(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`10 November 2011 (10.11.2011)
`
`PCT
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2011/138801 Al
`
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, 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, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SY, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, VG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, 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,
`LY, 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, ML, MR, NE, SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`as to the identity of the inventor (Rule 4.17 (i))
`
`as to applicant's entitlement to apply for and be granted
`a patent (Rule 4.17 (ii))
`
`as to the applicant's entitlement to claim the priority of
`the earlier application (Rule 4.17 (iii))
`
`ofinventorship (Rule 4.17(iv))
`
`Published:
`
`with international search report (Art. 21 (3))
`
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`(51) International Patent Classification:
`A61K 9100 (2006.01)
`A61K 3115377 (2006.01)
`A61K 311557 (2006.01)
`A61K 47132 (2006.01)
`
`(21) International Application Number:
`PCT/IN201 l/000320
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`6 May 2011 (06.05.2011)
`
`English
`
`(84)
`
`English
`
`(30) Priority Data:
`1448/MUM/20 l 0
`
`7 May 2010 (07.05.2010)
`
`IN
`
`(71) Applicant (for all designated States except US): SUN
`PHARMA ADVANCED RESEARCH COMPANY
`LTD. [IN/IN]; 17/B, Mahal Industrial Estate, Off Ma(cid:173)
`hakali Caves Road, Andheri - East, Mumbai 400 093
`(IN).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KHOPADE, Ajay
`Jaysingh [IN/IN]; Sun Pharma Advanced Research Cen(cid:173)
`tre, Nima Compound, Near Pratham Enclave, Tandalja
`Road, Baroda 390 020 (IN). HALDER, Arindam
`[IN/IN]; Sun Pharma Advanced Research Centre, Nima
`Compound, Near Pratham Enclave, Tandalja Road, Baro(cid:173)
`da 390 020 (IN). BHOWMICK, Subhas Balaram
`[IN/IN]; Sun Pharma Advanced Research Centre, Nima
`Compound, Near Pratham Enclave, Tandalja Road, Baro(cid:173)
`da 390 020 (IN).
`
`(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,
`
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`(54) Title: NOVEL OPHTHALMIC COMPOSITIONS
`
`(57) Abstract: An ophthalmic solution comprising therapeutically effective amount of a prostaglandin or its analog and water sol(cid:173)
`uble excipient( s) dissolved in a pharmaceutically acceptable vehicle, wherein the solution is free of a surfactant.
`
`ARGENTUM PHARM. 1016
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`000001
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`

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`WO 2011/138801
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`PCT/IN2011/000320
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`NOVEL OPHTHALMIC COMPOSITIONS
`
`The present invention relates to a novel ophthalmic solution prostaglandin or its analogs
`
`alone or in combination with other antiglaucoma agents.
`
`5
`
`BACKGROUND OF THE INVENTION
`
`Prostaglandins are well known active substances administered to humans or animals via
`
`the topical route in the form of ophthalmic solutions for the treatment of glaucoma. The
`
`prostaglandins may also be used in combination with a second anti-glaucoma agent such
`
`10
`
`as a beta-blocker, a carbonic anhydrase inhibitor or an alpha-adrenergic agonist.
