Issue:January 2013

DRUG DELIVERY – EyeSol: a Novel Topical Ocular Drug Delivery System for Poorly Soluble Drugs


INTRODUCTION

One of the biggest challenges currently facing the pharmaceutical industry is the development of more efficient drug delivery systems. For instance, the anterior part of the eye is amongst the most readily accessible organs, in terms of location in the human body; however, drug delivery to eye tissue is particularly problematic. This is reflected by the notoriously poor bioavailability of topical ocular drug formulations of 5% or less.1

To make matters even more complicated, due to combinatorial chemistry and high throughput screening implemented throughout the past 20 years, up to 75% of new chemical entities (NCEs) are considered poorly soluble even for oral administration, according to the biopharmaceutics classification system (BCS), where the considered volume is 5000-fold higher compared to an aqueous eye drop.2-4

Three major issues need to be addressed for ocular formulations: safety, bioavailability and stability. If this wasn’t hard enough, the final cost of goods has to be reasonable and handling has to be simple to achieve good compliance. At best, current ophthalmic formulations are a compromise with significant room for improvement.

CHALLENGES OF TOPICAL OCULAR DRUG DELIVERY

The very nature of the eye makes any drug treatment particularly challenging. The eye is a very sensitive organ immediately reacting to both mechanical and chemical irritation Therefore, formulation options are limited. The amount of fluids that may be applied to the eye without creating a “spill over” effect, drained away through the lacrimal duct, or just running down the cheek is less than 20 microliters. A standard water drop of about 40 to 50 microliters will activate the blinking reflex and most of the topically administered drugs are washed away within 15 to 30 seconds following instillation.5 To achieve good bioavailability, sufficient drug needs to be incorporated into the ocular delivery system fitting into a drop. In a second step, the hurdles of rapid turnover, lacrimal drainage, reflex blinking, and dilution by tears must all be overcome.

The issue of poorly water-soluble drugs is well known in the scientific community, resulting in the BCS classification system for oral drug delivery.6 In short, a drug is considered poorly soluble if the required dose is not dissolved in 250 milliliters of aqueous medium. An aqueous eye drop is only 40 to 50 microliters or about 5000 times less volume. This exacerbates the solubility problem by several orders of magnitude.

For other routes of administration, we have a wide variety of excipients, including solvents and/or surfactants to overcome such issues. Due to the sensitivity of the eye, they either cannot be used at all or only in very minute quantities. Surfactants like sodium lauryl sulphate or solvents like acetone cannot be used for ophthalmic delivery. Indeed, the amount of alcohol approved for an ophthalmic dosage form is very much limited (according to the FDA inactive ingredient list); the highest approved concentration is 1.4%, in contrast to intravenous (iv) applications with 49%.

The drug load of oil-in-water emulsions is also limited. The drug has to be dissolved in the inner phase, the oil. The amount of the inner phase very much depends on the amount of surfactants used; which in turn is also limited to avoid irritation, thereby limiting the inner phase. In addition, only liquid or semi-solid dosage formulations may be applied. The number of solvents that can be administered into the eye is also very limited. The same applies for surfactants used regularly in topical and oral formulations. Everyone has personal experience with dish soaps, hair shampoo, etc.

To make the situation even more complicated, there is also a risk of infection when contaminated preparations are administered. Even if they are well tolerated, such as certain oils, they may affect vision due to having a different refractive index compared with water, enviably leading to blurred vision. The natural choice for ophthalmic formulations appears to be aqueous solutions. However, water is only the starting point; factors such as selection of the appropriate salt of the drug substance, solubility, therapeutic concentration required, ocular toxicity, pKa, pH effect on stability and solubility, tonicity, buffer capacity, viscosity, choice of preservative for ocular comfort, and ease of manufacturing all must be considered.

Salts are used in order to dissolve a drug in a protic solvent, such as water; however, being presented in a charged form affects the bioavailability, as the upper cell layers of the cornea are hydrophobic. In order to increase bioavailability, the contact time with eye tissue may be increased by increasing the viscosity. An alternative approach may be to increase the drug concentration in the formulation; obviously, this is problematic for poorly soluble drugs. Already very small particles > 10 microns in the anterior part of the eye lead to mechanical irritation, including blinking, and increased tear flux causing irritation to the patient.

Aqueous formulations have to be manufactured aseptically, undergoing sterile filtration or whenever possible, heat sterilization. Manufacturing requires specially designed, environmentally controlled areas. All of which increases the cost substantially.

All-in-all, this leaves a very limited formulation window for aqueous-based ocular drug delivery, including emulsions and suspensions. Therefore, a non-protic, aqueous-free ocular delivery system has the potential to provide an alternative approach in particular for poorly soluble drugs.

EYESOL(TM) OCULAR DRUG DELIVERY PLATFORM

EyeSolTM, Novaliq’s proprietary ocular drug delivery technology, offers such an alternative. EyeSolTM is based on Semi-Fluorinated Alkanes (SFAs), which are a special class of fluorocarbon compounds that have been thoroughly investigated and have gained increasing interest in the biomedical field throughout the past 20 years.

