(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`18 February 2016 (18.02.2016)
`
`WIPO!IPCT
`
`\=
`
`(10) International Publication Number
`WO 2016/025560 Al
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HIN, HR, HU,ID,IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`Mk, MN, MW,MX, MY, MZ, NA, NG, NI NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`GD)
`
`International Patent Classification:
`A61TF 1/05 (2006.01)
`BOID 39/16 (2006.01)
`A6L1F 9/00 (2006.01)
`BOID 71/06 (2006.01)
`BOLD 35/02 (2006.01)
`B6SD 51/24 (2006.01)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/US2015/044782
`
`(22)
`
`International Filing Date:
`
`12 August 2015 (12.08.2015)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`(74)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`62/036,670
`62/160,233
`
`13 August 2014 (13.08.2014)
`12 May 2015 (12.05.2015)
`
`US
`US
`
`Applicant: UNIVERSITY OF FLORIDA RESEARCH
`FOUNDATION,
`INC.
`[US/US];
`223 Grinter Hall,
`Gainesville, FL 32611 CUS).
`
`Inventors: CHAUHAN, Anuj; 4071 N.W. 63rd Street,
`Gainesville, FL 32606 (US). HSU, Kuan-Hui; 2330 8S. W.
`Williston Road, #2924, Gainesville, FL 32608 (US).
`
`Agents: BUESE, Mark A.. et al.; Saliwanchik, Lloyd &
`Eisenschenk, P.O. Box 142950, Gainesville, FL 32614-
`2950 (US).
`
`(54)
`
`Title: PRESERVATIVE REMOVAL FROM EYE DROPS
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK,EE,ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM, ML, MR, NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`
`
`FIG. 1A
`
`(57) Abstract: A BAK removal device is constructed as a plug of microparticles of a hydrophilic polymeric gel that displays a hy -
`draulic permeability greater than 0.01 Da. The polymer hydrophilic polymeric gel comprises poly(2-hydroxyethyl methacrylate)
`(pHEMA). Theparticles are 2 to 100 um andthe plug has a surface area of 30 mm?” to 2 mm? and a length of 2 mm to 25 mm and
`wherein the microparticles of a hydrophilic polymeric gel has a pore radius of 3 to 60 wm.
`
`
`
`
`
`wo2016/025560A1|IMIINNNINNIIMTNMITTVACUACTNAIAATA
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`WO 2016/025560
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`PCT/US2015/044782
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`1
`
`DESCRIPTION
`
`PRESERVATIVE REMOVAL FROM EYE DROPS
`
`CROSS-REFERENCE TO A RELATED APPLICATIONS
`
`This application claims the benefit of U.S. Provisional Application Serial No. 62/160,233,
`filed May 12, 2015 and U.S. Provisional Application Serial No. 62/036,670, filed August 13,
`2014,
`the disclosures of which are hereby incorporated by reference in their entireties,
`
`includingall figures, tables and drawings.
`
`BACKGROUND OF INVENTION
`
`Ophthalmic diseases are most commonly treated by instillation of eye drops with
`frequencies varying from one or two a day fordiseases like glaucomato as many as ten a day
`for severe infections. The drug solutions in eye drop bottles can get contaminated during use
`due to contact of the tip with hands or tears while instilling the drops.
`In a recent study with
`204 glaucomapatients, only 39% were able to instill the eye drops without touching the
`bottle to the eye surface. There are additional risks of cross-contamination when multiple
`patients share a bottle, such as in a family or in hospitals. The high potential for the
`contamination after opening the bottles has led to regulations that require the addition of an
`antimicrobial agent in multi-dose eye drop formulations. Several preservatives have been
`researched and used in commercial formulations,
`including: alcohols, parabens, EDTA,
`chlorhexidine, and quaternary ammonium compounds.
`In addition to antimicrobial efficacy,
`the preservatives require suitable physical properties for incorporation into the formulations,
`such as chemical and thermal stability, compatibility with the eye drop container and other
`compoundsin the formulation, and, more importantly, negligible toxicity to oculartissues.
