Introducing Ocusurf™ Nanostructured Emulsion As a 505(B)(2) Strategy

Integral BioSystems

INTRODUCING OCUSURF™ NANOSTRUCTURED EMULSION AS A 505(B)(2) STRATEGY

Here, Dr Shikha P Barman, Chief Executive Officer and Chief Technology Officer, Integral BioSystems, describes how the company is developing a series of ophthalmic products with its OcuSurf platform, an aqueous nano-dispersion of dissolved hydrophobic drug in nanostructured “cores” that rapidly absorb into the lipid bilayers of target ocular tissues. The platform is suitable for application as an enabling technology for new products but here the focus is on employing a 505(b)(2) strategy on the reformulation of existing products.

GLOBAL OPHTHALMIC MARKET ing differentiated technologies has risen Globally, the ophthalmic drugs market dramatically, with fewer NDA 505(b)(1) is witnessing significant growth due to applications for new chemical entities increasing prevalence of ophthalmic dis- (NCEs) than there were in previous years. orders, both for the anterior and pos- terior segments of the eye. As a result, THE 505(B)(2) STRATEGY this market is expected to grow at 2 a compound annual growth rate (CAGR) The 505(b)(2) NDA is one of three US FDA drug approval pathways and repre- sents an appealing regulatory strategy for “The composition of the many clients. The pathway was created by the OcuSurf nano-dispersion Hatch-Waxman Amendments of 1984, allows interaction and with 505(b)(2) referring to a section of the bioadhesion with the Federal Food, Drug, and Cosmetic Act. The provisions of 505(b)(2) were created, in ocular surface mucosa, part, to help avoid unnecessary duplication “melting” of the nanocores, of studies already performed on a previously release of drug and approved (“reference” or “listed”) drug. The section gives the FDA express permis- rapid absorption.” sion to rely on data not developed by the NDA applicant. A 505(b)(2) NDA contains full

1 safety and effectiveness reports but of about 5.2% during 2013-2018. Dr Shikha P Barman Accordingly, the ophthalmic drug indus- allows at least some of the information Chief Executive Officer try has witnessed a plethora of technolo- required for NDA approval, such as Chief Technology Officer gies that are business driven and aimed at safety and efficacy information on the T: +1 781-258-4039 E: sbarman@integralbiosystems. product extensions for lifecycle manage- active ingredient, to come from studies com ment of existing products. Each of these not conducted by or for the applicant. extensions offers improvements and benefits This can result in a much less expensive Integral BioSystems, LLC over current technologies, such as offer- and much faster route to approval, compared with a traditional development path 19A Crosby Drive, Suite 200 ing preservative-free options, or “non-set- Bedford, MA 01730 [such as 505(b)(1)], while creating new, tling formulations,” amongst others. From United States a regulatory perspective, in the US, the differentiated products with tremendous number of 505(b)(2) applications claim- commercial value. www.integralbiosystems.com

