP of 27.55 ± 3.25 mmHg, the mean IOP decreased within 1 h to 14.52 ± 3.31 mmHg (range 10-18 mmHg). This represented a mean decrease of 13.03 ± 2.88 mmHg (range 9-17 mmHg), or 47.43 ± 10.05 % (range 37-63 %). A clinically and statistically significant IOP reduction (≥20 % IOP reduction, P = 0.001 to 0.049) was observed through 3 months after injection. The nanomedicine reported here is the first nanocarrier formulation that has an extended duration of action in humans, beyond a couple of weeks. The findings in this study open up a new treatment modality, which will greatly enhance patient compliance and improve treatment outcomes. The current study provides the evidence and support for further clinical studies of liposomal latanoprost in the treatment of glaucoma.

This review focuses on polymer- and liposome-based nanoparticles used in targeted delivery of bioactive molecules, from drugs to siRNA to pDNA. The perspective centers around commercial and clinical successes, and a rationalization of these successes. Microparticulate systems are not covered, and only those applications that truly utilize the advantages of nano size are covered. "Stealth" systems dominate in this review, as most of the clinical successes are for passive targeting rather than for active targeting of tissue. The relevance of nano size to gene delivery is also discussed with relevant examples.