`Regulations require that ophthalmic preservatives achieve 1.0 and 3.0 log reduction
`by days 7 and 14, respectively, along with no increase in survivors from days 14-28 and no
`increase in survivors for the fungi from day 0 to day 28 after inoculation with 10° colony
`forming units (cfu)/mL. (Baudouin ef al. “Preservatives in Eyedrops: the Good, the Bad and
`the Ugly”. Progress in Retinal and Eye Research, 2010, 29, 312-34) Duc to high efficacy and
`low corneal
`toxicity,
`the quaternary ammonium compounds are preferred preservatives.
`
`Benzalkonium chloride:
`
`10
`
`20
`
`25
`
`30
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`WO 2016/025560
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`PCT/US2015/044782
`
`cr
`yeCatan
`7%
`
`where a mixture of n being 8, 10, 12, 14, 16, and 18, is the most commonchoice with n = 12
`and 14 being the primary homologues. Eye drop formulations require BAK at concentrations
`ranging from 0.004 to 0.025% (w/w) to achieve the regulatory effectiveness.
`In spite of the
`positive safety profile of BAK, achievement of the targeted antimicrobial and antifungal
`effects is not possible without levels that cause some toxic side effects to the cornea. BAK
`can cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia and
`
`apoptosis, disruption of the corneal epithelium barrier, and damage to deeperoculartissues.
`The potential for ocular damage from the preservatives is particularly high among
`patients suffering from chronic diseases that require daily eye drop instillations for periods of
`years to decades, such as glaucomapatients. Several clinical and experimental studies have
`shown that toxic side effects from preservative free eye drops are significantly lower than
`from their preserved counterparts. A multicenter cross-sectional epidemiologic study using
`preservative or preservative-free beta-blocking eye drops
`showed that patients on
`preservative free eye drops exhibit significantly fewer ocular symptomsandsignsofirritation
`compared to those using preserved eye drops. (Jaenen ef al. “Ocular Symptoms and Signs
`with Preserved and Preservative-free Glaucoma Medications”, European Journal of
`
`Ophthalmology. 2007, 17, 341-9) Preserved glaucoma drug timolol causes significantly
`higher tear film instability and disruption of corneal barrier function than preservative-free
`timolol in healthy subjects. (Ishibashi ef a/., “Comparison of the Short-term Effects on the
`Human Corneal Surface of Topical Timolol Maleate with and without Benzalkonium
`Chloride”, Journal of Glaucoma, 2003, 12, 486-90)
`Similar results were found when
`comparing preservative-free and BAK-containing carteolol. (Baudouin e¢ a/., “Short Term
`Comparative Study of Topical 2% Carteolol with and without Benzalkonium Chloride in
`Healthy Volunteers”, British Journal of Ophthalmology. 1998, 82, 39-42) Goblet cell loss
`and increased cytoplasmic/nucleus ratio, two characteristics of dry eye disease, have been
`shown to occur when using BAK containing tear substitutes. (Rolando ef al., “The Effect of
`
`Different Benzalkonium Chloride Concentrations on Human Normal Ocular Surface”. The
`
`10
`
`15
`
`20
`
`25
`
`Lacrimal System, Kugler and Ghedini, New York 1991, 87-91) A significant reduction in
`Schirmer test values was observed for subjects receiving BAK cye drops compared with
`
`30
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`53
`
`subjects not receiving therapy.
`
`(Nuzzi et al., “Conjunctiva and Subconjunctival Tissue in
`
`Primary Open-angle Glaucomaafter Long-term Topical Treatment: an Immunohistochemical
`
`and Ultrastructural Study”, Graefe's Archive for Clinical and Experimental Ophthalmology,
`
`1995, 233, 154-62) Patients using preserved eye drops and experiencing toxicity symptoms,
`
`such as allergy, blepharitis or dry eye, experienced rapid improvements upon switching to
`
`preservative-free formulations.
