ivi
`
`Innovation, Sciences et
`Développement économique Canada
`Office de la Propriété Intellectuelle du Canada
`
`Innovation, Science and
`Economic Development Canada
`CanadianIntellectual Property Office
`
`CA 2747095 C 2020/02/18
`(11)(21) 2 147 095
`12) BREVET CANADIEN
`CANADIAN PATENT
`13) C
`
`(86) Date de dépét PCT/PCTFiling Date: 2008/12/15
`
`(87) Date publication PCT/PCT Publication Date: 2009/06/25
`
`(45) Date de délivrance/Issue Date: 2020/02/18
`
`(85) Entrée phase nationale/National Entry: 2011/06/15
`
`(86) N° demande PCT/PCTApplication No.: GB 2008/004129
`
`(87) N° publication PCT/PCT Publication No.: 2009/077736
`
`(30) Priorité/Priority: 2007/12/15 (GB0724558.2)
`
`(61) Cl.Int./int.Cl. AG7K 37/138 (2006.01),
`AG1K 31/385 (2006.01), AG1K 31/4168 (2006.01),
`AG1K 31/4178 (2006.01), AG1K 31/496 (2006.01),
`AG1K 31/498 (2006.01), AG7P 27/02 (2006.01)
`
`(72) Inventeur/Inventor:
`SHARMA, ANANT, GB
`
`(73) Propriétaire/Owner:
`SHARMA, ANANT, GB
`
`(74) Agent: MARKS & CLERK
`
`
`
`(54) Titre : UN MEDICAMENT RENFERMANT DE LA PILOCARPINE ET DE LA THYMOXAMINE OU DU DAPIPRAZOLE
`(54) Title: A MEDICAMENT COMPRISING PILOCARPINE AND THYMOXAMINE OR DAPIPRAZOLE
`
`(57) Abrégé/Abstract:
`A medicament for topical administration to a human or animal eye comprises at least two pharmacologically active agents. One of
`the active agents is a parasympathetic agonist, such as pilocarpine, and the other active agentis either a sympathet-ic antagonist
`such as dapiprazole or thymoxamine, or a sympathetic agonist such as brimonidine or iopidine. The medicamentis preferably in
`the form of a liquid composition, such as eye drops, or a gel or ointment and may comprise a slow-release composition. The
`medicament acts to improve visual acuity for a period of several hours, and may be beneficial in cases of presbyopia, myopia,
`hypermetropia, astigmatism and/or impaired night vision.
`
`50 rue Victoria
`50 Victoria Street
`
`e Place du Portage1 ¢ Gatineau, (Québec) K1A0OC9
`* www.opic.ic.gc.ca
`¢ Place du Portage 1
`* Gatineau, Quebec
`K1A0C9 ¢ www.cipo.ic.gc.ca
`
`bd
`( ‘al ) ada
`
`

