DELIVERING INJECTABLES:
`FORMULATIONS, AUTO-INJECTORS AND NEEDLE-FREE
`
`www.ondrugdelivery.com
`
`Opiant Exhibit 2091
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 1
`
`

`

`“Delivering injectables: formulations,
`auto-injectors and needle-free”
`
`CONTENTS
`
`This edition is one in a series of sponsored themed
`publications from ONdrugDelivery Ltd. Each issue focus-
`es on a specific topic within the field of drug delivery,
`and is supported by industry leaders in that field.
`Full contact information appears alongside each article.
`Contributing companies would be delighted to hear
`from interested readers directly. ONdrugDelivery
`would also be very pleased to pass on to authors, or
`answer as appropriate, any queries you might have in
`relation to this publication or others in the series.
`
`During 2008 we will be covering the following topics:
`
`February: Transdermal Drug Delivery
`April: Prefilled Syringes
`June: Pulmonary Drug Delivery
`August: Oral Drug Delivery
`October: Delivering Injectables
`
`SUBSCRIPTIONS:
`To arrange your FREE subscription (pdf or print)
`to ONdrugDelivery’s sponsored series, contact:
`Nicki Macadam, Marketing & Subscriptions Manager
`T: +44 (0) 1273 320 279
`E: nicki.macadam@ondrugdelivery.com
`
`SPONSORSHIP/ADVERTISING:
`To find out more about how your company can become
`a participant in any of our sponsored issues, contact:
`Guy Furness, Publisher
`T: +44 (0) 1273 320 279
`E: guy.furness@ondrugdelivery.com
`
`MAILING ADDRESS:
`ONdrugDelivery Ltd, 48, Albany Villas, Hove,
`East Sussex, BN3 2RW, United Kingdom
`
`“Delivering injectables: formulations, auto-injectors
`and needle-free” is published by ONdrugDelivery Ltd.
`Registered Office: Cedar Cottage, Newtimber Place
`Lane, Newtimber, West Sussex, BN6 9BU, United
`Kingdom. Registered in England: No 05314696.
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`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
`acceptliability 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 “Hydrated liquid crystal depots in water, FluidCrystal®”
`reproduced with kind permission from Camurus AB.
`
`Introduction
`Guy Furness
`ONdrugDelivery
`
`Lipid self-assembly in drug delivery:
`Pretty structures and a seriously
`handsome commercial proposition
`Fredrik Joabsson and Fredrik Tiberg
`Camurus AB
`
`Solid dose injection of therapeutics and
`vaccines: effective, convenient and
`cost-effective alternative to needles
`Simon Bennett and Charles Potter
`Glide Pharma
`
`Market Trends: Disposable Mono-Dose
`Auto-Injectors and Pen-Injectors
`Ian Thompson
`Ypsomed AG
`
`Nasal delivery as an alternative
`to injection: science and technology meet
`market demand
`Matthias Birkhoff
`Ing Erich Pfeiffer GmbH
`
`3
`
`6-9
`
`11-13
`
`15-17
`
`20-22
`
` IN WHICH EDITION
`SHOULD YOUR
`COMPANY APPEAR?
` WWW.ONDRUGDELIVERY.COM
`
`2
`
`www.ondrugdelivery.com
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`Opiant Exhibit 2091
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 2
`
`

