OPHTHALMIC DRUG DELIVERY 63 O 2016 • ISSUE N 2016 TH JANUARY 27 JANUARY Contents

INTELLIGENT DESIGN TOPICAL OCULAR RING BIODEGRADABLE FOR PRESERVATIVE-FREE TO REPLACE DROPS IN SILICA MATRIX P04 EYE DROPS P20 GLAUCOMA P28 SR DELIVERY SYSTEM OPHTHALMIC DRUG DELIVERY 63 O 2016 • ISSUE N 2016 TH JANUARY 27 JANUARY Contents

ONdrugDelivery Issue No 63, January 27th, 2016 OPHTHALMIC DRUG DELIVERY CONTENTS This edition is one in the ONdrugDelivery series of publications from Frederick Furness Publishing. Each issue focuses on a specific topic within the field of Expert Overview: Development of Sustained-Release Ocular drug delivery, and is supported by industry leaders Delivery Technologies in that field. 4 - 5 Michael O’Rourke, President and Founder Scotia Vision Consultants 12 MONTH EDITORIAL CALENDAR Using Intelligent Design to Deliver Safe Preservative-Free Feb Prefilled Syringes Multi-Does Eye Drops Mar Transdermal Delivery & Microneedles 6 - 9 Fanny Sellier, Global Category Manager Apr Pulmonary & Nasal Drug Delivery Nemera May Injectable Drug Delivery: Devices Focus Introducing Ocusurf™ Nanostructured Emulsion as a 505(B)(2) Strategy Jun Connected Delivery Devices Shikha P Barman, Chief Executive Officer, Chief Technology Officer Jul Novel Oral Delivery Systems 12 - 15 Integral BioSystems Sep Wearable Injectors Oct Prefilled Syringes Improving Ophthalmic Drug Delivery With Novel Emulsion Nov Pulmonary & Nasal Delivery Technologies for Sterile Ustained-Release Injectables Dec Delivering Biotherapeutics Robin de Bruijn, Chief Technology Officer and 17 - 19 Frank de Jong, Chief Executive Officer 2017 Jan Ophthalmic Delivery EmulTech

SUBSCRIPTIONS: A Topical Ocular Ring Designed to Replace Glaucoma Eye Drops 9-10 issues of ONdrugDelivery Magazine published Anne Brody Rubin, Vice-President, Marketing per year, in PRINT & PDF. 20 - 21 ForSight VISION5 PDF subscription is always completely free. Scalability of Micro Intraocular Implants and Devices PRINT subscription costs £189/year. Donna Bibber, Chief Executive Officer Print subscription includes delivery of a printed copy 22 - 24 Micro Engineering Solutions of each issue to one address anywhere in the world. E: [email protected]. Therapy without Drops: A Reality Chris Muller, Chief Commercial Officer and Deepank Utkhede, Chief Scientific Officer EDITORIAL AND ADVERTISING: 26 - 27 Mati Therapeutics Contact: Guy Furness, Proprietor & Publisher T: +44 (0) 1273 47 28 28 New Solutions for Ophthalmic Drug Delivery Using Biodegradable Silica Matrix E: [email protected] Mika Jokinen, Research Director, 28 - 30 Lasse Leino, President and Chief Executive Officer and MAILING ADDRESS: Cora Griffin, Business Development Director Frederick Furness Publishing Ltd DelSiTech The Candlemakers, West Street, Lewes, Opsisporin: A Long-Acting Drug Delivery Approach for Uvetitis East Sussex, BN7 2NZ, United Kingdom Paul Seaman, Head of Sustained Delivery and ONdrugDelivery Magazine is published by 32 - 35 Daniel Palmer, Chief Scientific Officer Midatech Pharma Frederick Furness Publishing Ltd. Registered Office: The Candlemakers, West Street, Lewes, East Sussex, BN7 2NZ, United Kingdom. Registered in England: No 8348388. VAT Registration No: GB 153 0432 49. ISSN 2049-145X print ISSN 2049-1468 pdf Copyright © 2016 Frederick Furness Publishing Ltd All rights reserved

The views and opinions expressed in this issue are those of the authors. Due care has been used in producing this publication, but the publisher makes no claim that it is free of error. Nor does the publisher accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

Front cover image courtesy Nemera (2015). Reproduced with kind permission.

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3164_Pharma16_297x210+3mm_MP408.indd 1 11/12/2015 12:44 Introduction

EXPERT OVERVIEW: DEVELOPMENT OF SUSTAINED-RELEASE OCULAR DELIVERY TECHNOLOGIES

The global cost of vision loss is nearly retinopathy (DR), diabetic macular edema US$3 billion (£2.1 billion) for the 733 (DME) and glaucoma, due to their whole million people living with low vision and or partial impact on the posterior and ante- blindness worldwide in 2010.1 The global rior segments of the eye, and their growing pharmaceutical market was estimated at market sizes, may offer the most promising $18.1 billion at year-end 2013, estimated to opportunities for future ocular drug delivery grow to approximately $23 billion by year- technologies. They affect large numbers of end 2018. Within this time period, retinal people and pose significant risk of vision indications are demonstrating the greatest loss and blindness for those affected. growth from $6.9 to $9.9 billion or 7.5% compounded annual growth rate (CAGR). Glaucoma is the second largest segment, “Only four posterior forecast at $5 billion by the end of 2018, segment products to which is 3.1% CAGR followed by dry-eye at $3.1 billion, or 4.3% CAGR.2 date have overcome the There have been major advances in recent challenges of development years in developing and launching new sus- and achieved broad tained-release ocular drug delivery systems to treat vision loss better. However, only regulatory approval with a small number have achieved both global a degree of commercial regulatory approval and commercial suc- success since 1995.” cess. Only four posterior segment products to date have overcome the challenges of development and achieved broad regulatory Current therapeutic options for these approval with a degree of commercial suc- diseases may at best manage the condition, cess since 1995. These include: slowing or halting further deterioration or disease progression. New breakthrough • Vitrasert ® (ganciclovir 4.5mg) treatments would benefit from robust sus- – approved 1995 tained delivery of the drug to the tar- • Retisert ® (fluocinolone 0.59 mg) get tissues in the posterior segment and, – approved 2005 importantly, enhance compliance of patients • Ozurdex ® (dexamethasone 0.7 mg) with long-term treatment regimens for these – approved 2009 chronic diseases, for example avoiding or Michael O’Rourke • Iluvien ® (fluocinolone acetonide 0.19mg) reducing the need for frequent injections. President and Founder – approved 2011. In addition, from a product “market T: +1 813 323 1438 E: [email protected] need” perspective, there are arguably at Yet despite the challenges there remains least five “Holy Grails” that would offer a significant market opportunity to enhance not only significant clinical and medical Scotia Vision Consultants current delivery technologies or develop new progress but would also offer multi billion 1027 South Dakota Ave Tampa technologies offering improved treatment dollar market opportunities and provide FL 33606 options for patients suffering from the major major competitive advantages over today’s United States blinding eye diseases. therapeutics; some or all could include sustained-release therapy: www.scotiavisionllc.com THERAPEUTIC FOCUS Michael O’Rourke is a specialised 1. Sustained release glaucoma therapy ophthalmic pharma consultant with The major blinding diseases, wet age-related 2. Sustained-release large molecules includ- expertise in pharmaceutical, drug macular degeneration (w-AMD), diabetic ing proteins, peptides, and aptamers delivery and medical device strategies.

3. Sustained anterior delivery to posterior terior segment conditions, such as w-AMD Some examples of such technologies in segment and diabetic related retinal disease, remains development include: 4. Dry AMD Rx therapy intravitreal injection (IVT) with anti VEGf 5. Neuroprotection. agents. In 2005, approximately 22 million Posterior Segment Delivery IVTs were administered globally.4 However, • Refillable drug reservoirs Drug-delivery developments to the this multi-billion dollar IVT injection market • Encapsulated cell technology posterior and anterior segments of the has demonstrated that a proven sustained- • Cell-based programs, including stem eye, for both small and large molecules release implantable technology itself is not cells for neovascular AMD may therefore provide a pathway to new a prerequisite for commercial success, but • Iontophoresis market advances for the launch of new that a sustained clinical and targeted effect • Novel adeno-associated viral (AAV) therapies based on enhanced current of the drug may be critical. The onerous variant technology for long-term protein technologies or through innovation with need for monthly or bi-monthly injections delivery to the eye in DME, neovascular new innovative approaches. may not be ideal from a patient adherence AMD, glaucoma and other conditions or comfort perspective and, potentially, for • Prostaglandin analogue delivery systems MEETING THE CHALLENGES OF safety reasons. • Hydrogel technology SUSTAINED DRUG DELIVERY The future for sustained-release ocular • Supra choroidal implants or injectable drug delivery will include reducing the treat- suspensions Several factors contribute to the challenge ment burden of IVTs through innovations • Injectable protein delivery systems of developing new sustained-release drug in delivery technology for both small and • Microparticle and nanoparticle systems. delivery systems including: large molecules and in all cases combining effective therapeutics with the appropri- Anterior Segment delivery 1. The primary need to match the drug with ate drug delivery system. Established big • Topical systems for example semi-fluor- the delivery technology. This requires pharma companies will need to consider inated alkane delivery, enhancing drug the demonstration of sustained delivery product lifecycle extension strategies to solubility pharmacokinetics and using the appro- include new drug delivery technologies, • Contact lens delivery systems priate animal models for testing the although it is most likely that the innovation • Mucosal delivery drug’s safety and efficacy. for the technology will come from the start- • Topical peptides for neovascular AMD 2. Tolerability of drug with the technology. up environment. and corneal injuries. 3. The right clinical trial design and under- All technologies approved today incor- standing that platform compatibility dif- porate existing generic drugs, so the choice CONCLUSION fers with compound solubility and mol- of drug comes first, then is matched with a ecule size. delivery technology, although the process Novel technologies required to deliver 4. The identification and ultimate granting itself is not an exact science. It may be ideal agents specifically and effectively to the eye of intellectual property rights. to have a broad drug delivery platform tech- are rapidly evolving. These will have the 5. In addition, sourcing the appropriate nology, customised to new drugs, or a class potential to radically alter the way many funding or partnerships to move the of drugs, remembering each drug compound ocular conditions are treated, especially technology through its IND and clinical will require a different release profile and retinal blinding diseases and glaucoma. stages is a critical success factor. formulation. The next decade promises great strides in Due to the large numbers of products therapy achieved through sustained-release Despite these barriers, multiple technolo- in the pipeline, the selected product devel- drug delivery for many currently poorly- gies and approaches, both posterior and opment strategy must offer a disruptive treated or untreatable ocular diseases. anterior, are in either pre - or clinical devel- technology; that is, disrupting the mar- REFERENCES

“New breakthrough treatments would benefit from 1. Access Economics, prepared for AMD Alliance International, “The robust sustained delivery of the drug to the target tissues Global Economic Cost of Visual in the posterior segment and, importantly, enhance Impairment”. March 2010. compliance of patients with long-term treatment 2. Market Scope estimates; Ophthalmic Innovation Summit Data, November regimens for these chronic diseases, for example 14 2013. avoiding or reducing the need for frequent injections.” 3. “Market Analysis – New Ocular Drug Delivery Technologies in Development”. Scotia Vision Market opment. Based on recent analysis conducted ket compared with what already exists or Report, 2016 (data on file). by Scotia Vision for new or enhanced tech- is in the development pipeline. It should 4. “VEGF Injections Source: Market nologies in development, there are at least offer true innovation both to patients and Scope Estimates Market Scope 11 in retina, 20 in glaucoma and six anterior doctors, meet a significant market need, Source”. Ophthalmic Innovation delivery technologies.3 and offer both clinical feasibility and poten- Summit 2015, Courtesy Dave The current gold-standard to treat pos- tial reimbursement. Harmon.