`

`CA 02747095 2011-06-15
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`
`25 June 2009 (25.06.2009)
`
`(10) International Publication Number
`WO 2009/077736 A4
`
`(51) International Patent Classification:
`A61K 31/138 (2006.01)
`AGIK 31/385 (2006.01)
`AG6IK31/4178 (2006.01)
` A61K 31/4168 (2006.01)
`A61K 31/496 (2006.01)
`AG6IP 27/02 (2006.01)
`A61K 31/498 (2006.01)
`.
`(21) International Application Number:
`PCT/GB2008/004 129
`
`EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID,IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO,
`NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG,
`SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA,
`UG,US, UZ, VC, VN, ZA, ZM, ZW.
`
`(22)
`
`ue
`.
`InternationalFiling Date:
`15 December 2008 (15.12.2008)
`English
`
`(25) Filing Language:
`
`(26) Publication Language:
`(30) Priority Data:
`0724558.2
`
`15 December 2007 (15.12.2007)
`
`English
`
`GB
`
`(84) Designated States (unless otherwise indicated, for every
`kind ofregional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FL, FR, GB, GR, HR, HU,
`IE,IS, IT, LT, LU, LV,
`MC, MT, NL, NO,PL, PT, RO, SE, SI SK, TR), OAPI
`(BF, BJ, CF, CG, CL CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
`
`
`
`
`
`wo2009/077736Ad|IIITINMINIUIATTNIAIAICANTAATAA
`
`.
`(71) Applicant and
`[GB/GB]; 37 Pemberley Published:
`(72)
`Inventor: SHARMA, Anant
`Avenue, Bedford MK40 2LE(GB) with international search report (Art. 21(3))
`(74) Agent: BANFORD, Jonathan; Franks & Co (South) — with amended claims (Art. 19(i))
`.
`.
`Limited, Carlton House, 26 Billing Road, Northampton
`sigs
`.
`NN1 SAT (GB).
`(88) Date of publication of the international search report:
`30 December 2009
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
`
`Date of publication of the amended claims: 25 February 2010
`
`(54) Title: A MEDICAMENT COMPRISING A PARASYMPATHETIC AGONIST AND A SYMPATHETIC ANTAGONIST
`OR A SYMPATHETIC AGONIST
`
`(357) Abstract: A medicament for topical administration to a human or animal eye comprises at least two pharmacologically active
`agents. One of the active agents is a parasympathetic agonist, such as pilocarpine, and the other active agent is either a sympathet-
`ic antagonist such as dapiprazole or thymoxamine, or a sympathetic agonist such as brimonidine or iopidine. The medicamentis
`preferably in the form of a liquid composition, such as eye drops, or a gel or ointment and may comprise a slow-release composi-
`tion. The medicament acts to improve visual acuity for a period of several hours, and may be beneficial in cases of presbyopia,
`myopia, hypermetropia, astigmatism and/or impaired night vision.
`
`

`

`A MEDICAMENT COMPRISING PILOCARPINE AND THYMOXAMINE OR
`
`DAPIPRAZOLE
`
`Thepresentinventionrelates to topical compositions to improve visual acuity and to methods
`
`for their use. More particularly, but not exclusively, it relates to eye-drops and the like to
`
`ameliorate the effects of presbyopia, myopia, hypermetropia, astigmatism and combinations
`
`thereof.
`
`Oneprevalent form of visual defect is presbyopia,
`
`in which the lens of the eye becomes
`
`relatively rigid, particularly with age, so that it becomes increasingly difficult to focus. This
`
`leads to eyestrain, and ultimately to recession of the near point, such that a sufferer of
`
`presbyopia may be unable to read or work on objects at arm’s length.
`
`The conventional response to presbyopia is the use of reading glasses of appropriate strength
`
`to move the wearer’s near point sufficiently close to allow clear vision at convenient reading
`
`and working distances. However, since this will probably also move the wearer’s far point
`
`closer, sacrificing their distance vision, reading glasses must usually be removed for driving,
`
`for example.
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`
`Alternatively or additionally, reading glasses are produced whose lenses cover only a small
`
`portion of the visual field, so that the wearer may look round them for distance vision.
`However, the field covered by the lenses may not be sufficient for all purposes.
`
`Bifocal spectacles comprise lenses having zones of different curvatures (or refractive
`
`indices), one zone producing a close-in near point for reading, etc, and the other producing a
`
`far point at or near infinity for distance work. Varifocal lenses are similar, but with the zones
`
`graduating into one another, rather than having a sharp division. Again, the restricted field
`
`covered by the “reading”portion ofthe lens maynotbesatisfactory, and many people cannot
`
`get used to bifocal lenses. Bifocal lenses are usually more expensive than standard lenses.
`
`Furthermore, many people dislike wearing any form of spectacles for reasons of comfort or
`
`for reasons of personal style. Contact lenses have been proposed that are akin to bifocal
`
`spectacle lenses, but many people are uncomfortable with wearing contact lenses.
`
`Surgical interventions include laser surgery to change corneal curvature, and intraocular
`
`implants. Many sufferers from presbyopia would not be prepared to risk (or pay for)
`
`corrective surgery.
`
`There are thus drawbacks with each of the known approaches for improving a presbyope’s
`
`ability to see nearby objects.
`
`Myopiais a visual defect in which the cornea is too steeply curved, or the eyeball is too long,
`for light from significant distances to be focussed on the retina,
`irrespective of the
`performance of the lens. A sufferer from myopia thus has a far point closer than infinity,
`
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`conventionally known as “short sight”. The converse defect is hyperopia or hypermetropia,
`
`in which the corneais too flat, or the eyeball too short, for light from nearby objects to be
`
`focussed on the retina (again, irrespective of the condition of the eye lens). This leads to a
`
`near point a significant distance from the eye, and similar problems to those resulting from
`
`presbyopia.
`
`Myopia and hypermetropia may be corrected with spectacles or contact lenses of appropriate
`
`curvature, or by surgical intervention, akin to the approaches described above in respect of
`
`presbyopia. However, the same drawbacks are also experienced.
`
`Similar drawbacks are found in existing ‘approaches to correcting various other minor
`
`refractive errors of the eye. A further complication is that it is not uncommonto suffer from
`
`more than one vision defect; for example, a degree of astigmatism is often present for
`
`myopes and hypermetropes.
`
`It is hence an object of the present invention to provide a meansfor improving close-in vision
`
`for those suffering from presbyopia or hypermetropia, and/or for improving distance vision
`
`for those suffering from myopia, that is simple, convenient and comfortable to use and which
`
`obviates the disadvantages of existing approaches.
`
`It
`
`is also an object of the present
`
`invention to provide a means for ameliorating refractive errors of the eye that has the same
`benefits and/or obviates the same disadvantages.
`It is a preferred object of the present
`
`invention to provide a meansof addressing multiple vision problems at once.
`
`It is a further
`
`object of the present invention to provide a method for ameliorating the effects of presbyopia,
`
`myopia, hypermetropia and/orrefractive error.
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`
`Accordingto a first aspect of the present invention, there is provided a medicament adapted
`
`for
`
`topical administration to a human or
`
`animal
`
`eye,
`
`comprising at
`
`least
`
`two
`
`pharmacologically active agents, a first said active agent comprising a parasympathetic
`
`agonist, and a second said active agent comprising either a sympathetic antagonist or a
`
`sympathetic agonist.
`
`Preferably, said medicament comprises a liquid composition.
`
`Advantageously, the medicament comprises a liquid composition applicable to the eye in
`
`drop form.
`
`Alternatively, the medicament may comprise a gel or ointment.
`
`The medicament may comprise a slow release composition, optionally comprising slow
`
`release insert means.
`
`Preferably,
`
`said parasympathetic agonist comprises a substance adapted to act on
`
`acetylcholine receptors.
`
`Advantageously, said parasympathetic agonist comprises pilocarpine.
`
`The medicament may then comprise between 0.05% and 4% pilocarpine, optionally at least
`
`0.25% and optionally no more than approximately 0.5%.
`
`