`

`INTRODUCTION
`
`Welcome to ONdrugDelivery’s first issue of 2008,
`and our third publication focusing on the topic
`“delivering injectables”. Inside, I am pleased to
`present a selection of articles tackling issues from
`across the range of injectable drug delivery. At the
`“small” end of the spectrum, we discover advanced
`nanoparticles which self assemble in vivo to form
`drug carriers. Zooming-out to look at the bigger
`picture, we explore market trends in the area of
`advanced injection devices.
`From the patient’s perspective, needle-based injec-
`tion is seldom the most attractive route of administra-
`tion, but it is often the only viable option. There was a
`period of hopeful optimism during the last decade when
`scores of non-invasive alternatives were promised;
`some even seemed to hint at the end of the needle and
`syringe altogether. In reality, of course, drug delivery
`has not succeeded in banishing the hypodermic needle
`to the history books, but it would not be at all fair to
`suggest that the quest to do so has achieved nothing.
`Important lessons have been learnt along the way.
`Although there is not a needleless alternative
`for every currently injected product, considerable
`progress has been made. Numerous technologies
`offering non-invasive alternatives to injection have
`been developed and many products using these sys-
`tems have reached the market.
`The nasal route of administration is one which
`has proven successful at bearing viable alternatives to
`injections. Although not without its own challenges
`and problems, nasal delivery has several attributes,
`including rapid onset of action which is crucial in
`the context of replacing an injection. Systemic nasal
`products such as nicotine, sumatriptan, nafarelin and
`calcitonin, as well as nasal vaccines such as the live
`influenza vaccine, FluMist, have been launched in
`recent years, with numerous other products coming
`through the pipeline.
`On page 20 of this issue, Matthias Birkhoff of
`Pfeiffer (Randolfzell, Germany) comments further on
`the commercial success that nasal drug delivery has
`had in offering an alternative to injection. He draws
`particular attention to lifestyle drugs – a $23 billion
`global market enjoying double digit annual growth –
`as an important growth area for nasal products.
`An interesting point that Pfeiffer makes is that
`its devices are Drug Master File supported and all
`materials used are known and approved by the US
`FDA. In terms of regulatory scrutiny of material
`contact, this brings their nasal spray products into
`the same league as injectable products.
`
`A NEW TAKE ON NEEDLE-FREE
`
`If the example of nasal drug delivery can be linked
`with realistic product opportunities for alternatives
`to injection, many people might hold up needle-
`
`free injection as an example of a sector that, while
`chasing attractive dreams, has yet to achieve market
`success. Personally I have always believed that the
`needle-free sector has much to offer and that com-
`mercial success – although hampered by misfortune
`and bad press – would eventually arrive.
`And then along came a man with an elegant new
`approach to needle-free injection that decisively
`changed the question hanging over the commercial
`success of needle-free injector from an “if” into a
`“when” and then into a “how soon”. His name is
`Charles Potter, founder and chief executive of Glide
`Pharma (Abingdon, UK).
` I am particularly pleased to present in this issue
`an article from Glide Pharma. It describes the compa-
`ny’s Glide SDI technology which, instead of acceler-
`ating a liquid jet across the skin like other needle-free
`injectors (NFIs), uses a solid dose. With innovative
`ideas such as this progressing through development,
`perhaps the needle-free sector will blossom a little
`sooner than we previously imagined.
`
`NEEDLES ARE STILL NEEDED
`
`We have learnt how better to identify the instances
`where it really is possible to substitute the needle for a
`non-invasive delivery system and, as described above,
`technology is moving on apace. However, crucially,
`the industry has also learnt to spot those instances
`where it is not yet possible to avoid injection. This
`latter point is significant because being realistic about
`the limits of non-invasive delivery allows proper
`attention to be given to developing the best possible
`needle-based injectable delivery systems.
`The injectables market continues to expand, par-
`ticularly with advances in subcutaneous self-injection
`technology moving injections from the professional
`clinical setting into the home, and thus edging into the
`market that non-invasive delivery systems have not
`been able to fill.
`Those involved in developing improved injec-
`tion delivery systems will be looking in detail at all
`aspects of the device or the formulation, with the
`aim of optimising:
`
`• Needle safety
`• Comfort
`• Cost-effectiveness
`• Ease of use
`• Manufacturability
`• Stability
`• Storage
`• Frequency of injection
`• Applicability across different types of compound
`• Applicability across therapeutic categories
`• Product differentiation
`• IP position
`
`In his article on page
`15, Ian Thompson, Head
`of Business Development
`at Ypsomed (Burgdorf,
`Switzerland), gives an
`excellent overview of factors influencing the injection
`device market, and the criteria for selecting different
`types of device, or combinations of device characteris-
`tics – pen or auto-injector; standard prefilled syringe or
`safety-enhanced syringe; dual chamber or single cham-
`ber; mono-dose disposable or multi-dose reusable. He
`describes some of the recent technology developments,
`such as the emergence of the mono-dose disposable
`dual chamber injector for lyophilised products.
`Turning from devices to injectable formula-
`tion technology, Camurus (Lund, Sweden), is
`developing self assembling lipid liquid crystal and
`nanoparticle systems which overcome some of the
`limitations commonly encountered by formula-
`tion approaches such as liposomes, emulsions and
`micro-emulsions. A summary of the advantages
`of self assembling lipid liquid crystal formula-
`tions – in terms of patient benefits, pharmaceutical
`benefits and technical/commercial benefits – can
`be found in the boxed text on page nine.
`One fascinating characteristic of the systems
`Camurus is developing stems from the fact that
`they self assemble in vivo on contact with aqueous
`fluid inside the body. This means that the single
`formulation can exist in effect in two different
`conformations – pre-delivery and post-delivery.
`Thus the formulation can be designed optimally to
`fulfil the requirements on it before delivery (stor-
`age, high drug payload, no need to re-constitute,
`low viscosity etc). Then, once inside the body the
`pre-delivery requirements no longer apply, so the
`formulation can change its structure and related
`functional properties for the optimal timed and/or
`targeted in vivo drug release profile.
`From needle-based injection devices and for-
`mulations to needle-free and nasal alternatives, I
`hope that this publication provides you with an
`interesting and informative insight into the world
`of injectable drug delivery.
`
`Our next injectables-related publication is out in
`April 2008 and focuses in on the topic of prefilled
`syringes.
`
`Guy Furness
`Publisher
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`www.ondrugdelivery.com
`
`3
`
`Opiant Exhibit 2091
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 3
`
`