`
`Prostaglandin or its analogs, particularly the ester derivatives such as latanoprost,
`
`travoprost or the amide derivatives such as bimatoprost have notoriously low water
`
`solubility. The use of compounds which exert a surfactant like activity in to solubilize
`
`them is therefore, very common. Currently available prostaglandin ophthalmic solution,
`
`15
`
`are found to contain a typical surfactant or a quaternary ammonium salt which is known
`
`to have a surfactant like activity apart from preservative property. Representative
`
`examples of typical surfactants incorporated in the ophthalmic solutions of prostaglandin
`
`analogs alone or in combination with other antiglaucoma agent, like for example, beta
`
`adrenergic blocking agent or alpha adrenergic blocking agent or any other active agent,
`
`20 . are tabulated here:
`
`Product
`Xalatan®
`Travatanz®
`Xalacom®
`Lumigan®
`Ganfort®
`Duotrav®
`
`Surfactant
`Active Ingredient
`Benzalkonium chloride
`Latanoprost
`polyoxyl 40 hydrogenated castor oil
`Travoprost
`(Cremphore)
`Benzalkonium chloride
`Latanoprost and timolol
`Benzalkonium chloride
`Bimatoprost
`Bimatoprost and timolol Benzalkonium chloride
`Benzalkonium chloride
`Travoprost and timolol
`
`Rescula®
`
`Unoprostone isopropyl
`
`Polyoxyethylene-20-sorbitan-monooleate
`
`Apart from the approved products, the patent literature also represents numerous efforts
`
`of solubilizing prostaglandins with the help of solubilizers such as polyoxyethylene-20-
`
`sorbitan-monooleate, polyoxy stearates like Solutol® with or without other antiglaucoma
`
`25
`
`agent like beta adrenergic blocking agent. Below is a list of patent documents that
`
`000002
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`WO 2011/138801
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`PCT/IN2011/000320
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`disclose the use of surfactant in a prostaglandin ophthalmic solution alone or in
`
`combination with other antiglaucoma agent.
`
`Product disclosed in
`Literature
`
`Prostaglandin
`
`Surfactant
`
`US7074827
`
`Latanoprost
`
`US20100201720
`
`Prostaglandin
`
`W0/2009/145356
`
`Tafluprost
`
`US20030018079
`
`Latanoprost and Timolol
`
`Polyoxyethylene-20-sorbitan(cid:173)
`monooleate
`Solutol
`Polyoxyethylene-20-sorbitan(cid:173)
`monooleate
`Polyoxyethylene-20-sorbitan(cid:173)
`monooleate and Benzalkonium
`chloride
`
`5 Generally, the formulation development of ophthalmic solution of prostaglandin or their
`
`combination with other active ingredient, over the years, is directed towards achieving a
`
`stable composition particularly in view of the fact that prostaglandins are also known to
`
`chemically unstable. Further, the literature provides evidences that the prostaglandins
`
`were associated with an adsorption problem to the poly-ethylene multidose containers.
`
`10
`
`Some solutions to solve these problems are described in patent documents such as, for
`
`example, United States patent number US 6,235,781 which discloses that use of a
`
`surfactant to prevent the adsorption of prostaglandin analogues on to the plastic
`
`containers. The inventor of the present invention also faced and tackled this problem of
`
`adsorption of prostaglandin as described in WO 2009/084021. It was found out by
`
`15
`
`inventors that a micro-emulsion formulation of prostaglandin containing polyoxy
`
`hydroxystearate (commonly known as Solutol HS) provides the solution to stability
`
`problem associated with adsorption. Another patent application, namely, United States
`
`Patent number US 20090234013Al, discloses a solution which include a therapeutic
`
`agent and a relatively low amount of surfactant for providing higher bioavailability of
`
`20
`
`prostaglandin such as travoprost. Thus, this prior art as well teaches to include some
`
`amount of a surfactant such as ethoxylated and/or hydrogenated vegetable oil. This
`
`implies that the surfactant is always desirable to make the solution however it is
`
`preferable to keep it as low as possible.
`
`2
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`000003
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`

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`WO 2011/138801
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`PCT/IN2011/000320
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`Now, the inventors surprisingly and unexpectedly found that the prostaglandin analogs
`
`can be effectively formulated into an ophthalmic solution vehicle having a water soluble
`
`excipient(s) dissolved in the vehicle, wherein the ophthalmic solution is free of a
`
`5
`
`surfactant. When the efficacy of the ophthalmic solution was compared with an
`
`ophthalmic solution comprising a surfactant, it was found that the ophthalmic solution
`
`provided equivalent or improved efficacy in reducing the
`
`intraocular pressure.
