Journal of Controlled Release 206 (2015) 108–121
`
`Contents lists available at ScienceDirect
`
`Journal of Controlled Release
`
`j o u rn a l h o m e p a g e : w w w. e l s e v i e r . c o m/ l o c a t e / j c o n r e l
`
`Oral films: Current status and future perspectives II — Intellectual
`property, technologies and market needs
`Ana Filipa Borges a,b, Cláudia Silva a, Jorge F.J. Coelho c, Sérgio Simões a,b
`a Bluepharma, Indústria Farmacêutica, S.A., Portugal
`b Faculty of Pharmacy, University of Coimbra, Portugal
`c CEMUC, Department of Chemical Engineering, University of Coimbra, Portugal
`
`Contents
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`1.
`2.
`3.
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`Introduction .
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`Intellectual property .
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`Technological platforms .
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`3.1.
`Pharmfilm® .
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`3.2.
`RapidFilm® .
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`VersaFilm™ .
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`3.3.
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`3.4.
`Orally and adhesive disintegrating films
`3.5.
`SmartFilm® .
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`3.6.
`BEMA® .
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`3.7.
`Bio-FX® Fast-Onset Oral-Cavity ODF .
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`3.8.
`Quicksol® .
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`3.9.
`Fast-onset sublingual bilayer film .
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`3.10.
`Biodegradable transmucosal film .
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`3.11.
`Eluting Bandage Platform .
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`Xgel™ .
`3.12.
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`Thinsol™ .
`3.13.
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`3.14.
`Schmelzfilmen .
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`3.15.
`Others .
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`4. Market overview .
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`5. Market outlook .
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`6.
`Conclusion .
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`Acknowledgments .
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`References
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`
`1. Introduction
`
`The oral route remains the most preferred for the general population
`[1]. It is easier, non-invasive, convenient and flexible, and generally oral
`formulations have a lower cost of production for the pharmaceutical
`companies. These facts justify why the oral delivery market holds 52%
`of the market share remaining the largest sector in the overall drug
`delivery market [2–4]. Although the majority of drugs are administered
`in the form of tablets and capsules, several groups of patients have
`serious swallowing difficulties. It is estimated that almost 28% of the
`general population have frequent problems in swallowing medicines
`that is often the cause of poor patient compliance [5]. This is commonly
`associated with dangerous tablets and capsules' modifications, such as
`
`splitting or crushing, related with dosage inaccuracy and drug therapy
`inefficiency or overdosing [6]. In order to overcome these issues, fast
`dissolving delivery systems are gaining considerable attention. Among
`them, oral films have emerged and have been dragged by this urgent
`market need.
`There is no strong evidence or consensus about the date for the first
`reference of orodispersible delivery systems [7] but the most likely
`pioneer in the conception of orodispersible films was Deadman Frederic
`in the 1960s [8]. Nevertheless, it remained just a concept until 2001
`when Pfizer introduced in the market the major orodispersible film
`blockbuster, the Listerine® Pocket Packs® [9].
`There is an evident trend that the pharmaceutical field is moving from
`the conventional and traditional to the innovative and patient-centered
`
`http://dx.doi.org/10.1016/j.jconrel.2015.03.012
`0168-3659/© 2015 Elsevier B.V. All rights reserved.
`
`MONOSOL RX EXHIBIT 2009 page 0001
`
`Plaintiffs' Exhibit
`
`Reckitt Benckiser Pharms. Inc., et al.
`v. Watson Labs., Inc., et al.
`(1:13-cv-01674-RGA)(Con.)
`
`PTX 210
`
`

`
`A.F. Borges et al. / Journal of Controlled Release 206 (2015) 108–121
`
`109
`
`developments. There is also an increase in the demand of the authorities
`for knowledge, in order to improve the quality of the products, and the
`optimization and lean of the resources.
`This section of the review highlights the Intellectual Property devel-
`oped in this field, looking over the major players in the area, their
`platform technologies and all the commercial evolution through a
`summary market outlook and trends.
`
`2. Intellectual property
`
`The drug delivery technology is an area with extensive intellectual
`property protection which is extremely important and required consid-
`ering the high competitiveness of this fast-evolving field. There are a
`considerable number of institutions developing oral films, which can
`be easily confirmed by the constant growing number of patent applica-
`tions. In fact, the increasing number of patents filled each year is impres-
`sive and more than 132 patent families have been identified and at least
`30 companies/institutions are developing these technological platforms
`[10]. Until 2011, the majority of the patents were filled in the US and
`Japan, by the top players such as MonoSol and Kyukyu Pharmaceuticals
`Co., Ltd, with Europe gaining some ground in the recent years with LTS
`Lohmann Therapy-Systems (LTS), Labtec Pharma, Hexal Pharmaceuti-
`cals and others. Additionally, LTS and MonoSol are clearly the major
`players with a broader technology coverage concerning the intellectual
`property, highlighting the diversified and fuelled research of these com-
`panies in the field [10]. At the moment according to the recent pub-
`lished Root Analysis report, MonoSol is the most prominent player in
`the oral thin films, with nine products already on the market based on
`its own technology [11].