`
`Such studies
`
`suggest a role of preservatives in the
`
`preponderance of dry eye symptoms in glaucoma patients, who typically use multiple drugs
`
`with multiple instillations each day.
`
`BAK is considered a ‘necessary evil’ for prevention of microorganism growth in the
`
`10
`
`bottles while displaying toxic effects on the ocular tissue.
`
`‘The industry has taken a few
`
`approaches to solve this problem. One approach is to develop more efficacious glaucoma
`
`therapies, such as: use of prostaglandins that require instillation of only one eye drop each
`
`day; and combinations that contain multiple drugs in the same formulation to eliminate
`
`instillation of multiple eye drops. Nevertheless, both of these approaches still permit a
`
`15
`
`cumulative effect to preservatives over long periods of time.
`
`Furthermore, only a few
`
`combination products are available, generally combinations from a single manufacturer.
`
`A second approach is to provide single dose packages, and several glaucoma
`
`formulations are now available as preservative free single doses. While this approach can
`
`eliminate exposure to preservatives, in addition to increasing manufacturing costs and the
`
`20
`
`environmental impact of packaging, single dose formulations contain about 0.3 to 0.4 mL of
`
`formula, which is significantly more than the typical eye drop volume of 30 Lu, leading to
`
`wastage or possibly misuse of the same package for multiple days. This approach can suffer
`
`if bacterial contamination occursprior to packaging.
`
`Another approach is to replace BAK with a less toxic preservative, such as: Purite®, a
`
`25
`
`stabilized oxychloro complex; and Sofzia®, which is composed of boric acid, propylene
`
`glycol, sorbitol, zinc chloride and polyquaternium compounds, some of which are used in
`
`contact lens care solutions. While these alternatives may be promising, no data on long term
`
`impact from use of these preservatives is available, and consistent use of these preservatives
`
`over extended periods of years may well prove them toxic.
`
`30
`
`The solution in a bottle is typically contaminated during the instillation of the eye
`
`drops dueto the contact of the bottle tip with the eye surface, contact of the tip with hands, or
`
`both. As the eye drop detaches from the bottle, a small volumeofliquid remainingat the tip
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`WO 2016/025560
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`A
`
`is sucked back, which can take the bacteria into the bottle, leading to the contamination. An
`
`ABAK® (Laboratoires Théa, France) design introduces a 0.2 umfilter at the top of the bottle
`
`to filter out bacteria from the re-entering solution, thereby preventing contamination. Though
`
`effective, this approach does not protect against contamination prior to packaging. Also the
`
`0.2 wm filter could require additional pressure to push the drops, making drop instillation
`
`difficult, particularly for the elderly. Additionally, any leak in the filter or bacteria transport
`
`through the pores could allow the formulation in the bottle to get contaminated.
`
`It is also not
`
`clear whether this design can protect against growth of bacteria trapped in the filter. The
`
`COMOD® (Ursapharm, Germany) system combinesan air free pump and an inner lining that
`
`10
`
`retracts as the liquid is pushed out to avoid contamination of the contents ofthe bottle. While
`
`this design is innovative and useful, its complexity and increased cost are major concerns. As
`
`with ABAK®, COMOD® cannot protect against any microorganisms introduced due to
`
`errors in the manufacturing processes causing loss ofsterility. This makes the filling of these
`
`devices complicated becausesterility is essential at each step.
`
`15
`
`US Patent No. 5,080,800 teaches a process for removing components from solutions,
`
`including preservatives from eye-drops. The process involves the use of ion exchange resins
`
`to sclectively remove ocular preservatives.