`
`Particularly, the ophthalmic solution of present invention was found to provide equivalent
`
`efficacy at half the dose compared to the marketed product available under the tradename
`
`10
`
`of Xalatan® when tested in animals. This achievement of equivalent efficacy at half the
`
`dose of latanoprost was indeed unexpected and surprising. It was further found that the %
`
`intraocular pressure reduction at 12 hour time point, which apparently provides a peak
`
`IOP reduction was higher compared to the% intraocular pressure reduction at 12 hours,
`
`for Xalatan® which is a latanoprost ophthalmic solution having benzalkonium chloride as
`
`15
`
`a surfactant. This effect of improved efficacy inspite of the absence of a surfactant, was
`
`also observed when the ophthalmic solution of the present invention was made of a
`
`prostaglandin or its analog and another antiglaucoma agent like a beta adrenergic
`
`blocking agent. The ophthalmic composition comprising prostaglandin or its nalog and a
`
`beta-adrenergic blocking agent that is free of surfactant, the composition remained stable
`
`20
`
`and did not show any hazyness. The composition was clear on storage and was
`
`chemically stable .. Thus, the invention not only provided a physically stable composition
`
`comprising the two active ingredients, but also provided an ophthalmic composition that
`
`was more efficacious. Since the compositions are intended for ophthalmic purposes, it is
`
`always desirable that the compositions are devoid of excessive additives. Therefore, the
`
`25
`
`present invention can be said to achieve not only the patient compliance but also achieved
`
`an improved efficacious composition.
`
`Thus, the ophthalmic composition of the present invention comprises a combination of a
`
`prostaglandin and a beta-adrenergic blocking agent, characterized in that it does not use
`
`30
`
`any surfactant or a surfactant preservative in a concentration that acts as a solubilizer
`
`such as those from alkyl quaternary ammonium surfactant like benzalkonium chloride,
`
`3
`
`000004
`
`

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`WO 2011/138801
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`PCT/IN2011/000320
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`benzdodecinium chloride and like and mixtures thereof. In one preferred embodiment,
`
`the ophthalmic composition includes a vehicle that is free of surfactants and added
`
`preservatives and is able to provide a beta-adrenergic blocking agent when administered
`
`topically such that effect is sustained for 24 hours, that is the ophthalmic composition is
`
`5
`
`said to be suitable for once-a-day administration. Therefore, one of the embodiment of
`
`the present invention can be said to provide an ophthalmic composition comprising
`
`latanoprost and once-a-day composition of a beta-adrenergic blocking agent, wherein the
`
`composition is free of surfactant and optionally, free of added preservative and is found
`
`to be suitable for treating the affected eye of a glaucoma patient.
`
`10
`
`The ophthalmic solution of the present invention is free of a surfactant as well as free of
`
`anti-microbial preservatives defined by the class of quaternary ammonium compounds,
`
`organo-mercurials and substituted alcohol and phenols. It is known that these
`
`antimicrobials are often toxic to the sensitive tissues of the eye. The present invention
`
`15
`
`thereofore fulfils the need of an ophthalmic solution which is stable as well having
`
`improved efficacy while not compromising on the antimicrobial activity. The present
`
`invention provides an ophthalmic solution comprising prostaglandins which obtains dual
`
`benefits of improved efficacy and avoidance of undesirable effects of the preservatives.
`
`20 OBJECTS OF THE INVENTION
`
`The object of the invention is to provide an ophthalmic solution that allows dose
`
`reduction of the prostaglandin while achieving equivalent efficacy.
`
`The present invention relates to an ophthalmic solution comprising therapeutically
`
`25
`
`effective amount of a prostaglandin analogue and another active ingredient, wherein the
`
`solution provides therapeutic effect sustaining for 24 hours i.e. to provide a once -a-day
`
`therapy.
`
`The object of the present invention to provide a stable ophthalmic solution of
`
`prostaglandin analogs.
`
`30
`
`The object of the present invention to provide a stable ophthalmic solution of
`
`prostaglandin analogs and beta adrenergic active agents.