USING INTELLIGENT DESIGN TO DELIVER SAFE PRESERVATIVE- FREE MULTI-DOSE EYE DROPS

A significant patient population requires the long-term use of eye drops multiple times a day. Maintaining the sterility of eye drops is important for patient health. Single-use doses are expensive and preservatives can cause allergies and irritation but, as Ms Fanny Sellier, Global Category Manager, Ophthalmic, Nemera, explains here, the intelligent design of multi-dose bottles provides a viable means of delivering safe, preservative-free eye drops.

PATIENTS NEED STERILE EYE DROPS PRESERVATIVE-FREE BETTER FOR PATIENT HEALTH A large number of patients have conditions that require the long-term daily use of eye One way of keeping multi-dose eye drop- drops. For example, dry-eye syndrome is pers safe for patients is to add preservatives associated with aging, contact lens use and to the formulation. environmental factors such as windy and However, the use of preservatives can sunny weather. It affects an estimated 5% cause allergies or ocular irritation, and some of over 50s in the US 1 and is usually man- can even cause a toxic response, damag- aged using an artificial tear solution which ing patients’ eyes.4 Any such reactions is a needs to be applied up to four to six times particular issue for patients who rely on a day, often for the rest of the patient’s life. the long-term use of eye-drops for chronic Conditions such as hay fever and glaucoma conditions. also require the long-term use of self-admin- In 2009, the European Medical Agency istered eye drops. stated that the “inclusion of antimicrobial It is important that all eye drops are preservatives or antioxidants in a finished kept free from bacteria. The microbial con- product needs special justification”. Even tamination of eye drops is a significant risk when preservatives are tolerated in an adult factor in the development of bacterial kerati- population there are still questions over tolerance for the paediatric The EMA has stopped short of a general population. The EMA has recommendation not to use preservatives stopped short in eye drops, but they recommend that of a general “preservative free formulations whenever recommendation not to use possible should be considered” and that preservatives Ms Fanny Sellier “ophthalmic preparations without preservatives in eye drops, Global Category Manager are strongly recommended for use in but they rec- Ophthalmic Products ommend that T: +33 4 74 94 06 54 E: [email protected] paediatric patients, especially neonates.” “preservative free formulations whenever Nemera tis.2 Post-operative patients are at particular possible should be considered” and that 20, avenue de la gare BP 30 – 38290 La Verpillière risk of infection, as are patients who have “ophthalmic preparations without preserva- France used topical steroids, since these lower the tives are strongly recommended for use in ocular defences.3 paediatric patients, especially neonates”. www.nemera.net

PRESERVATIVE-FREE UNIDOSES: genic, bacteria (which are nominally larger WHAT MAKES FILTERS UNRELIABLE? EFFECTIVE BUT EXPENSIVE than 0.2 μm) can cross a 0.2 μm nylon membrane.6 All of the bacteria crossed from The evidence that bacteria can pass through Unidose eye droppers are a commonly used the upper membrane surface to the solid 0.2 μm filters is clear, but the reasons delivery method for preservative-free eye medium below the membrane; this ability are not obvious. One possibility for the drops. By virtue of being single use, there is was highly repeatable and did not depend on observed passage of bacteria through filters no opportunity for bacterial contamination the make of membrane used. Bacteria grow- could be due to the nature of the mate- at the point of use. ing below the membrane exhibited normal rial of the filters. The sponge-like structure Unidoses are ideal for clinical settings, size and morphology.” includes holes of varying sizes (Figure 2), especially during surgery. However, they some of which are statistically likely to are too costly and inconveniently bulky to be larger than 0.2 μm. In fact, one study be suitable for home use in chronic condi- found that 0.2 μm filters have a distribution tions. Single-unit, preservative-free drops of pore sizes that includes some as big as have been calculated to be 1169% more 0.5 μm.8 expensive to produce than the equivalent Individual testing would eliminate preserved eye drops in a multi-dose bottle.5 doubt over the viability of each filter, but the process used to test filters is INTELLIGENT DESIGN FOR destructive.9 The testing method PRESERVATIVE-FREE MULTIDOSES introduces bacteria and liquid onto the surface of the filter. This starts bacterial The alternative way to keep eye droppers growth on the filter and therefore decreases clean is by the intelligent use of technology. the subsequent shelf life of the dispens- Rather than relying on the anti-microbial er. Therefore, in-line testing of multi-dose properties of preservatives to kill any bacte- Figure 1: Scanning electron dispensers that rely on filter technology ria that enter the bottle, the ideal approach micrograph of nylon membrane is not possible. Instead, testing is carried is to prevent any entry of bacteria into the filter (pore size 0.22 μm). out statistically on only a proportion of bottle in the first place. the dispensers. Multi-dose bottles dispense drops using However, it is likely that the presence either a non-return valve or a filtering sys- of larger holes in the filters is not the tem. Most commercially available bottles sole mechanism of bacterial penetration. designed for multi-dose preservative free eye Hasegawa et al found that “Pseudomonas drops rely on a filtering system to stop the aeruginosa passed through a 0.22 μm pore entry of bacteria. When a drop is dispensed, size filter. The membranes which allowed the volume of the dose is compensated by passing-through of bacteria showed nor- air. Eye drops can become contaminated in mal bubble point values in the integrity two main ways: by contaminated air enter- test”. This demonstrates that bacteria are ing the device or by contaminated liquid still capable of passing through a reliable re-entering through the filter. 0.22 μm pore size filter.

FILTERING OUT THE BACTERIA? BACTERIAL MOTILITY IS A CAUSE Figure 2: Scanning electron micrograph OF FILTER PENETRATION Anti-microbial filters are typically made of a Millipore membrane filter (pore size 0.22 μm) showing a distribution of from a nylon fibre membrane that con- Bacteria come in a variety of shapes and pore sizes.10 (Bar in bottom right hand sists of tightly packed layers of strands of corner of image is 1 μm long.) sizes, but many of them share the ability to nylon fibres (see Figure 1). Filters work on self-propel by twitching, rotating or glid- the mechanical principle that bacteria are Even where filters are shown to be effec- ing. Twitching is the most common form large molecules that do not fit through the tive, the filtered bacteria clearly remain on of motility and is achieved through move- very small holes, while air and non-viscous the filter. A 2006 study on the efficacy of ment of the flagella in a way that makes solutions are able to pass through without single-use bacterial filters showed “a sig- the bacteria appear to swim. Studies have hindrance. nificantly greater bacterial growth on the shown that this motility enables bacteria to Sterile 0.22 μm filters are industry stand- proximal side of the filter compared with move through very small channels relative ards, but their effectiveness as bacterial the distal side”.7 Eye-drop filters act in to their size. filters has been challenged in the literature. two directions: pressure on the sides of the Hasegawa et al also experimented Unfortunately it has been found that bacte- plastic bottle dispenses a dose through the with a strain of P aeruginosa that was ria are capable of routinely penetrating 0.22 filter to the patient’s eye. When the pressure defective in twitching motility and found μm filters, even when the molecules seem to is released, air and a small amount of liquid that it was unable to pass through the be too big to fit through the holes. passes back through the filter and into the 0.22 μm filter. They concluded that it In a 2002 paper, “Big bacteria pass bottle. Therefore, bacterial growth on the is the flagellum-dependent motility of through very small holes,” Wainwright et filter represents a contamination risk for the P aeruginosa that enables it to penetrate al found that: “Common, potentially patho- delivered dose. fine filters.

BACTERIA ALSO PENETRATE BY GROWTH & DIVISION

Männik et al went on to find that Escherichia coli lose their ability to swim in channels narrower than their diameter.13 Surprisingly, they found that despite this they are still able to penetrate narrow channels. They observed that over time, through the mechanism of growth and division, E coli were able to penetrate filter channels “with a width that is smaller than their diameter by a factor of approximately two. Within these channels, bacteria are considerably squeezed but they still grow and divide”. Figure 4: The PureFlow™ technology This has clear implications for the effec- consists of using the air permeation tiveness of filters for multi-dose, preserv- property of the silicone to allow the air flow and avoid any bacterial ative-free eye droppers. Filtering liquid penetration. several times a day means that the filter remains wet throughout the usable lifetime but completely preventing the passage of of the device, presenting ideal conditions for any liquid or solid, including bacteria. bacterial growth. The function of the silicone membrane can be compared with an inflated balloon. AN ALTERNATIVE TO FILTERS The balloon is a continuous, waterproof BASED ON SILICONE: NOVELIA® material, yet gas slowly passes through the Figure 3: The Novelia® system uses wall of the balloon until the pressures inside A viable alternative to the use of sterile a non-return valve that removes and outside reach equilibrium. the need to filter the liquid. This filters for multi-dose, preservative-free eye makes it possible to use a silicone droppers is a non-return valve system used membrane to filter the air. in conjunction with a silicone membrane to “Devices that use filter the returning air (Figure 3). The one- the intake of air using a very fine membrane way valve ensures that no contaminated manufactured from silicone polymer. this PureFlow™ liquid can be re-introduced to the container The silicone membrane is a solid, non- technology can be tested after the drop has been dispensed, complete- porous material. It is homogenous and individually in-line as a ly removing the need to filter the liquid. The does not contain any holes therefore its intake of air into the dispenser takes place characteristics can be precisely engineered. consistent part of the via a separate venting system with a silicone The membrane’s intermolecular distance manufacturing process.” membrane called the PureFlow™ technol- is of the order of nanometres, allowing ogy (Figure 4). The venting system filters the passage of air through the membrane, The separation of the dose delivery from the venting system means that the membrane ® NOVELIA KEY ADVANTAGES is kept dry. This minimises the risk of bacterial growth on the surface of the membrane, For the pharmaceutical company: And of course for the patient: and also means that the testing process is non-destructive. In fact, devices that use • 100% controlled and safe thanks to • Preservative-free to protect the this PureFlow™ technology can be tested itspatented PureFlow™ technology ocular surface individually in-line as a consistent part of • Functional with suspensions and • User-friendly and intuitive, as easy to the manufacturing process to ensure robust solutions up to high viscosities use as any standard eyedropper quality standards. This provides an even • Large range of bottles • Blue tip for a better precision when greater assurance of safety for the patients. • Compatible with most existing filling targeting the eye lines (screw cap) • One drop at a time in the patient’s SUMMARY • Simplified manufacturing pro- eye, calibrated drops cess thanks to preassembled cap • Low squeeze force A non-return valve combined with a sili- and nozzle. • More sustainable and affordable cone membrane venting system demon- compared to unit-dose, easier to carry. strates how intelligent design can be used to prevent the entry of bacteria into a With Novelia®, preserve patient’s eyes, not drugs! bottle, making it possible to deliver safe, multi-dose preservative free eye drops.