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`
`Preferably, the second active agent comprises a sympathetic antagonist adapted to act as an
`
`a-receptor blocker.
`
`Said sympathetic antagonist may advantageously comprise dapiprazole.
`
`The medicament may then comprise between 0.05% and 4% dapiprazole, optionally at least
`
`0.25% and optionally no more than approximately 0.5%.
`
`Said sympathetic antagonist may comprise thymoxamine.
`
`The medicament may then comprise between 0.05% and 4% thymoxamine, optionally at
`
`least 0.25% andoptionally no more than approximately 0.5%.
`
`The sympathetic antagonist may comprise a B-blocker.
`
`Alternatively, the second active agent may comprise a sympathetic agonist.
`
`Said sympathetic agonist may comprise brimonidine.
`
`The medicament may then comprise between 0.01% and 4% brimonidine, and optionally at
`
`least about 0.1% thereof.
`
`Said sympathetic agonist may comprise iopidine.
`
`

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`
`The medicament may comprise at least one further component adapted to reduce discomfort
`
`of an eye treated with the medicament.
`
`According to a second aspect of the present invention,
`
`there is provided a use of a
`
`combination of a first pharmacologically active agent comprising a parasympathetic agonist
`
`and a second pharmacologically active agent comprising a sympathetic antagonist or a
`
`sympathetic agonist in the manufacture of a medicament adapted for topical application to a
`
`human or animal eye in order to improve visual acuity.
`
`Said medicament may be adapted to treat presbyopia.
`
`Said medicament may be adaptedto treat myopia.
`
`Said medicament maybe adapted to treat hypermetropia.
`
`Said medicament may be adapted to improve night or low-light vision.
`
`Said medicament maybe adaptedto treat defects of visual acuity such as astigmatism,
`
`Said medicament may be adapted to treat more than one of the above conditions
`
`simultaneously.
`
`According to a third aspect ofthe present invention, there is provided a methodfor improving
`visual acuity comprising the step of administering to an eye a combination ofa first
`
`pharmacologically active agent comprising a parasympathetic agonist and a second
`
`