`
`4
`
`000005
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`

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`WO 2011/138801
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`PCT/IN2011/000320
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`SUMMARY OF THE INVENTION
`
`Thus, the present invention provides an ophthalmic solution comprising prostaglandins
`
`5 which obtains dual benefit of improved efficacy and avoidance of undesirable effects of
`
`the preservatives. The ophthalmic solution of the present invention is free of a surfactant
`
`as well as free of anti-microbial preservatives defined by the class of quaternary
`
`ammonium compounds, organo-mercurials, and substituted alcohol and phenols, It is
`
`known that these antimicrobials are often toxic to the sensitive tissues of the eye. A need
`
`10
`
`therefore exists for ophthalmic solutions which have a stability, efficacy, but whose
`
`antimicrobial efficacy is not compromised.
`
`The present invention provides an ophthalmic solution compnsmg therapeutically
`
`effective amount of a prostaglandin or its analog and optionally, one or more other
`
`15
`
`therapeutic agents and water soluble excipient(s) dissolved in a pharmaceutically
`
`acceptable vehicle, wherein the solution is free of a surfactant.
`
`The present invention also provides a method of treating glaucoma or ocular hypertension
`
`which comprises topically administering to an affected eye an ophthalmic solution
`
`20
`
`comprising therapeutically effective amount of a prostaglandin or its analog and
`
`optionally, one or more other therapeutic agents and water soluble excipient(s) dissolved
`
`in a pharmaceutically acceptable vehicle, wherein the solution is free of a surfactant.
`
`BRIEF DESCRIPTION OF FIGURE
`
`25
`
`Figure I: A comparative % reduction in the intraocular pressure of the dogs within 24
`
`hours when the ophthalmic solution of the present invention was administered and %
`
`reduction in the intraocular pressure after the administration of already available
`marketed products like Xalatan®, Xalacom®, Timoptic®·. It was found that the ophthalmic
`
`30
`
`solution of example 3 provided a 29.43 % IOP reduction at 2 hr compared to 18.19 %
`
`IOP reduction when Xalatan® was administered or 12.02% IOP reduction when
`
`Xalacom®was administered or 19.82 %IOP reduction when Timoptic®was administered.
`
`5
`
`000006
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`WO 2011/138801
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`Similarly, example 3 provided a 29.67 % IOP reduction at 12 hr compared to 25.31 %
`
`IOP reduction when Xalatan® was administered or 21.28 %IOP reduction when
`
`Xalacom®was administered or 7.16 %IOP reduction when Tim.optic® was administered.
`
`Similarly, example 3 provided a 24.87 % IOP reduction at 24 hr compared to 12.77 %
`
`5
`
`IOP reduction when Xalatan® was administered or 9.84 %IOP reduction when Xalacom®
`
`was administered or 9.72 %IOP reduction when Tim.optic® was administered.
`
`Figure II: A comparative % mean reduction in the intraocular pressure of the affected eye
`
`of dogs when the solution of the present invention was administered Vs % mean
`
`10
`
`reduction in the intraocular pressure after the administration of marketed reference
`
`products such as like Xalatan®, Xalacom®, Tim.optic®. The % mean reduction of the
`
`intraocular pressure was found to be higher compared to the marketed product which
`
`either contains a beta-adrenergic blocking agent such as Tim.optic® or a Xalatan® which
`
`alone or their combination (Xalacom®). It was found that the mean intraocular pressure
`
`15
`
`reduction achieved by administration of the ophthalmic solution of Example 3, was
`
`34.377 % compared to 26.765 % achieved by Xalatan® or 28.258 % achieved by
`
`Xalacom® or 21.088 % achieved by Tim.optic® alone.
`
`Figure III: It is a graph of comparison % IOP reduction when the ophthalmic solution of
`
`20
`
`the present invention was administered, with % IOP reduction after the concomitant
`
`administration of marketed latanoprost and timolol products like Xalatan® and Timoptic®
`
`to the dogs· It was found that the overall, mean intraocular pressure reduction achieved by
`
`the ophthalmic solution of the present invention administered once a day was 28.63 %
`
`compared to 26.49 % which was achieved by the concomitant administration of the
`
`25 marketed product of latanoprost (once a day) and timolol (twice a day) present alone in
`
`the products.
