Drug delivery: Novel methods?


A new method of drug delivery for ocular hypertensive therapies cannot be expected to be generally available for 4 or more years from now.

Orlando, FL-A new method of drug delivery for ocular hypertensive therapies cannot be expected to be generally available for 4 or more years from now. That time is expected to be even longer for a neuroprotective therapy, according to Gary D. Novack, PhD, who explained the basis for his prediction during Glaucoma Subspecialty Day at the annual meeting of the American Academy of Ophthalmology.

When Dr. Novack developed his presentation, the subject that he was charged with- "Novel Methods of Drug Delivery: When Should We Be Expecting a Breakthrough?"-implied that the current delivery systems are lacking.

"The entire body is being treated when local therapy . . . is really needed," Dr. Novack said. "Systemic therapy may not safely deliver an adequate concentration to the eye."

A few alternative systems are currently available to deliver anti-glaucoma drugs. Dr. Novack considers prodrugs to be a delivery system.

"Prodrugs are a more efficient drug delivery system that go back to dipivefrin (Propine, Allergan). Levo bunolol and the prostaglandins have active metabolites," he said.

In addition, drugs that are formulated as thicker eyedrops can remain on the eye longer. Examples include pilocarpine ophthalmic (Adsorbocarpine, Alcon Laboratories) and timolol (Timoptic-XE, Merck & Co.)

Finally, some drugs are delivered in controlled- release form into the lower cul-de-sac of the eye, such as pilocarpine ophthalmic (Ocusert, Alza).

Investigational drugs

Some investigational drugs for use in patients with glaucoma are in clinical development. One such product is hydrophilic contact lenses, which have been a consideration for more than 30 years, that contain an antihistamine for allergic conjunctivitis (ketotifen, Vistakon). Other products are lyophilization on Teflon strips, plastic rods, and erodible implants for the cul-de-sac.

Also in clinical development are upper and lower punctal plugs (QLT Inc.) that contain latanoprost. The manufacturer has reported drug retention of about 56% at 4 weeks after insertion and a mean reduction in IOP of about 5.7 mm Hg. The plugs contain about 140 µg of drug, which should equal 90 days of eyedrop instillation. Another manufacturer, Ocular Therapeutix, has released punctal plugs containing moxifloxacin.

Alcon Laboratories evaluated the use of anecortave acetate administered by sub-Tenon injection, but the company has stopped development of the product.

Unpreserved latanoprost 0.005% emulsion (Catioprost, Novagali Pharma) was compared with travoprost (Travatan, Alcon Canada, Inc.) preserved with Sofzia and found to have equivalent efficacy with less corneal staining in patients with ocular surface disease.

Finally, pSivida is evaluating a bioerodible system that contains sustained-release latanoprost. Investigational drugs for use in patients without glaucoma include an anterior segment iontophoretic delivery system from EyeGate that contains dexamethasone to treat dry eye and uveitis, and ICON Biosciences has an intracameral triamcinolone acetonide gel under development.

"These drugs might have potential to be used in a different form to treat glaucoma," he said. Investigational drugs that are in the pre-clinical stage include: an insert and conjunctival implant from Aerie that is designed to deliver a drug for from 6 to 12 months; EyeGate is investigating nanoparticle and protein/posterior segment approaches to drug delivery; Replenish from Replenish Inc., is a refillable intraocular pump delivery system; and other iontophoretic technology from IOMED, according to Dr. Novack.

There are currently no neuroprotective drugs approved for use in the posterior segment in glaucoma. Some intraocular drug delivery systems have been approved for use in other subspecialties: non- erodible systems, Vitrasert containing ganciclovir (Bausch + Lomb) and Retisert containing fluocinolone acetonide (Bausch + Lomb) for cytomegalovirus retinitis and uveitis, respectively; an erodible system, Ozurdex (Allergan) containing dexamethasone for retinal disorders; fluocinolone acetonide (Iluvien,Alimera) for diabetic macular edema; ciliary neurotrophic factor (NT-501, Neurotech) in encapsulated cell technology for retinitis pigmentosa and geographic atrophy; and delivery into the suprachoroidal space of triamcinolone acetonide and dyes using a microcannula with fiber-optic illumination (iScience).

The challenge of novel systems

As mentioned previously, eyedrops have to satisfy a range of requirements. However, novel delivery systems present even greater challenges.

When using a novel delivery system, it must deliver the drug at the intended rate, ideally "zero-order" or flat over time, but this does not work for every system. With non-erodible systems, a consideration is disposing of the shells. Importantly, support must be found for development of the delivery system.

"The least risky approach is to use an already approved molecule to deliver the drug," Dr. Novack said. " An alternative is to develop a new molecule, which has a higher value and a higher risk."


Gary D. Novack, PhD
E-mail: gary_novack@pharmalogic.com

Dr. Novack consults for numerous pharmaceutical companies, but he has no proprietary interest in any aspect of this report.

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