`

`wad
`
`pharmacologically active agent comprising a sympathetic antagonist or a sympathetic
`
`agonist.
`
`Preferably, the method comprises the steps of providing a single composition comprising
`
`eachofsaid first and second active agents, and administering said composition to the eye.
`
`Alternatively,
`
`the method comprises the steps of administering sequentially to the eye
`
`respective compositions containing said first and second active agents.
`
`The step of administering the first active agent may precede the step of administering the
`
`second active agent.
`
`The step of administering the second active agent may alternatively precede the step of
`
`administering the first active agent.
`
`According to an aspect of an embodiment, there is provided a use of a combinationofa first
`
`pharmacologically active agent comprising pilocarpinc and a second pharmacologically
`
`active agent comprising thymoxamine,
`
`in the manufacture of a medicament adapted for
`
`topical application to a humanor animal eye in order to improve visual acuity in one or more
`
`of presbyopia, myopia, hypermetropia, emmetropia and astigmatism, and/or to improve night
`
`or low-light vision.
`
`According to another aspect of an embodiment, there is provided a use of a combination of a
`
`first pharmacologically active agent comprising pilocarpine and a second pharmacologically
`
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`

`-7a-
`
`active agent comprising dapiprazolc, in the manufacture of a medicament adapted for topical
`
`application to a human or animal eye in order to improve visual acuity in one or more of
`
`presbyopia, myopia, hypermetropia, emmetropia and astigmatism, and/or to improve night or
`
`low-light vision.
`
`According to yet another aspect of an embodiment, there is provided a use of a combination
`
`of
`
`a
`
`first pharmacologically active
`
`agent
`
`comprising pilocarpine
`
`and
`
`a
`
`second
`
`pharmacologically active agent comprising brimonidine, in the manufacture of a medicament
`
`adapted for topical application to a humanor animal eye in order to improve visual acuity in
`
`one or more of presbyopia, myopia, hypermetropia, emmetropia and astigmatism, and/or to
`
`improve night or low-light vision.
`
`Embodiments of the present invention will now be more particularly described by way of
`
`example.
`
`An otherwise conventional eye-drop formulation was prepared, into which was incorporated
`
`0.5% by weight dapiprazole and 0.5% by weight pilocarpine, to produce a first eye-drop
`
`formulation embodying the present invention. Dapiprazole is classified as a sympathetic
`
`antagonist; pilocarpine as a parasympathetic agonist.
`
`In a first example, a patient aged sixty-three presented as an emmetrope (not requiring
`
`glasses for functional distance vision). The patient’s vision was tested, the first eye-drop
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`formulation was administered, and the patient’s vision was then re-tested. Within twenty
`
`minutes of administration, the patient’s unaided distance vision in each eye had improved by
`
`a line on the Snellen chart, from 6/6 to 6/5, The refraction did not change. The patient’s
`
`unaided reading vision improved from N12 to N4.5 at a reading distance of one third of a
`
`meter. The patient’s night vision improved qualitatively, as the patient noted less haloes and
`
`glare, and quantitatively, from 6/6 to 6/5 in dim conditions. These effects were maintained
`
`for at least two hours and someforat least four hours.
`
`Thefirst eye-drop formulation thus improves both near and distance vision.
`
`In a second example, a patient aged fifty presented as a -4 Dioptre myope (requiring glasses
`
`for functional distance vision). Again, the patient’s vision was tested before and after the
`first eye-drop formulation was administered. Within half an hour of administration, the
`
`patient’s unaided distance vision improved from being able to count fingers (but not to read
`
`the Snellen chart) to 6/36 on the chart. Wearing distance-corrected glasses, the patient’s
`
`reading vision at a distance of one third of a meter improved from N12 to N4.5. The
`
`refraction did not change. Quality of night vision improved as the patient noted less haloes
`and glare, and night vision also improved quantitatively from 6/6 to 6/5 in dim conditions.
`
`The effects again were maintainedfor at least two hours and someforat least four hours.
`
`In a third example, a patient aged forty-nine presented as a +4 Dioptre hypermetrope
`
`(longsighted and requiring glasses for useful reading vision). The patient’s vision was tested
`before and after administration of the first ‘eye-drop formulation. Within half an hour of
`
`administration, the patient’s unaided distance vision improved on the Snellen chart from 6/60
`
`to 6/24. Thepatient’s unaided reading vision at one third of a meter improved from N18 to
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`
`N4.5. The refraction did not change. Quality of night vision improved, the patient noting
`
`less haloes and glare, and night vision also improved quantitatively from 6/6 to 6/5 in dim
`
`conditions. The effects were maintained for at least two hours and some for at least four
`
`hours.
`
`In all three examples,no significant discomfort was reported.
`
`A second eye-drop formulation embodying the present
`
`invention was prepared by
`
`incorporating 0.1% by weight brimonidine and 0.25% by weight pilocarpine into an
`
`otherwise conventional eye-drop formulation. Brimonidine is classified as a sympathetic
`
`agonist; pilocarpine, as noted above, is considered to be a parasympathetic agonist.
`
`The second eye-drop formulation was tested on the three patients referred to above. In each
`
`case, administration of the second eye-drop formulation produced almostidentical effects to
`