`Regarding intellectual property protection, an exhaustive search in
`free patent databases (Google patents, Espacenet, WIPO) reveals that
`the composition patents are the larger slice in the overall patents filled.
`Among them, few are restricted to a specific therapy or drug substance,
`and the majority is therapeutically broader and focused in the composi-
`tion of the technology, claiming essentially the film forming polymer(s),
`crucial for the matrix formation. The process patents have also some
`relevance, but only a few are restricted to a specific drug, therapy or
`method of use.
`The most patented polymers are polysaccharides, including starch,
`cellulose and its derivatives (Fig. 1). As already described in part 1
`of this review, these are two large groups of polymers that can be
`
`Fig. 1. Overall scenario of polymers usage. The polysaccharide group comprises starch de-
`rivatives, pectin, gums, dextrans and alginates; other polymers group includes polyvinyl
`and polyethylenoglycol polymers and co-polymers; the protein group consists of soy pro-
`teins, casein, zein, collagen and others; the acrylate group refers mainly to methacrylate
`and polyacrylic polymers.
`
`subdivided into subclasses according to the modifications and substitu-
`ents added to the native natural polymer backbones.
`The use of the majority of hydrophilic polymers in formulations of
`oral films is already protected by several patents, restricting the possi-
`bility of developing formulations that do not infringe existing patents
`and capable of being protected by new ones. During the last years the
`development of new polymers suitable to this technological platform
`was scarce, leading to an increasing number of process patent applica-
`tions, and patent formulations related with specific drug substances or
`therapies.
`Furthermore, the difficulty in innovating in the formulation com-
`position due to the small number of suitable excipients had probably
`contributed to new directions in this research field, such as the develop-
`ment of new manufacturing processes [12,13] (see part 1 review), or
`the usage of oral films as drug delivery systems for biotechnology prod-
`ucts (e.g. vaccines and insulin) [14–17].
`
`3. Technological platforms
`
`The majority of the top player companies referred above followed a
`similar pattern. Generally, a new and innovative technological platform
`is developed (like an oral film placebo) and then several drug candi-
`dates are evaluated and considered to be incorporated in the film.
`Obviously, this strategy implies necessarily the development of a versa-
`tile oral film platform, which in turn may suffer some modifications de-
`pending on the drug substance characteristics and the desired final
`dosage form performance.
`Furthermore, in this market segment the establishment of partner-
`ships between oral film developers/manufacturers and other pharma-
`ceutical companies researching new chemical entities, developing
`novel uses for existing drugs (repurposing) or companies looking for in-
`novative formulations for their drugs (life-cycle management) is com-
`mon. This strategy is beneficial to share fixed expenses associated
`with the product licensing and marketing [18]. Therefore, two different
`major players may be distinguished in this field: the oral film platform
`developers, usually the technology owners, and the marketing partners.
`Several oral film platforms have been already developed, the major-
`ity is listed in Table 1 and some are revised herein.
`
`3.1. Pharmfilm®
`
`MonoSol, one of the pioneer companies in the oral film industry
`owns a protected drug delivery technology, PharmFilm®. MonoSol's
`film technology is supposed to be more stable and robust than other
`conventional dosage forms with a loading capacity up to 80 mg. The
`Pharmfilm® is a polymeric matrix based on polyethylene oxide and
`hydroxypropylmethyl cellulose, which normally is related with fast dis-
`solution rates and rapid drug absorption [19]. However, MonoSol claims
`that this technological platform can be used for both fast dissolving sys-
`tem or buccal delivery. In fact, ondansetron hydrochloride had been
`successfully incorporated into the PharmFilm® technology as fast-
`dissolving system and other drug substances such as montelukast
`sodium, rizatriptan, escitalopram oxalate, donezepil hydrochloride and
`epinephrine are being considered or under development as oral quick
`release formulations [20–25]. Additionally, as previously referred, the
`Pharmfilm® technology is also available as a slower release sublingual
`formulation (Suboxone® sublingual film) [25].
`Moreover, MonoSol has established strategic partnerships to devel-
`op biotechnology sublingual and buccal films based on PharmaFilm®
`technology, such as anti-diabetic oral films or films to deliver a vaccine
`for universal flu. Together with Midatech, MonoSol has developed
`Nanoinsulin (insulin gold nanoparticles, MidaForm insulin) to incor-
`porate in the MonoSol's PharmaFilm® buccal film technology, for the
`potential treatment of diabetes. In the beginning of 2013, this inves-
`tigational medicinal product was listed as being in clinical development.