`
`Jon exchange resins have not been tested
`
`extensively for biocompatibility and cytotoxicity and inherently are non-selective, adsorb
`
`ionic drugs as readily as any ionic preservative such as BAK. The hydraulic permeability of
`
`20
`
`these resins is not addressed although this characteristic is critical for devices that allow
`
`formation of drops without excessive pressure. US Patent No. 5,080,800 also does not teach
`
`on the importance of ensuring that the filters are designed to resist growth of microorganisms
`that may remain trapped. US Patent No. 5,080,800 does not teach on the possibility of
`
`dilution of the BAK concentration in the formulation because of draining of the BAK free
`
`25
`
`formulation from the filter into bottle after each eye drop instillation. Hence a practical way
`
`of retaining the beneficial behavior of preservatives while avoiding their toxic effects in the
`
`eye remains a need.
`
`BRIEF SUMMARY
`
`30
`
`Embodiments of the invention are directed to a preservative removing device having a
`
`plug of microparticles that are a hydrophilic polymeric gel. The plug has a shape that
`
`matches an outlet to a container for a solution, emulsion, or suspension. The hydrophilic
`
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`5
`
`polymeric gel swells in the presence ofthe solution, emulsion, or suspension and selectively
`
`absorbs a preservative contained therein.
`
`The plug of microparticles has a hydraulic
`
`permeability greater than 0.01 Da, even greater than 10 Da in some embodiments. The
`
`hydrophilic polymeric gel can be poly hydroxyl ethyl methacrylate (pHEMA) or a pHEMA
`
`copolymer
`
`such as poly hydroxyl
`
`ethyl methacrylate-co-methacrylic acid, or other
`
`biocomptabile polymer,
`
`including but not
`
`limited to, dimethyl acrylamide, methyl
`
`methacrylate, and silicones.
`
`The hydrophilic polymeric gel has interconnected pores,
`
`wherein the pores have an average radius of 1 to 60 um. The microparticles can be from 2 to
`
`100 um in cross-section. The preservative removing device can remove the preservative
`
`10
`
`benzalkonium chloride (BAK).
`
`In an embodiment of the invention, the hydrophilic polymeric gel is a preservative
`
`containing device, for example, a gel that is preloaded with the BAK at a concentration of
`
`one to 100 times that of the solution, emulsion, or suspension in the container.
`
`The
`
`preservative incorporation into the device would impart sterility, which is a requirement [or
`
`15
`
`all ophthalmic preparations and dispensers. The preservative incorporated device could also
`
`act as a preservative removal device if the initial loading is below the equilibrium capacity.
`
`Additionally, the plug can include antibacterial microparticles, such as, silver particles.
`
`In an embodiment of the invention, the polymeric material can be pretreated with a
`
`drug in the solution, emulsion, or suspension in the container, wherein the polymer is less
`
`20
`
`than saturated or saturated with the drug to reduce or eliminate further drug uptake during the
`
`dispensing of the solution, emulsion, or suspension.
`
`In an embodimentof the invention the preservative removing device is included in a
`multi-dosing device for delivery of an ophthalmic solution isa compressible bottle that has an
`outlet extension containing the preservative removing device. When the hydrophilic
`
`polymeric gel is dry,
`
`it has dimensions smaller than the internal dimensions of the outlet
`
`extension but has larger than the internal dimensions of the outlet extension when swollen
`
`with the ophthalmic solution. The multi-dosing device can include an ophthalmic agent
`
`selected from timolol, dorzolamide, dexamethasone phosphate, dexamethasone,
`
`latanoprost
`
`or other prostaglandins, rewetting eye drops, or any other compounds that is delivered to the
`
`30
`
`eye for disease treatment or comfort improvement.
`
`In another embodiment of the invention, a method of administering an ophthalmic
`
`agent involves providing a compressible bottle with a preservative removing device at the
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`PCT/US2015/044782
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`6
`
`outlet of the compressible bottle containing an ophthalmic agent and a preservative, which
`
`upon applying pressure to the compressible bottle;
`
`the solution is forced through the
`
`preservative removing device.
