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WO2018033854A1 - Ophthalmic composition and a method for treating ocular hypertension and glaucoma - Google Patents

Ophthalmic composition and a method for treating ocular hypertension and glaucoma Download PDF

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Publication number
WO2018033854A1
WO2018033854A1 PCT/IB2017/054963 IB2017054963W WO2018033854A1 WO 2018033854 A1 WO2018033854 A1 WO 2018033854A1 IB 2017054963 W IB2017054963 W IB 2017054963W WO 2018033854 A1 WO2018033854 A1 WO 2018033854A1
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WO
WIPO (PCT)
Prior art keywords
tafluprost
aqueous solution
ophthalmic
ophthalmic aqueous
timolol
Prior art date
Application number
PCT/IB2017/054963
Other languages
French (fr)
Inventor
Timo Reunamäki
Olli Oksala
Päivi Alajuuma
Jukka Lokkila
Pertti Pellinen
Minna JÄRVINEN
Original Assignee
Santen Pharmaceutical Co., Ltd.
Asahi Glass Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd., Asahi Glass Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO2018033854A1 publication Critical patent/WO2018033854A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to an improved ophthalmic aqueous composition containing tafluprost, to an improved ophthalmic aqueous composition containing tafluprost and timolol, and to methods for treating ocular hypertension and glaucoma by administering said compositions to subjects in need of such treatment.
  • a further object of the invention is a method for improving local tolerability and for reducing unnecessary systemic exposure of an ophthalmic composition comprising tafluprost, particularly a method for lowering conjunctival hyperemia and for reducing the periorbital skin pigmentation of an ophthalmic composition comprising tafluprost.
  • Another object of the invention is a method for improving local tolerability and for lowering systemic adverse effects of an ophthalmic composi- tion comprising tafluprost and timolol.
  • Glaucoma is an eye disorder characterized by optic nerve damage and progressive visual field loss in which one cause is abnormally elevated intraocular pressure (IOP). Because the optic nerve damage and visual field loss is generally considered to be irreversible, glaucoma therapy primarily focuses on reduction and control of IOP over an extended period of time.
  • Prostaglandin F2a (PGF2a) analogues have been widely used for the treatment of glaucoma and ocular hypertension because of their effectiveness in lowering IOP.
  • PGF2a analogues include for example latanoprost, tafluprost, isopropyl unoprostone, travoprost and bimatoprost.
  • Tafluprost is a new-generation, fluorinated PGF2a isopropyl ester analogue that promotes the uveoscelar outflow of aqueous humor, making the com- pound a potent ocular hypotensive agent (EP 0850 926).
  • a concentration of PGF2a analogues used for a treatment of glaucoma is very low due to their high affinity for the prostanoid FP receptor (FP), which is expressed in human ocular tissues such as the ciliary body and sclera.
  • FP prostanoid FP receptor
  • the effective concentration of tafluprost of about 0.0015% (w/v) in an ophthalmic composition has been found to be sufficient for the treatment of ocular hypertension and glaucoma.
  • tafluprost is effective in low amounts, there is still a need to reduce that minor amount to its effective minimum in order to avoid any local adverse effects to the eye and concurrent- ly reduce the systemic exposure to the drug substance.
  • EP 1916002 discloses eye drops containing a thermally unstable medicament (latanoprost) wherein an organic amine such as trometamol is added to prevent the degradation of the medicament.
  • EP 2269575 relates to a method for improving ocular bioavailability of preservative-free latanoprost in an aqueous eye drop composition wherein an organic amine is included in the composition.
  • PGF2a analogues Since almost all PGF2a analogues are practically insoluble in water, nonionic surfactants have been added to ophthalmic formulations to solubilize the prostaglandin in the solution and to prevent it from being adsorbed to container walls (EP 1321144).
  • Preservatives such as benzalkonium chloride (BAK), which exhibit sufficient antimicrobial effect on bacteria and fungi, have traditionally been used in ophthalmic compositions.
  • preservatives are also known to have detrimental effects on ocular surface and also not pre- ferred in the treatment of ophthalmic disorders in children, preservative free ophthalmic solutions have recently been developed.
  • a preservative free ophthalmic aqueous solution comprising PGF2a analogue as an active ingredient has been disclosed in EP 2306977.
  • Carboxy vinyl polymers have been used particularly in ophthalmic gel compositions for increasing the viscosity of the composition in order to provide a longer contact time with the cornea of the eye.
  • the amount of polymer in the composition rather than the viscosity has been found important from the point of view of obtaining good absorption of a drug into the eye (EP 0752847).
  • ophthalmic administration of prostaglandin analogues including tafluprost has some disadvantageous local effects such as conjunctival hyperemia (redness) and periorbital skin pigmentation which seem to be dose related. Lowering the tafluprost concentration from 0.0015% would decrease these adverse effects resulting in improved quality of life of the patients.
  • tafluprost concentration dependent conjunctival hyperemia has been found in clinical trials, i.e. incidence of more severe hyperemia has been found to increase in accordance with increased tafluprost concentration.
  • the risk of any systemic adverse effects can be minimized if the amount of tafluprost in the ophthalmic solution could be lowered.
  • the amount of the active agent in an eye drop composition is lowered, a sufficient penetration may become critical or impossible to achieve.
  • Timolol is a nonselective beta-adrenergic receptor antagonist, indicated in its ophthalmic form to treat open-angle glaucoma and ocular hypertension by reducing aqueous humor production through blockage of ⁇ -receptors.
  • Combinations of timolol and various PGF2a analogues have in recent years been approved for glaucoma treatment since they significantly improve IOP reduction in comparison to monotherapy.
  • PGF2a analogues have in recent years been approved for glaucoma treatment since they significantly improve IOP reduction in comparison to monotherapy.
  • FDC fixed dose combinations
  • Ophthalmic compositions comprising timolol and a prostaglandin analogue have been disclosed for example in EP 0286903.
  • a composition comprising timolol and bimatoprost has been disclosed in EP 1392319.
  • an ophthalmic composition comprising timolol and dorzolamide (a carbonic anhydrase inhibitor) is disclosed.
  • EP 1496912 relates to an ophthalmic composition of timolol maleate and brimonidine tartrate (an a-adrenergic agent).
  • tafluprost and timolol comprising 0.0015% tafluprost and 0.5%) timolol and dosed once daily is currently commercially available for ophthalmic use.
  • 0.5% timolol when administered topically onto the eye, causes potentially serious systemic adverse effects due to blockage of ⁇ -receptors, such as lowering of blood pressure and decreased heart rate.
  • Systemically absorbed timolol from ophthalmic preparations may also cause severe respiratory problems in the patients suffering from bronchial hyperactivity or asthma.
  • Timolol 0.1%) viscous eye gel is also commercially available. It has been reported to decrease the IOP about as effectively as timolol 0.5% eye drops dosed twice daily (Rouland et al 2002). Yet, the administration of 0.1%> timolol eye gel leads to lower plasma timolol concentrations and cardiac toxicity compared to 0.5% timolol eye drops (Nino et al 2002, Uusitalo et al 2005, Uusitalo et al 2006). However, no fixed dose combination with timolol 0.1% is commercially available. Frequently in the treatment of glaucoma, the intraocular pressure cannot be adequately controlled with a single ocular hypotensive agent.
  • Efficacy of timolol 0.1 % gel and a prostaglandin analogue (latanoprost, travoprost or bimatoprost) in an unfixed combination versus a commercial fixed combination of respective prostaglandin and timolol 0.5% has been investigated in a study by Nucci et al (2013). It was found that the prostaglandins and 0.1% timolol seemed to be more effective in glaucoma treatment when administered as unfixed combinations once a day in the evening and in the morning, respectively, compared to fixed combinations, which were administered once a day in the evening. However, a combined regimen of two medicines at 12 hours apart may challenge the degree of adherence of the patient to a prescribed treatment. It has been shown that adding a second medication may even decrease adherence to the first medication (Robin and Covert 2005).
  • Quaranta et al. (2013) performed a meta-analysis of 18 prospective randomized clinical studies comparing fixed combinations of prostaglandin analogues and timolol to prosta- gladin monotherapy or to the two medications taken as an unfixed combination in separate bottles.
  • the fixed-combination therapies were associated with significantly lower hyperemia risk ratio (RR) of 0.61 (95% confidence interval [CI]: 0.53-0.70) (Quaranta et al 2013).
  • RR hyperemia risk ratio
  • the novel tafluprost formulation according to the invention which comprises a lower concentration of the active ingredient than the currently commercially available product is preservative-free and has a low viscosity, which makes the product more user friendly to glaucoma patients.