`Nevertheless, another buccal PharmaFilm® loaded with MidaForm
`
`MONOSOL RX EXHIBIT 2009 page 0002
`
`

`
`110
`
`A.F. Borges et al. / Journal of Controlled Release 206 (2015) 108–121
`
`nanoparticles, containing insulin and GLP-1, is also in preclinical devel-
`opment [14,25,26].
`MonoSol in association with BiondVax Pharmaceuticals is develop-
`ing a sublingual film formulation for vaccination, with the Multimeric-
`001 (M-001), for the potential prevention of universal influenza infec-
`tion. It is expected that this type of formulation will allow the stability
`of the vaccine at room temperature [15,27].
`
`3.2. RapidFilm®
`
`RapidFilm® is another patented technology developed by Labtec
`GmBH. The Rapidfilm® is a fast dissolving thin film based on water
`soluble polymers, non-mucoadhesive, which can vary from single to
`multilayer design system. This oral film platform is based in a PVA-
`Starch mixture plasticized with a medium Mw PEG. The composition
`used allows its fast dissolution rate when in contact with the oral muco-
`sa [28]. It is claimed that RapidFilm® can accommodate up to 30 mg of
`the drug substances [20,29]. The ondansetron Rapidfilm® was the first
`Rx oral film approval worldwide, but at the moment, there are at least
`three more Rapidfilm® products in the European market [30] (see
`Table 1).
`
`3.3. VersaFilm™
`
`VersaFilm™ technology was developed and patented by IntelGenx
`Technologies Corp. Initially developed as an edible film for the instant
`delivery of savory flavors to food substrates, VersaFilm™ is now used
`as a system of choice for indications requiring an immediate onset of
`action. Thus, the company advances that VersaFilm™'s disintegration
`time may be wrought from 30 s to 10 min, and it can be sublingual, de-
`pending on the intended application. The maximum drug load claimed
`is around 40 mg. According to IntelGenx pipeline there are several drug
`substances in consideration or being incorporated in the Versafilm™
`technology. However, only one has recently received a complete re-
`sponse letter from FDA, the rizatriptan VersaFilm™, an oral quick re-
`lease film for migraine, developed together with RedHill Biopharma
`Ltd [31,32].
`
`3.4. Orally and adhesive disintegrating films
`
`KyuKyu Pharmaceuticals Co., Ltd is a Japanese company that also has
`its own oral film platform technology. Actually, KyuKyu has 2 different
`technologies the “Orally Disintegrating Film”, which dissolves in 10 to
`30 s and the “Adhesive and Disintegrating Film” that adheres to the
`oral mucosa and the disintegration time can vary between 30 min and
`8 h [33]. KyuKyu presents a large pipeline with several oral dispersible
`films in the market, mainly in the Asian market. Recently, it started to
`develop buccal films for the treatment of cancer-related pain and
`nicotine dependence. In collaboration with Nippon Kayaku, a buccal
`formulation of fentanyl is being developed and a phase II trial is being
`conducted [34]. Regarding to the nicotine mucoadhesive disintegrating
`film, it was in the fourth quarter of 2013 listed as being in lead
`optimization.
`
`3.5. SmartFilm®
`
`to mask the bitter taste of the drug substance. Seoul Pharma is currently
`seeking and researching other molecules to incorporate in its own oral
`film technology [37,38].
`
`3.6. BEMA®
`
`BioDelivery Sciences International owns the worldwide rights of
`BEMA®, bio-erodible muco-adhesive, drug delivery technology. This
`drug delivery technology consists of a bioerodible polymer film which
`adheres quickly to the oral mucosa (less than 5 s) with a backing layer
`that assures the unidirectional diffusion of the drug substance. This mul-
`tilayer buccal film technology can rapidly deliver a dose of drug across
`the oral mucosa and is completely dissolved within 15 to 30 min. The
`BEMA® technology may be developed to incorporate several drug sub-
`stances, especially if a quick onset of action is required, the oral admin-
`istration dose is not optimal (low oral bioavailability) or if parental
`administration is not an option [39]. Onsolis®, fentanyl buccal film,
`was the first product developed and marketed based on BEMA®'s tech-
`nology, for the management of cancer pain in opioid-tolerant adults. It
`was launched in 2009 [40], but by March 2012, the Onsolis® production
`had been temporarily closed in the US, due to FDA concerns regarding
`the manufacturing process [41]. In January 2014, it was announced
`that the re-launch of the product is planned to occur in the second
`half of 2014 [42,43]. In Europe, the product was approved in October
`2010 as Breakyl® [44]. Currently the BEMA® technology is being ap-
`plied to improve the delivery of other therapies, as the opioid depen-
`dence with Bunavail™, previously referred. The base formulation of
`the BEMA® layers is very similar. Both the active and the backing layers
`are composed by hydroxypropyl cellulose and hydroxyethyl cellulose,
`but the active layer presents additional mucoadhesive polymers, as
`polycarbophil and carboxymethylcellulose sodium. Interestingly the
`sweetener and flavor are only present in the backing layer [19,45].