REFERENCES for the preparation and maintenance der Kosten mit Mehrdosis”. of sterile ophthalmic solutions”. Am J Ophthalmologe, 1994, Vol 91, pp 1a. Schaumberg DA, Sullivan DA, Buring Ophthalmol, 1952, Vol 35, pp 656-659. 602-605. JE, Dana MR, “Prevalence of dry eye 2f. Vaugh Jr DG, “The contamination 6. Wainwright M, Al Talhi A, Gilmour syndrome among US women”. Am J of fluorescein solutions with special DJ, Anderson RW, Killham K, “Big Ophthalmol, 2003, Vol 136, pp 318-326. reference to Pseudomonasaeruginosa bacteria pass through very small 1b. Schaumberg DA, Dana R, Buring (Bacillus pyocyaneus)”. Am J holes”. 2002, Vol 58(6), pp 558-560. JE, Sullivan DA, “Prevalence of dry Ophthalmol, 1955, Vol 39, pp 55-61. 7. Unstead M, Stearn MD, Cramer D, eye disease among US men: estimates 3. Rahman MQ, Tejwani D, Wilson Chadwick MV, Wilson R, “An audit from the Physicians’ Health Studies”. JA, Butcher I, and Ramaesh K, into the efficiency of single usebacte- Arch Ophthalmol, 2009, Vol 127, pp £Microbial contamination of pre- rial/viral filters for the prevention of 763-768. servative free eye drops in multi- equipment contamination during lung 2a. Templeton 3rd WC, Eiferman RA, ple application containers”. Brit J function assessment”. Respir Med, Snyder JW et al, “Erratia keratitis Ophthalmol, 2006, Vol 90(2), pp 2006, Vol 100, pp 946-950. transmitted by contaminated eye 139–141. 8. Osumi M, Yamada N, Toya M, droppers”. Am J Ophthalmol, 1982, 4. Report of the International Dry Eye “Bacterial retention mechanisms of Vol 93, pp 723-726. [PubMed] Workshop. Ocul Surf 2007, Vol 5(2), membrane filters”. PDA J Pharm Sci 2b. McCulloch JC, “Origin and patho- pp 65-204. Technol, 1996, Vol 50, pp 30-34. genicity of Pyocyanea in conjunctival 4b. EMEA Public Statement on 9. Benezech T, “A method for assess- sac”. Arch Ophthalmol, 1943, Vol Antimicrobial Preservatives in ing the bacterial retention ability 29, pp 924-936. Ophthalmic Preparations for Human of hydrophobic membrane filters”. 2c. Hogan M J, “The preparation and Use (Doc Ref: EMEA/622721/2009). Trends in Food Sci & Technol, 2001, sterilization of ophthalmic solutions”. http://www.ema.europa.eu/docs/en_GB/ Vol 12, pp 36-38. Calif Med, 1949, Vol 71, pp 414-416. document_library/Presentation/2010/09/ 10. Männik J, Driessen R, Galajda P, 2d. Theodore FH, “Contamination of eye WC500096784.pdf) Keymer JE, Dekker C, “Bacterial solutions”. Am J Ophthalmol, 1951, 5. Hertel F, Pfeiffer N, growth and motility in sub-micro- Vol 34, pp 1764. “Einzeldosisapplikationen in nconstrictions”. PNAS, 2009, Vol 2e. Theodore FH, “Practical suggestions der Glaukomtherapie. Vergleich 106(35), pp 14861–14866.

Media Pack

ONdrugDelivery 2016 EDITORIAL CALENDAR

Publication Month Issue Topic Materials Deadline

March 2016 Skin Drug Delivery: Dermal, Transdermal & Microneedles February 22nd

April 2016 Pulmonary & Nasal Drug Delivery March 7th

May 2016 Injectable Drug Delivery: Devices Focus April 11th

June 2016 Connected Drug Delivery Systems May 2nd

July 2016 Novel Oral Delivery Systems June 6th

Sepetember 2016 Wearable / High Volume Injectors August 8th

October 2016 Prefilled Syringes September 12th

November 2016 Pulmonary & Nasal Delivery October 10th

December 2016 Delivering Biotherapeutics November 14th

January 2017 Ophthalmic Drug Delivery December 12th

Media Pack

ophthalmic

pulmonary THE NEW PRESERVATIVE-FREE MULTIDOSE EYEDROPPER, COMMERCIALIZED AS A PACKAGING OF MEDICAL DEVICES AS WELL AS DRUG PRODUCTS ACROSS 4 CONTINENTS.

dermal/ transdermal Nemera provides solutions for the pharmaceutical industry, including standard innovative products, development of custom devices and contract manufacturing.

parenteral

nasal/ buccal/ auricular

www.nemera.net [email protected] Phone: +33 (0)4 74 94 06 54 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 posterior 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 represents 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 demonstrated 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 frequent 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.

EmulTechxxx

IMPROVING OPHTHALMIC DRUG DELIVERY WITH NOVEL EMULSION TECHNOLOGIES FOR STERILE SUSTAINED-RELEASE INJECTABLES

In this article, Robin de Bruijn, MSc, Chief Technology Officer, and Frank de Jong, MSc, Chief Executive Officer, both of EmulTech, describe the company’s ET4ME micro-encapsulation process, and its suitability as a particle formation technology for enhancing and enabling injectable ophthalmic pharmaceutical products.

In the ophthalmic pharmaceutical world, (fluocinolone acetonide), Ozurdex® (dexa- there is a large need for and challenge to methasone), and Iluvien® (fluocinolone ace- develop effective long-term delivery sys- tonide). Unfortunately, the aforementioned tems to solve problems with the retina. complications as a result of these (often Typically, only systemic doses by admin- non-absorbable) implantations are still not istration directly into the eye are the only fully resolved. way to deliver sufficient concentrations of Micro-encapsulation of small- and large- drugs. These are done by injections which molecule APIs is a very advanced solution to injectable delivery problems. Micro-encapsulation is one of “Encapsulation in biodegradable the most interesting areas in modern pharmaceutical technol- matrices is used for controlling the ogy. It is a complex, interdisci- release of all kinds of compounds. plinary field requiring specialist Demand for the process has led to knowledge of polymer science and familiarity with emulsion the creation of advanced emulsion technology. It includes the pro- solvent evaporation/extraction cess in which the active pharma- based micro-encapsulation ceutical ingredient is trapped in small microparticles. Due to its technologies. It is advanced process complexity, micro-encapsula- knowledge that can translate the tion is extensively studied inside major pharmaceutical compa- formulation complexity into to a Mr Robin de Bruijn nies, universities and research Chief Technology Officer successful drug product” institutes. Encapsulation in bio- T: +31 40 751 6162 degradable matrices is used for E: [email protected] controlling the release of all can be very problematic. An increasing kinds of compounds. Demand for the pro- Mr Frank de Jong number of drugs designed to prevent or cess has led to the creation of advanced Chief Executive Officer treat these diseases require repeated and emulsion solvent evaporation/extraction T: +31 40 751 6160 E: [email protected] high-dose injections due to the high ocu- based microencapsulation technologies. It lar clearance rate, leading to clinical chal- is advanced process knowledge that can lenges in the form of side effects (infections, translate the formulation complexity into to EmulTech BV haemorrhages and cataract formation). One a successful drug product. De Lismortel 31 NL-5612 AR Eindhoven successful approach has been the surgi- The process of micro-encapsulation can The Netherlands. cal implantation of drug-releasing devices, address complex modern drug delivery issues. such as Vitrasert® (ganciclovir), Retisert® EmulTech has developed, and put to use in www.EmulTech.nl

Following the preclinical formulation and lab-scale process development, EmulTech is in the process of installing the capability to validate the equipment further and to formulate products according to cGMP requirements.

EMULSION TECHNOLOGY BENEFITS

Droplet formation in microfluidic devices has always been an interesting approach. EmulTech has made a breakthrough by modelling droplet formation on the cross-intersection of a microfluidic channel structure. Process parameters can be identified by feeding measurable material specific parameters (e.g. viscosity, interfacial tension) and particle characteristics (e.g. particle size) into the model. When the process parameters are set correctly, each droplet is formed to the same characteristics, ensuring the uniformity of the batch and thus its quality. This way ET4ME translates the trial-and-error approach of many processes into a quality-by-design approach. Scale-up is done through process inten- sifications (more channels per device) and Figure 1: SEM image of 40 µm PLGA particles created with ET4ME. numbering out (cartridges containing multiple devices). Process parameters identified in the formulation of drugs for clinical trials, a with world experts in partnered academic a single-channel setup can easily be translat- microfluidic process that creates a measurable institutions that require small volumes. The ed to a multi-channel setup to create larger microparticulate suspension where particle company offers a parallel strategy for swift volumes (up to Phase II clinical depending size is uniform and reproducible. and reproducible scale-up whilst providing on the application). This novel emulsion technology for product and process support throughout In principle, the technology is a highly micro-encapsulation, ET4ME, is usable in a product’s development cycle. CMOs in controlled emulsification technology hav- the formulation of multiple APIs, from the network provide a varied palette of ing various applications in different mar- small molecules right through to complex formulation development expertise, analyt- kets, such as the food industry (taste mask- biomolecules, with high levels of batch con- ics and GMP services and expert guidance ing, protection of additives against its sur- sistency and reproducibility upon scale-up. through the processes of new medicine and rounding, delivery to the gastro-intestinal By utilising a closed system, sterile for- material development for Phase I and Phase system), cosmetics (stability enhancement mulations can be achieved, coupled with II clinical trials. of uniform micro-emulsions), chemicals resistance to oxidative degradation. After validation for several biodegradable microparticulate systems and successful aseptic “This novel emulsion technology for micro-encapsulation, process simulation trials using the ET4ME process, the technology’s potential for phar- ET4ME, is usable in the formulation of multiple APIs, maceutically acceptable, sterile injectable from small molecules right through to complex product formulation has been demonstrated. biomolecules, with high levels of batch consistency BUSINESS MODEL BRINGING and reproducibility upon scale-up” EMULSION TECH TO LIFE

EmulTech has adopted a flexible and By collaborating, such companies are (increased control over reactions), phar- professional model to pool collective able to maximise budget effectiveness and maceutical industry (drug delivery, mark- experiences and co-operate in a multi- minimise experimentation without sacrific- ers, radiotherapeutics, etc). EmulTech’s disciplinary network to advance the use ing quality levels, and enhance productivity, prime markets are the inhaled and inject- of innovative technologies in product for- thereby providing increased value to cus- able drug delivery markets, because of the mulation. For example, EmulTech has the tomers and achieving significantly shorter significant added value ET4ME provides capability to test formulations together development times. in these markets.