`the first eye-drop formulation, above.
`
`A third and fourth eye-drop formulation were made up, containing 0.5% dapiprazole and
`0.5% pilocarpine, respectively. Administration of the third and fourth eye-drop formulations
`
`immediately sequentially to a patient’s eyes produced results substantially identical to those
`
`from the first eye-drop formulation (which contained the same active components, pre-
`
`mixed). Thus, the eye-drop formulations of the present invention may in effect be produced
`
`in situ in the patient’s eye, should this be convenient.
`
`(NB: the effects of the third or fourth
`
`eye-drop formulations if administered alone would be substantially inferior to those of the
`
`first formulation, or to those of the third and fourth formulations, either mixed before
`
`administration or mixed in the eye).
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`There are signs that the eye-drop formulations of the present invention also obviate the
`
`effects of astigmatism. Thus, they will be useful for the many patients who suffer from
`combinations of vision problems, such as myopia coupled with astigmatism.
`(Such effects
`
`make prescribing and producing appropriate spectacle lenses, or other conventional
`
`approaches, particularly difficult).
`
`It is particularly notable from the above results that not only do the compositions of the
`
`present invention significantly improve the unaided distance vision of myopes and the
`
`unaided close-up vision of hypermetropes, but they also improve the ‘clarity of close-up
`
`vision for myopes, distance vision for hypermetropes and vision both near and far for
`
`emmetropes, while wearing their respective corrective spectacles.
`
`It is also evident from these results that presbyopes would also benefit from treatment with
`these compositions. Presbyopia usually takes the form of difficulty in focussing on nearby
`
`objects (accommodation). Compositions such as those of the present invention, which do not
`
`act by changing refraction, are thus likely to be more desirable and effective than those
`
`compositions that have occasionally been proposedin the past, which do changerefraction.
`
`Theeffect on night vision haloes, etc, suggests that other form of refractive error might also
`
`be ameliorated.
`
`The eye-drops of the present invention may-thus be used temporarily to alleviate the effects
`
`of conditions such as myopia and hypermetropiaor to improve adequate vision further.
`
`It is
`
`envisaged that, due to the lack of side-effects and drawbacks discovered in testing to date,
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`these eye-drops might well be suitable for self-selection and self-administration, rather than
`
`needingto be prescribed by a qualified medical practitioner.
`
`Thus, the eye-drops of the present invention could be used in place of corrective glasses or
`
`contact lenses, either as 2 general practice; for variety; or in particular circumstances where
`
`glasses and/or contact lenses might not be practical or convenient(e.g. contact sports).
`
`The exact physiological modeof action of these combinations of pharmaceuticals has not yet
`
`been established. The most significant and amexpected feature of their action appears to be
`
`that combining parasympathetic agonists and sympathetic antagonists, agents having largely
`
`opposite modes of action, produces beneficial synergies relative to either agent used
`
`separately, while their possible adverse effects appear largely to cancel out.
`
`It is also most unexpected that parasympathetic agonists and sympathetic agonists appear to
`
`co-operate synergistically, without significant adverse side-effects.
`
`It is believed that at least part of the benefit of the combinations described is because they
`
`seem to havelittle or no net effect on the ciliary muscles of the eye, which act to alter the
`
`shape and hence refraction of the lens.
`
`While the examples above describe application in the form of eye-drops, other forms of
`
`topical application to the eye may be possible. There is no reason to believe that spraying
`
`compositions with the same combinations of active agents into the eye; applying a gel or
`
`ointment to the eye; or even using an ocular insert containing a slow-release preparation of
`
`one of the above combination ofactive agents would not work similarly well.
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`
`It is possible that certain otherwise suitable active agents might lead to issues with general
`
`discomfort in the eye, or even specific side-effects such as red-eye, in which blood vessels of
`
`the sclera dilate so far that someorall of the white of the eye appears red. The treatment
`
`could be completed with separate administration of further compositions selected on a
`
`symptomatic basis. However, it is probably more convenient to incorporate the appropriate
`treatment agents into the compositions of the present invention, particularly where the side-
`
`effect is frequently encountered.
`
`As well as the active agents exemplified above, others that are believed to be particularly
`
`suitable for the compositions of the present invention include: thymoxamine, a sympathetic
`
`antagonist (substitutable for dapiprazole); and iopidine, a sympathetic agonist (substitutable
`
`for brimonidine). The class of drugs generally referred to as beta-blockers may be considered
`
`as sympathetic antagonists, and hence someorall of that class may well be usable in place of
`
`dapiprazole, above.
`
`It is also believed that an opiate could be substituted for either the parasympathetic agonist or
`
`the sympathetic antagonist/agonist
`
`in the compositions above.
`
`Indeed, a composition
`
`containing an opiate as its sole or main active componentis predicted to be effective in the
`
`treatmentof the conditionslisted above.
`
`