`
`3.7. Bio-FX® Fast-Onset Oral-Cavity ODF
`
`Another technology platform is the Bio-FX® Fast-Onset Oral-Cavity
`ODF from NAL Pharmaceuticals Ltd. Briefly, it is an oral film formulated
`with a Bio-FX® absorption enhancer system, which increases the
`absorption of the drug substances through the oral mucosa with the
`aim to improve the oral bioavailability of drugs by avoiding the first-
`pass metabolism and gastrointestinal degradation. This technology
`also incorporates a specially designed taste-masking system to improve
`taste and mouthfeel [46]. Currently, there are no available products on
`the market with this technology, but several are under development.
`
`3.8. Quicksol®
`
`Quicksol® technology is the oral film platform from SK Chemicals
`that can accommodate a wide variety of drug substances. According to
`the company's pipeline, several drug substances were loaded, but only
`two are already on the market, Montfree (Montelukast) ODF and
`Mvix-S (Mirodenafil) ODF [47]. Mvix-S is a thin, light and portable
`50 mg oral film, available since January 2012, with a mirodenafil rate
`absorption 16.7% higher than Mvix tablet. Additionally, 15 days after
`its launch, Mvix-S sold over 1 billion units [48].
`
`Seoul Pharma has developed the SmartFilm® technology, an oral
`film with a high loading dose capacity, over 140 mg, capable of incor-
`porating both hydrophilic and hydrophobic drugs, with unique taste
`masking technology and an eco-friendly manufacturing process
`(aqueous solution based). This South Korean pharmaceutical company
`launched Vultis® in the Korea market in 2012, a 140.45 mg film formu-
`lation of sildenafil citrate. At the end of the same year, Seoul Pharma
`licensed it out to Pfizer which rebranded it as Viagra [35,36]. The
`Sidenafil SmartFilm® technology is a fast dissolving film composition
`that uses a combination of magnesium oxide and sodium hydroxide
`
`3.9. Fast-onset sublingual bilayer film
`
`Cynapsus developed a fast-onset sublingual bilayer film of apomor-
`phine, the APL-130277. The apomorphine in its neutral form (which
`may permit its fast mucosal absorption) is easily oxidized making its in-
`corporation in a film difficult. Therefore, the apomorphine non-neutral
`form is loaded in one film layer, and a neutralizing agent is incorporated
`in another film layer, physically separated from each other. The neutral-
`izing agent's layer dissolves quickly upon contact with saliva, allowing a
`fast reaction with the drug substance for a rapid absorption. Clinical
`
`MONOSOL RX EXHIBIT 2009 page 0003
`
`

`
`A.F. Borges et al. / Journal of Controlled Release 206 (2015) 108–121
`
`111
`
`(continuedonnextpage)
`
`[14,20–25,70,74–82]
`
`HPMC
`oxideand
`Polyethylene
`
`Buccal
`
`Dispersible
`Dispersible
`
`Dispersible
`
`Dispersible
`Dispersible
`
`Dispersible
`
`Dispersible
`Dispersible
`
`Dispersible
`
`Phase1clinical
`Discovery
`reported
`Nodevelopment
`Discovery
`reported
`Nodevelopment
`
`*
`
`(MidaForminsulin)
`Insulinnanoparticles
`Testosterone
`
`Epinephrine
`Rizatriptan
`
`Discovery
`
`Discontinued
`Discontinued
`
`Launched
`
`Escitalopram
`hydrochloride
`Diphenhydramine
`MontelukastsodiumClinical
`prodrug+ligand
`Methylphenidate
`acid
`(Pectin)+Ascorbic
`Benzocaine
`Hydrochloride
`Naloxone
`Hydrochloride+
`Buprenorphine
`
`Discontinued
`
`Sennosides
`
`Phase/status
`
`(ifany)
`Drugsubstance
`
`Ref
`
`Polymer
`
`Oralfilmtype
`
`[20,55–57,73]
`
`[31,32,72]
`
`Dispersible
`Dispersible
`
`Discovery
`
`Dispersible
`
`Pilotstudy
`
`Dispersible
`
`Pilotstudy
`
`Dispersible
`Dispersible
`
`Dispersible
`Dispersible
`
`Dispersible
`
`Dispersible
`
`Phase1clinical
`Phase1clinical
`
`Phase2clinical
`Phase2clinical
`Q12014
`studyplannedfor
`Phase2clinicalpilot
`FDA
`Approvedbythe
`
`INT0036—CNS
`healthVetafilm
`INT0030—Animal
`prostatichyperplasia
`INT0031Benign
`hyperplasia
`INT-0025—prostate
`INT-0023—allergy
`anti-psychoticagent
`INT-0022;
`INT0020Insomnia
`
`Tadalafilfilm
`
`Rizatriptanfilm
`
`Launched
`
`Discontinued
`Discontinued
`
`Nicotine
`hcL
`Diphemhydramine
`Phenylephrine
`
`[70,71]
`
`Dispersible
`
`Launched
`
`Phase/status
`
`(ifany)
`Drugsubstance
`
`Ref.