`
`Figure IV: A comparative % mean reduction in the intraocular pressure of the affected
`
`eye of dogs when the solution of the present invention Example.3 was administered Vs %
`
`30 mean reduction in the intraocular pressure after the administration of marketed reference
`
`products Xalacom ® over 2 h and 12 h which represent the peak effect of Timolol and
`
`6
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`000007
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`WO 2011/138801
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`PCT/IN2011/000320
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`latanoprost, respectively. It is noted that the solution of example 3 has a significantly
`higher IOP reductions at both time points. At 2 hp= 0.0054, p < 0.01, at 12 hp= 0.0019,
`p < 0.01.
`
`5 DETAILED DESCRIPTION OF THE INVENTION
`
`The term 'surfactant' as used herein means an amphiphilic compound that has the
`
`following properties
`
`•
`
`It has hydrophobic groups and hydrophilic groups
`
`• Can form micelles
`
`10
`
`• Capable of migrating to the water surface, where the insoluble hydrophobic alkyl
`
`chains may extend out of the bulk water phase, either into the air or, if water is
`
`mixed with oil, into the oil phase, while the water soluble head group remains in
`
`the aqueous phase.
`
`• Can solubilize water insoluble substances through micellar solubilization.
`
`15
`
`The ophthalmic solutions of the present invention are characterized as being clear
`
`aqueous solution. These "solution" as stated herein, are defined as those solutions which
`
`do not cause any visual disturbance and/or do not affect vision, upon topical instillation
`
`to the eye and when examined under suitable conditions of visibility, are practically clear
`
`20
`
`and practically free from particles. Ophthalmic solutions containing polymers which
`
`show percent transmission greater than 90% are referred to as 'solution'. When light is
`
`allowed to pass through the ophthalmic solution of the present invention, the percentage
`
`of incident light which is transmitted through the solution is referred to as "Percent
`
`Transmission". The clarity of the solution is poor if percent transmission is less than
`
`25
`
`85%. Preferably the percent transmission is greater than 90%. Generally, the percent
`
`transmission is determined at a wavelength of about 650 nm, but any other suitable
`
`wavelength may be selected for determining the clarity of the solution.
`
`The prostaglandin or its analog used in the ophthalmic solution of the present invention
`
`30
`
`includes, but are not limited to, all pharmaceutically acceptable prostaglandins, their
`
`derivatives and analogs, and their pharmaceutically acceptable esters and salts
`
`7
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`000008
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`WO 2011/138801
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`PCT/IN2011/000320
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`(hereinafter collectively referred to as "prostaglandins" or "PG's"), which are useful for
`
`reducing intraocular pressure when applied topically to the eye. Such prostaglandins
`include the natural compounds, such as for example PGE i, PGE 2, PGE 3, PGD 2, PGF
`1a, PGF 2a, PGF 3a, PGii (prostacyclin), as well as analogs and derivatives of these
`
`5
`
`compounds which are known to have similar biological activities of either greater or
`
`lesser potencies. Analogs of the natural prostaglandins include but are not limited to:
`
`alkyl substitutions (e.g., 15-methyl or 16,16-dimethyl), which confer enhanced or
`
`sustained potency by reducing biological metabolism or alter selectivity of action;
`
`saturation (e.g. 13, 14-dihydro) or unsaturation (e.g., 2,3-didehydro, 13, 14-didehydro ),
`
`10 which confer sustained potency by reducing biological metabolism or alter selectivity of
`
`action; deletions or replacements (e.g. 11-deoxy, 9-deoxo-9-methylene), which enhance
`
`chemical stability and/or selectivity of action; and omega chain modifications (e.g.,
`
`18, 19,20-trinor-17-phenyl, or
`
`17, 18, 19,20-tetranor-16-phenoxy), which
`
`enhance
`
`selectivity of action and reduced biological metabolism.