  • tafluprost oph- thalmic solution which comprises a lower concentration of the active ingredient than the currently commercially available product.
  • the present invention relates to an ophthalmic aqueous solution for treating ocular hyper- tension and glaucoma comprising tafluprost in an aqueous solution, which also contains a polyacrylic acid and is substantially preservative-free.
  • the present invention also relates to an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost in an aqueous solution, which also con- tains an organic amine, a polyacrylic acid, and substantially no preservatives.
  • the present invention also relates to an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost and timolol in an aqueous solution which also contains a polyacrylic acid, a nonionic surfactant, tonicity agent(s) and substantially no preservatives.
  • the present invention also relates to a method for treating ocular hypertension and glaucoma, which method comprises administering a preservative-free ophthalmic aqueous solution comprising tafluprost as active ingredient thereof to a subject in need of said treat- ment, wherein the ophthalmic aqueous solution further comprises polyacrylic acid, and substantially no preservatives.
  • the present invention also relates to a method for treating ocular hypertension and glaucoma, which method comprises administering an ophthalmic aqueous solution comprising tafluprost as active ingredient thereof to a subject in need of said treatment, wherein the ophthalmic aqueous solution further comprises an organic amine, a polyacrylic acid, and substantially no preservatives.
  • the present invention also relates to a method for treating ocular hypertension and glau- coma, which method comprises administering an ophthalmic aqueous solution comprising tafluprost and timolol as active ingredients thereof to a subject in need of said treatment, wherein the ophthalmic aqueous solution further comprises a polyacrylic acid, a nonionic surfactant, tonicity agent(s) and substantially no preservatives.
  • the present invention relates to a method for improving local tolerability and for reducing unnecessary systemic exposure of an ophthalmic composition comprising tafluprost for treatment of ocular hypertension and glaucoma, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution containing significantly lower amounts of tafluprost than conventional formulations, the solution further comprising an organic amine and a polyacrylic acid, and administering the composition to a subject in need of such treatment.
  • the present invention also relates to a method for improving local tolerability and for low- ering systemic adverse effects of an ophthalmic composition comprising tafluprost and timolol for treatment of ocular hypertension and glaucoma, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution containing significantly lower amounts of tafluprost and timolol than conventional fixed dose combinations, the solution further comprising polyacrylic acid, nonionic surfactant and tonicity agent(s), and administering the composition to a subject in need of such treatment.
  • a further object of the invention is to provide a method for lowering conjunctival hyperemia and for reducing the periorbital skin pigmentation which are connected to the administration of tafluprost containing ophthalmic solutions, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution containing significantly lower amounts of tafluprost than conventional formulations, the solution further comprising an organic amine and a polyacrylic acid, and administering the composition to a subject in need of such treatment.
  • Figure 5A and Figure 5B show results of an ocular penetration study disclosed in Example 3.
  • Figure 5 A the amount of tafluprost acid in aqueous humor of rabbits after administration of Formulation I according to the invention or commercial Taflotan ® PF eye drops (preservative-free 0.0015% tafluprost) is shown.
  • Figure 5B shows the amount of tafluprost acid in aqueous humor of rabbits after administration of Formulation II according to the invention or commercial Taflotan ® PF eye drops.
  • Figure 6 shows intraocular pressure (IOP) after a single topical administration in rats when a composition according to the invention (Formulation I) was used in comparison with commercial Taflotan ® PF eye drops (preservative-free 0.0015% tafluprost).
  • Figure 8 shows results of an ocular penetration study of Tafluprost 0.0005%-Timolol 0.1% FDC (fixed dose combination) eye drops compared to commercial product Taflotan ® PF eye drops (preservative-free 0.0015% tafluprost).
  • Figure 9 shows redness differences in the eye after a single instillation of test and reference products during one day in Part 1 of an irritation test disclosed in Example 8, comparing the tafluprost-timolol composition according to the invention and currently commercially available fixed dose combination of Tafluprost and Timolol.
  • Figure 10 shows redness differences in the eye after ten consecutive instillations in 30 minute intervals during one day in Part II of an irritation test disclosed in Example 8, comparing the tafluprost-timolol composition according to the invention and currently commercially available fixed dose combination of Tafluprost and Timolol.
  • substantially no preservatives or “preservative-free” means that the solution contains no preservatives, or the solution contains preservatives at a concentration that is undetectable or does not provide a preservative effect.
  • preservatives in oph- thalmic solutions include for example benzalkonium chloride (BAK), chlorhexidine gluconate, benzethonium chloride, sorbic acid, potassium sorbate, ethyl p-hydroxybenzoate and butyl p-hydroxybenzoate.
  • prostaglandin includes, without limitation, natural prostaglandins, prostaglan- din analogues, prostaglandin derivatives or any combinations thereof.
  • one of the objects of the present invention is an ophthalmic aqueous solu- tion for treating ocular hypertension and glaucoma comprising tafluprost in a solution which contains polyacrylic acid and is substantially preservative-free.
  • a further object of the present invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost in a solution which also contains an organic amine, polyacrylic acid, and substantially no preservatives. More specifically, one object of the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising
  • a preferred amount of tafluprost in the ophthalmic aqueous solution according to the invention is from 0.0003% to 0.0008%), preferably 0.00075%.
  • Another object of the present invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost and timolol in a solution which also contains polyacrylic acid, nonionic surfactant, tonicity agent(s) and substantially no preservatives. More specifically, one object of the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising
  • concentrations of the active agents in the novel formulations according to the invention are significantly lower compared to the currently commercially available tafluprost formulation or the currently commercially available fixed dose combination of tafluprost and timolol.
  • concentration of tafluprost from the composition according to the invention is almost equivalent to and results in equivalent IOP reducing effect as a commercial tafluprost product although the concentration of tafluprost in the composition according to the invention is only half of that of the commercial product.
  • the systemic exposure of tafluprost is half of that of the commercial tafluprost product.
  • the ocular penetration of tafluprost from the tafluprost-timolol composition according to the invention is equivalent to that of a commercial tafluprost product although the concentration of tafluprost in the tafluprost-timolol composition according to the invention is only one third of that of the commercial combination product. Also the concentration of timolol can be decreased to one fifth of that of the commercial combination product without losing the therapeutical effect.
  • the lower active ingredient concentrations provide less local and systemic adverse effects and reduced systemic exposure which is beneficial for the patient during long-term, even life-long treatment. Furthermore, the low viscosity of the products makes the manufacturing process simple and cost effective. Additionally, low viscosity of the solution as well as the non-newtonian characteristics of polyacrylic acid improve the local tolerability and make the compositions more user friendly. The lower active ingredient concentrations also bring savings in the API costs.
  • the formulations according to the invention with a low tafluprost concentration effectively reduced conjunctival hyperemia compared to a commercial tafluprost product.
  • a further advantage of the ophthalmic aqueous solutions according to the invention is that they alleviate symptoms of keratoconjunctivitis sicca (dry eye syndrome).
  • dry eye syndrome Several glaucoma patients suffer from dry eye syndrome and while the compositions according to the invention reduce ocular hypertension, they also alleviate the symptoms relating to dry eye syndrome, such as burning, itching, sandy-gritty feeling, redness and eye irritation.
  • Poly- acrylic acid (carboxy vinyl polymer, carbomer) used in the compositions according to the invention provides the formulations with properties needed in the treatment of keratocon- juctivitis sicca.
  • the organic amine in the ophthalmic aqueous tafluprost solution according to the invention is a water-soluble organic amine, examples of which include organic amines having a hy- droxyl group.
  • Organic amines having a hydroxyl group include for example monoethano- lamine, diethanolamine, triethanolamine, trometamol and meglumine.
  • a preferred organic amine is trometamol.
  • a preferred amount of the organic amine in the ophthalmic aqueous solution according to the invention depends on the particular organic amine and may vary for example from 0.02 to 0.08%, preferably from 0.04 to 0.06%. For example in the case of trometamol the preferred amount is approximately 0.04-0.06%), preferably about 0.05%>.
  • the polyacrylic acid in the compositions and methods according to the invention is typically a high molecular polyacrylic acid polymer, which are known as carbomers.
  • Carbomers are available at different molecular weights, densities and crosslinkage levels, for example under the trade name Carbopol.
  • the polyacrylic acid or carbomer is used for example in an amount of 0.005 - 0.07%, such as 0.005 - 0.04%, or preferably 0.01 - 0.03%).
  • a preferred amount depends on the particular carbomer and is for example in the case of Carbopol 981 F about 0.01%.