`

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`engineering. Co-located with INTERPHEX, the world’s largest annual
`event for pharmaceutical and biotechnology manufacturing, and BIOTECHNICA
`AMERICA, a global biotechnology exhibition, this transformational event delivers
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`Opiant Exhibit 2091
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`IPR2019-00685
`Page 4
`
`

`

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`
`Opiant Exhibit 2091
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 5
`
`

`

`LIPID SELF-ASSEMBLY IN DRUG DELIVERY:
`PRETTY STRUCTURES AND A SERIOUSLY
`HANDSOME COMMERCIAL PROPOSITION
`
`Here, Fredrik Joabsson, PhD, Director, Drug Delivery Systems, Technical Business Development,
`and Fredrik Tiberg, PhD, President and CEO, both of Camurus AB, describe a novel type of
`self assembling lipid structures – liquid crystal gels and their corresponding nanoparticles
`– which overcome the problems associated with previously used lipid-based, self-assembling
`structures such as micro-emulsions and liposomes.
`
`Camurus was founded in 1991 by scientists pio-
`neering the discovery and characterisation of self-
`assembling lipid structures. The potential such
`structures had in drug delivery was clear and had
`been demonstrated by several products which,
`using such systems, had achieved market success.
`Examples include Novartis’s Sandimmun Neoral®
`(a micro-emulsion); AstraZeneca’s Diprivan® (an
`emulsion); and J&J’s Doxil® (which uses Alza’s
`STEALTH® liposome technology).
`However, it was also apparent that many
`formulation technologies based on simple lipid
`self-assembly structures, such as the commonly
`used micelle, micro-emulsion, emulsion and
`liposome systems, had limited applicability for
`numerous reasons.
`Use of micellar and emulsion systems is basi-
`cally limited to the handling of solubility issues
`of sparingly water-soluble substances, and they
`are sometimes associated with limitations in
`local and systemic tolerability. Liposomes are
`used to load and encapsulate water-soluble
`compounds. However, high encapsulation effi-
`ciencies typically require active loading by use
`of, for example, pH gradients, limiting their
`applicability to charged water-soluble com-
`pounds. Moreover, the preparation, scale-up,
`manufacturing, and storage is in many cases
`hampered by an inherent physical instability.
`High manufacturing and excipient costs are
`also potential hindrances for the use of lipo-
`somal drug delivery systems, as is their limited
`ability to slow down and control the release of
`active agents in sustained-release applications.
`The latter fact is due to the single bilayer barrier
`of more physically stable unilamellar liposomes
`(compared with multilamellar liposomes).
`
`In light of these drawbacks, Camurus
`began developing a number of novel structures
`– lipid-based, self-assembling liquid crystal
`gels of interconnected non-lamellar cubic,
`hexagonal, sponge (denoted L3), and discrete
`micellar cubic phases and their corresponding
`nanoparticles.
`
`LIPID LIQUID CRYSTALS
`
`Lipid liquid crystals are well-defined three-
`dimensional structures comprised of coexisting
`lipophilic and hydrophilic nanodomains that can
`be either interconnected or isolated depending
`on the phase structure.
`As shown in figure 1, lipid liquid crystals
`self assemble to form complex and very
`beautiful natural structures. Yet what these
`structures can actually do represents some-
`thing far more interesting and attractive than
`their mere appearance.
`Lipid liquid crystals offer a unique means
`of solubilising, encapsulating, and transport-
`ing active pharmaceutical ingredients (APIs),
`including small molecules, peptides and pro-
`teins. Importantly these structures also offer a
`means to control their release in the body and
`to protect sensitive molecules from degrada-
`tion in vivo.
`Most pharmaceuticals have a therapeutic
`window, below which they are essentially not
`effective and above which they may be toxic.
`By using transport facilitating and/or controlled
`release drug-delivery systems it is possible to
`develop new therapies that otherwise would be
`ineffective or potentially toxic to the patient.
`Examples of current drug delivery chal-
`
`Fredrik Tiberg, PhD, Prof.
`President and CEO
`
`T: +46 46 286 5730
`F: +46 46 286 5739
`E: fredrik.tiberg@camurus.com
`
`Fredrik Joabsson, PhD
`Director, Drug Delivery Systems,
`Technical Business Development
`
`T: +46 46 286 5747
`F: +46 46 286 5739
`E: fredrik.joabsson@camurus.com
`
`Camurus AB
`Ideon Science Park
`SE-223 70 Lund
`Sweden
`
`www.camurus.com
`
`6
`
`www.ondrugdelivery.com
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`Opiant Exhibit 2091
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 6
`
`