`
`15
`
`Derivatives of these prostaglandins that may be formulated in the solution of the present
`
`invention include all pharmaceutically acceptable esters or amides, which may be
`
`attached to the 1-carboxyl group or any of the hydroxyl groups of the prostaglandin by
`
`use of the corresponding alcohol or organic acid reagent, as appropriate. The terms
`
`20
`
`"analogs" and "derivatives" include compounds which exhibit functional and physical
`
`responses similar to those of prostaglandins per se. Prostaglandins are well known in the
`
`art. Particular prostaglandins that may be formulated in the solutions of the present
`
`invention include for example trimoprostil, rioprostil, cloprostenol, fluprostenol,
`
`luprostiol, etiproston,
`
`tiaprost,
`
`latanoprost,
`
`travoprost, bimatoprost,
`
`tafluprost,
`
`25
`
`unoprostone and its derivatives like unoprostone isopropyl, misoprostol, sulfoprostone,
`
`gemeprost, alfaprostol, delprostenate, and the like. Pharmaceutical solutions of the
`
`present invention include one or more prostaglandins as described above in an amount
`
`between about 0.0001 % w/v and about 0.2% w/v. The presently preferred amount of
`
`prostaglandin or its derivative is from about 0.001 % to 0.05%, preferably about 0.0015%
`
`30
`
`to about 0.03%.
`
`8
`
`000009
`
`

`
`WO 2011/138801
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`PCT/IN2011/000320
`
`In one embodiment, the ophthalmic solution of the present invention is free of surfactant
`
`and preservative as well as free of any cyclodextrin which solubilizes the prostaglandins
`
`by inclusion complexes. The ophthalmic solutions disclosed in patent application
`
`EP0435682 A2 uses cyclodextrin to solubilize the TRIS derivatives of the prostaglandins.
`
`5 This patent also teaches to include one or more preservatives.
`
`In one embodiment of the present invention, latanoprost which is a prostaglandin F2a
`
`analogue, namely
`
`isopropyl-(Z)-7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-
`
`phenylpentyl]cyclopentyl]-5- heptenoate is used. It may be present in an amount ranging
`
`10
`
`from about 0.0001 % w/v to about 0.2% w/v. Preferably, latanoprost is used in amounts of
`
`about 0.005% w/v. In another embodiment, travoprost is used as ·the prostaglandin
`
`derivative in amounts ranging from about 0.0001 % w/v to about 0.2% w/v preferably in
`
`an amount 0.004% w/v. In yet another embodiment, bimatoprost is used as the
`
`prostaglandin derivative in amounts ranging from about 0.0001 % w/v to about 0.2%w/v,
`
`15
`
`preferably in an amount 0.03% w/v. In yet another embodiment tafluprost is used in
`
`amounts ranging from about 0.0001 % w/v to about 0.2%w/v, preferably in an amount
`
`0.0015% w/v.
`
`In one preferred embodiment of the present invention, the ophthalmic solution is free of
`
`20
`
`surfactant as well as free of a preservative or antimicrobial preservatives defined by the
`
`class of quaternary ammonium compounds, organic mercurial compounds, and
`
`substituted alcohol and phenol. Particularly, the ophthalmic solution is free of surfactant
`
`as well as free of a antimicrobial preservatives defined by the class of quaternary
`
`ammonium compounds such as for example, benzalkonium chloride. These classes of
`
`25
`
`compounds are known to have a surfactant effect as well.
`
`In one embodiment, the ophthalmic solution of the present invention consisting
`
`essentially of therapeutically effective amount of a prostaglandin esters or amides,
`
`cosolvent(s) and self preserving systems and optionally, pharmaceutically acceptable
`
`30
`
`excipients selected from the group consisting of viscosity enhancing agents and buffers.