  • the polyacrylic acid or carbomer is used in an amount of 0.1 - 0.5%, preferably 0.2 - 0.4%.
  • a preferred amount depends on the particular carbomer and is for example in the case of Carbopol 98 INF about 0.3%.
  • the amount of tafluprost in the ophthalmic tafluprost solution according to the invention is from 0.0001 to 0.0010%, preferably from 0.0003 to 0.0008%.
  • a preferred amount of tafluprost in the ophthalmic tafluprost composition according to the invention is 0.00075%).
  • the amount of tafluprost in the ophthalmic tafluprost-timolol solution according to the invention is from 0.0001 to below 0.0010%, preferably from 0.0003 to 0.00075%.
  • a preferred amount of tafluprost in the ophthalmic tafluprost-timolol composition according to the invention is 0.0005%.
  • timolol in the composition according to the invention is timolol male- ate but also timolol hemihydrate can be used.
  • the amount of timolol may vary from 0.075 to 0.15%) and is most preferably 0.1%.
  • nonionic surfactants are added to the ophthalmic solution according to the invention, particularly to an ophthalmic solution comprising tafluprost and timolol, for their solubilizing effect and to prevent the absorption of tafluprost to the resinous walls of the container.
  • nonionic surfactants are polyoxyethylene fatty esters such as polysorbate 80 [poly(oxyethylene) sorbitan monooleate], polysorbate 60 [poly(oxyethylene)sorbitan monostearate], polysorbate 40
  • poly(oxyethylene)sorbitan monopalmitate poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate and polysorbate 65
  • polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50 and polyoxyethylene hydrogenated castor oil 60
  • polyoxyethylene polyoxy- propylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol [Pluronic F68], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], polyoxyethylene (54) polyoxypropylene (39) glycol [Pluronic P85], polyoxyethylene (196) polyoxypropylene (67) glycol [Pluronic F127] and polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L-44], polyoxyl 40 stearate and sucrose fatty esters.
  • the nonionic surfac- tants can be used solely or in combination.
  • a preferred example of the nonionic surfactants is polysorbate 80 [poly(oxyethylene)sorbitan monooleate].
  • Other preferred nonionic surfactants are polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate.
  • the amount of nonionic surfactant(s) in the ophthalmic solution according to the inven- tion can be chosen depending on the amount of tafluprost and timolol and the specific surfactants) and is within the skill of a person in the art.
  • the concentration is for example in the range of 0.001 to 0.01% (w/v), even more preferably 0.002 to 0.006%, and most preferably about 0.005%. It has also been found that a too high concentration of the nonionic surfactant has an irritative effect on the cornea-conjunctival epithe- Hum layer and an adverse effect on the ocular bioavailability of prostaglandin from the ophthalmic solution.
  • an upper limit of 0.5% of the nonionic surfactant polysorbate 80 should not be exceeded.
  • the ophthalmic aqueous tafluprost-timolol solution according to the invention may contain a water-soluble organic amine, examples of which include the organic amines mentioned above.
  • the ophthalmic tafluprost-timolol solution according to the invention may also contain tonicity agents.
  • suitable tonicity agents are glycerol, sorbitol, mannitol and other sugar alcohols, propylene glycol, sodium chloride, potassium chloride and calcium chloride.
  • a preferred tonicity agent is glycerol.
  • the amount of tonicity agent depends on the particular tonicity agent in question and the other components of the formulation. In the case of glycerol, a preferred amount is approximately 0.1%.
  • the required tonicity may also be effected by using a buffer system which is strong enough to provide tonicity and at the same time adjusts the pH to the desired level.
  • stabilizing agents in the ophthalmic solutions according to the invention is not required but the composition may also contain stabilizing agents to inhibit decomposi- tion of tafluprost in the ophthalmic solution. If stabilizing agents are used, preferred examples of stabilizing agents are ethylenediaminetetraacetic acid and salts thereof, such as disodium edetate, and dibutylhydroxytoluene.
  • stabilizing agents such as sodium nitrite, ascorbic acid, L-ascorbic acid stearate, sodium hydrogensulfite, alphathioglyc- erin, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol acetate, potassium di- chloroisocyanurate, 2,6-di-t-butyl-4-methylphenol, soybean lecithin, sodium thioglycollate, sodium thiomalate, natural vitamin E, tocopherol, ascorbyl pasthyminate, sodium pyrosul- fite, butylhydroxyanisole, 1,3-butylene glycol, pentaerythtyl tetrakis[3-(3,5-di-t-butyl-4- hydroxyphenyl)]propionate, propyl gallate, 2-mercaptobenzimidazole and oxyquinoline sulphate, may be used.
  • stabilizing agents such as sodium nitrite, ascorbic
  • the amount of stabilizing agents in the ophthalmic solutions according to the invention can be selected depending on the specific stabilizing agent and is within the skill of a person in the art.
  • the concentration is usually 0.005 to 0.2% (w/v), preferably 0.01 to 0.1%, even more preferably about 0.05%.
  • the ophthalmic solutions according to the invention may also comprise conventional ex- cipients used in ophthalmic compositions, such as buffering agents, solvents, pH adjusters, and the like.
  • buffering agents include but are not limited to sodium dihydrogen phosphate dihydrate, boric acid, borax, citric acid, or ⁇ -aminocaproic acid.
  • the pH of the ophthalmic aqueous solutions according to the invention is preferably from 4 to 8, for example from 6 to 7,5, preferably about 7.
  • pH adjusters common pH adjusting agents such as sodium hydroxide and/or hydrochloric acid may be used.
  • Containers for packaging and storing the aqueous ophthalmic solution according to the invention include all container forms suitable for user-friendly topical ophthalmic deliver ⁇ '. Consequently, the containers may be selected for example from the group consisting of bottles, tubes, ampoules, pipettes and fluid dispensers, in single unit dose form or in multi- dose form. According to a preferred embodiment of the invention, the aqueous ophthalmic solution is in a single dose or unit dose form.
  • a unit dose ophthalmic container manufactured by blow moulding method has a volume of about 1 ml and about 0.2 to 0.5 ml of solution is filled.
  • the material of the container consists essentially of polyethylene.
  • the container material may contain minor amounts of other materials than polyethylene, for example polypropylene, polyethylene terephthalate, polyvinyl chloride, acrylic resins, polystyrene, polymethyl methacrylate and nylon 6.
  • the amount of said materials is preferably no more than about 5 to 10% of the total container material.
  • Polyethylene is classified to several types by the density thereof, namely low density polyethylene (LDPE), middle density polyethylene (MDPE), high density polyethylene (HDPE), etc and these poly ethylenes are included in this invention.
  • a preferred polyethylene is LDPE.
  • a preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
  • a preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which consists essentially of
  • a further preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
  • a further preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which consists essentially of
  • Another preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
  • a further preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
  • nonionic surfactant Polysorbate 80
  • tonicity agent glycerol
  • buffering agents and pH adjusters conventionally used in ophthalmic solutions.
  • Example 1 Formulations containing tafluprost
  • tafluprost compositions according to the invention were compared to that of the currently commercially available tafluprost formulation (Taflotan ® PF 15 ⁇ g/ml eye drops) in rabbits.
  • Taflotan ® preservative-free eye drops contain 0.0015% tafluprost and the following excipi- ents: Glycerol
  • the rabbits were assigned to three treatment groups and a reference (control) group, 6 rabbits in each group, by block randomization based on body weights.
  • Part I (10 doses during one day)
  • Treatment group I Tafluprost 7.5 ⁇ g/ml eye drops (Formulation I of Example 1) was applied 10 times at 30 min intervals during one day.
  • Treatment group II Tafluprost 7.5 ⁇ g/ml eye drops (Formulation II of Example 1) was applied 10 times at 30 min intervals during one day.
  • Treatment group III Tafluprost 7.5 ⁇ g/ml eye drops (Formulation III of Example 1) was applied 10 times at 30 min intervals during one day.
  • the upper eyelid of the left/right eye was extended and 30 ⁇ of the test product or the reference product was instilled with a micropipette dorsally on the bulbar conjunctiva. The dose was applied into one eye and the fellow eye of each rabbit remained as a non-treated control.
  • Parts I and II There was a wash-out period of one week between Parts I and II.
  • the treatment groups were the same as in Part I, but the formulations were applied once during one day. Administration was as defined for Part I. Macroscopic examinations were made at 0.5, 2 and 4 hours post-dose on Day 1 and once on Day 2 (approximately 24 hours post-dose).
  • the formulation according to the invention with a low tafluprost concentration reduces conjunctival hyperemia.
