An unprecedented example for sole cyclodextrins as API: an ophthalmic composition with hydroxypropyl betadex, alone

A paradigm shift in cyclodextrin technology started with the design, development and marketing of Sugammadex®/Bridion®, and followed by designation of hydroxypropyl-betadex (HPBCD) as orphan drug for Nieman Pick type C disease. These two parenterally applied products opened a new field for therapeutic application of CDs themselves as active ingredients in finished products.

A number of studies are currently evaluating utility of lipid-mobilizing CDs in different lysosomal storage disorders and other related rare diseases.   

In 2019, an interesting patent application (1) was filed which disclosed ophthalmic compositions where HPBCD alone was used as active ingredient. The patented compositions were really simple: they contained 10 % HPBCD in an aqueous buffered (phosphate salts and water for injection) solution. (See Table below)

  Ophthalmic compisition disclosed in the Patent (1):

The efficient, non-invasive delivery of a therapeutic agent (in this case the HPBCD itself), to the back of the eye represents a convenient, low cost, patient-friendly way of treatments. The practical value and significance of such delivery systems becames obvious in the light of the below-listed diseases affecting the posterior part of the human eye:

• dry or neovascular age-related macular degeneration,
• diabetic retinopathy,
• diabetic macular oedema,
• retinal venous occlusions,
• proliferative vitreoretinopathy,
• inherited retinal diseases,
• uveitis,
• neovascularization or macular oedema

These diseases require due attention in order to prevent the loss of vision.

 The formulation challenge:

Posterior eye diseases present unique anatomical, physiological and biochemical barriers to drug delivery. These result in the failure of conventional dosage forms such as eye drops, ointments and suspensions, to deliver any drug to these back areas of the eye in required therapeutic concentrations.  The patent (1) disclosure does not detail the assumed or proven way how the HPBCD in the formulation moves from the cornea and reaches the posterior segment of the human eye in order to be effective.  The disclosure relates to pharmaceutical formulations comprising cyclodextrin that are topically applied to the external surface of the human eye, preferably as a liquid. The formulations according to the invention, have been found capable of providing the HPBCD to the posterior portions of the eye and are therefore, effective in removing drusen and treating other related conditions in the posterior of the eye. Due to the ability to deliver cyclodextrin to the back of the eye, especially the retina, even though applied topically to the external surface of the eye, the formulations can be used for several related conditions associated with age-related degeneration of the human eye, such as wet or dry age-related macular degeneration.

Here we have to remember the pioneering role and previous results achieved by Professor Loftsson’s team, working on the CD-assisted delivery of an API to the back of the eye. They reported on the successful delivery of dexamethasone to the posterior part of the eye by creating a gamma-CD based microparticular system. Such concept was communicated in a paper already in 2007. (2) Loftsson’s novel ophthalmic delivery system utilized the high aggregation propensity of gamma-CD in water, in presence of an API, which resulted in the formation of binary drug-CD micro- and nanoparticles. These particles provided extended release and longer residence time of the API in the eye. The concept and process for the efficient delivery of APIs to the posterior segment of the eye in a non-invasive manner (simple instillation of an eye drop) were also patented (3). The gamma-CD-based microparticulate formulation is currently under clinical testing. Oculis, the company behind this development process announced in this year positive top line results from Phase 3 trial of their „OCS-01” drops for diabetic macular edema. (4)

References:

1. OPHTHALMIC COMPOSITIONs COMPRISING A CYCLODEXTRIN AS SOLE ACTIVE AGENT, Pub . No .: US 2019/0328772 A1, Pub. Date: Oct. 31, 2019.
Inventor: Graham Edward Priestley,
Applicant: WARNEFORD HEALTHCARE Ltd. Weybridge (GB)

2. Thorsteinn Loftsson, Dagný Hreinsdóttir and Einar Stefánsson: Cyclodextrin microparticles for drug delivery to the posterior segment of the eye: aqueous dexamethasone eye drops, J. Pharmacy and Pharmacology, 2007, 59: 629–635. DOI: 10.1211/jpp.59.5.0002

3. WO 2018100434- Preparation of Solid Cyclodextrin Complexes for Ophthalmic Active Pharmaceutical Ingredient Delivery.
Inventors: Thorsteinn Loftsson and Einar Stefansson
Assignee: Oculis

4. https://www.ophthalmologytimes.com/view/oculis-announces-positive-top-line-results-from-phase-3-trial-of-ocs-01-drops-for-diabetic-macular-edema