`
`Examples of the self preserving systems are used in the ophthalmic solution of the
`
`9
`
`000010
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`WO 2011/138801
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`PCT/IN2011/000320
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`present invention are Polyquad®, disappearing preservatives include stabilized hydrogen
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`peroxide, stabilized oxy-chlorocomplex, sodium perborate, borate-polyol complex and
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`like.
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`5 Therefore, the present invention may be further described as an ophthalmic solution
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`consisting essentially of therapeutically effective amount of a prostaglandin or its analog
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`and, cosolvent(s) and self preserving systems and optionally, pharmaceutically acceptable
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`excipients selected from the group consisting of viscosity enhancing agents and buffers.
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`Since the quaternary ammonium compounds are known to exhibit surfactant activity, the
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`term
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`'consisting essentially of means that the ophthalmic solution is free of
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`preservatives, particularly, quaternary ammonium preservatives such as Benzalkonium
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`Chloride
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`(BAK), Benzethonium Chloride, Benzyl Alcohol, Busan, Cetrimide,
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`Chlorhexidine, Chlorobutanol, Mercurial Preservatives, or · phenylmercuric Nitrate,
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`Phenylmercuric Acetate, Thimerosal, phenylethyl Alcohol and like. However, the safer
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`preservative systems and preservative efficacy enhancers such as edetate disodium,
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`borates, pyruvates, parabens, stabilized oxychloro compounds, Sorbic Acid/Potassium
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`Sorbate Polyaminopropyl Biguanide, Polyquaternium-1, Polyhexamethylene biguanide
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`(PHMB), PVP-Iodine complex, metal
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`ions, peroxides, aminoacids, arginine,
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`tromethamine and mixtures thereof may be included within the scope of the present
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`invention. These compounds are generally regarded as safe and are recommended for
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`long term use.
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`In certain embodiments qf the present invention, another active ingredient may be
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`included in the ophthalmic solution. The another active ingredient that may be included
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`in the ophthalmic solution of the present invention, may be a beta-adrenergic blocking
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`agent which is selected from the group consisting of timolol maleate, betaxalol,
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`levobunolol hydrochloride and their therapeutically active salts or esters. The most
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`commonly used and first line drug for the treatment of glaucoma is timolol maleate.
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`Timolol, a non-selective beta-adrenergic blocking agent, when applied topically as an
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`ophthalmic solution, reduces the intraocular pressure in the eye. It is thus indicated in
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`patients with ocular hypertension or open angle glaucoma. It also shows certain systemic
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`effects which includes (1) beta-adrenergic blockade in the heart causing reduction in
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`cardiac output in both healthy subjects and patients with heart disease and (2) beta(cid:173)
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`adrenergic receptor blockade in the bronchi and bronchioles resulting in increased airway
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`resistance from unopposed parasympathetic activity. Therefore, the drug must be used
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`5 with caution in patients in whom beta-adrenergic blockade may be undesirable. Timolol
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`for glaucoma therapy is thus contraindicated in patients with compromised pulmonary
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`functions and in patients who cannot tolerate its systemic cardiovascular action. Hence it
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`is also desirable to reduce the frequency of the use of Timolol maleate wherever possible,
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`preferably as a solution that provides once-a-day administration. Timolol maleate is used
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`in the solutions of the present invention in therapeutically effective amounts. Timolol
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`maleate may be used in an amount ranging from about 0.01 % w/v to about 2.0 % w/v by
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`weight of the solution, preferably from about 0.05 % w/v to about 1.0 % w/v by weight of
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`the solution and most preferably from about 0.1 % w/v to about 0.5 % w/v by weight of
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`the solution. Other beta-adrenergic blocking agent, that is suitable for the present
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`invention is levobunalol or its pharmaceutically acceptable salt. It is used m
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`therapeutically effective amounts 0.5 %. In another embodiment, betaxolol or its
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`pharmaceutically acceptable salt is used in amounts ranging from 0.1 % w/v to 0.8 %
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`w/v, preferably, 0.5 % w/v of the ophthalmic solution of the present invention. The
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`preferred amount of beta-adrenergic blocking agent may be included in the concentration
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`of 0.1 % w/v to 0. 7% w/v, preferably from 0.25% w/v to 0.5% w/v.