Parameter Benefit standard droplet formation techniques. Quantifiable Based on measurable parameters, particle formation is now “measure-and-make.” Particles in this purely physical process Compatible APIs ranging from small molecules to complex biomolecules can be used. are produced in separate microchan- Uniform Particles are individually formed in the same way, leading to uniform size, nels, which protect APIs during particle loading and morphology. formation. Consistent Droplet formation is based on a physical process: fixed process parameters give The particles in this versatile process are fixed product characteristics. formed under very low shear conditions and Scalable Highly reproducible using mass parallelization. the absence of temperature modifications. Closed system Degradation by air/oxygen can be eliminated. With the ability to process any two liquids Aseptic Inline filtration in a closed system ensures sterility. in a drug delivery system, the optimal excipient and active blend can be achieved, Static system No moving parts, no high temperatures or high shear. Very reliable and stable. resulting in the optimised product. Figure 2: Benefits of ET4ME as a particle formation process. BIOMOLECULES The inhaled market requires particles Product benefits include: in the range 1-5 µm, preferable 2-3 µm for • Microparticles with a very narrow particle Highly potent biologically active ingre- optimal lung deposition. ET4ME, because size distribution dients are often easily deactivated and are of its uniformity, is well suited to meet • Improved injectability a challenge to deliver in a pharmaceutical these requirements. • Broad variety of APIs and carrier materi- formulation. Technologies like ET4ME pre- The ophthalmic injectable market als possible serve the fragile three-dimensional structure requires sterile suspensions with high syring- • New products are feasible of these actives; and the ability to define the ability, preferably with very small gauge optimal composition and release proper- needles (>28G). The closed system, com- The technology is a highly versatile ties, via superior particle formation control, bined with the 0.22 µm inlet filters, ensures particle formation technology based on a meaning that the challenges that accompany the creation of sterile suspensions. Also the microfluidic process (see Figure 2). The these highly potent active drug substances uniform particle size reduces the suspen- process enables the particle size, loading can be overcome. sion’s viscosity, making it more syringable and carrier material to be changed so as to and thus less painful for the patient. Also the create an optimal drug delivery system by FASTER DEVELOPMENT, uniform particle-size distribution of ET4ME offering a high level of control over droplet BETTER PRODUCTS ensures that large particles that may block formation. Size ranges of 1–1000 µm (with the needle are not present. Very small par- a distribution of <1%) are possible, with up This type of technology enables ticles that may result in immune response to 100% encapsulation in perfect spheres products to be developed with better dose dumping are also absent. In short, the with no porosity. therapeutic effects and improved patient optimal particle size both to ensure release The process is applicable to small compliance in a cost-efficient and time- and deliver by small-gauge needles is now molecules and biomolecules, is highly repro- ly manner. By eliminating poor batch- possible to achieve (see Figure 1). ducible during scale-up and offers reliable to-batch consistency, variable particle Main advantages of the technology are: batch-to-batch consistency. formation and numerous rounds of • Quality-by-design approach Parameter optimisation is of criti- inaccurate, costly and time-consum- • Reproducibility between batches and dur- cal importance with such emulsion tech- ing screening, ET4ME allows for more ing scale up nologies, particularly for criteria such as rapid, reliable and efficient prototyping. • No end sterilisation as a result of closed size, API load and morphology. ET4ME, Such versatile enabling technologies are system with inlet filters for example, facilitates the combination used for the non-destructive testing of • Benign process; no shear, no heat increase. of two fluids that cannot be mixed using fragile compounds, inhalables, injectables (including for ocular injection) and solid dosage forms. INJECTABLE PLGA DELIVERY SYSTEMS Many different formulations and multiple parameters can be scanned and Current APIs often exhibit poor solubility and/or a short half-life, requiring novel tested, facilitating more efficient R&D and approaches such as sustained release to achieve acceptable bioavailability. Injectable accelerating the development, scale-up and biodegradable and biocompatible polymer systems that utilise copolymers of lactic and commercialisation of highly potent APIs in glycolic acid (PLGA) are a promising advanced delivery system for week- to month-long the product pipeline. controlled release and have been around for decades. ET4ME type technologies address head-on the challenges of large-scale manufactur- CONCLUSION ing/scale-up needs and convoluted production schemes. Polymer microspheres can be formulated with a highly defined size, encapsulating the API in a polymer matrix. The The important development steps correct matrix sets the release duration (from weeks to months) and perfecting the mono- made by EmulTech resulting in the dispersed particle size establishes the zero order kinetics of the release. ability to produce sterile suspensions and The system operates under aseptic, closed conditions and eliminates the need for reducing the need for end-sterilisation complex work-up steps. Scale-up is achieved by massive parallelisation, ensuring product provide the pharmaceutical world with a consistency throughout the pharmaceutical development pipeline. new tool in their development programs.

A TOPICAL OCULAR RING DESIGNED TO REPLACE GLAUCOMA EYE DROPS

Here, Anne Brody Rubin, Vice-President, Marketing, ForSight VISION5, introduces the company’s ring-shaped ocular insert containing prostaglandin for the lowering of intra-ocular pressure in glaucoma. The product, which has been successful in Phase II trials, is due to enter Phase III this year.

Eye drops that lower intra-ocular pressure tant since it aligns well with established (IOP) are very effective at slowing the loss of practice patterns for lower-risk glaucoma visual field progression in glaucoma patients and ocular hypertension patients, and will – when patients take their drops regularly. therefore not require additional visits. However, fewer than 50% of patients who The Bimatoprost ring has been studied are initially prescribed prostaglandin eye in Phase I and II trials involving more than drops continue to refill their prescriptions 300 subjects. It is a soft, bimatoprost- reliably one year later.1 infused ring that rests under the eye lids Reasons patients cite for nonadherence and is applied at the regular eye-care visit include forgetfulness, physical challenges by the eye-care provider. In clinical trials, (such as tremor and arthritis) making self- patients have found it to be comfortable and administering drops difficult, and discom- well-retained.2 The company intends to start fort from the eye drops. The Bimatoprost Phase III testing in 2016. ring from ForSight VISION5 is designed The ring (see Figure 1a) comes in multi- to provide a solution for these nonadher- ple sizes to ensure it will be comfortable for ent patients. the patient. Once the eye is measured, the Elevated IOP is associated with a loss ring can be placed under the upper eye lid of vision and reducing IOP is the only and then under the lower lid (Figure 1b) and proven way to prevent vision loss. So, there then rests comfortably under the lids (Figure remains an unmet need to provide clinically 1c). In Phase I studies, approximately 90% relevant IOP reduction with a simple, non- of patients were comfortable wearing a non- invasive product for patients who do not or medicated ring and retention of the rings in cannot take their medications. Such a prod- both eyes for up to six months of continual uct can delay and prevent visual field loss use has been excellent. in patients who are otherwise not receiving An extensive clinical program has been adequate treatment. conducted on the Bimatoprost ring to date: The Bimatoprost ring is a topical solu- a total of nine clinical studies, including two tion for sustained IOP control. This sus- fully-masked, randomised, controlled, Phase II tained release ring delivers a prostaglandin efficacy studies with safety extensions. Ms Anne Brody Rubin for six months. The ring has a durable The ring delivers clinically significant IOP Vice-President, Marketing effect, is non-invasive, well-retained and is reduction for six months. Open-label Phase I T: +1 650 325 2050 x119 dispensed by the physician in a simple, in- studies in 27 subjects demonstrated that at E: [email protected] office procedure. The ring is designed with screening subjects had a diurnal mean IOP the goal of providing IOP control for non- of 16.3 mmHg and had been historically ForSight VISION5, Inc adherent patients. titrated to a single medication that had given 191 Jefferson Drive Menlo Park A single administration of the ring is them excellent IOP control. After a four- CA 94025 designed to provide six months of clinically week washout, IOPs rose to approximately United States significant IOP control. The six-month 24 mmHg. After a single placement of the durability profile of the product is impor- ring in each eye, diurnal IOP control was www.forsightvision5.com

maintained at about 18-19 mmHg with approximately a 5 mmHg reduction from baseline at six months. Overall, diurnal IOP reduction in the range of 4.7-6.5 mmHg was observed. IOP reduction in this range should provide clinically significant benefit to patients who do not adhere to their eye drops. Results from the first of the Phase II studies were presented by the principal investigator, Dr James Brandt, at American Academy of Ophthalmology 2016, and the data have been submitted for publication. In that study, sustained IOP-lowering from a) a single Bimatoprost ring for six months was observed. A dose-ranging trial has also recently been completed and longer-term safety data on the product will be presented in March 2016. Patients had a positive experience wearing the Bimatoprost ring. After participat- ing in the dose-ranging study, patients were asked to submit an anonymous survey by mail describing their interest in the product. These data show that 85% of patients who have worn the ring-shaped ocular inserts either strongly agreed or agreed with the statement, “I would will- ingly recommend ocular inserts to a friend b) or family member with glaucoma with adherence challenges.” Physicians have also demonstrated a strong preference for the ring. More than 80% of ophthalmologists questioned pre- fer the prostaglandin ring concept with a profile of close to 100% adherence and clinically significant IOP reduction to a prostaglandin eye drop that has slightly more efficacy but uncertain adherence.3 Furthermore, physicians have indicated that they would expect to prescribe the ring to more than half of the patients to whom they currently prescribe eye drops. In the future, patients may have an c) alternative to daily eye drops not only for glaucoma but for other indications. Because Figure 1: The Bimatoprost ring (a) comes in multiple sizes to ensure it will be the ring has a relatively large volume for a comfortable for the patient. Once the eye is measured, the ring can be placed under sustained release system, it has the capabil- the upper eye lid (b) and then under the lower lid to complete the application (c). ity of delivering two drugs for significant duration, for example bimatoprost and tim- therapy for major eye diseases. The first REFERENCES: olol. The company plans to start this fixed product is the bimatoprost ring to treat combination clinical study this year. The glaucoma and ocular hypertension; this 1. Nordstrom BL, Friedman DS, ring technology can be used to address addi- product is designed to enter and expand Mozaffari E, et al, “Persistence and tional clinical needs. Formulations for prod- a market that is currently more than adherence with topical glaucoma ucts for allergy and dry eye are currently in US$6 billion worldwide. Furthermore, the therapy”. Am J Ophthalmol, 2005; development. One can envision a future in excellent comfort, durability, retention Vol 140, pp 598-606. which there is a full line of products that and safety data have validated the ring 2. Data on file at ForSight VISION5, can replace eye drops and address a variety as a delivery system for pipeline products Inc. of clinical needs. in fixed combination glaucoma, dry eye, 3. Gerson Lehrman Group Survey, In summary, the ocular ring is designed allergy, as well as for use in several active 2015. Data on file at ForSight as a “best in class” non-invasive sustained research collaborations. VISION5, Inc.