These compounds have a characteristic linear or branched molecular structure consisting of a fluorocarbon segment (CF2)nF (RF) linked to a hydrocarbon segment H(CH2)n as a diblock (RH). In the case of triblock compounds (RFRHRF), a (CH2)m spacer is linked symmetrically to two fluorocarbon segments F(CF2)n. The molecular structures are hence F(CF2)n (CH2)mH and F(CF2)n (CH2)m (CF2)nF with n and m = 2 to 20

Liquid, water-insoluble SFAs are physically, chemically, and physiologically inert. They are colorless, laser-stable compounds with densities of 1.1 to 1.7 g/cm3.7 Despite the intramolecular CF2-CH2 bond, SFAs are very stable compounds biochemically and biologically because the RH segment with its electron density has a bond-stabilizing effect on the overall molecule. The use of SFAs in the field of ophthalmology has mainly been focused in the past on the treatment of disorders in the posterior segment of the eye. For the treatment of complicated retinal detachment, these compounds have been injected intraocularly as temporary endotamponades for more than 10 years (eg, Densiron® 68, Vitreous Substitute®). They are very well tolerated and have shown an excellent safety profile. SFAs are chemically and biologically inert and thus do not cause ocular tissue irritation.

The use of SFAs in the anterior segment of the eye is currently a promising field of research. Recently, these compounds have been investigated by Novaliq regarding the major requirements for an anterior ocular drug delivery system safety/tolerability, drug stability, and bioavailability with favorable results.

EXCELLENT SAFETY PROFILE

The EVEIT test is an excellent ex vivo test to evaluate and compare the tolerability of different eye drops in a standardized setting. After placing artificial lesions on the cornea, the corneas were treated with EyeSolTM, Hyaluronic acid 0.1% (HA, gold standard), and Benzalconium chloride (common preservative) solutions as comparators. Eight drops each of the three formulations were administered continuously every hour for 72 hours. After 3 days of treatment, the endothelia recovered under both EyeSolTM and the current gold standard HA therapies, in contrast to the preservative compound, benzalconium chloride which resulted in extensive, irreversible damage.8

The local tolerability of EyeSolTM was confirmed in another sensitive eye irritation test, the Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) assay. In the HETCam assay, chemicals are placed in direct contact with chorioallantoic membrane of the hen’s egg. The occurrence of vascular injury or coagulation is an indication for the damage of mucus membranes (especially the eye) in vivo.9,10

Microbiological testing has clearly demonstrated that this water-free preparation does not require preservatives. Therefore, it is provided preservative-free even in multi-dose units. Lacking preservatives, most of them with irritating potential, have clearly demonstrated that the formulation will not cause cornea damage, as frequently reported from using other substances upon prolonged use and demonstrated in the EVEIT study with the Benzalconium chloride, for example. Furthermore, as a multi-dose unit, cost of goods will be substantially reduced, and the manufacturing process will be substantially simplified.

The extraordinary spreading properties support the drug distribution on the corneal surface. In addition, their low viscosity and low surface tension result in much smaller droplet size compared to water with 15 microliters instead of 40 to 50 microliters for a conventional aqueous drop. Thus, spill over and the immediate loss of the majority of the administered dose are avoided. The implication of the avoidance of the spill over on the bioavailability is obvious. It should also be noted that the refractive index of SFAs is similar to water so that vision is not impaired in contrast to emulsions and oily drops.

Due to their amphiphilic nature, SFAs can also dissolve a variety of therapeutically relevant poorly watersoluble compounds, such as cyclosporine A and tacrolimus. For other compounds, the free base may be used instead of a salt, for example lodocaine. It is obviously very advantageous to present the drug in an uncharged form to facilitate penetration into the cornea. This is a big step forward for the delivery of poorly soluble drugs, as it offers a new approach delivering such compounds as a solution instead of an emulsion.

Obviously, one of the main degradation pathways for aqueous-based formulations is hydrolysis. By using a non-aqueous environment, compounds such as tacrolimus, which have hydrolysable bonds such as a lactone, will demonstrate a superior stability profile compared to aqueous-based formulations. In summary, it can be stated that SFAs resemble many requirements for a “perfect carrier.”

PENETRATION PROFILE OF CYCLASOLTM INTO THE LACRIMAL GLAND

The lacrimal gland is regarded a relevant target organ for cyclosporine A. In a pharmacokinetic study in rabbits, CyclASolTM applied on top of the rabbit’s eye was compared with an oil-in-water emulsion (current gold standard). A major difference of Cmax (14-fold increase in favour of CyclASolTM) and between the two formulations was detected in the lacrimal gland. Regarding the cornea the difference of Cmax was two fold in favor of CyclASolâ„¢. The spreading properties of the SFAs in the EyeSolâ„¢ technology may be responsible for the altered pharmacokinetics compared to a standard aqueous formulation.