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`The ophthalmic solution of the present invention comprises one or more water soluble
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`excipients selected from a group consisting of a water soluble polymer and a penetration
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`enhancer and mixtures thereof. Examples of the water soluble polymers that may be used
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`in the ophthalmic solution of the present invention, include, but are not limited to,
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`polymers- natural and synthetic, polysaccharides, polyaminoglycosides, cellulose
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`derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluroante, chondroitin sulfate,
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`locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methyl
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`cellulose, hydroxyethyl cellulose, carbopol, polystyrene sulfonate and like and mixtures
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`thereof.
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`The ophthalmic solution of the present invention may further comprise pharmaceutically
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`acceptable excipients conventional
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`to
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`the pharmaceutical art. Typical of such
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`pharmaceutically acceptable excipients include osmotic/tonicity-adjusting agents, one or
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`more pharmaceutically acceptable buffering agents and pH-adjusting agents, viscosity
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`enhancing agents, penetration enhancing vehicles and other agents conventional in art
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`that may be used in formulating an ophthalmic solution or imparting a functional
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`property such as gel-forming, bioadhesion, penetration enhancement and like. In certain
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`embodiments, a combination of two water soluble such as hydroxypropyl methylcellulose
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`and guar gum; hydroxypropyl methylcellulose and a carboxyvinyl polymer;
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`hydroxypropyl
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`methylcellulose
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`and
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`hydroxyethylcellulose;
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`hydroxypropyl
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`methylcellulose and hyaluronic acid; hyaluronic acid and a carboxyvinyl polymer;
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`hyaluronic acid and guar gum; or a carboxyvinyl polymer and guar gum may be
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`incorporated.
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`The ophthalmic solution of the present invention may be required to be isotonic with
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`respect to the ophthalmic fluids present in the human eye. These solutions are
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`characterized by osmolalities of 250-375 mOsm/kg. Osmolality of the solutions is
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`adjusted by addition of an osmotic/tonicity adjusting agent. Osmotic agents that may be
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`used in the solutions of the present invention to make it isotonic with respect to the
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`ophthalmic fluids present in the human eye, are selected from the group comprising
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`sodium chloride, potassium chloride, calcium chloride, sodium bromide, sodium
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`phosphate sodium sulfate, mannitol, glycerol, sorbitol, propylene glycol, dextrose,
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`sucrose, polyethylene glycols (PEG), PEG-400, PEG-200, PEG300 and the like, and
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`mixtures thereof. In preferred embodiments of the present invention, PEG-400 is used as
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`the osmotic agent. PEG-400 may be present in the solutions of the present invention in an
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`amount ranging from about 1.0 % to about 5.0 % by weight of the solution, preferably
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`from about 2.5 % to about 4.0 % by weight of the solution and most preferably in an
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`amount of about 3.0 % by weight of the solution.
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`30 According to one embodiment, the preservative systems that are considered safer than
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`quaternary ammonium preservatives are preferred such as polyquad®, stabilized oxy-
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`WO 2011/138801
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`chlorocomplex, stabilized peroxides and perborates, EDT A, tromethamine, borates,
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`sorbates (such as potassium sorbate and sodium sorbate), parabens (such as methyl(cid:173)
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`propyl, isopropyl and butyl- paraben) may be used. According to another embodiment of
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`the present invention, the ophthalmic solution may be self preserving. The ingredients
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`5
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`that make the solution self preserving includes, but are not limited to, inorganic metal
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`salts such as zinc salts, boric acid, pyruvic acid presence of tromethamine, arginine,
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`histidine, guanidine, disodium edetate or like and mixtures thereof.
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`In order to achieve, and subsequently maintain, an optimum pH, the ophthalmic solution
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`10 may contain a pH adjusting agent and/or a buffering agent. The preferred range of pH for
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`an ophthalmic formul