`
`In another embodiment of the invention, a method of administering an ophthalmic
`
`agent involves providing a compressible bottle with a preservative removing device at the
`
`outlet of the compressible bottle containing an ophthalmic agent and a preservative, and a
`
`preservative loaded film at the bottom of the bottle which upon applying pressure to the
`
`compressible bottle; the solution is forced through the preservative removing device.
`
`10
`
`15
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`FIG. 1A shows a photograph of a prototype design with a filter, according to an
`
`embodiment of the invention, incorporated into the neck of the eye drop bottle and FIG 1B
`
`shows a CAD design ofa bottle, filter, tip and cap assembly of the device.
`FIG. 2A shows a photograph of a prototype design with the filter incorporated into the
`tip of the eye drop bottle and FIG. 2B shows a CAD design ofa bottle, filter, tip, and cap
`
`assembly of the device
`
`FIG. 3 showsa plot of hydraulic permeability of the BAK filter plug if the plug area is
`
`78.5 nam2 and model predicted design parameters of length, pore radius where the solid lines
`
`indicate the upper limit and the minimum requirement of the pore size and the respective
`
`20
`
`hydraulic permeability.
`
`FIG. 4 shows an SEM image of macroporous pHEMAhydrogel.
`
`FIG. 5 shows a schematic of the experiment setup for measuring the hydraulic
`
`permeability of any material by packing it in a syringe. The syringe is filled with water and
`
`then a known force is applied to push out the water.
`
`25
`
`FIG. 6 shows a plot of measured hydraulic permeability for macroporous pHEMA
`
`hydrogel packed in a syringe. For each packed sample, the permeability was measured 10
`
`times to determine whether compaction occurs due to flow. The data was measured for 12
`
`independent samples with data points representing the mean + SD for n = 12 data points per
`
`sample.
`
`30
`
`FIG. 7 showsa bar chart of the percentages of BAK and timolol that are removed
`
`after passing 2.5 mL of timolol/BAK solution through 5 mm thick macroporous pHEMAgel
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`PCT/US2015/044782
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`7
`
`packed into a 1 cm dia syringe for a series of 10 consecutive passes, where the data are
`
`presented as mean + SD with n= 3.
`
`FIG. 8 shows a bar chart of the percentages of BAK and dorzolamide that are
`
`removed after passing 2.5 mL of dorzolamide /BAK solution through S mm thick
`
`macroporous pHEMA gel packed into a 1 cmdia syringe for a series of 10 consecutive
`
`passes, where the data are presented as mean + SD withn = 3.
`FIG. 9 showsa bar chart of the percentages of BAK and latanoprost that are removed
`
`after passing 2.5 mL of latanoprost /BAK solution through a 5 mm thick macroporous
`pHEMAgel packed into a 1 cm dia syringe for a series of 10 consecutive passes, where the
`
`data are presented as mean + SD withn=3.
`FIG. 10 shows a bar chart of the percentages of BAK and dexamethasonethat are
`removed after passing 2.5 mL of dexamethasone/BAK solution through a 5 mm thick
`macroporous pHEMAgel packed in a 1 cm diameter syringe for a series of 10 consecutive
`
`passes, where the data are presented as mean + SD with n= 3.
`FIG. 11 shows a bar chart of the percentages of BAK and timolol that are removed
`
`after passing 2.5 mL of timolol/BAK solution through 5 mm thick plug formed by packing
`crushed macroporous pHEMAgelin a 1 cm dia syringe for a series of 10 consecutive passes
`where each pass is separated by 24 hours, where the data are presented as mean + SD with n
`
`= 3.
`
`FIG. 12 shows a bar chart of the percentages of BAK and dorzolamide that are
`removed after passing 2.5 mL of dorzolamide /BAK mixture solution through 5 mm thick
`plug formed by packing crushed macroporous pHEMAgel in a 1 cmdia syringe for a series
`of 10 consecutive passes where each pass is separated by 24 hours, where the data are
`
`presented as mean + SD withn=3.