`
`Polymer
`
`Oralfilmtype
`
`strip
`Littlecoldsorethroat
`Chloraseptic®
`
`Film
`
`MidatechMidaSolTherapeutics
`MonoSolRxLLC
`
`WO-2012177326
`WO-2013026002
`
`MonoSolRxLLC
`MonoSolRxLLC
`
`MonoSolRxLLC
`
`MonoSolRxLLC
`MonoSolRxLLC
`
`KemPharm's
`
`Prestigebrands
`
`WO-2012040262
`WO-2008098151
`WO-2013019187
`
`ReckittBenckiserPharmaceuticalsSuboxone®Sublingual
`
`DissolveStrips
`PediaLax®Quick
`
`C.B.FleetCompany
`
`WO-2011017483
`7,824,588
`U.S.patentNo.
`
`MonoSolRxLLC
`
`Pharmfilm®
`
`Products
`
`companies/partner/distributor
`Active
`
`Patent(s)
`
`company
`Owner/originator
`
`name/designation
`
`Brand
`
`WO-2009055923
`
`BioEnvelop's™
`PaladinLabs
`
`Thinsol™
`
`MONOSOL RX EXHIBIT 2009 page 0004
`
`oralfilm
`NiQuitinStrips2.5mg
`
`Benadryl®
`SudafedPE™
`Packs®
`Listerine®Pocket
`
`RedHillBiopharma
`
`GlaxoSmithKline
`
`McNeil-PPC
`McNeil-PPC
`
`US-20110136815
`
`TechnologyCorp.
`Intelgenx
`
`VersaFilm™
`
`Pfizer
`
`US-07407669B2
`
`LTSLohmann
`
`Buccalwafer
`
`Commercialproducts
`
`companies/partner/distributor
`Active
`
`Patent(s)
`
`company
`Owner/originator
`
`name/designation
`Brand
`
`Oralfilms'technologyplatforms,theirownersordevelopers,relatedpatentsandassociatedmarketedproducts.*—meansthatthereisnospecificinformationaboutthedesignationand/orstatusofthetechnology/product.
`Table1
`
`

`
`112
`
`A.F. Borges et al. / Journal of Controlled Release 206 (2015) 108–121
`
`[98]
`
`[97]
`
`[96]
`
`HPC,HEC
`
`orodispersibleBackinglayer—
`Orodispersible
`Orodispersible
`
`Orodispersible
`
`Launched
`Launched
`Launched
`
`*
`
`*
`
`Aripiprazole
`
`HPMC
`
`OrodispersibleEthylcellulose
`
`Launched
`
`Dispersible
`
`Registered
`
`Donepezil
`
`Dispersible
`
`Dispersible
`
`Registered
`reported
`Nodevelopment
`
`Olanzapine
`
`Aripiprazole
`
`[94,95]
`
`Dispersible
`
`Launched
`
`Zolmitriptan
`
`[20,75,90–93]
`
`[70]
`
`[89]
`
`MediumMwPEG
`Starch
`PVA
`
`Dispersible
`Dispersible
`Dispersible
`Dispersible
`Dispersible
`Dispersible
`Dispersible
`
`Launched
`Discontinued
`Discontinued
`Launched
`
`Buccal
`
`Discovery
`
`[33,34,84–88]
`
`[83]
`
`Dispersible
`Dispersible
`
`Dispersible
`
`Dispersible
`
`Dispersible
`Dispersible
`
`Dispersible
`
`Dispersible
`
`Dispersible
`Buccal
`
`Launched
`
`Launched
`
`Launched
`
`Discovery
`Launched
`
`Launched
`
`Launched
`
`Launched
`Discovery
`
`Dispersible
`Dispersible
`
`Launched
`Discovery
`
`Phase/status
`
`Ref.
