The goal of this study was to develop a stable, preservative containing liposome-encapsulated diclofenac formulation for topical ophthalmic application. Small-scale development focused on production of a formulation that was non-irritating to the eye (isotonic, with a pH of 7.2-7.4 and containing little or no organic solvent), resistant to bacterial growth (contained one FDA-approved ophthalmic preservative), stable (resistant to settling of liposomes), and clear. In addition to these criteria, it was also important to determine whether such a formulation could be scaled up for manufacture. Multiple small-scale formulations were created using methods of physical homogenization (sonication, homogenization, heating, freeze/thaw), while a large-scale preparation was created using a proprietary mixing technology (OPTIMIXTM, patent pending). One of the small-scale formulations, (0.1% w/v diclofenac), was tested in rabbits for ocular absorption against a commercially available topical ophthalmic diclofenac formulation (Voltaren ophthalmic (0.1% diclofenac)®). The liposome-encapsulated formulation was found to boost ocular diclofenac concentration 2 fold over Voltaren in the iris-ciliary body, 2.3 fold in the bulbar conjunctiva, 2.5 fold in the aqueous humor, and 3.2 fold in the cornea. No significant drug uptake was seen in the retina, choroid, or vitreous humor, and the liposome-encapsulated formulation did not change the half-life of diclofenac in various ophthalmic tissues. In summary, it appears that liposome-encapsulation of diclofenac increases the ocular absorption of drug over topical application of drug solution alone. Furthermore, using a proprietary mixing technology, it appears to be both feasible and economical to produce large-scale batches of liposome-encapsulated diclofenac formulation for ophthalmic use.

Introduction

Eyedrops are an inefficient means of ophthalmic drug delivery. Approximately 90% of the applied dose is cleared from the ocular surface within 2 minutes through blinking, nasolacrimal drainage, and tear production. Consequently, numerous methods have been developed in an effort to increase the retention and absorption of ophthalmic drugs. One of the least invasive of these methods includes topical delivery of suspensions of drug-loaded micro- or nano-particles. Liposomes are a type of particulate suspension composed of biocompatible and biodegradable phospholipid. They have the added advantage over polymeric delivery systems in that, if required, they may be easily filter sterilized and the possess none of the gritty, sticky or irritating properties often associated with polymeric drug delivery systems.

Liposomes form spontaneously when phospholipids are added to water. Drugs can be incorporated into the lipid bilayer or into the aqueous core of the liposome, depending on the lipophilicity or hydrophilicity of the drug. Studies examining liposome encapsulation of drugs for ophthalmic use have indicated that this delivery method can be considerably more effective than topical application of drug solution alone. Drugs that have been encapsulated into liposomes include pilocarpin, penicillin G, tropicamide, cyclosporine, acyclovir, triamcinolone, and dihydrostreptomycin.

In spite of their apparent effectiveness, there are no commercially available liposome-encapsulated drugs for ophthalmic use. Difficulty of manufacturing drug-encapsulated liposomes on a large scale may be the main reason for this. Also, methods most commonly used to produce liposomes require the use of chloroform or other organic solvents. Potential carry over of these organic compounds to the final product could result in ocular irritation and is pharmaceutically unacceptable. In addition, ophthalmic formulations require buffering and the presence of a preservative, which will often cause the disruption of liposomal structures. One more criteria for liposomes to be successful and pharmaceutically acceptable for ophthalmic use is their size. Smaller liposomes will render a more stable suspension, which is less turbid. With these hurdles in mind, it is not difficult to understand why drug-encapsulated liposomes have yet to be developed into commercial products for ophthalmic use.

The present study addresses both the problems associated with liposome formulation and large-scale production. A liposome-encapsulated formulation of the non-steroidal anti-inflammatory drug (NSAID) diclofenac was produced without the use of organic solvents. Four different methods were used to hydrate the lipids and homogenize the liposome suspension (heating, homogenization, sonication, and freeze/thaw). The effect of different ophthalmic preservatives on formulation stability and particle size was also studied. Large-scale production of the final formulation was achieved by using our proprietary OPTIMIX™ mixing device (US and international patents pending). Finally, this study also demonstrated that liposome-encapsulated diclofenac increased the amount of diclofenac absorbed by ocular tissues over 0.1% w/v diclofenac solution alone.

Conclusions

This work adds to the growing body of information supporting the use of liposomal suspensions as unique and powerful vehicles for ophthalmic drug delivery. It clearly demonstrates an improvement over an aqueous formulation, with respect to the amount of drug absorbed into several ocular tissues. Although liposome-encapsulated diclofenac formulation increased the total amount of drug delivered, it did not increase the Tmax beyond that seen with Voltaren Ophthalmic®. Future formulation strategies need to include agents that improve the retention of the liposome at the ocular surface. Such agents could include cationic lipids, lectins, or viscosity enhancing agents, and are currently being investigated.