`

`CLAIMS
`
`-13-
`
`1,
`
`A use of a combination of a first pharmacologically active agent comprising
`
`pilocarpine and a second pharmacologically active agent comprising thymoxamine,in
`
`the manufacture of a medicament adapted for topical application to a human or
`
`animal eye in order to improve visual acuity in one or more of presbyopia, myopia,
`
`hypermetropia, emmetropia and astigmatism, and/or to improve night or low-light
`
`vision.
`
`Z.
`
`The use of a combination of pharmacologically active agents as claimed in claim 1,
`
`wherein the medicament is adapted for topical application to treat defects of visual
`
`acuity in one or more of presbyopia, myopia, hypermetropia, emmetropia and
`
`astigmatism, and/or to improve night or low-light vision.
`
`3.
`
`The use of a combination of pharmacologically active agents as claimed in either
`
`claim 1 or claim 2, wherein the medicament is adapted for topical application to
`
`correct defects of visual acuity in one or more of presbyopia, myopia, hypermetropia,
`
`emmetropia and astigmatism, and/or to improve night or low-light vision.
`
`4.
`
`The use of combination of pharmacologically active agents as claimed in any one of
`
`claims |
`
`to 3, wherein the medicament comprises a liquid composition, gel or
`
`ointment.
`
`Wi
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 1 to 4, wherein the medicament comprises a slow release composition.
`
`CA 2747095 2019-10-02
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`

`

`-14-
`
`6.
`
`The use of a combination of pharmacologically active agents as claimed in claim 5,
`
`wherein the medicament comprises slow release insert means.
`
`7.
`
`The use of a combination of pharmacologically active agents as claimed in claim 1,
`
`wherein the medicament comprises between 0.05% and 4% pilocarpine.
`
`&.
`
`The use of a combination of pharmacologically active agents as claimed in claim 7,
`
`wherein the medicament comprisesat least 0.25% pilocarpine.
`
`9,
`
`The use of a combination of pharmacologically active agents as claimed in either
`
`claim 7 or claim 8, wherein the medicament comprises no more than 0.5%
`
`pilocarpine.
`
`10.
`
`The use of a combination of pharmacologically active agents as claimed in claim 1,
`
`wherein the medicament comprises between 0.05% and 4% thymoxamine.
`
`11.
`
`The use of a combination of pharmacologically active agents as claimed in claim 10
`
`wherein the medicament comprisesat least 0.25% thymoxamine.
`
`12.
`
`The use of a combination of pharmacologically active agents as claimed in either
`
`claim 10 or claim 11, wherein the medicament comprises no more than 0.5%
`
`thymoxamine.
`
`CA 2747095 2019-10-02
`
`