  • test product I The ocular penetration of tafluprost compositions according to the invention was compared to commercial preservative-free Taflotan ® eye drops (0.0015% tafluprost).
  • the tested compositions according to the invention were Formulation I (test product I) and Formulation II (test product II) disclosed in Example 1.
  • Taflotan ® preservative-free eye drops contain 0.0015% tafluprost and the following excipi- ents: Glycerol Sodium dihydrogen phosphate dihydrate
  • NZW male rabbits were used in Parts I and II of the study. The rabbits were assigned to three groups with 4 rabbits in each group.
  • test product I Part I
  • test product II Part II
  • Aqueous humor samples were collected at 0.5, 1 and 2 hours post-dose from anaesthetized animals.
  • Tafluprost acid was analyzed using LC-MS/MS. Results are shown in Figures 5 A and 5B.
  • the improved tafluprost formulation according to the invention thus provides a practically comparative corneal penetration and less harmful ocular effects including conjunctival hyperemia compared to the commercial preservative-free Taflotan ® eye drops (0.0015% tafluprost).
  • Spraque Dawley rats were used to study the effects of ophthalmic solutions on the intraocular pressure (IOP).
  • the test product according to the invention was Formulation I disclosed in Example 1.
  • Reference product was commercial preservative-free Taflotan ® eye drops (0.0015% tafluprost).
  • the test solutions were dosed topically as a single instillation of 10 ⁇ of the test product onto one eye and 10 ⁇ of the reference product onto the other eye of the rat. Twelve Spra- gue Dawley male rats were used in the study.
  • IOP was measured with a TonoLab rebound tonometer prior to dosing (0 h) and at 0, 2, 4, 6 and 8 hours after the dosing.
  • composition according to the invention was Formulation IV disclosed in Example 1.
  • Tafluprost acid concentrations in the rabbit plasma at different time points are illustrated in Figure 7. It can be seen that tafluprost acid concentrations in the plasma are proportional to the tafluprost concentration in the eye drops. Tafluprost acid concentration in the plasma following topical application of tafluprost 7.5 ⁇ g/ml eye drops is about half of that after administration of tafluprost 15 ⁇ g/ml eye drops. This indicates that, differently from local ocular penetration, the new tafluprost formulation does not seem to have any effect on systemic absorption of tafluprost after topical administration.
  • Example 6 A formulation comprising tafluprost and timolol
  • Taflotan ® preservative-free eye drops contain 0.0015% tafluprost and the following excipi- ents:
  • the ocular irritation effect of the tafluprost-timolol composition according to the invention was compared to that of the currently commercially available tafluprost-timolol fixed dose combination in rabbits.
  • a total of 12 male rabbits were chosen for the experiment based on careful macroscopic ophthalmic examination. Animals showing any eye irritation or pre-existing corneal injury were excluded from the study. Scoring of conjunctival redness, chemosis and discharge were done according to the modified Draize scoring method. After the ophthalmic examinations, the rabbits were assigned to one treatment group or one reference group, 6 rabbits in each, by block randomization based on body weights.
  • composition of the test product :
  • Tafluprost 0.0015% - Timolol 0.5% eye drops brand name Taptiqom
  • Polysorbate 80 q.s.
  • Test group Preservative-free Tafluprost 0.0005% - Timolol 0.1% eye drops, a single instillation during one day
  • the upper eyelid of the left/right eye was extended and 30 ⁇ of the test product or the reference product was instilled with a micropipette dorsally on the bulbar conjunctiva. Observations, examinations and measurements:
  • the day of administration was defined as Day 1.
  • the following observation and examination days after Day 1 were Days 2 and 3.
  • Test group Preservative-free Tafluprost 0.0005% - Timolol 0.1% eye drops, 10 consecutive instillations at 30 minute intervals during one day

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Abstract

The present invention relates to an improved ophthalmic aqueous composition containing tafluprost, to an improved ophthalmic aqueous composition containing tafluprost and timolol, and to a method for treating ocular hypertension and glaucoma by administering said compositions to subjects in need of such treatment. A further object of the invention is a method for improving local tolerability and for reducing unnecessary systemic exposure of an ophthalmic composition comprising tafluprost. Another object of the invention is a method for improving local tolerability and for lowering systemic adverse effects of an ophthalmic composition comprising tafluprost and timolol.

Description

Ophthalmic composition and a method for treating ocular hypertension and glaucoma
Technical field of the invention
The present invention relates to an improved ophthalmic aqueous composition containing tafluprost, to an improved ophthalmic aqueous composition containing tafluprost and timolol, and to methods for treating ocular hypertension and glaucoma by administering said compositions to subjects in need of such treatment. A further object of the invention is a method for improving local tolerability and for reducing unnecessary systemic exposure of an ophthalmic composition comprising tafluprost, particularly a method for lowering conjunctival hyperemia and for reducing the periorbital skin pigmentation of an ophthalmic composition comprising tafluprost. Another object of the invention is a method for improving local tolerability and for lowering systemic adverse effects of an ophthalmic composi- tion comprising tafluprost and timolol.
Background of the invention
Glaucoma is an eye disorder characterized by optic nerve damage and progressive visual field loss in which one cause is abnormally elevated intraocular pressure (IOP). Because the optic nerve damage and visual field loss is generally considered to be irreversible, glaucoma therapy primarily focuses on reduction and control of IOP over an extended period of time. Prostaglandin F2a (PGF2a) analogues have been widely used for the treatment of glaucoma and ocular hypertension because of their effectiveness in lowering IOP. Known PGF2a analogues include for example latanoprost, tafluprost, isopropyl unoprostone, travoprost and bimatoprost. Tafluprost is a new-generation, fluorinated PGF2a isopropyl ester analogue that promotes the uveoscelar outflow of aqueous humor, making the com- pound a potent ocular hypotensive agent (EP 0850 926).
A concentration of PGF2a analogues used for a treatment of glaucoma is very low due to their high affinity for the prostanoid FP receptor (FP), which is expressed in human ocular tissues such as the ciliary body and sclera. For example, the effective concentration of tafluprost of about 0.0015% (w/v) in an ophthalmic composition has been found to be sufficient for the treatment of ocular hypertension and glaucoma. However, although tafluprost is effective in low amounts, there is still a need to reduce that minor amount to its effective minimum in order to avoid any local adverse effects to the eye and concurrent- ly reduce the systemic exposure to the drug substance.
Organic amines have been used in several ophthalmic compositions, mostly as buffers and pH adjusting agents. EP 1916002 discloses eye drops containing a thermally unstable medicament (latanoprost) wherein an organic amine such as trometamol is added to prevent the degradation of the medicament. EP 2269575 relates to a method for improving ocular bioavailability of preservative-free latanoprost in an aqueous eye drop composition wherein an organic amine is included in the composition.
Since almost all PGF2a analogues are practically insoluble in water, nonionic surfactants have been added to ophthalmic formulations to solubilize the prostaglandin in the solution and to prevent it from being adsorbed to container walls (EP 1321144). Preservatives such as benzalkonium chloride (BAK), which exhibit sufficient antimicrobial effect on bacteria and fungi, have traditionally been used in ophthalmic compositions. However, since preservatives are also known to have detrimental effects on ocular surface and also not pre- ferred in the treatment of ophthalmic disorders in children, preservative free ophthalmic solutions have recently been developed. A preservative free ophthalmic aqueous solution comprising PGF2a analogue as an active ingredient has been disclosed in EP 2306977.
Carboxy vinyl polymers have been used particularly in ophthalmic gel compositions for increasing the viscosity of the composition in order to provide a longer contact time with the cornea of the eye. However, the amount of polymer in the composition rather than the viscosity has been found important from the point of view of obtaining good absorption of a drug into the eye (EP 0752847). As stated above, ophthalmic administration of prostaglandin analogues including tafluprost has some disadvantageous local effects such as conjunctival hyperemia (redness) and periorbital skin pigmentation which seem to be dose related. Lowering the tafluprost concentration from 0.0015% would decrease these adverse effects resulting in improved quality of life of the patients. For example, tafluprost concentration dependent conjunctival hyperemia has been found in clinical trials, i.e. incidence of more severe hyperemia has been found to increase in accordance with increased tafluprost concentration. Also the risk of any systemic adverse effects can be minimized if the amount of tafluprost in the ophthalmic solution could be lowered. However, when the amount of the active agent in an eye drop composition is lowered, a sufficient penetration may become critical or impossible to achieve.