This study also documents a continuous process for the large-scale production of dilute liposomal solutions.

I. Introduction To Methods Of Ophthalmic Drug Delivery

Commonly accepted methods of ophthalmic drug delivery, including topical application, injection and oral administration, are often inefficient and hampered by undesirable local and systemic side effects. Topical ophthalmic preparations, while among the most popular method of ophthalmic drug delivery, are quickly lost through blinking, systemic absorption and naso-lacrimal drainage, and must be re-applied frequently (Le Bourlais et al. 1998, Joshi 1994).

Injected ophthalmic drugs are also cleared and may need to be administered multiple times during the course of treatment (Joshi 1994). While injection may be the most direct route of ocular drug delivery, there is the additional risk of vitreous hemorrhage, endophthalmitis, and retinal detachment every time a drug is applied in this fashion (Jaffe et al. 2000).

Finally, systemic drugs used for ophthalmic indications may be unable to penetrate the blood-brain or blood-ocular barrier. Even if they do, they may not reach levels that are of therapeutic value. Therefore, throughout the last decade, there has been a significant increase in the development of new methods and delivery devices to improve the bioavailability of ophthalmic drugs (Le Bourlais et al. 1998). Such novel methods include how a drug is physically delivered, retained and/or maintained at the ocular surface or within ocular tissue.

Drug Delivery Systems

Over the last two decades, there has been intense focus on developing ways to improve topical or intra-ocular delivery and sustained release of ophthalmic drugs. The most basic of these include soft drugs, which target ocular tissues and which are ultimately converted to inactive metabolites within the eye (Gaynes et al. 1996, Bodor 1994). Other delivery systems range anywhere from crystalline suspensions, liposomes, nano- and micro-particles to gels, foams and moldable polymeric implants. Other delivery systems include non-biodegradable implants, systems that specifically deliver proteins, peptides, DNA, or anti-sense oligonucleotides to the eye and cell-encapsulated technology. .

II. Ophthalmic Drug Delivery Techniques

• Ophthalmic Rods
• Iontophoresis
• Microdialysis
• Photodynamic therapy
• Transient disruption of blood-ocular and blood-brain barrier and drug delivery
• Liposomal Delivery Systems

III. Ophthalmic Drug Delivery Systems

Drug bioavailablity may be improved significantly by altering the drug delivery vehicle in order to promote drug retention at the ocular surface (Joshi 1994). This may be achieved by increasing the viscosity of the delivery system. Sasaki et al, increased the viscosity of tilisolol by adding 3% carboxymethylcellulose. Subsequent retrobulbar and palpebral injections of this solution versus topical instillation increased the concentration of tilisolol in the vitreous body by 3.1and 1.4 fold, respectively (Sasaki et al. 1999).

Enhancing the corneal penetration of a drug is another way to increase intra-ocular uptake of a drug. Wang et al. found that the more lipophilic a drug, the greater the corneal penetration (Wang et al. 1991). Corneal penetration of ophthalmic drugs may also be enhanced by adding surfactants. The ophthalmic preservatives benzalkonium chloride and 2-phenylethanol were found to increase corneal penetration of tilisolol by 3.5 and 2.7 times, respectively. Benzalkonium chloride was found to increase the corneal penetration of 4400 Da and 9900 Da FITC-dextrans (as models of peptide drugs) by 29 and 37 times, respectively (Sasaki et al. 1995).

Finally, loading a drug onto or encapsulating a drug within a mucoadhesive substance is a good way to increase drug bioavailability (Le Bourlais et al. 1998, Joshi 1994). Such substances ate retained at the site of instillation, where the drug is released in a controlled manner through erosion, chemical modification, diffusion, or ion exchange (Joshi 1994).

A number of delivery systems have been developed based on these different strategies and include drug design, drug binding to cyclodextrins, crystalline suspensions of drugs, or drug incorporation into nano- or micro-particles, nanocapsules, liposomes, gels, and polymers.

Liposomes are composed of a lipid bilayer enclosing an aqueous core, and are spontaneously formed when phospholipids assemble in an aqueous environment. They are capable of encapsulating drugs with a wide range of solubilities. Hydrophilic drugs are enclosed within the aqueous core while hydrophobic compounds are sequestered within the lipid membrane. Typically, liposomes are produced from naturally occurring sphingolipids or phospholipids, but may also contain cholesterol or other modified lipids. In general, they range in size from nanometers to several micrometers in diameter, and may contain a single or multiple lipid bilayers (small or large unilamellar vesicles, or multilamellar vesicles) (Sharma 1997).

View Ophthalmic Diclofenac Formulation Powerpoint Presentation

(Please note: Depending on your computer, this will take a few moments to download. We believe that you will find that it is worth the wait!)