SCALABILITY OF MICRO INTRAOCULAR IMPLANTS AND DEVICES

Scaling devices from tens to hundreds of thousands or millions sometimes requires a tightrope balancing act of economies of scale and product and process robustness. Micro molding is a proven, scalable, and economical process for thermoplastic micro-intraocular implants and devices. In this article, Donna Bibber, Plastics Engineer & Chief Executive Officer of Micro-Engineering Solutions, discusses some of these devices and the scalability challenges associated with each, from the perspective of a plastics engineer.

Recent developments and new-to-market focused, research-driven specialists, includ- intra-ocular devices and implants have led ing and micro fabrication specialists, such as: to the successful treatment of a number of ophthalmological conditions of varying • Small, innovation-support funding seriousness and complexity such as: programs • Development companies that easily find a • Glaucoma large marketing partner • Cataracts • Big pharma funding the outsources of the • Retinal detachment development instead of doing it in-house. • Diabetic retinopathy • Age-related macular degeneration To design and build scalable intra-ocular • Uveitis implants and devices, the design and fabrica- • Dry-eye syndrome. tion plan must include highly precise, micro sized component made from ultra-thin “In micro-moulded ophthalmologic yet strong materials. These materials must implants and devices, parting lines be selected and char- where the mould’s halves come together, acterised carefully to and surface finish of the moulds that be robust enough to last for many years create the moulded parts, must meet in a moist and warm Ms Donna Bibber Chief Executive Officer environment. stringent comfort standards required T: +1 774 230 3459 for them to be worn or implanted. In order to scale- F: +1 508 434 0281 up a polymer device E: donnabibber The implications for compliance are clear.” that may have been @microengineeringsolutions.com born in an academic or laboratory setting, Micro Engineering Solutions, LLC Treatment of these conditions often one must first understand the physical char- 102 City Depot Road requires collaboration between ophthal- acteristics of the eye (Figure 1) and how PO Box 952 mological surgeons, pharmacologists, and the surgeon will be installing the implant Charlton City MA 01508 micro-specific contract manufacturers. or device. The eye is a complex and sensi- United States Development of these devices and implants tive organ with many structures and tar- occurs through a large number of highly gets located closely together. These some- www.microengineeringsolutions.com

Ophthalmologists are meticulously detailed surgeons with extremely good dex- terity and their instruments must match their character traits, as their instruments and implants are considered an extension of meticulously planned and executed procedures. The many layers of the eye require the surgeons to switch quickly and accurately from one instrument to another because of the different surfaces they encounter in the eye. US baseball star Yogi Berra once stated: “I’d give my right arm to be ambidextrous.” But having the ability to switch hands and instruments and use both hands during eye surgery enables quick and precise position- ing of instruments and safety and efficacy is maintained with instruments designed for the comfort and use in either hand. This Figure 1: Sectional anatomy of the eye (photo credit: Visionbesteyecare.com). requires a look at not only human factors, but also design-for-manufacturability, as the times conflicting structures have significant components of the eye are gelatinous, flimsy, features and tolerances of the device and defence mechanisms (tear film, cornea) that easily punctured, and sensitive. As a result, wall thickness and aspect ratios approach make it difficult for medication to enter. the implants and devices that are installed “design challenges” for a particular material Vitreous fluid is difficult for injected medica- must be free of sharp edges, excess mate- selection. tion to traverse to the posterior of eye. rial or flash, and have absolutely pristine When designing and fabricating micro- surface finishes to help ensure both surgeon MATERIAL & DESIGN moulded devices and implants for the human and patient compliance. The instruments, CHARACTERISTICS eye, the physical characteristics and material however, which cut or slice into the various consistency of the components of the eye are components of the eye to install the implants Understanding the body’s reaction to critical to understand. Figure 2 summarises and devices must be very sharp and precisely polymeric implants is complex. Not only the physical characteristics and function of made to create correctly sized and shaped is the natural response affected by the each section of the anatomy of the eye. incisions. Conversely, the instrument to chemical properties of the polymer but also The anatomy and physiology of the eye hold or expand the eye open during surgery by the physical properties of the implant. is one of the most complex and unique must be free from parting lines, flash, or Development of an ophthalmologic drug systems in the human body. Many of these sharp edges. delivery device requires design criteria compatible with the delicate nature of the eye, including proper materials, size, shape, and porosity.

Material Selection Some materials, although tested for biocompatibility, may still cause inflammation and immuno-responses leading to long term effects on the eye. It is advantageous for safety, regulatory robustness, and speed to market reasons to select not only select a predicate material (PMMA, silicone), but also the predicate grade used in an intraocular application. Families of materials vary greatly from grade to grade in terms of both physical and chemical properties. For example, leachables and extractables over time can vary greatly with different grades of silicone and PMMA and these factors are critical to long term implant and device safety and efficacy. Additional material selection considerations include materials that are slippery , flexible, and non-hydroscopic for Figure 2: Physical characteristics and functional elements of the eye. compliance adherence.

Pupil Iris Cornea

Posterior chamber Anterior chamber (aqueous homour) Zonular fibres Lens Ciliary muscle Suspensory ligament Retina

Choroid Vitreous humour Sclera Figure 4: A polypropylene glaucoma drain.

Hyaloid canal

Optic disc

Optic nerve Fovea

Retina Figure 5: Pupil-expanding devices blood vessels (photo credit: APX Ophthalmology). Figure 3: Sclera Image courtesy of Wikipedia.

Size made up of highly sensitive Ophthalmologic implants or devices must pain receptors. Cornea pain be very small and pliable to fit into the receptor density is up to 600 sections of the eye. For example, a glau- times that of skin, which is coma drain must fit into the sclera which why even a slight injury to is from 0.3-1.0mm thick (see Figure 3). the eye is extremely painful. A part’s thickness and size is dependent on the ocular area and location of the Surface Finish/Porosity implant, but also chosen on the melt flow of In micro-moulded ocular Figure 6: Silicone corneal drug delivery device. the materials. implants and devices, parting lines where the mould’s halves come togeth- CONCLUSION Shape er, and surface finish of the moulds that cre- Implants within the wall of the sclera are ate the moulded parts, must meet stringent The anatomy and physiology of the eye is radial in nature to rest within the semi-cir- comfort standards required for them to be one of the most complex and unique sys- cular outer wall of the eye. Figure 4 shows a worn or implanted. The implications for tems in the human body. Micro-moulding polypropylene glaucoma drain with a centre compliance are clear. Surface finish, blend- is a scalable process with particular design wedge bore which acts with a Venturi effect ing parting lines, spherical radii, and match- criteria met, including proper size, three- to allow the pressure of the eye to drain ing cores and cavities to ultra-precision dimensional shape, wall thickness, material behind the eye. Glaucoma is a result of tolerances (A2 or A1 finishes) are the keys selection, and surface finish. the increased fluid pressure in the eye due to creating implants that can stand the test Micro-injection moulding is a viable to the reduction or blockage of fluid from of time in an intra-ocular environment. and scalable process for fabricating ultra- the anterior to posterior chambers. Devices In the context of an ocular implant, precise, micro-sized, ultra-thin, yet robust such as these are possible using micro- smooth materials can have very different implants and devices located in a highly injection moulding and micro-automation. tissue and nerve responses compared with complex environment such as the eye. Figure 5 shows a pupil expander device micro-structured materials. Tissue encap- Scalability is an important consider with micro features and surface finishes sulation of a foreign body (such as the stionat the initial product and process necessary to fit comfortably in the eye implant) is higher with rougher surfaces design phase in order to achieve the econ- and provide tensile strength with fine because there is more surface area for the omies of scale – tens, to hundreds of alignment and mechanical strength to hold implant to attach to tissue. Nerve response thousands of parts, to millions annually – them in place. to surface finish needs to be considered in that micro-moulding offers. Figure 6 shows a delivery device that implant design. Wear or degradation of Careful consideration of surface fin- sits on the cornea – it’s a thin membrane- a rough surface is more prevalent as well ish, feature size and material selection is like, silicone structure with radial design, because the smaller porous particles in the paramount to the successful integration of and a 50 µm wall thickness to fit inside surface can be toxic to tissue, can spread marrying micro-moulding technology with the upper eyelid. The cornea has 5-6 lay- throughout the eye, and also trigger an the internal chambers and inter-connective ers varying from 2-20 µm in thickness, allergic response. functions of the eye.

7th Annual Global Drug Delivery & Formulation Summit 23 – 25 May 2016 | Berlin

Speakers Include Philippe Lienard, Head of Early Pharmaceutical Development, Sanofi Amardeep Bhalla, Principal Scientist / Group Leader – Vaccines R&D, Pfizer Hans de Waard, Formulation Expert and Project Leader Drug Product – Continuous Manufacturing, Novartis Steve Brown, Executive Director, Pharmaceutical Technology West Europe, Actavis Aditya Tatavarti, Principal Scientist, Formulation Sciences, PSCS, Merck Prof. Clive Roberts, Chair of Pharmaceutical Nanotechnology, University of Nottingham Daniel Bar-Shalom, Associate Professor, Pharmaceutical Design & Drug Delivery, University of Copenhagen www.ddfevent.com

6th Annual American Drug Delivery & Formulation Summit 13 – 14 June 2016 | San Diego

Speakers Include Arvind Srivastava, Director of Formulation Development, Eli Lilly Avinash Nangia, VP, R&D, Lupin Pharmaceuticals John Higgins, Director, Basic Pharmaceutical Sciences & Senior Principal Scientist, Merck & Co Sathish Hasige, Associate Director of Strategic Planning: Formulation & DP Process Development, MedImmune Sotirios Koutsopoulos, Research Scientist, Center for Biomedical Engineering, MIT Produced by www.ddfsummit.com

[email protected] | +44 (0) 20 7202 7500

DDF A4 Advert.indd 1 26/01/2016 15:43 Mati

THERAPY WITHOUT DROPS: A REALITY

Here, Chris Muller, Chief Commercial Officer, and Deepank Utkhede, Chief Scientific Officer, both of Mati Therapeutics Inc, introduce the company’s Evolute® ocular delivery system, a non-invasive, sustained-release platform that combines a novel punctal plug with a sustained release drug eluting core.