Timolol is a nonselective beta-adrenergic receptor antagonist, indicated in its ophthalmic form to treat open-angle glaucoma and ocular hypertension by reducing aqueous humor production through blockage of β-receptors. Combinations of timolol and various PGF2a analogues have in recent years been approved for glaucoma treatment since they significantly improve IOP reduction in comparison to monotherapy. However, as therapy with multiple drugs usually requires frequent doses and complicated dosing schedule, it has been found advantageous to combine two or more types of IOP-lowering drugs in a single formulation (fixed dose combinations, FDC).
Ophthalmic compositions comprising timolol and a prostaglandin analogue have been disclosed for example in EP 0286903. A composition comprising timolol and bimatoprost has been disclosed in EP 1392319. In EP 0509702, an ophthalmic composition comprising timolol and dorzolamide (a carbonic anhydrase inhibitor) is disclosed. EP 1496912 relates to an ophthalmic composition of timolol maleate and brimonidine tartrate (an a-adrenergic agent).
A fixed dose combination of tafluprost and timolol comprising 0.0015% tafluprost and 0.5%) timolol and dosed once daily is currently commercially available for ophthalmic use. However, it is known that in some patients 0.5% timolol, when administered topically onto the eye, causes potentially serious systemic adverse effects due to blockage of β-receptors, such as lowering of blood pressure and decreased heart rate. Systemically absorbed timolol from ophthalmic preparations may also cause severe respiratory problems in the patients suffering from bronchial hyperactivity or asthma.
Timolol 0.1%) viscous eye gel, dosed once daily, is also commercially available. It has been reported to decrease the IOP about as effectively as timolol 0.5% eye drops dosed twice daily (Rouland et al 2002). Yet, the administration of 0.1%> timolol eye gel leads to lower plasma timolol concentrations and cardiac toxicity compared to 0.5% timolol eye drops (Nino et al 2002, Uusitalo et al 2005, Uusitalo et al 2006). However, no fixed dose combination with timolol 0.1% is commercially available. Frequently in the treatment of glaucoma, the intraocular pressure cannot be adequately controlled with a single ocular hypotensive agent. Efficacy of timolol 0.1 % gel and a prostaglandin analogue (latanoprost, travoprost or bimatoprost) in an unfixed combination versus a commercial fixed combination of respective prostaglandin and timolol 0.5% has been investigated in a study by Nucci et al (2013). It was found that the prostaglandins and 0.1% timolol seemed to be more effective in glaucoma treatment when administered as unfixed combinations once a day in the evening and in the morning, respectively, compared to fixed combinations, which were administered once a day in the evening. However, a combined regimen of two medicines at 12 hours apart may challenge the degree of adherence of the patient to a prescribed treatment. It has been shown that adding a second medication may even decrease adherence to the first medication (Robin and Covert 2005).
Quaranta et al. (2013) performed a meta-analysis of 18 prospective randomized clinical studies comparing fixed combinations of prostaglandin analogues and timolol to prosta- gladin monotherapy or to the two medications taken as an unfixed combination in separate bottles. Compared to monotherapy with a prostaglandin analogue, the fixed-combination therapies were associated with significantly lower hyperemia risk ratio (RR) of 0.61 (95% confidence interval [CI]: 0.53-0.70) (Quaranta et al 2013). To conclude, it seems that timolol protects the eye from the well known adverse effect of hyperemia caused by prostaglandins.
Yet it would be advantageous to provide the patients with improved and effective treatment of ocular hypertension and glaucoma, with reduced local and systemic side effects compared to the current treatment employed and also with better patient compliance, particularly compared to unfixed combinations of tafluprost and timolol.
It has now been found out that it is possible to lower the concentration of the active ingredient tafluprost compared to the currently available commercial tafluprost composition, resulting in reduction of local and systemic side effects as well as decreased drug concentration in circulation without a need to change dosage regimen or without losing the de- sired therapeutic effect. Moreover, the novel tafluprost formulation according to the invention which comprises a lower concentration of the active ingredient than the currently commercially available product is preservative-free and has a low viscosity, which makes the product more user friendly to glaucoma patients.
It has also been found that it is possible to lower the concentrations of the active ingredients in a formulation comprising tafluprost and timolol, compared to the currently available fixed dose combination of tafluprost and timolol, resulting in reduction of the systemic and local side effects without need to change dosage regimen or without losing the desired therapeutic effect. Moreover, the novel fixed dose combination of tafluprost and timolol according to the invention, which comprises lower concentrations of active ingredients than the currently commercially available combination products, is preservative-free and has low viscosity which provides further advantages for glaucoma patients. It is therefore an object of the present invention to provide an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, comprising tafluprost in an aqueous solution which comprises a polyacrylic acid and is substantially preservative-free.
It is another object of the present invention to provide an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost in an aqueous solution which comprises an organic amine, a polyacrylic acid and substantially no preservatives.
It is another object of the invention to provide an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost and timolol in an aqueous solu- tion which also contains a polyacrylic acid, a nonionic surfactant, tonicity agent(s) and substantially no preservatives.
It is a further object of the present invention to provide a method for lowering local ocular and systemic side effects of tafluprost by providing a novel composition of tafluprost oph- thalmic solution, which comprises a lower concentration of the active ingredient than the currently commercially available product. Particularly it is an object of the present invention to provide a method for lowering conjunctival hyperemia and periorbital skin pigmentation which is connected to the administration of tafluprost containing ophthalmic aqueous solutions. Summary of the invention
The present invention relates to an ophthalmic aqueous solution for treating ocular hyper- tension and glaucoma comprising tafluprost in an aqueous solution, which also contains a polyacrylic acid and is substantially preservative-free.
The present invention also relates to an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost in an aqueous solution, which also con- tains an organic amine, a polyacrylic acid, and substantially no preservatives.
The present invention also relates to an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost and timolol in an aqueous solution which also contains a polyacrylic acid, a nonionic surfactant, tonicity agent(s) and substantially no preservatives.
The present invention also relates to a method for treating ocular hypertension and glaucoma, which method comprises administering a preservative-free ophthalmic aqueous solution comprising tafluprost as active ingredient thereof to a subject in need of said treat- ment, wherein the ophthalmic aqueous solution further comprises polyacrylic acid, and substantially no preservatives.
The present invention also relates to a method for treating ocular hypertension and glaucoma, which method comprises administering an ophthalmic aqueous solution comprising tafluprost as active ingredient thereof to a subject in need of said treatment, wherein the ophthalmic aqueous solution further comprises an organic amine, a polyacrylic acid, and substantially no preservatives.
The present invention also relates to a method for treating ocular hypertension and glau- coma, which method comprises administering an ophthalmic aqueous solution comprising tafluprost and timolol as active ingredients thereof to a subject in need of said treatment, wherein the ophthalmic aqueous solution further comprises a polyacrylic acid, a nonionic surfactant, tonicity agent(s) and substantially no preservatives. Further, the present invention relates to a method for improving local tolerability and for reducing unnecessary systemic exposure of an ophthalmic composition comprising tafluprost for treatment of ocular hypertension and glaucoma, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution containing significantly lower amounts of tafluprost than conventional formulations, the solution further comprising an organic amine and a polyacrylic acid, and administering the composition to a subject in need of such treatment.
The present invention also relates to a method for improving local tolerability and for low- ering systemic adverse effects of an ophthalmic composition comprising tafluprost and timolol for treatment of ocular hypertension and glaucoma, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution containing significantly lower amounts of tafluprost and timolol than conventional fixed dose combinations, the solution further comprising polyacrylic acid, nonionic surfactant and tonicity agent(s), and administering the composition to a subject in need of such treatment.
A further object of the invention is to provide a method for lowering conjunctival hyperemia and for reducing the periorbital skin pigmentation which are connected to the administration of tafluprost containing ophthalmic solutions, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution containing significantly lower amounts of tafluprost than conventional formulations, the solution further comprising an organic amine and a polyacrylic acid, and administering the composition to a subject in need of such treatment. Brief description of the figures
Figure 1 shows redness differences in the eyes after 10 consecutive instillations during one day in Part I of the ocular irritation study in rabbits disclosed in Example 2, comparing Formulations I, II and III according to the invention and commercially available Taflotan® PF eye drops (preservative-free 0.0015% tafluprost). Redness difference = "score of treated eye" minus "score of non-treated eye".
Figure 2 shows discharge differences in the eyes after 10 consecutive instillations during one day in Part I of the ocular irritation study in rabbits disclosed in Example 2, comparing Formulations I, II and III according to the invention and commercially available Taflotan® PF eye drops (preservative-free 0.0015% tafluprost). Discharge difference = "score of treated eye" minus "score of non-treated eye". Figure 3 shows redness differences in the eyes after a single instillation during one day in Part II of the ocular irritation study in rabbits disclosed in Example 2, comparing Formulations I, II and III according to the invention and commercially available Taflotan® PF eye drops (preservative-free 0.0015% tafluprost). Redness difference = "score of treated eye" minus "score of non-treated eye".