KEY STRATEGY FOR GENERICS ket need exists for highly bioavailable, high the lipid bilayers of target ocular tissues. tissue absorbing formulation compositions. The composition of the OcuSurf nano-dis- Generics company CEOs report that they In one example, anti-inflammatories persion allows interaction and bioadhesion are considering a spectrum of solutions to and anti-infectives are administered post with the ocular surface mucosa, “melting” bridge the revenue gap, but perhaps none operatively after cataract surgery to counter of the nanocores, release of drug and rapid are more valid than the FDA’s 505(b)(2) inflammation and infection. Multiple drugs absorption. approval pathway, which can offer acceler- are often administered simultaneously, with Products that have been enabled in this ated approval, reduced development costs, a regimen often 4-6 times daily, over three delivery system are loteprednol etabonate, lower risk and, in certain cases, market weeks. This regimen, combined with inef- 0.1% (OcuSurf-LP), moxifloxacin, 0.5% exclusivity. Given the benefits, many gener- ficient drug absorption, results in a less (OcuSurf-MOX), dexamethasone, 0.1% ics developers are leveraging 505(b)(2) to than ideal scenario for wound healing and (OcuSurf-DX), fluticasone propionate, carve out niche markets because there are disease management. To solve this problem, 0.1% (OcuSurf-FP). opportunities for specialisation; 505(b)(2) most eye-drops are now formulated with Integral BioSystems is developing a series development is more than a regulatory path- viscosity-enhancing polymers that enhance of ophthalmic products with the OcuSurf way, it is a competitive business strategy. the residence time of the drug and hinder In the next section, we introduce rapid clearance of fluid from the ocular OcuSurf™, a novel, patent-pending, dif- surface. These viscosity-enhancing poly- ferentiated and improved formulation mers range from cellulose derivatives (like approach for medications to treat disor- hydroxypropyl cellulose and carboxymethyl ders of the ocular surface and the anterior cellulose) to polyvinyl alcohol, xanthan chamber. gum, guar gum, hyaluronic acid and polyvinyl pyrrolidone.3 NANOSTRUCTURED EYE-DROP To counter the need for multiple WITH HIGH OCULAR PERMEABILITY drugs administered simultaneously, fixed drug combinations have been developed A substantial number of ophthalmic drug and commercialised (e.g. Tobradex™ and Figure 1: Chemical structure of products for disorders of the ocular sur- Zylet™).4,5 These approaches have had syn- loteprednol etabonate (OcuSurf-LP). face are hydrophobic, or sparingly soluble ergistic advantages in ophthalmic therapy. in water. Thus, in order to administer the However, there is still a need for rapidly platform, employing a 505(b)(2) strategy on drugs as eye-drops, they are formulated as absorbing ophthalmic formulations that the reformulation of existing products. multi-dose drug suspensions in a biocom- enable a lower drug concentration and In particular, a loteprednol etabonate patible, pH-adjusted aqueous vehicle. The achieve equivalent, or more effective, thera- topical product (OcuSurf-LP) (Figure 1) for process of drug absorption by ocular tissue pies. the prevention of inflammation post cataract is comprised of dissolution of the drug in the Integral BioSystems has developed a surgery is underway. An elegant structural tear fluid, followed by diffusion of the dis- proprietary platform, OcuSurf™, that can design improvement, loteprednol etabonate solved drug into the tissue, a process that is be formulated easily with multiple drugs is a novel carbon 20 (C-20) ester-based counteracted by the high rate of fluid turno- and fixed drug combinations as product corticosteroid 6 that has been developed as ver and consequent drainage via the naso- improvements of existing drug products, a topical treatment for ocular inflammation. lacrimal duct. This results in less than 5% new applications of existing drug products Loteprednol etabonate was developed using of each eye-drop actually being absorbed or high performing products of new drug retro-metabolic design, in which an inac- by the target tissue. Consequently, drug actives. tive and nontoxic metabolite of a reference suspensions are typically formulated with OcuSurf™ is an aqueous nano-disper- compound is used as the starting point for a high concentration of drug to achieve a sion of dissolved hydrophobic drug in nano- the synthesis of a therapeutically active, but therapeutic effect. Thus, a clinical and mar- structured “cores” that rapidly absorb into metabolically unstable, compound that can Integral BioSystems Specialized Formulations We are your partner in formulation development. And, we deliver. Services Expertise in Delivery Systems Stability Testing of R&D Prototypes Routes Pre-formulation Microspheres ICH conditions at 25ºC 40ºC, 60ºC Topical Analytical Methods Nanospheres Arrhenius modeling available IV/IM/SQ Deformulation Nanocrystals Ophthalmic Rapid Testing Services Formulation Development Liposomes Intranasal NMR, UV-Vis, DSC/TGA, SEM, R&D Compatibility and Stability Testing Emulsions Rectal Microscopy, others Scale up and Design of Experiments (DOE) Injectables Ungual (nail) Container Closure Selection Dispersions Permeability Studies Otic (ear) Formulations for Animal Studies Cornea Sublingual CMC Consulting Services Technology Transfer Dermal Throat Pharmaceutical Development Intestine CMC Writing Your API. Our Formulation. Integral BioSystems, LLC; 19A Crosby Drive, Suite 200, Bedford, MA 01730 www.integralbiosystems.com - [email protected] - 781.258.4039