`FIG. 13 shows a bar chart of the percentages of BAK and latanoprost that are
`
`removed after passing 2.5 mL of latanoprost /BAK solution through 5 mm thick plug formed
`by packing crushed macroporous pHEMA gel
`in a | cm dia syringe for a series of 10
`consecutive passes where each pass is separated by 24 hours, where the data are presented as
`
`mean + SD with n = 3.
`
`FIG. 14 shows a bar chart of the percentages of BAK and dexamethasone that are
`
`removed after passing 2.5 mL of dexamethasone/BAK solution through 5 mm thick plug
`formed by packing crushed macroporous pHEMAgel in a 1 cm dia syringe for a series of 10
`
`10
`
`15
`
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`8
`
`consecutive passes where each pass is separated by 24 hours, where the data are presented as
`
`mean + SD with n= 3.
`
`FIG. 15 shows a plot of the hydraulic permeability of crushed macroporous pHEMA
`particles packed in a syringe with measurements for a series of 10 consecutive passes where
`each pass is separated by 24 hours, where the data are presented as mean = SD, with n= 12.
`FIG. 16 shows a bar chart of the percentages of BAK and dexamethasone that are
`
`removed after pushing 2.5 mL of dexamcthasone/BAK mixture solution through a 5 mm
`thick macroporous HEMA-co-MAA copolymer hydrogel packed in a | cm dia syringe,
`
`where measurement wasrepeated 3 times in immediate succession.
`
`10
`
`FIG. 17 shows a bar chart of the percentages of BAK and dexamethasonethat are
`
`removed after pushing 2.5 ml of dexamethasone/BAK mixture solution through the 5 mm
`thick macroporous pHEMA hydrogel treated with 1% of MAAsolution packed in a lcmdia
`syringe, where measurement was repeated 3 times in immediate succession.
`FIG. 18 shows an SEM photographic image of pHEMA particles synthesized by
`
`15
`
`thermally initiated polymerization with EGDMAascross-linker.
`
`FIG. 19 shows an eye drop bottle prototype packed with BAK removal plug on the
`tip. The extra space after the plug was kept in this design to facilitate measurement ofthe
`
`hydraulic permeability.
`FIG. 20 shows a plot of the total flowrate from the bottle containing the plug as a
`function of time. The hydraulic permeability was calculated by fitting the data to the
`
`20
`
`theoretical equation.
`
`FIG. 21 shows a bar chart of the percentages of BAK and latanoprost that are
`
`removed after passing 1.5 mL of a latanoprost/BAK solution through 8-mm thick crushed
`macroporous pHEMAparticles packed in the tip of the eye drop prototype for 10 daily runs
`
`25
`
`over 10 days where the data points are mean + SD withn = 3.
`
`FIG. 22 shows a SEM image of pHEMAparticles synthesized by UV polymerization
`
`using EGDMAascross-linker, where the pHEMAparticle size ranges from 10 to 200 um
`
`with near spherical particles with smooth surface.
`
`FIG. 23 is a bar chart of the percentages of BAK and timolol that are removed after
`
`30
`
`passing the timolol/BAKsolution through 8-mm thick plug of pHEMAparticles prepared by
`photo-polymerization packed in the tip of the eye drop prototype bottle with 1.5 mL of
`drug/BAKsolution passing through the plug for each of 5 passes in immediate succession.
`
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`%)
`
`FIG. 24 is a bar chart plot of the percentages of BAK and timolol that are removed
`
`after passing a timolol/BAKsolution through 8-mmthick plug of pHEMAparticles prepared
`
`by heat-initiated polymerization packed in the tip of an eye drop prototype bottle, where 1.5
`
`mL of drug/BAK solution was passed through the packing in each run for 10 passes in
`
`immediate succession.
`
`FIG. 25 shows the SEM image of pHEMAparticles prepared by UV polymerization
`
`using SR454HPas cross-linker.