`

`Figure 1: Schematic representation of nanostructured lipid liquid crystals formed
`in water or aqueous body fluids. From left to right: lamellar phase Lα; bicontinuous
`cubic phase QΙΙ; reversed hexagonal phase HΙΙ; reversed cubic micellar phase I2.
`
`A
`
`B
`
`C
`
`D
`
`Figure 2. Schematic illustration of the evolution of the FluidCrystal depot illustrating
`the A) injection, B) hydration and aqueous self assembly, C) release, and D)
`biodegradation phases.
`
`liquid pre-concentrate. Only after injection,
`in situ on contact with minute quantities of
`aqueous fluid, does the inactive precursor
`transform into the active delivery system – a
`controlled release liquid crystal matrix (see
`figure 2). FluidCrystal® products are thus
`precursors to the to the in vivo active liquid
`crystal delivery systems.
`So, pre-injection, the formulation has a
`different structure to that which it has after
`it has been administered. This brings several
`unique advantages because, clearly, before
`injection a formulation actually needs to fulfil
`very different functions to those it must fulfil
`after injection.
`FluidCrystal® in effect allows one single for-
`mulation to inhabit two structural identities each
`suited to the different functional requirements
`pre and post administration.
`
`PRE INJECTION:
`
`Manufacturing of products based on Camurus
`depot technology involves just a few standard
`pharmaceutical processing steps. Poor drug sta-
`bility and complex processing requirements are
`avoided because encapsulation of the drug in the
`nanopores of the liquid crystal phase structure
`does not take place until after injection.
`Products are ready to inject, without the
`need for complicating reconstitution and mix-
`ing steps, thus making them ideal for prefilled
`syringes. The low viscosity of our injectable
`formulations permits the use of thin needles –
`23-25 gauge is standard – so there is less pain
`on injection compared with most conventional
`microparticle depots typically requiring 19-21
`gauge needles. Moreover, the high solubilisation
`capacity of FluidCrystal® with drug payloads of
`
`100
`
`10
`
`1
`
`Subcutaneous
`Intramuscular
`
`0.1
`
`0
`
`10
`
`20
`
`30
`
`50
`40
`Time (days)
`
`Plasma peptide concentration (ng/ml)
`
`OCT saline s.c.
`
`FluidCrystal® once daily
`
`FluidCrystal® once weekly
`
`50
`
`100
`
`150
`Time (hours)
`
`1000
`
`100
`
`10
`
`1
`
`0.1
`
`0
`
`Plasma peptide concentration (ng/ml)
`
`Figure 3: Pharmacokinetic profiles
`demonstrating 24 hours and 1 week
`release duration of octreotide (OCT)
`from subcutaneous FluidCrystal®
`injections in rats.
`
`Figure 4: Long-acting release of
`octreotide from subcutaneous and
`intramuscular FluidCrystal® injections
`in dogs.
`
`lenges and opportunities addressed by lipid
`liquid crystals are:
`• Continuous delivery of peptide and protein
`therapeutics by use of biocompatible eroding
`depots
`• Delivery to and targeting of cancer cells with
`e.g. cytotoxic agents
`• Lipid-mediated cellular delivery of RNA
`therapeutics
`• High drug load requirements of sparingly solu-
`ble or amphiphilic drugs
`• Stability enhancement – enabling of new
`therapeutic products
`
`Aside from facilitating development of new ther-
`apeutic products, many existing products have
`suboptimal properties which can be improved
`by exploiting the inherent delivery properties of
`lipid-based systems. Such improvements include
`increasing patient convenience and compliance,
`reducing side-effects, and improving efficacy.
`The broad solubilisation and encapsulation
`spectrum together with high drug payloads, as well
`as the ability to protect sensitive substances like
`peptides and proteins, and facilitate absorption,
`make lipid liquid crystals all the more interesting
`and attractive alternatives to simple lipid carriers.
`Similar to micro-emulsions, emulsions and
`liposomes, they can be designed to self-disperse
`into colloidal particles. This property is essen-
`tial in many applications where the delivery
`system should have a carrier function and where
`water-free liquid or powder pre-concentrates are
`the desired dosage forms.
`Camurus’ liquid crystal-based technologies
`are applicable in oral, topical and parenteral
`drug delivery. The lipid liquid crystal gel tech-
`nology is known as FluidCrystal® and the nano-
`particle systems are known as FluidCrystal®
`NP, featuring Cubosome®, Hexosome®, and
`Flexosome® nanoparticle carriers.
`
`Within the injectables field, there are two
`principle uses, one for each of the two systems:
`1. FluidCrystal® is applied in the formulation
`of depot injection products for subcutaneous,
`intramuscular and intracavital administration.
`2. FluidCrystal® NP is applied in the formula-
`tion of intravenous (IV) products
`
`FLUIDCRYSTAL® FOR DEPOT
`INJECTIONS
`
`One key feature differentiating FluidCrystal®
`from other formulation systems such as micro-
`spheres and liposome foam structures is that the
`structure of the lipid liquid crystal drug carrier
`matrix self assembles in vivo.
`Be it in a prefilled syringe or vial, the
`product is presented as a simple non-aqueous
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`www.ondrugdelivery.com
`
`7
`
`Opiant Exhibit 2091
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 7
`
`