Ophthalmologists are in agreement that a nature they expose the patient to potential better option to administer ocular therapies sight-threatening infection and decreasing rather than eye drops is needed for their the overall health of the eye by undergoing patients since the lack of compliance is a multiple surgical procedures per year. The serious and leading cause for concern. repeated tissue trauma increases scaring When we consider the associated dis- over time and could complicate future surgi- orders that these medications treat such as cal procedures needed to control the disease. glaucoma, inflammation, allergy or dry eye, each of these can be very problematic if not sight threatening if the treatment regimen is “The ophthalmic not followed. The therapeutic agents avail- community relies on able for each of these conditions are very effective when prescribed and used appro- the patient to adhere to Chris Muller Chief Commercial Officer priately. However, the problem is that they the treatment regimen. E: [email protected] are rarely used appropriately or in accord- However, due to a number ance to the dosing regimen that is required and for diseases such as glaucoma, which of factors such as age of Mati Therapeutics Inc 4317 Dunning Lane is initially asymptomatic, this can lead to the patient population, Austin TX 78746 irreversible vision loss. the complexity of the United States The ophthalmic community relies on the patient to adhere to the treatment regimen. dosing regimen or However, due to a number of factors such discomfort caused by as age of the patient population, the com- drops, it is not realistic to plexity of the dosing regimen or discomfort caused by drops, it is not realistic to expect expect that the majority that the majority of these patients will com- of the these patients will ply with the required treatment regimen. comply with the required There have been many attempts to solve this issue but the sustained-release innovation treatment regimen.” Deepank Utkhede by Mati Therapeutics may be the perfect Chief Scientific Officer answer for a majority of patients. T: +1 778 991 3301 There are multiple approaches to the Mati has developed a completely non- E: [email protected] administration of sustained-release systems. invasive sustained-release platform by com- One is invasive, where a physician either bining a novel punctal plug with a sustained Mati Therapeutics Inc through incision or injection enters the release drug eluting core (see Figures 1 and 2). Suite 201 anterior chamber of the eye to deliver the This platform is known as the Punctal Plug 4475 Wayburne Drive drug depot or creates an incisional pocket in Delivery System (PPDS) or Evolute®, as it Burnaby, BC V5G 4X4 the sclera or conjunctiva to house the depot. will be known commercially. The Evolute® Canada The problem with both of these method- is inserted into the patient’s punctal duct ologies is that because they are invasive in by a simple in-office, non-invasive proce- www.matitherapeutics.com

matories for post-cataract surgery, allergy medications, and glaucoma therapies. Through extensive formulation development, Mati has developed the capability to adjust the elution profile for any of these therapies to potentially meet the needs of the ophthalmic community. For example, the Evolute® can be designed to deliver a high initial amount of medication followed by a consistent lower concentration over time or a much more limited initial delivery and increased delivery of medication over the treatment period. ® Figure 1: Evolute combines a novel There are several additional benefits to punctal plug with a sustained-release the Evolute® system, such as that it allows drug eluting core. for the formulation of hydrophilic or hydrophobic compounds and it is a preservative free therapy so there is no need to worry The Evolute’s® unique configuration cre- about long-term exposure to preservatives ates a unidirectional system that delivers such as benzalkonium chloride, which has therapy primarily to the tear film and ocular been shown to cause ocular surface issues surface. This is a distinct advantage for any such as conjunctival inflammation, tear sustained release system because virtually film instability, corneal toxicity, anterior all the formulated medication in the system can be directed to the targeted site rather than being absorbed by non-targeted tissue or lost down the canaliculus into the “In clinical studies, the nasal cavity and/or systemically absorbed. vast majority of patients Another advantage to the Evolute® is that preferred the Evolute® Figure 2: An Evolute® device, shown on both the punctal plug portion and the drug a finger-tip for scale. eluting core are non-bio-erodible and non- system to their usual eye biodegradable. This leads to the ability to drops. This isn’t surprising dure. After placement, the Evolute® delivers predict accurately when and how much of because of the passive therapy to the ocular surface or tear film the formulated drug is delivered over the over a predetermined period of time. At the course of therapy. Also the punctal plug nature of the system. end of the treatment period for acute condi- retention features will be unchanged over The patient doesn’t have tions, Evolute® is removed from the puncta the treatment period which has resulted in to do anything once the without any further follow-up. At the end very high retention rates for the Evolute®. of the Evolute® elution period for chronic Clinical studies have demonstrated a device is inserted.” conditions, the patient returns to the clinic reproducible and predictable retention rate in range of 92% to 96% over a 90-day targeted treatment period. Another advan- chamber inflammation, and cataract devel- “Mati has developed a tage of a non-biodegradable and non-bio- opment among other issues. In addition, erodible system is that if removal is required since the Evolute® prevents loss of drug into completely non-invasive for any reason, the Evolute® is easily observ- the canaliculus, it will likely lead to less sustained-release platform able and removable with a pair of forceps. systemic absorption of the therapy in ques- by combining a novel A bio-erodible platform will become smaller tion, which may greatly reduce undesired and/or weaker, during the implantation systemic side effects associated with some punctal plug with a period potentially making removal more ocular medications. sustained release drug complicated. In clinical studies, the majority of ® ® eluting core.” The Evolute is a platform technology patients preferred the Evolute system to that can be tailored to treat multiple front- their usual eye drops. This isn’t surprising of-the-eye conditions. Depending on the because of the passive nature of the system. ocular condition, the elution rate and period The patient doesn’t have to do anything to have the depleted Evolute® removed and of delivery can be adjusted for short-term, once the device is inserted. This may prove a new Evolute® placed to continue treat- high levels (for example, in post-cataract to be substantial benefit for ophthalmol- ment. The Evolute® has the advantage of surgery treatment), to long-term, low levels ogists and their patients insuring better being easily removed unlike the more inva- (for example, in glaucoma therapy) of drug adherence and more consistent administra- sive techniques previously described, which delivery. Multiple products have been devel- tion of the therapeutic agent leading to require a surgical procedure for removal. oped for the Evolute® including anti-inflam- superior outcomes.

NEW SOLUTIONS FOR OPHTHALMIC DRUG DELIVERY USING BIODEGRADABLE SILICA MATRIX

DelSiTech, a Finnish drug delivery company, has developed a proprietary non- mesoporous, biodegradable silica matrix technology where release of the active pharmaceutical ingredient (API) is based on the dissolution of silica in tissue. Here, Mika Jokinen, DSc, Research Director, Cora Griffin, PhD, Business Development Director, and Lasse Leino, PhD, President and Chief Executive Officer, all of DelSiTech, describe the novel opportunities that biodegradable silica matrix technology offers to ophthalmic drug delivery, and the different silica dosage forms for various types of APIs, ranging from large biological agents, such as proteins and viruses, to small molecules, covering injectable silica hydrogels, silica microsphere-silica hydrogel composites and silica implants.

Due to the aging population, chronic ocular of the eye, which prevents the penetration diseases are becoming more common, and of active compounds at the site of action, the number of patients suffering from condi- e.g. the retina, after systemic administra- tions such as age-related macular degeneration. Although topical administration of eye drops is an easy and non-invasive method of ocular drug therapy, it suffers from low and easily saturated dose, poor bioavailability “The injectable silica (less than 5% even in the front part of the hydrogel composites can eye) due to rapid drainage, and low patient be used both in IVT and compliance, especially in elderly patients. Invasive systems such as intravitreal subconjunctival delivery (IVT) injections are used to treat the back where at least one month’s of the eye. However, IVT injections cannot sustained release of the be given repeatedly in a short period of time because they are associated with potential API is needed. It is also severe side effects, such as increased pres- possible to develop much sure in the eye or infection, and they would longer acting composite generate a significant burden in ophthalmology clinics. For small molecules, which are Dr Mika Jokinen formulations with 3-6 typically rapidly eliminated within hours in Research Director months’ controlled release the vitreous, immediate-release IVT formula- of API … With a very potent tions are not a realistic option because of the Dr Lasse Leino need for frequent injections. It is clear that President & Chief Executive Officer molecule, it would be there are unmet medical needs in ophthalmic possible to design products drug treatment and these needs are not well Dr Cora Griffin with more than 12 months served by current drug delivery systems. Business Development Director New concepts, tools and approaches should T: +44 7876 067623 E: [email protected] release profile.” be generated and tested for the development of novel ocular therapies. Amorphous silica matrix prepared DelSiTech Ltd tion (AMD), glaucoma, dry eye and diabetic by the sol-gel method is a well-known Itäinen Pitkäkatu 4 20520 Turku retinopathies is increasing steadily. Drug biomaterial for controlled drug delivery. Finland treatment for ocular diseases is challenging Silica can be processed into several dosage due to the complex and protected structure forms, addressing a number of challenges in www.delsitech.com

the development of sustained release parenteral products. DelSiTech, a Finnish drug delivery company, has developed a proprietary non- mesoporous, biodegradable silica matrix technology where release of the active pharmaceutical ingredient (API) is based on the dissolution of silica in tissue, i.e. it is controlled by bulk matrix erosion rather than API diffusion. The properties of the sol-gel derived silica can be adjusted to ensure proper encapsulation of APIs and the desired degradation rate (dissolution of silica in vivo) from days to months, even up to years.1-3 In addition, silica is an inert material that Figure 1: Cumulative in vitro silica dissolution rates in Tris buffer pH 7.4 (in sink) of is compatible with different types of APIs, four silica microsphere formulations which differ only in the water-to-TEOS ratio in including biologics and advanced-therapy the sol-gel reaction. The ratio is (from up to down) 3:1, 5:1, 10:1 and 15:1. medicinal products. Even compounds with either very low or very high water-solubility that have different surface characteristics. hydrogel structure, which remains stable can be successfully encapsulated inside the Figure 1 shows an example of how a for prolonged times, but at the same time, silica matrix. simple change in water-to-TEOS ratio in the structure has to be loose enough to be the sol-gel process affects the dissolution injectable through thin needles when shear INJECTABLE SILICA DOSAGE rate of silica microspheres in aqueous buff- stress is applied by pushing the plunger of FORMS IN PREFILLED SYRINGES er, i.e. the biodegradation time. The other the syringe. The resulting unique silica-sil- manufacture and microsphere parameters ica composite hydrogel is easily injectable DelSiTech has developed several types of were kept constant (sol pH, spray-drying with needle sizes of 27-30G as illustrated injectable, silica matrix-based formulation parameters, and particle size distribution in Figure 2. Although the hydrogel part of platforms that can be used in ophthalmic which was 1.5-10 µm, D50=3-4 µm). the silica-silica composite most often con- drug delivery. In all cases, the flowing (liq- Spray-drying is the main form-giving trols the injectability and homogeneity, it uid) form of silica, a silica sol, is used to mix method to produce API-containing silica may also fine-tune the release of API from different components and API with silica microspheres. It is inexpensive, fast and microspheres by controlling/removing the before the system turns into a hydrogel. The an easily scaleable manufacturing method burst, the initial fast phase of the release. silica sol-gel processing is a flexible, low- that can be operated in a GMP envi- temperature method allowing the adjust- ronment, even in aseptic conditions. The ment of the silica sol properties, such as pH spray-drying parameters are optimised for to ensure the optimum pH environment on each API and formulation. Spray-drying different types of APIs. is also gentle enough to preserve the bio- The first dosage form is a silica-sili- logical activity and therapeutic effect of ca composite material consisting of silica the encapsulated proteins and peptides. microspheres embedded in a silica hydro- The temperatures in the process are kept gel. The API, either a small molecule or low and the presence of silica protects sen- a biologic, is encapsulated in the silica sitive molecules. microspheres, which act as the API elut- After spray-drying, the API-silica micro- ing reservoir and control the drug release spheres are mixed with a flowing aqueous by matrix dissolution. By controlling the silica sol and the mixture is transferred into silica microsphere (bio)degradation rate, it a syringe before the sol turns into a hydro- is possible to obtain an accurate control of gel. The filling of the syringes is controlled API release. by careful rheological measurements to Silica matrix itself is water-soluble and ensure homogeneous product, long-term when placed in the body it dissolves in stability and good injectability. Shear rate- aqueous tissue fluids. Water-solubility of dependent viscosity is measured to study silica microspheres is a tuneable property the shear-thinning behaviour, to ensure that mainly depends on the number and easy injectability, and oscillation measure- density of OH-groups on the surface of ments (for elastic and viscous modulus and silica matrix. By simply adjusting and vary- their ratio, loss factor that describes the ing the silica sol-gel composition and reac- stiffness of the hydrogel) are conducted to tion parameters, such as concentrations of ensure a non-flowing, gel-like structure at the main precursors (water and tetraethyl rest in the syringe. orthosilicate (TEOS), the source of silica), The goal of the rheological optimisa- Figure 2: Injectable silica-silica it is possible to produce silica microspheres tion is to form a non-flowing composite hydrogel composite depot.