`
`FIG. 26 showsa bar chart of the percentages of BAK and timolol that are removed
`
`after passing 1.5 mL of a timolol/BAK mixture solution through 1.8 cm thick plug of
`
`10
`
`pHEMAparticles prepared by using SR454HP as cross-linker packed in the tip of the eye
`
`drop prototype for 10 daily runs over 10 days where the data points are mean + SD with n=
`
`3.
`
`FIG. 27 shows a bar chart of the percentages of BAK and timolol that are removed
`
`after passing 1.5 mL of a timolol/BAK mixture solution through 1.8 cm thick plug of
`
`15
`
`pHEMAparticles prepared by using SR9035 as cross-linker packed in the tip of the eye drop
`
`prototype for 10 daily runs over 10 days where the data points are mean + SD with n=3.
`
`DETAILED DISCLOSURE
`
`Embodiments of the invention are directed to a multi-dosing device and method that
`
`20
`
`eliminates patients’ exposure to preservatives, particularly BAK, in delivered eye drops while
`
`retaining BAK in the contained formulation and ensuring that the eye drop bottle remains
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`sterile. Benefit of the BAK for storage is retained while the potential for ocular toxicity from
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`BAKis eliminated.
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`In an embodiment of the invention, a porous preservative removing
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`device, also referred to herein as a plug,is situated in the neck of the eye drop bottle leading
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`to the drop exit, as shown in FIG. 1.
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`In another embodiment of the invention, the plug is
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`situated in a section of the tip of the eye drop bottle, as shown in FIG. 2. A largetip is
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`included in the bottle to allow a long plug to be positioned therein The preservative
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`removing device can be separate filter that is attached to the formulation dispensing unit
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`through a suitable connector for use. The plug must display a high hydraulic permeability
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`such that relatively little pressure is required to dispense a fluid. The needed hydraulic
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`permeability depends on the design of the filter, where larger pores allow higher liquid flow
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`for a given pressure drop.
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`In embodiments of the invention, hydraulic permeability is larger
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`than about 0.0] Da and a permeability of about 0.1 Da is adequate for the typical embodiment
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`of the invention where the plug is one that fits a size that fits state of the art eye drop
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`packages. A hydraulic permeability of 1 to 10 Da can ensurethat the fluid that remains in the
`filter after instillation of the eye drop is sucked back into the bottle. A larger hydraulic
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`permeability allows the same plug to work for a wide range of formulations including high
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`viscosity formulations, such as, rewetting eye drops.
`The plug is of a material with high affinity for the preservative BAK and low affinity
`for the drug or other ophthalmological agent, such that at least 50 percent of the preservative
`is removed from the solution by the plug and at least 50 percent of the drug is retained by the
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`solution that is dispensed from the device. The high affinity is a necessary but not a
`sufficient requirement because the concentration in the eluting liquid may not be in
`equilibrium with that in the plug due to the short contact time of 1-3 sec.
`In addition to the
`high partition coefficient, the adsorption rate constant must be sufficiently high so that the
`time for adsorption of a drug molecule to the polymer is less than the contact time of 1-3 sec.
`Furthermore it is also important that the pore size in the plug is small enough so that the
`molecules that are initially far away from the surface of the polymer in the plug can diffuse
`towards the polymer and adsorb. Whenthe plug material has a high partition coefficient and
`adsorption rate and the pore size in the plug is optimized, all or most of the preservative will
`adsorbs on the pore surfaces in the plug and the eluting drops will be preservative-free. The
`preservative free liquid that elutes through the plug is instilled directly into the eyes. The
`highly porous plug material selectively extracts the preservative, allowing the eye drop
`formulation to flow through the plug with only a small pressure drop, yet allowing sufficient
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`time and surface area to bind the preservative.