`

`-|[5-
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 1 to 12, wherein said medicamentis adapted to treat presbyopia.
`
`14.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims | to 13, wherein said medicamentis adapted to treat myopia.
`
`15.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims | to 14, wherein said medicament is adapted to treat hypermetropia.
`
`16.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims |
`
`to 15, wherein said medicament is adapted to improve night or low-light
`
`vision.
`
`17.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims | to 16, wherein said medicamentis adapted to treat astigmatism.
`
`18
`
`A use of a combination of a first pharmacologically active agent comprising
`
`pilocarpine and a second pharmacologically active agent comprising dapiprazole, in
`
`the manufacture of a medicament adapted for topical application to a human or
`
`animal eye in order to improve visual acuity in one or more of presbyopia, myopia,
`
`hypermetropia, emmetropia and astigmatism, and/or to improve night or low-light
`
`vision.
`
`The use of a combination of pharmacologically active agents as claimed in claim 18,
`
`wherein the medicament is adapted for topical application to treat defects of visual
`
`CA 2747095 2019-10-02
`
`

`

`-16-
`
`acuity in one or more of presbyopia, myopia, hypermetropia, emmetropia and
`
`astigmatism, and/or to improve night or low-light vision.
`
`20.
`
`The use of a combination of pharmacologically active agents as claimed in either
`
`claim 18 or claim 19, wherein the medicament is adapted for topical application to
`
`correct defects of visual acuity in one or more of presbyopia, myopia, hypermetropia,
`
`emmetropia and astigmatism, and/or to improve night or low-light vision.
`
`21.
`
`The use of combination of pharmacologically active agents as claimed in any one of
`
`claims 18 to 20, wherein the medicament comprises a liquid composition, gel or
`
`ointment.
`
`22.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 18 to 21, wherein the medicament comprises a slow release composition.
`
`23.
`
`The use of a combination of pharmacologically active agents as claimed in claim 22,
`
`wherein the medicament comprises slow release insert means.
`
`24.
`
`The use of a combination of pharmacologically active agents as claimed in claim 18,
`
`wherein the medicament comprises between 0.05% and 4%pilocarpine.
`
`25.
`
`The use of a combination of pharmacologically active agents as claimed in claim 24,
`
`wherein the medicament comprisesat least 0.25% pilocarpine.
`
`CA 2747095 2019-10-02
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`

`

`-17-
`
`26.
`
`The use of a combination of pharmacologically active agents as claimed in either
`
`claim 24 or claim 25, wherein the medicament comprises no more than 0.5%
`
`pilocarpine.
`
`27,
`
`The use of a combination of pharmacologically active agents as claimed in claim 18,
`
`wherein the medicament comprises between 0.05% and 4% dapiprazole.
`
`28.
`
`The use of a combination of pharmacologically active agents as claimed in claim 27
`
`wherein the medicament comprisesat least 0.25% dapiprazole.
`
`29.
`
`The use of a combination of pharmacologically active agents as claimed in either
`
`claim 27 or claim 28, wherein the medicament comprises no more than 0.5%
`
`dapiprazole.
`
`30.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 18 to 29, wherein said medicamentis adapted to treat presbyopia.
`
`31.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 18 to 30, wherein said medicamentis adapted to treat myopia.
`
`32.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 18 to 31, wherein said medicamentis adapted to treat hypermetropia.
`
`CA 2747095 2019-10-02
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`

`

`-18-
`
`33.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 18 to 32, wherein said medicament is adapted to improve night or low-light
`
`vision.
`
`34.
`
`The use of a combination of pharmacologically active agents as claimed in any one of
`
`claims 18 to 33, wherein said medicamentis adaptedto treat astigmatism.
`
`CA 2747095 2019-10-02
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`