bonate formulated in OcuSurf demonstrat- ed high corneal permeability. In addition, corneal drug concentrations were many-fold higher for the OcuSurf group (2176 µg/g) versus the LoteMax groups (1109 µg/g: LoteMax gel; 987 µg/g LoteMax Ointment). Characterised by optical microscopy, the OcuSurf Platform is a uniform nano-dispersion with drug-containing “cores” (Figure 3 & 4). The cores contain dissolved drug, released at 37ºC in the eye. The drug-containing cores are dispersed in an aqueous, bio-adhesive, polymeric phase (the continuous phase), with a viscos- Figure 2: High permeability of loteprednol etabonate formulated in OcuSurf ity of 350 centipoise (measured at 25ºC, nanodispersion. by Brookfield (Middleboro, MA, US) viscometer).

Figure 5: OcuSurf-LP particle size distribution measured by laser A) B) light diffraction. Figure 3: Optical microscopy of OcuSurf formulations using an Olympus BX51P, using an oil immersion objective at 1100X; A= OcuSurf-LP (LP=loteprednol Particle size distribution of OcuSurf- etabonate); B=OcuSurf-DX (DX=dexamethasone). LP was measured by laser light diffraction (Figure 5), using a Horiba LA-950 particle size analyser. The statistical mode (most fre- quent occurrence) and mean (average particle size, d50) of the nanodispersion was <200 nm. Over three months at room temperature, there was no significant change in the particle size distribution. OcuSurf-LP was placed on stability (see Figure 6); no significant change in assay was observed at any temperature over three months. As seen in Figures 7A and B, OcuSurf plat- Figure 4: OcuSurf™ nanostructured dispersion. form is a non-settling delivery system. In vivo pharmacokinetic assessment with OcuSurf-LP be rapidly deactivated. In the case of lotep- perature storage and demonstrates high is underway. rednol etabonate, the drug is rapidly deacti- bioavailability. The OcuSurf platform can being devel- vated to inactive metabolites by nonspecific In a comparative ex vivo corneal per- oped as part of a 505(b)(2) strategy to treat tissue esterases in the ocular tissue, thereby meability study using a Franz-cell set- disorders of the eye, which include glaucoma, limiting its potential to cause adverse effects up with a donor and receptor chamber, corneal keratitis, blepharitis, allergic conjunc- such as ocular hypertension and glaucoma, the diffusive characteristics of loteprednol tivitis, cataracts, dry eye, bacterial and fungal side effects commonly known to occur with etabonate was compared with commer- infections. To that effect, Integral BioSystems steroids. Products containing loteprednol cial LoteMax Gel and LoteMax Ointment. is working on products for dry eye and ocular etabonate (LoteMax™ Ointment, 0.5%, 500 µg of each product was loaded in the methicillin-resistant Staphylococcus aureus LoteMax™ Gel, 0.5%) have been FDA donor chamber of the Franz cells with a (MRSA). approved, with high patient acceptance. freshly excised bovine cornea as the mem- In addition to the applications in ocular Both product formulations contain micro- brane. 0.1% HPCD in phosphate buffered delivery described here, OcuSurf platform is nised drug. OcuSurf™-LP is non-settling, saline, pH 7.4, was used as the receptor applicable as a topical delivery system for der- membrane-adherent, stable for room tem- fluid. As shown in Figure 2, loteprednol eta- matological, urological and otic medications.

REFERENCES:

1. Persistence Market Research, 2016, Article 3188, “Global Market Study on Ophthalmic Devices: Asia to Witness Highest Growth by 2020”. 2. US FDA Guidance for Industry, Figure 6: Stability data for OcuSurf-LP, 0.1%. Applications Covered by Sections 505(b)(2), 1999 Kompella UB, Kadam RS, Lee V, “Recent Advances in Ophthalmic Drug Delivery,” Ther Deliv, 2010, Vol 1(3), pp 435-456. 3. Tobradex US product insert. 4. Zylet US product insert. 5. Bodor N, Buchwald P, “Ophthalmic Drug Design Based on the Metabolic Activity of the Eye: Soft Drugs and Chemical Delivery Systems.” AAPS J, A) B) 2005, Vol 7(4), pp E820-833.