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`The material selected is critical, allowing for construction of a safe, biocompatible
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`filter for preservative removal. Previous patents have proposed ion exchange resins for
`similar applications but such materials may also remove ionic drugs. For example, BAK is
`cationic and a number of ophthalmic drugs such as timolol are cationic at physiological pH
`and thus the ion exchange resins may remove both. A number of materials have been widely
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`used for ophthalmic applications and such materials are compatible with the eye. Poly(2-
`hydroxyethyl methacrylate) (pHEMA)is one of the most commonly used material for devices
`used in the eye, but has never been explored for its use as a permeable liquid plug for
`removal of any ionic materials. Since pHEMAin non-ionic, high binding of BAK or other
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`ionic compoundsis not possible in the mannerof an ion exchange material. We started with
`pHEMAdueto its excellent biocompatibility and assumed that we would need to incorporate
`other components into the material to obtain the desired selectivity for BAK. Surprisingly,it
`was observed that pHEMA is extremely effective in adsorbing BAK without any
`modifications.
`The pHEMA material has a high partition coefficient for BAK and the
`adsorption times were determined to be less than the transit time of 3s, implying that BAK
`solution flowing through a pLIEMAplugwill have sufficient time to adsorb on the polymer.
`Furthermore, pHEMAis already used as an ophthalmic material, making it the ideal choice
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`for the plug material.
`In an embodiment of the invention, the plug material is a hydrogel, such as poly(2-
`hydroxyethyl methacrylate) (pPHEMA). The pIIEMA hydrogel displays an extremely high
`binding capacity for BAK with a partition coefficient of about 100-500 depending on the
`BAKconcentration and the structure of the pHEMA matrix used in the measurement.
`In
`contrast, the partition coefficients of most hydrophilic ophthalmic drugs into the pHEMA
`matrix range from about 1 to 10, and partition coefficients of hydrophobic drugs are in the
`range of 10 to 50. When a drug’s partition coefficient into the plug is lower by at least an
`order of magnitude than the plugs affinity for BAK,
`the porous pHEMA plug permits
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`selective removal of BAK from eye drop formulations.
`In an embodiment of the invention, the pHEMAplugis highly porous, having large
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`interconnected pores that allow easy solution flow with the preservative BAK adsorbing on
`the walls of the pores. The plug can be formed as a porous gel, a packed bed, or a structure
`formed by 3D printing, soft lithography, electrospinning, or any other method. Use of a
`macroporous gel, according to an embodiment of the invention, permits a relatively simple
`scalable preparation process that is cost effective. Macroporous gels are biphasic materials
`consisting of large interconnected pores dispersed throughout the polymer. The macroporous
`hydrogels can be prepared by free radical polymerization of a monomer in a diluent that
`dissolves the monomerbut not the polymer.
`If the concentration of the diluent is more than
`the equilibrium swelling capacity of the polymer, the extra diluent phase separates and forms
`pores. Although macroporous pHEMAhydrogels can be prepared using water as the diluent,
`such gels are typically weak mechanically. Organic diluents with good solubility for HEMA
`but poor solubility for pHEMA include dodecan-l-ol and 1, 2-dichloroethane, and such
`solvents result in robust gels. However, significant amount of organic liquids is undesirable
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`for biomedical applications. Therefore, the macroporous hydrogels are prepared by enhanced
`phase separation using aqueous NaCl solution. In another embodimentof the invention, the
`macroporous gel could be prepared from other suitable polymers such as poly acrylamide and
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`pHEMAparticles could be dispersed as the matrix for scquestration of the preservative.
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`Alternatively, in an embodiment of the invention,
`the plug can be prepared as a
`packed bed of pHEMAor other polymeric particles. The particles can be macroporous. The
`packed beds of macroporousparticles can have three levels of porosity: the space between the
`spherical particles providing inter-connected channels for the liquid flow; the macropores in
`the spherical particles to allow BAK diffusion into the particles and adsorb on the surface of
`these pores; and the pHEMA polymer’s inherent porosity having nano-sized pores which
`provide the surface area for high BAK uptake into the gel.
`In a packed bed, the multiple
`levels of porosity avoids any tradcoff between increased permeability and reduced area, and,
`thus, increasing the particle size to increase the hydraul