Figure 4 shows discharge differences in the eyes after a single instillation during one day in Part II of the ocular irritation study in rabbits disclosed in Example 2, comparing Formulations I, II and III according to the invention and commercially available Taflotan® PF eye drops (preservative-free 0.0015% tafluprost). Discharge difference = "score of treated eye" minus "score of non-treated eye".
Figure 5A and Figure 5B show results of an ocular penetration study disclosed in Example 3. In Figure 5 A, the amount of tafluprost acid in aqueous humor of rabbits after administration of Formulation I according to the invention or commercial Taflotan® PF eye drops (preservative-free 0.0015% tafluprost) is shown. Figure 5B shows the amount of tafluprost acid in aqueous humor of rabbits after administration of Formulation II according to the invention or commercial Taflotan® PF eye drops.
Figure 6 shows intraocular pressure (IOP) after a single topical administration in rats when a composition according to the invention (Formulation I) was used in comparison with commercial Taflotan® PF eye drops (preservative-free 0.0015% tafluprost).
Figure 7 shows tafluprost acid concentrations in rabbit plasma following a single topical application of 0.00075%) tafluprost composition according to the invention (Formulation IV) or 0.0015%) tafluprost composition (commercial Taflotan® PF eye drops). Blood samples were taken at 5, 20, 40 and 60 minutes after the administration. n=6/time point. Values at 60 min time point represent half of LoQ (5 pg/ml). Figure 8 shows results of an ocular penetration study of Tafluprost 0.0005%-Timolol 0.1% FDC (fixed dose combination) eye drops compared to commercial product Taflotan® PF eye drops (preservative-free 0.0015% tafluprost). Figure 9 shows redness differences in the eye after a single instillation of test and reference products during one day in Part 1 of an irritation test disclosed in Example 8, comparing the tafluprost-timolol composition according to the invention and currently commercially available fixed dose combination of Tafluprost and Timolol. Figure 10 shows redness differences in the eye after ten consecutive instillations in 30 minute intervals during one day in Part II of an irritation test disclosed in Example 8, comparing the tafluprost-timolol composition according to the invention and currently commercially available fixed dose combination of Tafluprost and Timolol. Detailed description of the invention
As used herein, "substantially no preservatives" or "preservative-free" means that the solution contains no preservatives, or the solution contains preservatives at a concentration that is undetectable or does not provide a preservative effect. Common preservatives in oph- thalmic solutions include for example benzalkonium chloride (BAK), chlorhexidine gluconate, benzethonium chloride, sorbic acid, potassium sorbate, ethyl p-hydroxybenzoate and butyl p-hydroxybenzoate.
The term "prostaglandin" includes, without limitation, natural prostaglandins, prostaglan- din analogues, prostaglandin derivatives or any combinations thereof.
Percentages are given as weight/volume (w/v) unless otherwise indicated.
As stated above, one of the objects of the present invention is an ophthalmic aqueous solu- tion for treating ocular hypertension and glaucoma comprising tafluprost in a solution which contains polyacrylic acid and is substantially preservative-free.
A further object of the present invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost in a solution which also contains an organic amine, polyacrylic acid, and substantially no preservatives. More specifically, one object of the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising
(i) tafluprost in an amount of 0.0001 to 0.0010% (w/v);
(ii) organic amine;
(iii) polyacrylic acid;
and substantially no preservatives.
In an embodiment of the invention, a preferred amount of tafluprost in the ophthalmic aqueous solution according to the invention is from 0.0003% to 0.0008%), preferably 0.00075%.
Another object of the present invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising tafluprost and timolol in a solution which also contains polyacrylic acid, nonionic surfactant, tonicity agent(s) and substantially no preservatives. More specifically, one object of the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma comprising
(i) tafluprost in an amount of 0.0001 to 0.0010% (w/v);
(ii) timolol in an amount of 0.075 to 0.15%;
(iii) polyacrylic acid;
(iv) nonionic surfactant;
(v) tonicity agent;
and substantially no preservatives. The concentrations of the active agents in the novel formulations according to the invention are significantly lower compared to the currently commercially available tafluprost formulation or the currently commercially available fixed dose combination of tafluprost and timolol. However, the ocular penetration of tafluprost from the composition according to the invention is almost equivalent to and results in equivalent IOP reducing effect as a commercial tafluprost product although the concentration of tafluprost in the composition according to the invention is only half of that of the commercial product. At the same time the systemic exposure of tafluprost is half of that of the commercial tafluprost product. The ocular penetration of tafluprost from the tafluprost-timolol composition according to the invention is equivalent to that of a commercial tafluprost product although the concentration of tafluprost in the tafluprost-timolol composition according to the invention is only one third of that of the commercial combination product. Also the concentration of timolol can be decreased to one fifth of that of the commercial combination product without losing the therapeutical effect.
The lower active ingredient concentrations provide less local and systemic adverse effects and reduced systemic exposure which is beneficial for the patient during long-term, even life-long treatment. Furthermore, the low viscosity of the products makes the manufacturing process simple and cost effective. Additionally, low viscosity of the solution as well as the non-newtonian characteristics of polyacrylic acid improve the local tolerability and make the compositions more user friendly. The lower active ingredient concentrations also bring savings in the API costs.
As shown in the experimental part, the formulations according to the invention with a low tafluprost concentration effectively reduced conjunctival hyperemia compared to a commercial tafluprost product. A further advantage of the ophthalmic aqueous solutions according to the invention is that they alleviate symptoms of keratoconjunctivitis sicca (dry eye syndrome). Several glaucoma patients suffer from dry eye syndrome and while the compositions according to the invention reduce ocular hypertension, they also alleviate the symptoms relating to dry eye syndrome, such as burning, itching, sandy-gritty feeling, redness and eye irritation. Poly- acrylic acid (carboxy vinyl polymer, carbomer) used in the compositions according to the invention provides the formulations with properties needed in the treatment of keratocon- juctivitis sicca.
The organic amine in the ophthalmic aqueous tafluprost solution according to the invention is a water-soluble organic amine, examples of which include organic amines having a hy- droxyl group. Organic amines having a hydroxyl group include for example monoethano- lamine, diethanolamine, triethanolamine, trometamol and meglumine. A preferred organic amine is trometamol. A preferred amount of the organic amine in the ophthalmic aqueous solution according to the invention depends on the particular organic amine and may vary for example from 0.02 to 0.08%, preferably from 0.04 to 0.06%. For example in the case of trometamol the preferred amount is approximately 0.04-0.06%), preferably about 0.05%>.
The polyacrylic acid in the compositions and methods according to the invention is typically a high molecular polyacrylic acid polymer, which are known as carbomers. Carbomers are available at different molecular weights, densities and crosslinkage levels, for example under the trade name Carbopol.
In the tafluprost composition according to the invention, the polyacrylic acid or carbomer is used for example in an amount of 0.005 - 0.07%, such as 0.005 - 0.04%, or preferably 0.01 - 0.03%). A preferred amount depends on the particular carbomer and is for example in the case of Carbopol 981 F about 0.01%.
In the tafluprost-timolol composition of the invention, the polyacrylic acid or carbomer is used in an amount of 0.1 - 0.5%, preferably 0.2 - 0.4%. A preferred amount depends on the particular carbomer and is for example in the case of Carbopol 98 INF about 0.3%. The amount of tafluprost in the ophthalmic tafluprost solution according to the invention is from 0.0001 to 0.0010%, preferably from 0.0003 to 0.0008%. A preferred amount of tafluprost in the ophthalmic tafluprost composition according to the invention is 0.00075%).
The amount of tafluprost in the ophthalmic tafluprost-timolol solution according to the invention is from 0.0001 to below 0.0010%, preferably from 0.0003 to 0.00075%. A preferred amount of tafluprost in the ophthalmic tafluprost-timolol composition according to the invention is 0.0005%.
A preferred form of timolol in the composition according to the invention is timolol male- ate but also timolol hemihydrate can be used. The amount of timolol may vary from 0.075 to 0.15%) and is most preferably 0.1%.