`

`Figure 6: High-resolution
`cryo-transmission microscopy images
`of FluidCrystal® NP: a) Cubosome®, b)
`Hexosome®, c) Flexosome®, and
`d) Cubosome® (I2).
`
`CAM2029 was furthermore found to provide
`long-acting release of octreotide resulting in a
`statistically significant suppression of the clinical
`biomarker insulin-like growth factor 1 (IGF-1)
`over the target one-month therapeutic period.
`Crucially, FluidCrystal® has enhanced the
`formulation characteristics so that it has a
`number of key advantages over microparticle
`depot products:
`1 It can be administered subcutaneously, as well
`as intramuscularly, with similar pharmacoki-
`netic profiles (see figure 4)
`2 It provides immediate onset of release without
`the lag phase typically observed for the micro-
`particle systems
`3 It is presented as a ready-to-use formulation
`without the need for premixing or reconstitu-
`tion and is compatible with prefilled syringes
`4 The high drug loads and liquid nature of
`the FluidCrystal® products allows for small-
`volume injections using thin needles
`5 Product manufacturing is simplified, involv-
`ing only standard pharmaceutical processes
`
`FLUIDCRYSTAL NP® FOR IV
`INJECTIONS
`
`Micelles and oil-in-water (o/w) emulsions have
`traditionally been used extensively in parenteral
`formulations, using relatively mild surfactants
`or lipids, such as polysorbates, cremophors,
`egg lecithin, and soybean oil. Examples of
`drugs intended for IV administration, utilising
`micelles and o/w emulsions as solubilisation
`aids, include Taxol® (paclitaxel, Bristol-Myers
`Squibb), which takes advantage of Cremophore
`micelles, and Diprivan® (propofol, AstraZeneca),
`which is an o/w emulsion stabilised by lecithin.
`Conventional o/w emulsions are best adapted
`for strongly lipophilic drugs that require an oil
`
`the interconnected network of aqueous and oily
`domains in the bicontinuous to the discrete water
`domains of the reverse cubic phase schematically
`depicted in figure 1. Thus, this offers one way of
`controlling release properties. Further fine tuning
`of in vitro and in vivo release rates is achieved by
`including lipid components that facilitate fragmen-
`tation (faster erosion) and degradation of the depot
`or that specifically interact with the active agent.
`The main mechanism of drug release from
`the depot is the continuous biodegradation of the
`depot locally at the site of injection. Extensive
`toxicological, local tolerance, and biodegrada-
`tion data in different animal species is available
`to support the safe use of FluidCrystal® depot
`and its individual lipid components.
`
`PRODUCTS UNDER DEVELOPMENT
`
`FluidCrystal® is by no means just a technology
`concept. On the contrary, one product – a dental
`gel using FluidCrystal® – is on the market for the
`treatment of periodontitis, and pharmaceutical
`projects are under development both in-house and
`in collaboration with partners. Non-limiting exam-
`ples of active agents where desired sustained-
`release properties of the FluidCrystal® delivery
`system has been proven include: small molecules,
`such as testosterone derivatives and opiates; mul-
`tiple peptide agents including, octreotide, leupro-
`lide, somatostatin, salmon calcitonin, GLP-1 and
`analogues; and several therapeutic proteins.
`Two injectable products are currently in