`
`Polymer
`
`Oralfilmtype
`
`Zolmitriptan
`GLP-1peptides
`
`hydrochloride
`Ondansetron
`Multimeric-001
`
`(ifany)
`Drugsubstance
`
`Nicotine
`Acetonide
`Triamcinolone
`Loratadine
`
`ZolpidemTartrate
`Hydrochloride
`Donepezil
`Hydrochloride
`Olopatadine
`Loperamide
`
`Waplon
`LoratadineODFilm
`Film
`ZolpidemTartrateOD
`ODfilm
`DonepezilHydrochloride
`HydrochlorideODFilm
`Olopatadine
`
`Voglibose
`
`VogliboseODfilm
`
`AmlodipineBesilate
`
`AmlodipineODfilm
`
`KyukyuPharmaceuticalCoLtd
`
`TevaPharmaJapanInc.
`MochidaPharmaceuticalCoLtd
`
`MochidaPharmaceuticalCoLtd
`ElmedEisaico.,ltd.
`KyukyuPharmaceuticalCoLtd;
`MaruhoCo.,Ltd.
`KyukyuPharmaceuticalCoLtd;
`KyukyuPharmaceuticalCoLtd
`LTD.
`MOCHIDAPHARMACEUTICALCO.,
`
`BIOMEDIX.CO.,LTD
`KyukyuPharmaceuticalCoLtd;
`LLC;TesaLabtecGmbH
`APRAppliedPharma;MonoSolRx
`MonoSol/Midatech
`
`Zuplenz®
`
`PharmaceuticalsInc.
`MonoSolRxLLC;Vestiq
`BiondVax
`
`A1WO-03026654
`US20040126330
`
`WO-2013121663
`
`WO-2010023874
`
`WO-09917753
`WO-2011108643;
`WO-2005117803;
`
`CoLtd
`Pharmaceutical
`Kyukyu
`
`Film
`
`RapidDissolving
`
`WO-2011124570
`
`WO-2012040262
`WO-03030881;
`WO-2006031209;
`WO-2004066986
`
`Commercialproducts
`
`companies/partner/distributor
`Active
`
`Patent(s)
`
`company
`Owner/originator
`
`name/designation
`
`Brand
`
`Table1(continued)
`
`Olanzapine
`
`SildeHEXALSF(Tornetis)Sildenafil
`Donepezil-HClHexal®SFDonepezil
`Risperidon
`RisperidonHEXAL®SF
`Schmelzfilm
`AripiprazoleHEXAL®SF
`Anti-migraine
`Schmelzfilm
`OlanzapinHEXAL®SF
`
`DonepezilODF
`
`OlanzapineODF
`
`AripiprazoleODF
`
`RapidFilm®
`ZolmitriptanODF
`
`Dextromethorphan
`Simethicone
`
`Rapidfilm®/Ondissolve™
`Setofilm®/Ondansetron
`Triaminic®ThinStrips®Phenylephrine
`Theraflu®ThinStrips®
`Gas-X®
`
`Hydrochloride
`Ondansetron
`
`HexalSandoz
`
`LabtecGmbH
`FerrerInternacionalSA;tesa
`APRAppliedPharmaResearchSA;
`tesaLabtecGmbH
`APRAppliedPharmaResearchSA;
`
`GmbH
`MonoSolRxLLC;tesaLabtec
`APRAppliedPharmaResearchSA;
`(Canada)/MonosolRX§
`Vietnam)/TakedaCanada
`Pharmaceuticals,Inc.(Chinaand
`AfricaandAustralasia)/SciClone
`Norgine(EuropeandMiddleEast,
`
`WO-2011124570
`
`WO-2009043588
`WO-2008040534;
`
`Research
`AppliedPharma
`GmBH/APR
`Labtec
`
`NovartisConsumerHealth
`
`ARx
`
`WO-2012055947
`
`WO-2010115724
`WO-2007009800
`
`WO-2007009801
`
`EP-02213278
`WO-2009043588;
`
`WO-2012110222
`
`Pharmaceuticals
`Hexal
`
`Schmelzfilm
`
`RapidFilm®
`
`technology
`
`Dissolvablefilm
`
`film(ADF)
`disintegrating
`
`Adhesiveand
`
`MONOSOL RX EXHIBIT 2009 page 0005
`
`

`
`113
`
`(continuedonnextpage)
`
`[58,59,110]
`
`Pullulan
`
`Buccal
`
`Phase2Clinical
`
`[108,109]
`
`[47,106,107]
`
`Dispersible
`
`Dispersible
`
`Dispersible
`
`completed
`Phase1clinical
`
`Launched
`development
`initiatedEU
`Launched(Korea)
`
`A.F. Borges et al. / Journal of Controlled Release 206 (2015) 108–121
`
`[35,36,38]
`