In an embodiment of the invention, nonionic surfactants are added to the ophthalmic solution according to the invention, particularly to an ophthalmic solution comprising tafluprost and timolol, for their solubilizing effect and to prevent the absorption of tafluprost to the resinous walls of the container. Examples of nonionic surfactants are polyoxyethylene fatty esters such as polysorbate 80 [poly(oxyethylene) sorbitan monooleate], polysorbate 60 [poly(oxyethylene)sorbitan monostearate], polysorbate 40
[poly(oxyethylene)sorbitan monopalmitate], poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate and polysorbate 65 [poly(oxyethylene)sorbitan tri- stearate], polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50 and polyoxyethylene hydrogenated castor oil 60, polyoxyethylene polyoxy- propylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol [Pluronic F68], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], polyoxyethylene (54) polyoxypropylene (39) glycol [Pluronic P85], polyoxyethylene (196) polyoxypropylene (67) glycol [Pluronic F127] and polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L-44], polyoxyl 40 stearate and sucrose fatty esters. The nonionic surfac- tants can be used solely or in combination. A preferred example of the nonionic surfactants is polysorbate 80 [poly(oxyethylene)sorbitan monooleate]. Other preferred nonionic surfactants are polyoxyethylene hydrogenated castor oil 60 and polyoxyl 40 stearate.
The amount of nonionic surfactant(s) in the ophthalmic solution according to the inven- tion can be chosen depending on the amount of tafluprost and timolol and the specific surfactants) and is within the skill of a person in the art. For polysorbate 80, the concentration is for example in the range of 0.001 to 0.01% (w/v), even more preferably 0.002 to 0.006%, and most preferably about 0.005%. It has also been found that a too high concentration of the nonionic surfactant has an irritative effect on the cornea-conjunctival epithe- Hum layer and an adverse effect on the ocular bioavailability of prostaglandin from the ophthalmic solution. For example in the case of tafluprost an upper limit of 0.5% of the nonionic surfactant polysorbate 80 should not be exceeded.
Instead of or in addition to nonionic surfactants, the ophthalmic aqueous tafluprost-timolol solution according to the invention may contain a water-soluble organic amine, examples of which include the organic amines mentioned above.
The ophthalmic tafluprost-timolol solution according to the invention may also contain tonicity agents. Examples of suitable tonicity agents are glycerol, sorbitol, mannitol and other sugar alcohols, propylene glycol, sodium chloride, potassium chloride and calcium chloride. A preferred tonicity agent is glycerol. The amount of tonicity agent depends on the particular tonicity agent in question and the other components of the formulation. In the case of glycerol, a preferred amount is approximately 0.1%. The required tonicity may also be effected by using a buffer system which is strong enough to provide tonicity and at the same time adjusts the pH to the desired level.
The presence of stabilizing agents in the ophthalmic solutions according to the invention is not required but the composition may also contain stabilizing agents to inhibit decomposi- tion of tafluprost in the ophthalmic solution. If stabilizing agents are used, preferred examples of stabilizing agents are ethylenediaminetetraacetic acid and salts thereof, such as disodium edetate, and dibutylhydroxytoluene. Also other stabilizing agents, such as sodium nitrite, ascorbic acid, L-ascorbic acid stearate, sodium hydrogensulfite, alphathioglyc- erin, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol acetate, potassium di- chloroisocyanurate, 2,6-di-t-butyl-4-methylphenol, soybean lecithin, sodium thioglycollate, sodium thiomalate, natural vitamin E, tocopherol, ascorbyl pasthyminate, sodium pyrosul- fite, butylhydroxyanisole, 1,3-butylene glycol, pentaerythtyl tetrakis[3-(3,5-di-t-butyl-4- hydroxyphenyl)]propionate, propyl gallate, 2-mercaptobenzimidazole and oxyquinoline sulphate, may be used.
The amount of stabilizing agents in the ophthalmic solutions according to the invention can be selected depending on the specific stabilizing agent and is within the skill of a person in the art. For example, when the stabilizing agent is disodium edetate, the concentration is usually 0.005 to 0.2% (w/v), preferably 0.01 to 0.1%, even more preferably about 0.05%.
The ophthalmic solutions according to the invention may also comprise conventional ex- cipients used in ophthalmic compositions, such as buffering agents, solvents, pH adjusters, and the like. Examples of suitable buffering agents include but are not limited to sodium dihydrogen phosphate dihydrate, boric acid, borax, citric acid, or ε-aminocaproic acid.
The pH of the ophthalmic aqueous solutions according to the invention is preferably from 4 to 8, for example from 6 to 7,5, preferably about 7. As pH adjusters, common pH adjusting agents such as sodium hydroxide and/or hydrochloric acid may be used. Containers for packaging and storing the aqueous ophthalmic solution according to the invention include all container forms suitable for user-friendly topical ophthalmic deliver}'. Consequently, the containers may be selected for example from the group consisting of bottles, tubes, ampoules, pipettes and fluid dispensers, in single unit dose form or in multi- dose form. According to a preferred embodiment of the invention, the aqueous ophthalmic solution is in a single dose or unit dose form. Generally, a unit dose ophthalmic container manufactured by blow moulding method has a volume of about 1 ml and about 0.2 to 0.5 ml of solution is filled. The material of the container consists essentially of polyethylene. The container material may contain minor amounts of other materials than polyethylene, for example polypropylene, polyethylene terephthalate, polyvinyl chloride, acrylic resins, polystyrene, polymethyl methacrylate and nylon 6. The amount of said materials is preferably no more than about 5 to 10% of the total container material. Polyethylene is classified to several types by the density thereof, namely low density polyethylene (LDPE), middle density polyethylene (MDPE), high density polyethylene (HDPE), etc and these poly ethylenes are included in this invention. A preferred polyethylene is LDPE.
A preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
0.00075% tafluprost;
0.04-0.06% organic amine;
0.005-0.07% carbomer;
substantially no preservatives;
and optionally buffering agents and pH adjusters conventionally used in ophthalmic solutions.
A preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which consists essentially of
0.00075% tafluprost;
0.04-0.06% organic amine;
0.005-0.07% carbomer;
and buffering agents and pH adjusters conventionally used in ophthalmic solutions. A further preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
0.00075% tafluprost;
0.05% trometamol;
0.01% carbomer (Carbopol 981);
substantially no preservatives;
and optionally buffering agents and pH adjusters conventionally used in ophthalmic solutions. A further preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which consists essentially of
0.00075% tafluprost;
0.05% trometamol;
0.01% carbomer (Carbopol 981);
and buffering agents and pH adjusters conventionally used in ophthalmic solutions.
Another preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
0.0005% tafluprost;
0.1% timolol;
0.2-0.4% carbomer;
0.002-0.006% nonionic surfactant;
tonicity agent;
and optionally buffering agents and pH adjusters conventionally used in ophthalmic solu- tions.
A further preferred embodiment according to the invention is an ophthalmic aqueous solution for treating ocular hypertension and glaucoma, which comprises
0.0005% tafluprost;
0.1% timolol;
0.3% carbomer (Carbomer 98 INF);
0.005%) nonionic surfactant (Polysorbate 80);
0.1%) tonicity agent (glycerol); and optionally buffering agents and pH adjusters conventionally used in ophthalmic solutions.
The following examples illustrate the invention in more detail, without limiting the same in any way.
Example 1. Formulations containing tafluprost
Ophthalmic formulations according to the invention with the following compositions were made:
Formulation I
Tafluprost 0.0075 mg
Trometamol 0.5 mg
NaCl 12 mg
Carbopol 981 0.1 mg
HC1 q.s. (pH 7.0)
Water for injection ad 1 ml
Formulation II
Tafluprost 0.0075 mg
Trometamol 0.5 mg
NaCl 12 mg
Carbopol 981 0.3 mg
HC1 q.s. (pH 7.0)
Water for injection ad 1 ml
Formulation III
Tafluprost 0.0075 mg
Trometamol 0.5 mg
NaCl 12 mg
Carbopol 981 0.7 mg
HC1 q.s. (pH 7.0)
Figure imgf000019_0001
Figure imgf000019_0002
Example 2. Ocular irritation study in rabbits
The ocular irritation effect of the tafluprost compositions according to the invention was compared to that of the currently commercially available tafluprost formulation (Taflotan® PF 15 μg/ml eye drops) in rabbits.
Taflotan® preservative-free eye drops contain 0.0015% tafluprost and the following excipi- ents: Glycerol
Sodium dihydrogen phosphate dihydrate
Disodium edetate
Polysorbate 80
Water for injection
A total of 24 rabbits were chosen for the experiment based on careful macroscopic ophthalmic examination. Animals showing any eye irritation or pre-existing corneal injury were excluded from the study. Scoring of conjunctival redness, chemosis and discharge were done according to the modified Draize scoring method.