`clinical development, including CAM2032, a
`long-acting LHRH agonist for the treatment of
`prostate cancer. In May 2007, it entered a Phase
`I/II single-dose, dose-escalating, open-label, mul-
`ticentre, cohort trial in 24 male patients with
`advanced/metastatic prostate cancer, to determine
`the leuprolide drug serum profile and the serum
`testosterone suppressing effects after a single sub-
`cutaneous administration of three different doses.
`Assessment of safety was a further key objective.
`Another clinical-stage product is CAM2029,
`a long-acting formulation of octreotide, for
`the treatment of acromegaly, carcinoid syn-
`drome and vasoactive intestinal peptide (VIP)-
`producing tumours
`In a recent double-blind, randomized, par-
`allel-group, placebo-controlled Phase I trial
`for the assessment of safety, pharmacokinetics
`and pharmacodynamics, 32 healthy volunteers
`received single-dose injections of three sub-
`cutaneous doses and one intramuscular dose
`of CAM2029 and the corresponding placebo
`FluidCrystal® formulations.
`The local tolerability at the injection sites was
`very good. Systemic safety was also good with
`adverse events being limited to transient gastroin-
`testinal side-effects related to octreotide itself.
`
`15 mg/kg
`50 mg/kg
`75 mg/kg
`
`1000
`
`100
`
`10
`
`Plasma concentration (ng/ml)
`
`0
`
`5
`
`10
`
`15
`
`20
`
`30
`25
`Time (days)
`
`Figure 5: Long-acting release of
`buprenorphine from subcutaneous
`FluidCrystal® injections in rats.
`
`up to 30% allows smaller injection volumes.
`Combined with excellent stability with many
`active agents, the FluidCrystal® delivery system
`represents an integrated solution to classical for-
`mulation challenges encountered in the develop-
`ment of new injectable drug products.
`
`POST INJECTION:
`
`Once inside the body, the nanoscale matrices
`spontaneously form to create protective “cages”
`around delicate therapeutic molecules with coex-
`isting hydrophilic and hydrophobic domains.
`Proteins and peptides are stabilised in the nanos-
`tructured lipid membrane environment and are
`protected from degradation by endogenous
`enzymes, thus providing improved bioavailabil-
`ity and prolonged “effective” half-lives.
`that
`Rapid structure formation means
`FluidCrystal® avoids the common side effects
`associated with high initial plasma levels from
`rapid drug release on injection (drug burst).
`Thanks to the interior nanostructure, com-
`prising both hydrophilic and lipophilic domains
`forming discrete (mono-) or bi-continuous net-
`works, the liquid crystal depot system is capable
`of providing in vivo sustained release of a wide
`range of therapeutic agents over controlled peri-
`ods of time, as exemplified in figures 3, 4 and 5.
`Importantly the connectivity of the aque-
`ous domains can be changed, for example, from
`
`Buffer
`Cubosome®
`
`30
`
`60
`
`90
`
`120
`
`180
`150
`Time (minutes)
`
`107
`106
`105
`104
`103
`102
`101
`
`1
`
`0
`
`Plasma peptide concentration (pg/ml)
`
`Figure 7: Plasma profiles following IV
`bolus injections of a GLP-1 buffer solution
`and a GLP-1 Cubosome® formulation
`showing extended in vivo circulation.
`
`8
`
`www.ondrugdelivery.com
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`Opiant Exhibit 2091
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 8
`
`