SUMMARY

Despite the relatively recent emergence of SFAs in the pharmaceutical field, they have already demonstrated outstanding potential as novel drug-carrier solvents.

In addition, the unique combination of physico-chemical properties, including the excellent spreading behavior, the physical and chemical inertness, the solubility of poorly water-soluble compounds, together with the reduced drop volume, thus avoiding blinking, makes SFAs excellent candidates to overcome most of the challenges facing the drug delivery industry today. CyclASolTM is the first cyclosporine A solution for dry eye disease. This proprietary product is based on the EyeSol technology. So it is provided preservative free in multi-dose units. The absence of surfactants, irritating preservatives, and the avoidance of blurry vision associated with emulsions leads to improved tolerability and convenience of this non-aqueous product.

REFERENCES

1. Kompella UB, Kadam RS, Lee VHL. Recent advances in ocular drug delivery. Ther Deliv. 2010;1(3):435-456.
2. The Biopharmaceutics Classification System (BCS) Guidance, Food and Drug Administration, April 2009.
3. Löbenberg R, Amidon GL. Modern bioavailability, bioequivalence and biopharmaceutics classification system. new scientific approaches to international regulatory standards. Eur J Pharm Biopharm. 2000;(50)1,3:3-12. 44
4. Scherer D, Reidelshöfer A. Softgel capsules solve economic and safety issues posed by poorly soluble anticancer drugs Pharm Ind. 2012(74)5:745-749.
5. Peyman GA, Schulman JA, Sullivan B. Perfluorocarbon liquids in ophthalmology. Surv Ophthalmol. 1995;39(5):375-395.
6. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. The J AAPS. September 2010;12(3):348-360.
7. Meinert H, Roy T. Semifluorinated alkanes – a new class of compounds with outstanding properties for use in ophthalmology. Eur J Ophthalmol. 2000;10(3):189-197.
8. Schrage NF, Frentz M, Günther B, Spöler F. New and carrier efficient water free eye drops? a new solution containing perfluorohexyloctane supports healing in the ex vivo eye irritation test EVEIT. Greafe’s Archive (in press).
9. Tavasci J, Budai P. The use of Het-Cam test in detecting the ocular irritation. Commun Agric Appl Biol Sci. 2007;72(2):137-141.
10. Ardelean S, Feflea, Ionescu D, Nastase V, Dehelean CA. Toxicological screening of some surfactants using modern in vivo bioassays. Rev Med Chir Soc Med Nat Iasi. 2011;115(19):251-258.

Dr. Dieter Scherer joined Novaliq in April 2009 as its Chief Business Officer. His 20 years of experience covers the gamut from business development and licensing to product development in the field of drug delivery. His experience covers a wide variety of dosage forms, with his speciality in working with the delivery of poorly soluble drugs. After filling various staff and line functions with increasing responsibilities at LTS Lohmann in Germany and SkyePharma in Switzerland, he set up his own consultancy (Apis Pharma AG) in 2003 advising drug delivery companies throughout Europe. Dr. Scherer graduated as a Pharmacist at the J.W. Goethe University in Frankfurt and later earned his PhD in Pharmaceutical Technology from the same faculty.

Dr. Eva Alvarez-Gonzalez started her professional research activity 2 years ago at the Strathclyde Institute of Pharmacy and Biomedical Science (SIPBS) with Dr. Chris van der Walle in the formulation of bacteriophagecoated microcrystals. She is currently a Research Associate at SIPBS working with Professor Clive Wilson in the study of protein stability under novel solvents working closely with Novaliq GmbH. She graduated with a first class Master degree in Chemical Engineering from the University of Oviedo (Spain) in 2007. She was awarded an Erasmus grant to finalize her undergraduate studies at the Chemical and Process Engineering Department at the University of Strathclyde. At the end for her undergraduate studies, she was awarded with the prize to the best MEng. graduate at the University of Oviedo. She then moved to Glasgow (UK), where she earned her PhD in Chemical and Process Engineering from the University of Strathclyde. Her thesis Nucleation of Beta-Lactoglobulin Clusters in Solvent- Induced Denaturation introduced her in the pharmaceutical field, gaining experience in protein handling, formulation, and characterization.

Tony Pettigrew joined Novaliq GmbH in 2012 as Chief Protein Chemist. Within this role, he works on Novaliq’s proprietary drug delivery technology based on Semi??Fluorinated Alkanes (SFA) particularly in the area of biopharmaceutical formulation. Prior to his role at Novaliq, he has built up a solid background in the biotech field, his previous positions including being at a Manager in the Biopharma Application Development group at Novozymes Biopharma DK A/S and in the AD/QC group at Veloxis A/S DK (formerly LifeCycle Pharma A/S DK). Mr. Pettigrew graduated as a chemist at Liverpool John Moores University (1993) and later earned his MSc in Analytical Chemistry (1995) from the University of Huddersfield.

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