`Dispersible
`
`[46,105]
`
`Dispersible
`
`[20,54]
`
`Cellulosederivative
`
`[50,51,103,104]
`
`[20]
`
`[102]
`
`Buccal
`
`Buccal
`
`Buccal
`Buccal
`
`Buccal
`
`Dispersible
`
`Buccal
`
`Buccal
`
`Buccal
`
`Discovery
`Discovery
`
`Discovery
`
`Discovery
`
`Discovery
`Launched
`Discovery
`Discovery
`Discovery
`Discovery
`Discovery
`Discovery
`Phase1Clinical
`Discovery
`Discovery
`Discovery
`Discovery
`Phase1clinical
`Discovery
`reported
`Nodevelopment
`reported
`Nodevelopment
`reported
`Nodevelopment
`Discontinued
`trials(May2013)
`PhaseIIclinical
`
`reported
`Nodevelopment
`
`Rotavirus
`
`Zolpidem
`
`Discovery
`FDAonJuly2013
`NDAsubmittedto
`
`Triptan
`Naloxone
`Buprenorphine+
`
`Buccal
`
`Phase3clinical
`
`Buprenorphine
`
`Buccal
`
`Discovery
`
`Granisetron
`
`[99–101]
`
`NaCMC
`polycarbophiland
`Activelayer—
`
`Buccal
`
`Launched
`
`Fentanyl
`
`Tropicamide
`
`Anastrozole
`hydrochloride
`Mirodenafil
`
`Montelukast
`Dementia
`SPO-1112-
`SPO-1108Asthma
`Schizophrenia
`SPO-1113
`Depression
`SPO-1201
`disorder
`deficithyperactivity
`SPO-1202Attention
`Sildenafilcitrate
`Zolmitriptan
`Donezepil
`CetirizineHCl
`Fentanyl
`Montelukast
`Tadalafil
`Sildenafilcitrate
`Sumatriptan
`Zolmitriptan
`Levocetirizine
`Nicotine
`RizatriptanBenzoate
`Selegiline
`
`Nicotine
`
`Fentanyl
`
`Oxybutynin
`Testosterone
`
`AnastrozoleODF
`
`AstraZenecaplc
`
`WO-2006078998
`
`NeuroHealing
`
`Thinfilm
`
`film
`disintegration
`
`Orallyrapid
`
`WO-2013085276
`
`SKChemicalsCoLtd
`
`WO-2013100564
`
`Ltd
`SKChemicalsCo
`
`Quicksol®
`
`Vultis®
`
`PfizerInc
`
`WO-2013129889
`
`Ltd
`SeoulPharmaCo
`
`SmartFilm®
`
`MONOSOL RX EXHIBIT 2009 page 0006
`
`MeldexInternational
`
`WO-2010062688
`(A3)
`WO-2006114604
`
`WO-2009151574
`
`NALPharma
`
`Bio-FXFast-Onset
`
`ODF
`
`Bioprogress
`
`Soluleaves™
`
`Rotavax™
`
`WO-2010002418
`
`Pharmaceuticals
`Auxilium
`Corp
`
`technology
`PharmaForm
`
`FastdissolvingfilmHughesMedical
`
`BEMA®Zolpidem
`
`BEMA®Triptan
`
`AriusPharmaceuticalsInc
`Inc
`BioDeliverySciencesInternational
`
`BUNAVAIL™
`
`BEMA®Buprenorphine
`
`BEMA®Granisetron
`
`EndoPharmaceuticals
`Inc
`BioDeliverySciencesInternational
`
`WO2005016321
`
`WO-2010008863
`WO-2013096811;
`
`Onsolis®
`
`MedaAB;TTYBiopharmCoLtd
`KunWhaPharmaceuticalCoLtd;
`
`WO-2007070632
`WO-2008011194;
`WO-03086345
`
`(BDSI)
`International
`Sciences
`BioDelivery
`
`BEMA™
`
`

`
`114
`
`A.F. Borges et al. / Journal of Controlled Release 206 (2015) 108–121
`
`[126]
`[126]
`[125]
`
`[11,69,124]
`
`[123]
`
`[120–122]
`[119]
`[118]
`[117]
`
`[116]
`
`[115]
`
`[114]
`
`monovalentcation
`alginatesaltof
`comprisingan
`Film-formingagent
`
`[49,112,113]
`
`starch(MDX)
`and/ormodified
`Cellulose(HEC?)
`
`[111,52]
`
`Dispersible
`Dispersible
`Dispersible
`Dispersible
`
`Dispersible
`
`Sublingual
`
`Dispersible
`
`Buccal
`sublingual
`bi-layer
`Dispersible
`
`Buccal
`
`Buccal
`
`Ref.