The injectable silica hydrogel compos- limitations especially in repeated adminis- injectable dosage forms in cases where ites can be used both in IVT and sub- tration, as they should be removed after use. the API is not suitable for spray-drying conjunctival delivery where at least one DelSiTech has developed micro-implant form-giving. month’s sustained release of the API is technology for IVT delivery of drugs that needed. It is also possible to develop much is based on biodegradable silica matrix CONCLUSION longer acting composite formulations with (Figure 3). 3-6 months’ controlled release of API. Different biodegradable silica matrix based As with all drug delivery systems, the dosage forms can be used for ophthal- development of an ultra-long acting dos- mic drug delivery. The technology provides age form with silica matrix technology is potential formulation solutions both for the limited by the required daily dose of the anterior and posterior parts of the eye in active compound, which directly impacts the form of eye drops, injectable silica-silica the volume of the IVT injection material composite hydrogels, and micro-implants. (typically maximum 0.1 ml). With a very Also, the technology is mature enough to potent molecule, it would be possible to fulfil the pharma industry requirements design products with a release profile of such as GMP manufacture and sterilisation. more than 12 months. Currently, DelSiTech is actively working Topical application of the silica-silica on several projects developing novel drug hydrogel composite formulation in the formulations for ocular delivery. conjunctival cul-de-sac represents another drug delivery opportunity in the treatment REFERENCES of the front part of the eye. The silica composite material is sticky enough to stay in 1. Kortesuo P et al, “Silica xerogel the conjunctiva where it releases API in a as an implantable carrier for con- controlled fashion. Prototype formulations Figure 3: Intravitreal biodegradable trolled drug delivery-evaluation of have been produced where fluorescein as silica micro-implant (diameter 0.4 mm) drug distribution and tissue e!ects a surrogate molecule is encapsulated into on top of a finger. after implantation”. Biomaterials, silica microspheres that are further embed- 2000, Vol 21, pp 193-198. ded in the silica hydrogel. When these “eye Silica implants are typically trans- 2. Meseguer-Olmo L et al, drops” are administered in the rabbit eye, parent, especially when in contact with “Biocompatibility and in vivo they release fluorescein steadily for 24 water. The biological activity of biophar- gentamicin release from bioactive hours without any signs of local irritation. maceuticals and viral vectors can be main- sol–gel glass implants”. tained because the water content inside the J Biomed Mater Res, 2002, SILICA OCULAR MICRO-IMPLANTS implant can easily be controlled. Vol 61, pp 458–465. The silica microimplants are prepared 3. Jokinen M et al, “Rationale of Traditionally, drug-eluting implants have by casting the API-containing silica sol Using Conventional Sol-Gel been the first type of controlled-release into a mould before the silica sol turns into Derived SiO2 for Delivery of dosage forms used in ocular drug delivery. a gel. The gel is formed in the mould fol- Biologically Active Agents”. Most implant technologies are based on lowed by a controlled drying. Silica micro- Key Eng Mater, 2008, Vol 377, non-biodegradable materials that have their implants offer an attractive alternative to pp 195-210.

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30 www.ondrugdelivery.com Copyright © 2016 Frederick Furness Publishing Ltd HUMAN FACTORS ENGINEERING & USABILITY STUDIES February 10-11, 2016 SUMMIT Hilton San Francisco Airport Bayfront, South San Francisco, CA Design Validation Tests to Improve User Interfaces, Ensure Regulatory Compliance, and Achieve Market Success for Combination Products and Medical Devices

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OPSISPORIN: A LONG-ACTING DRUG DELIVERY APPROACH FOR UVEITIS

Here, Paul Seaman, PhD, Head of Sustained Delivery, and Daniel Palmer, PhD, Chief Scientific Officer, both of Midatech Pharma, discuss the company’s next- generation treatments for auto-immune ocular diseases, which use a combination of innovative, sustained-release drug products that are active for several months and designed for delivery through ultra-fine injections into the eye. The article focuses on OpsiSporin, an encapsulated sustained-release cyclosporin formulation for the treatment of uveitis.

Current treatments for eye diseases often AMD and non-infective uveitis. Long-acting do not achieve the required level of effect. treatment is achieved using formulations of Topical therapies have low efficacy and biodegradable polymers (including poly- bioavailability as a result of factors such as lactides) to control the release of API over anatomical and physiological barriers, tear a period of 3-6 months following a single formation, and lymphatic drug clearance. intravitreal or subconjunctival injection. Systemic therapies have high incidence of Monodisperse microspheres may be readily adverse effects, poor tolerability, and lim- injected via minimally-invasive needles as ited efficacy. Frequently, patients are non- fine as 30G. Dr Paul Seaman compliant due to unpleasantness, pain, or In formulating small molecules, biop- Head of Sustained Delivery inconvenience of the treatment options. harmaceuticals and PEGylated species, Midatech’s sustained-release technology, Midatech focuses on developing products delivered directly to a specific ocular space, that provide high drug loading, with mini- addresses these challenges. Localised long- mal initial burst release. These characteris- acting delivery of API offers marked advan- tics are essential to the development of safe tages and consistency over oral administra- and effective ophthalmic therapies. The tion since drugs are delivered to the target formulation tuning and process control to site in therapeutic concentrations, off-target achieve this requires precision know-how side effects of high-dose systemic delivery are and novel technology to ensure control avoided, and patient experience is improved over particle size, morphology and drug Dr Daniel Palmer via minimally-invasive, convenient and infre- kinetics. Chief Scientific Officer quent administration. Our technology represents a step-change T: +44 1235 888 300 in control for microsphere manufacturing, E: [email protected] TECHNOLOGY enabling emulsion-free synthesis with both product monodispersity and processing Midatech Pharma PLC Our proprietary microsphere engineering efficiency built-in. Further, the encapsula- 65 Innovation Drive platform can use a wide range of biomateri- tion process is engineered to avoid the Milton Park als to encapsulate ocular drug candidates use of poorly-tolerated organic solvents Abingdon into micron sized particles (of diameter such as dichloromethane. The manufac- Oxfordshire OX14 4RQ ~25µm). These include glucocorticoid anti- turing system has been designed for total United Kingdom inflammatories, anti-VEGFs and immuno- compatibility with the aseptic production suppressants for diseases such as glaucoma, environment and standard isolator technol- www.midatechpharma.com

ogy, and is proven for sterile synthesis and retinal edema are also notable features. It options available for patients with non- filling of clinical trial materials. is important to establish the correct diag- infectious uveitis of the posterior seg- This level of flexibility enables nosis so that specific treatment to address ment of the eye have recently improved, Midatech to formulate products to pro- the underlying aetiology can be initiated, none is ideal. Topical steroids often do vide release profiles and dosage regimes along with treatment to reduce ocular not work and systemic corticosteroid or that treat ocular disease states in the most inflammation. immunotherapy is limited by the risks of efficacious manner. The inflammatory process in the eye(s) adverse events with protracted use. Ocular must be reduced quickly to avoid long-term inflammation may require the addition of UVEITIS consequences. The treatment options for intravitreal steroid injections to prevent non-infectious uveitis affecting the pos- permanent damage to vision. These are One such application of the Midatech tech- terior or intermediate segment of the eye effective, but have a relatively short dura- nology is for the treatment of posterior include the use of local and systemic corti- tion of action as well as side effects. This uveitis, an intra-ocular inflammatory condi- costeroids, systemic immunosuppressants, medical need has been recognised and tion affecting one or more parts of the uvea and off-label use of anti-VEGF agents implants for the intravitreal administra- which includes the iris, the ciliary body, and and systemic biologic agents. Patients are tion of steroids have been developed, but choroid of the eye, although other ocular routinely initiated on systemic steroids, the again side effects are problematic and effi- structures such as the retina and the vitre- mainstay of posterior uveitis therapy, at cacy inconsistent. A product that achieves ous body may also be secondarily involved. high doses of up to 1 mg/kg/day and then control of inflammation without serious Aetiology is varied and includes infectious tapered to ideally less than 5 mg/day. If, steroid-related side effects would constitute causes (e.g. tuberculosis, toxocara) and after a period of time (ranging from 2-3 a significant benefit. non-infectious pathogenesis. Non-infectious causes include systemic auto-immune disorders (e.g. rheumatoid arthritis, sarcoidosis, Lupus, Behçet’s disease), trauma, and rarely “Depot-based drug delivery is strongly required in can also be drug induced. However, many ocular disease, due to the burden of frequent intravitreal cases of uveitis are idiopathic in nature. Uveitis is a major cause of significant injections and lack of any satisfactory treatments to date.” visual loss in young and middle aged adults in the Western world. The burden, to society and the patient, resulting from uncontrolled uveitis is significant. Uveitis is months), the steroids cannot be reduced or OPSISPORIN a major cause of new cases of blindness; in eliminated, systemic immunosuppressives the US, it is estimated that uveitis causes an are started such as cyclosporin, or off-label OpsiSporin is a treatment under develop- estimated 30,000 new cases of legal blind- adalimumab, azathioprine, cyclophospha- ment by Midatech. It comprises encapsu- ness and results in 2.8-10% of all blindness mide, infliximab, methotrexate, tacrolimus lated cyclosporine, a cyclic peptide of 11 annually. Uveitis can be classified on the and others. Each of these has the potential residues that has been routinely used as an basis of the aetiological factors (e.g. infec- for causing serious systemic adverse effects oral immunosuppressor for organ trans- tious, non-infectious, drug induced etc), or that limit the dose or their use altogether. plantation since first approval in 1983. The most commonly, on the anatomical loca- Intra-ocular administration of sustained drug’s mode of action is well understood, tion of the disease, anterior, intermediate, release steroids like fluocinolone and dexa- being the selective inhibition of interleu- posterior, and panuveitis. Until recently, methasone are an advance, but risk causing kin-2 release during the activation of T-cells, not all EU countries had uveitis as a listed cataracts, glaucoma, and increased intra- suppressing cell-mediated immune response. indication and it is still not an approved ocular pressure; and the duration of effect Cyclosporin forms a complex with the cyto- indication in the US. seems to be limited and with high relapse solic protein cyclophilin of lymphocytes, The presenting symptoms tend to vary rate. The systemic use of cyclosporin for especially T cells. This complex inhibits with the type of uveitis and the severity, the treatment of non-infectious uveitis of calcineurin, which, under normal circum- and may affect one or both eyes. Anterior the posterior segment is common prac- stances is responsible for activating the uveitis is often accompanied by ocular pain tice among uveitis specialists. However, transcription of interleukin-2. This results and photophobia. Blurring of vision is systemic drugs (corticosteroids and immu- in an immunosuppression that is reversible less of a characteristic of anterior uveitis, nosuppressive therapy) often fail because when treatment is ceased. Therefore, diseas- but may be reported in severe cases or of the presence of the blood-retinal barrier es that involve cytokines or immune–related by patients with secondary cataracts or that limits drug delivery into uveal tissues. disorders, such as non-infectious uveitis, macular oedema. Posterior uveitis may be The important, sometimes life threat- are potential indications for cyclosporin. accompanied by some degree of pain and ening, adverse effects of these drugs limit Through prevention of T-cell activation and photophobia, but these may not be the the maximum dose that can be recom- proliferation, cyclosporin has been hypoth- predominant symptoms. However, blurred mended. The dose given may, therefore, esized to be a suitable treatment for non- vision is common due to involvement of be suboptimal in terms of control of infectious uveitis. the macula (inflammation and macular inflammation in the eye even when maxi- Sustained-release of cyclosporin within oedema) and opacity of vitreous humour mum dosing is prescribed. the posterior eye is expected to reduce or (flare and cell infiltration). Vasculitis and In summary, although the treatment spare the need for oral drug treatments