ABOUT INTEGRAL BIOSYSTEMS Figure 7: (A) Vials were stored at room temperature and visually assessed periodically. (B) Settling kinetics was assessed by measurement of drug Integral BioSystems specialises in biode- concentrations over 120 hours at room temperature. gradable sustained-release dosage forms for proteins, peptides, nucleic acids and small molecules. Microspheres, liposomes, and micro-nano suspensions are Integral’s niche ABOUT THE AUTHOR specialisation. Integral BioSystems invites collabora- Named as one of “20 Women to Watch in Massachusetts High Technology in 2014”, tions that can be strictly on a CRO-basis Shikha Barman, PhD, has more than 20 years of experience in the translation of concepts to create drug products with compounds from the lab into clinical and commercial drug products. She is CEO, CTO and a found- that already have IP protection, or as a co- ing member of Integral BioSystems, LLC. developer with pharmaceutical companies Dr Barman’s expertise is in the design of cell-targeted delivery systems, to render repurposed drugs IP-protectable customised to permeate biological barriers such as the skin, ocular and with Integral’s proprietary drug delivery intestinal barriers. Prior to founding Integral BioSystems as a hybrid CRO/inno- innovations. vation-based company with Boston-area patent attorney Dave Karasic, she was Integral scientists have developed a pro- Vice-President of Pharmaceutical Development and Preclinical Sciences at prietary, bioengineered ocular surface mesh Follica, Inc (Boston, MA, US) responsible for multiple departments in CMC, (NanoM™) that releases precise, predict- preclinical DMPK and toxicology, developing dermal products in antimi- able concentrations of drug over time. The crobials, onychomycosis, hair growth and acne. Prior to Follica, she was Senior composition of the NanoM delivery system Director of CMC/Pharmaceutical Development at Inotek Pharmaceuticals, can be modulated for a drug regimen that Inc (Lexington, MA, US) developing products utilising novel small-molecule PARP lasts a week, to one that can be designed inhibitors and A-1 agonists into ocular treatments for glaucoma and diabetic last 3-6 months. retinopathy and an injectable for a fast-acting treatment for atrial fibrillation. The company also announces OcuSurf™, She was also Head of Vaccine and Transdermal Development at Sontra Medical a proprietary nanostructured delivery sys- Corporation (now Echo Therapeutics, Iselin, NJ, US), developing products deliv- tem designed to deliver drugs to the ocular ered using an innovative transcutaneous ultrasound device (SonoPrep™) developed surface, enhancing permeation into ocular at the Robert Langer Laboratory at MIT. One of these products is tissues. The company invites collabora- marketed as a continuous glucose monitoring device. At Zycos, Inc, Dr Barman tions with drug companies to co-develop was Head of Gene Delivery, targeting PLG microsphere-based DNA-based ophthalmic products utilising these delivery therapies for the treatment of HPV and cancer. Lastly, at Focal, Inc, modalities. she helped develop one of first lines of biodegradable tissue sealants, now As a CRO, Integral BioSystems offers marketed as FocalSeal, by Genzyme BioSurgery. pharma companies formulation develop- Dr Barman has 17 issued US Patents and 56 US applications/PCTs, 65 publications ment services, process engineering, scale-up, and four book chapters. technical transfer and CMC writing services for FDA submissions. Integral BioSystems Dr Barman’s PhD is in Polymer Science and Plastics Engineering from University of is based in the Boston, MA, US, area with Massachusetts at Lowell, an MS in Polymers from University of Massachusetts at Lowell, offices and fully equipped laboratories at and a BS / MS in Chemistry from Auburn University, AL, US. Bedford, MA, US.