`
`Polymer
`
`Oralfilmtype
`
`Phase/status
`
`(ifany)
`Drugsubstance
`
`Commercialproducts
`
`companies/partner/distributor
`Active
`
`Patent(s)
`
`company
`Owner/originator
`
`name/designation
`
`Brand
`
`Table1(continued)
`
`Launched
`
`Launched
`Launched
`Launched
`
`Launched
`Launched
`Launched
`Launched
`Out-licensed
`Underdevelopment
`Out-licensed
`Out-licensed
`negotiation
`pending/under
`Pre-clinical
`
`Discovery
`
`+VitaminB5
`VitaminB6+Biotin
`B12+VitaminE+
`Caffeine+Vitamin
`+Potassium
`VitaminC+Sodium
`VitaminB12+
`VitaminD3
`VitaminB12
`
`Hcl2.5mg
`Hbrphenylephrine
`Dextromethorphan
`Simethicone
`OndansetronHcl
`Tadalafil
`NRT/Nicotine
`Parkinson'sdisease
`Migraine
`Erectiledysfunction
`
`Cancerpain
`Adrenaline
`
`amodiaquine
`Artesunateand
`
`Launched
`Clinical
`Clinical
`Pre-registration
`
`Sildenafil
`Donepezil
`Tadalafil
`Clomipramine
`Aripiprazole
`MontelukastsodiumPre-registration
`
`reported
`Nodevelopment
`reported
`Nodevelopment
`
`Naloxone
`
`Midazolammaleate
`
`Discovery
`
`Dronabinol
`
`Energystrips
`
`Electrolytestrips
`VitaminD3strips
`VitaminB12strips
`cold)
`mgstrips(cough&
`phenylephrineHcl2.5
`DextromethorphanHbr
`Simethicone
`OndansetronHcl
`Tadalafil
`
`PediaSUNATE™
`
`CUREPharmaceuticalInc.
`PharmaceuticalCoLtd
`YangPharmCoLtd;KunWha
`Ltd;JeilPharmaceuticalCoLtd;Jin
`PharmaceuticalCoLtd;HuonsCo
`CTCBioInc.;DongKook
`
`WO-2012108738
`
`WO-2013002578
`WO-2014025206
`WO-2012121461
`WO-2010151020
`
`WO-2013143891
`
`OraldispersiblefilmAavishkar
`
`WO-2007073346
`
`FFTmedical
`Inc
`Pharmaceutical
`CURE
`
`delivery
`
`Trans-mucosaldrug
`
`Oralthinfilm
`
`MONOSOL RX EXHIBIT 2009 page 0007
`
`Phase1clinical
`reported
`Nodevelopment
`reported
`Nodevelopment
`
`Apomorphine
`
`APL-130277
`
`CynapsusTherapeutics
`
`WO-2010144817
`WO-2012083269;
`
`Therapeutics
`Cynapsus
`
`Cannabinoids
`
`Insulin
`
`WO/2012/104834
`
`Pharmedica
`Inc
`Pharmaceuticals
`
`CTCBioInc
`
`Oralthinfilm
`
`DiostechCoLtd
`CHABio&
`
`Pharmaceutical
`Aoxing
`Laboratories,Inc
`ElSohly
`
`*
`
`*
`
`matrixpatch
`Transmucosal
`
`film
`sublingualbilayer
`
`Fast-onset
`
`Platform
`
`ElutingBandage
`
`

`
`A.F. Borges et al. / Journal of Controlled Release 206 (2015) 108–121
`
`115
`
`trials demonstrated that the maximum blood levels were reached
`within 20 min of administration, in the majority of subjects, and that
`it has a good local tolerability (no irritation). The submission of a FDA
`505(b)(2) NDA is expected in 2016, since Cynapsus estimates to com-
`plete efficacy and safety studies by the end of 2014 and 2015, respec-
`tively. This sublingual formulation had already proved to work in the
`most severe cases of Parkinson's disease. Moreover, it may also present
`patient benefits and competitive advantages over the subcutaneous
`injection available and the inhaled and pulmonary approaches that are
`still in early development stages. According to their patent application
`the main polymer may be a cellulose, as HEC and/or a modified starch
`as maltodextrins, or even a mixture thereof [49].
`
`3.10. Biodegradable transmucosal film
`
`In the first quarter of 2005, Auxilium Pharmaceuticals had licensed
`an oral drug delivery system, based on the PharmaForm technology
`after their drug delivery platform acquisition. This platform is a bio-
`degradable transmucosal film that adheres to the upper gum, prefer-
`entially above the back molar, and after that it completely dissolves.
`PharmaForm technology may allow a more effective delivery of the
`substances through a higher rate of drug absorption, contributing
`to achieve the same therapeutic levels with lower doses when com-
`pared with the conventional dosage form, shorter onset of action, re-
`duction of first pass metabolism and probably less frequent dosing.
`Auxilium was using this technology platform to incorporate drug
`substances for the treatment of overactive bladder, management of
`pain and androgen replacement therapy. According to the company
`information, the overactive bladder transmucosal film candidate was
`supposed to be moving to phase II studie