used in the treatment of uveitis, in particu- i.e. an undesirable burst release of cyclo- sion stability. As a result, homogenous lar oral glucocorticosteroids and immuno- sporin. Therefore, the manufacturing pro- suspensions can be formed in under 30 suppressants; and the literature indicates cess involves a post-processing step during seconds and remain stable for several min- that the use of intravitreal cyclosporin is which the surface drug is removed and utes, meaning preparation in the clinic effective and well tolerated as described this burst release significantly attenuated. is minimal and the dosing need not be above. Hence, OpsiSporin is expected to be Particle-drug loading was generally very rushed. Data gathered to date indicate that effective in the treatment of uveitis affect- high (~19-21% w/w), and was not signifi- OpsiSporin is injectable through ½” 30G ing the posterior segment of the eye. In cantly affected by particle post-processing. needles. treating the disease and preventing recur- Similar to many microsphere-based SR rence, its use could remove the need for products, OpsiSporin is presented as a PROOF OF CONCEPT long-term steroid cover required to treat powder that is formed into a suspension ocular inflammation avoiding the compli- prior to dosing. Due to the intravitreal An in vivo study has illustrated the efficacy cations of chronic systemic or intravitreal route, where injection volume is limited of OpsiSporin in the treatment of experi- corticosteroids. Systemic immunosuppres- to 0.1 mL, and the hydrophobic nature of mental auto-immune uveitis (EAU) in a sion may still be required to address the cyclosporine-loaded microspheres, forma- murine model. EAU was induced in groups aetiology of the uveitis, but the dose may tion of a simply and reproducibly inject- of ten C57/BL6 mice by challenge with be tailored to this objective and not raised able suspension required significant devel- retinal antigens interphotoreceptor reti- excessively in an effort to suppress ocular opment. Midatech has worked to develop noid binding protein peptide (IRBPp) and inflammation with systemic dosing. the formulation to make reconstitution Freund’s adjuvant (subcutaneous admin- Sustained delivery of the cyclosporin rapid, consistent and safe. istration) and pertussis toxin (intraperito- is achieved by encapsulation with biore- The application of microsphere process- neal administration). Due to the sustained- sorbable polymer excipients, such that the ing expertise has resulted in the introduc- release properties of the OpsiSporin prod- endecapeptide is physically entrapped in tion of technology that enables OpsiSporin uct, intravitreal treatment was administered the polymer matrix. Cyclosporin is released to be reconstituted rapidly with nothing on a single occasion only (day zero) via 33G as the poly-ester backbone of the polymer more than water. The formulation excludes needle. A negative control group receiving undergoes hydrolysis and is broken in to its constituent monomers, resulting in the 10 gradual erosion of the polymer matrix. The development of the product 9 targeted a sustained release (SR), microparticle formulation, with the following 8 product attributes: 7 • Cyclosporin drug loading >15% w/w • Cyclosporin encapsulation efficiency 6 >80% • Formation of stable suspension, inject- 5 able via ½” 30G needle 4 • Linear release kinetics maintained for Mean TEFI Score 90-100 days. 3 Early formulation development focused on identifying parameters for satisfactory 2 drug encapsulation (suitable drug loading and stability) and applying knowledge of 1 SR formulations to produce early formula- 0 tions aimed at a three-month release dura- 7 14 21 28 tion (established via in vitro release mod- Time (Days) elling). Formulations have been focused on polymers from the polylactide-co-gly- Vehicle (i.vit) OpsiSporin (i.vit) 4.5µg CsA colide family, specifically those containing a high ratio of lactide to glycolide Figure 1: Proof of concept in murine model. (typically 75-100%). Increasing TEFI score of retinal imaging indicates worsening of the EAU disease Additionally, review of the literature state. Mice receiving intravitreal injection of OpsiSporin (4.5μg cyclosporin) showed indicated that higher-molecular-weight a significant reduction in EAU severity compared to those animals that received polymers were also well suited to this vehicle alone. application. It is known that drug loose- ly bound to the surface of microspheres novel excipients whilst preventing micro- vehicle only was also injected at day zero. In can give rise to a rapid drug dissolution sphere aggregation during storage and addition, two groups of ten animals received profile immediately upon administration; reconstitution, and maximising suspen- different doses of oral cyclosporin (in car-

boxylmethylcellulose solution), once daily, ing intravitreous injection of vehicle with by providing a long-acting, easy-to-use as positive control treatments. those receiving OpsiSporin containing efficacious product that spares the use and Increasing TEFI score of retinal imaging 4.5 µg cyclosporin. An equivalent reduc- thus side effects of treatment with systemic indicates worsening of the EAU disease tion in disease development was observed or local steroids, or immunosuppressants. state. Mice receiving intravitreal injection following daily oral administration of 6.7 of OpsiSporin (4.5μg cyclosporin) showed mg/kg/day cyclosporin, as compared with REFERENCES a significant reduction in EAU severity intravitreous injection of 4.5µg OpsiSporin; compared to those animals that received efficacy was equivalent whilst total amount 1. Caspi, Rachel R. “Understanding vehicle alone (Figure 1). of cyclosporine administered was 1000- Autoimmunity in the Eye: Topical endoscopic fundal imaging fold lower with OpsiSporin. The EAU From Animal Models to Novel (TEFI) is a technique used to monitor the model is self-limiting, and as such is only Therapies.” ResearchGate. progression of retinal degradation in ocular able to indicate efficacy for up to 28 days. Discovery Medicine, disease. In this study it was used to track In vitro modelling of drug release kinet- 1 Mar. 2014. Web. 18 Jan. 2016. 2. Jabs, Douglas A., and James T. 120 Rosenbaum. “Guidelines for the Use of Immunosuppressive Drugs in 100 Patients with Ocular Inflammatory Disorders: Recommendations of an 80 Expert Panel.” American Journal of Ophthalmology 131.5 (2001): 60 679. Web 3. Lallemand, F., O. Felt-Baeyens, K. 40 Besseghir, F. Behar-Cohen, and R. Gurny. “Cyclosporine A Delivery Cyclosporin released (µg) released Cyclosporin 20 to the Eye: A Pharmaceutical Challenge.” European Journal of 0 Pharmaceutics and Biopharmaceutics 0 14 28 42 56 70 84 98 56.3 (2003): 307-18. Web. Time (Days) 4. Pavesio, Carlos, Manfred Zierhut, Khaled Bairi, Timothy L. Comstock, Figure 2: In vitro testing of OpsiSporin models the release of API from the drug and Dale W. Usner. “Evaluation product, with the data plotted as a cumulative mass of drug released. Highly of an Intravitreal Fluocinolone linear release of cyclosporin lasting three months was observed with OpsiSporin. Acetonide Implant versus Standard These data show the mass of cyclosporin released per mg of OpsiSporin drug product, and predict a linear release of 0.96 μg/mg/day. Data are the mean of Systemic Therapy in Noninfectious three replicates, and error bars represent standard deviation. Posterior Uveitis.” Ophthalmology 117.3 (2010): n. pag. Web. the progress of EAU after administration ics indicated that the rate of cyclosporin 5. Thompson, Angus W. of the IRBPp / pertussis toxin insult. An release shown to be efficacious in vivo, “The Influence of Cyclosporin A increasing TEFI score denotes the advance- were maintained for three months (see on T Cell Activation, Cytokine ment of the EAU disease state, and hence Figure 2). It is therefore hypothesised that Gene Expression and Cell-mediated can be used to observe recovery or reduc- efficacy will be maintained over the entire Immunity.” Cyclosporin: Mode of tion in retinal damage and inflammation. target period, facilitating a three-monthly Action and Clinical Applications. Mice receiving intravitreal injection of dosing regimen. Dordrecht: Kluwer Academic, 1989. OpsiSporin (4.5μg cyclosporin) showed N. pag. Print. a significant reduction in EAU severity CONCLUSION 6. Trusko, B., J. Thorne, D. Jabs, R. compared to those animals that received Belfort, A. Dick, S. Gangaputra, vehicle alone (p<0.002), supporting the Depot-based drug delivery is strongly R. Nussenblatt, A. Okada, and J. hypothesis that delivery of cyclosporin via required in ocular disease, due to the Rosenbaum. “The Standardization the OpsiSporin product has potential for burden of frequent intravitreal injections of Uveitis Nomenclature (SUN) the treatment of non-infectious uveitis in and lack of any satisfactory treatments Project.” Methods Inf Med Methods man. A significant reduction in disease to date. Solid formulations that are pre- of Information in Medicine 52.3 development was observed at the later time cisely defined, easy to administer into (2013): 259-60. Web. points, as severity of disease increased in the eye, and able to provide steady drug 7. Vries, J. De, G. S. Baarsma, M. J. the untreated and negative control groups. release over 3-6 months are ideal alterna- Zaal, T. N. Boen-Tan, A. Rothova, Multiple t tests between untreated animals tives for chronic conditions such as non- H. J. Buitenhuis, C. M. Schweitzer, and those receiving cyclosporin either as infective posterior uveitis. In developing its R. J De Keizer, and A. Kijlstra. OpsiSporin or orally showed a significant ocular drug delivery platform, Midatech “Cyclosporin in the Treatment of reduction in disease from day 15. technology may provide a compelling Severe Chronic Idiopathic Uveitis.” In addition, a significant reduction was and unique platform to bring significant British Journal of Ophthalmology observed between those animals receiv- benefits to patients suffering from uveitis 74.6 (1990): 344-49. Web.

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