`

`Cubosome®
`
`Lipuro®
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`propofol / excipient (wt/wt)
`
`Propofol-Lipuro®
`Cubosome®
`
`104
`
`1000
`
`100
`
`10
`
`0
`
`1
`
`2
`
`3
`
`4
`
`6
`5
`Time (hours)
`
`Plasma propofol concentration (ng/ml)
`
`Figure 8: Plasma concentration after IV
`bolus injection of Propofol-Lipuro and
`a propofol Cubosome® formulation to
`rats. The insert shows the difference in
`drug load between the two systems.
`
`SUMMARY
`
`In summary, Camurus presents an attractive
`business proposition with:
`• An advancing clinical drug product pipeline
`• Innovative nanoscale drug delivery systems
`• Strong strategic partnerships in place:
`- >10 projects
`- Feasibility studies & co-developments
`- Five with top-ten pharma companies
`• Near-term clinical milestones
`• Growing revenue stream
`• Great teams
`
`BENEFITS OF LIPID LIQUID
`CRYSTALS: A SUMMARY
`
`Patient/clinical value
`• Increased convenience and compliance
`• Improved efficacy
`• Decreased side effects
`• Decreased health care costs due to simplified
`handling and less frequent administration
`• Decreased risks of drug misuse and
`misdirection
`
`Pharmaceutical value
`• Means of solubilising, encapsulating, and
`transporting APIs
`• Broadly applicable (to small molecules,
`nucleotides, peptides and proteins)
`• High drug loading
`• Allows true controlled release
`• Stability enhancement (improved shelf-life
`and/or in vivo stability)
`• Allows targeting (e.g. of cancer drugs)
`
`Technical/commercial value
`• Already proven safe and effective in
`the clinic
`• Extends patent-life
`• Attractive ROI
`• Enabling technology for the development
`of NCEs/NBEs
`• Scaleable and transferable process
`
`medium for optimal solubilisation. In contrast,
`amphiphilic drugs – and in particular peptides
`and proteins – are often less compatible with
`emulsion systems.
`More recently, liquid crystalline nanoparticles
`of cubic, hexagonal and “sponge” phases, denoted
`Cubosome®, Hexosome®, and Flexosome®, respec-
`tively, have emerged as potential new functional
`carriers for future drug products (see figure 6).
`Camurus has a robust intellectual property estate
`surrounding these particles and their use as drug
`delivery carriers. Cubosome® and Flexosome®
`nanoparticles of the cubic and “sponge” phases,
`respectively, are being used in different develop-
`ment products intended for injectable applica-
`tions, in particular for IV products.
`Especially noteworthy is the nanostructured
`interior of the particles, featuring both hydrophilic
`(aqueous) and lipophilic (lipid) domains. In con-
`trast to liposomes, which consist mostly of water
`even for relatively small liposome radii, the lipid
`content of typical liquid crystal nanoparticles
`is high (normally in the range of 50-80 wt%).
`Because of coexisting hydrophilic and lipophilic
`domains and an enormous surface area of several
`hundred square metres per gram, the FluidCrystal®
`NP carriers have a broad spectrum of applicabil-
`ity, comprising lipophilic and amphiphilic bioac-
`tive agents, and peptide and protein drugs.
`
`The key functionalities are:
`1 Encapsulation vehicle for aqueous soluble
`compounds, including peptides and proteins,
`offering protection against degradation
`2 Exceptional solubilising and carrying capac-
`ity of sparingly soluble and amphiphilic drug
`compounds
`3 Controlled release facilitating reduced expo-
`sure to toxic compounds, potentially eliminat-
`ing th