After the pre-dose examination, the rabbits were assigned to three treatment groups and a reference (control) group, 6 rabbits in each group, by block randomization based on body weights. Part I (10 doses during one day)
Treatment group I: Tafluprost 7.5 μg/ml eye drops (Formulation I of Example 1) was applied 10 times at 30 min intervals during one day.
Treatment group II: Tafluprost 7.5 μg/ml eye drops (Formulation II of Example 1) was applied 10 times at 30 min intervals during one day.
Treatment group III: Tafluprost 7.5 μg/ml eye drops (Formulation III of Example 1) was applied 10 times at 30 min intervals during one day.
Reference group: Taflotan (tafluprost) 15 μg/ml eye drops, solution in a single dose con- tainer was applied 10 times at 30 min intervals during one day.
The upper eyelid of the left/right eye was extended and 30 μΐ of the test product or the reference product was instilled with a micropipette dorsally on the bulbar conjunctiva. The dose was applied into one eye and the fellow eye of each rabbit remained as a non-treated control.
Observations of the animals for clinical signs were performed once a day and abnormal findings were recorded. All ophthalmological observations at specified time points were performed masked so that the observer did not know which product each eye had received.
Redness (scale 0-3), chemosis (scale 0-4) and discharge of the conjunctiva (scale 0-3) of both eyes were examined macroscopically on the starting date and at 0.5, 2 and 4 hours after the last (10th) instillation on Day 1 and once on Days 2 and 3. Part II (single dose during one day)
There was a wash-out period of one week between Parts I and II. The treatment groups were the same as in Part I, but the formulations were applied once during one day. Administration was as defined for Part I. Macroscopic examinations were made at 0.5, 2 and 4 hours post-dose on Day 1 and once on Day 2 (approximately 24 hours post-dose).
Results Groups were compared separately at each time point with Wilcoxon rank sum test. Treatment groups were classified dichotomously as all test formulas together vs. reference group. Consequently, N = 18 for the Test combination (including all 3 test formulations) and N = 6 for the Reference (commercial Taflotan® PF). The results are shown in Figures 1 to 4.
There was a statistically significant difference (P<0.05) in conjunctival redness between Test combination and the Reference on Day 1, at 0.5 hour time point both in Part I (P- value = 0.0495) and Part II (P -value = 0.0141) of the study.
There was a statistically significant difference in ocular discharge between Test combination and the Reference on Day 1, at 0.5 hour time point (P-value 0.0149) in Part II of the study. The frequency and severity of conjunctival redness were decreased in formulations containing only 0.00075% tafluprost compared to commercial Taflotan UD (0.0015% tafluprost). Redness increased slightly as the concentration of Carbopol 981 in the formulation was increased. This was most probably due to extended contact time on ocular surface. There were no redness observations on the following day after administration of any of the formulations.
Based on the results, the formulation according to the invention with a low tafluprost concentration reduces conjunctival hyperemia.
Example 3. Ocular pharmacokinetic study in rabbits
The ocular penetration of tafluprost compositions according to the invention was compared to commercial preservative-free Taflotan® eye drops (0.0015% tafluprost). The tested compositions according to the invention were Formulation I (test product I) and Formulation II (test product II) disclosed in Example 1.
Taflotan® preservative-free eye drops contain 0.0015% tafluprost and the following excipi- ents: Glycerol Sodium dihydrogen phosphate dihydrate
Disodium edetate
Polysorbate 80
Water for injection
Altogether 12 NZW male rabbits were used in Parts I and II of the study. The rabbits were assigned to three groups with 4 rabbits in each group.
A single 30 μΐ dose of test product I (Part I) or test product II (Part II) was applied onto the cornea of one eye. The reference product was applied to the fellow eye.
Aqueous humor samples were collected at 0.5, 1 and 2 hours post-dose from anaesthetized animals. Tafluprost acid was analyzed using LC-MS/MS. Results are shown in Figures 5 A and 5B.
It can be seen that there was no major difference in the penetration of tafluprost between low concentration (0.00075%) tafluprost formulation according to the invention and commercial Taflotan® PF (0.0015%) eye drops. A slightly less ocular penetration of Test for- mulations I and II compared to Taflotan® may still result in equal clinical efficacy. This is a significant result taking into account that the concentration of tafluprost in the composition according to the invention is only 50% of that of the commercial product.
The improved tafluprost formulation according to the invention thus provides a practically comparative corneal penetration and less harmful ocular effects including conjunctival hyperemia compared to the commercial preservative-free Taflotan® eye drops (0.0015% tafluprost).
Example 4. Ocular pharmadynamic study in rats
Spraque Dawley rats were used to study the effects of ophthalmic solutions on the intraocular pressure (IOP). The test product according to the invention was Formulation I disclosed in Example 1. Reference product was commercial preservative-free Taflotan® eye drops (0.0015% tafluprost). The test solutions were dosed topically as a single instillation of 10 μΐ of the test product onto one eye and 10 μΐ of the reference product onto the other eye of the rat. Twelve Spra- gue Dawley male rats were used in the study. IOP was measured with a TonoLab rebound tonometer prior to dosing (0 h) and at 0, 2, 4, 6 and 8 hours after the dosing.
The results are shown in Figure 6. From the results it can be seen that the effect of Formulation I (tafluprost 0.0075%) on the IOP in rats is slightly better than that of commercial Taflotan® PF 15 μg/ml.
Example 5. Tafluprost concentration in rabbit plasma after topical application
This study was performed to determine tafluprost acid concentration in rabbit plasma following a single topical application of a tafluprost composition according to the invention or of commercial preservative-free Taflotan® 15 μg/ml eye drops.
The composition according to the invention was Formulation IV disclosed in Example 1.
Six albino NZW male Charles River rabbis were used in the study. The test product at a dose volume of 30 μΐ was applied once onto the cornea of both rabbit eyes using a calibrated micropipette. Blood samples were taken at 5, 20, 40 and 60 minutes after the administration. The plasma was separated by centrifugation and stored in a freezer until analysed for tafluprost acid using a LC-MS/MS method. There was a two-week wash-out period after which the reference product was administered in the same animals and blood samples were taken at the same time points as in the first phase of the study. The plasma was separated and analysed for tafluprost acid similarly as in the first phase of the study. Results
Tafluprost acid concentrations in the rabbit plasma at different time points are illustrated in Figure 7. It can be seen that tafluprost acid concentrations in the plasma are proportional to the tafluprost concentration in the eye drops. Tafluprost acid concentration in the plasma following topical application of tafluprost 7.5 μg/ml eye drops is about half of that after administration of tafluprost 15 μg/ml eye drops. This indicates that, differently from local ocular penetration, the new tafluprost formulation does not seem to have any effect on systemic absorption of tafluprost after topical administration.
Example 6. A formulation comprising tafluprost and timolol
An ophthalmic formulation having the following composition was made:
Figure imgf000024_0001
Example 7 (Study 1, Ocular absorption study)
The ocular penetration of a tafluprost-timolol composition according to the invention (Tafluprost 0.0005%-Timolol 0.1% FDC) eye drops was compared to commercial preserv- ative-free Taflotan® eye drops (0.0015% tafluprost).
Sixteen rabbits for comparison to commercial preservative-free Taflotan® were used. The fixed dose combination according to the invention was administered to one eye while commercial Taflotan® was administered to the other eye.
Aqueous humor samples were taken 15, 30, 60 and 90 minutes post-dose from anaesthetized animals. The study was performed traditionally, i.e. one sample was taken from each eye, n=4 per time point. Composition of the test product according to the invention was as defined in Example 6.
Taflotan® preservative-free eye drops contain 0.0015% tafluprost and the following excipi- ents:
Glycerol
Sodium dihydrogen phosphate dihydrate
Disodium edetate
Polysorbate 80
Water for injection
Results are shown in Figure 8.
From the results it can be seen that ocular penetration of tafluprost is similar between Tafluprost 0.0005%-Timolol 0.1% and commercial Taflotan (0.0015%) product. This is a significant result taking into account that the concentration of tafluprost in the tafluprost- timolol composition according to the invention is only one third of that of the commercial product.
Example 8 (Study 2: Ocular irritation test)
The ocular irritation effect of the tafluprost-timolol composition according to the invention was compared to that of the currently commercially available tafluprost-timolol fixed dose combination in rabbits. A total of 12 male rabbits were chosen for the experiment based on careful macroscopic ophthalmic examination. Animals showing any eye irritation or pre-existing corneal injury were excluded from the study. Scoring of conjunctival redness, chemosis and discharge were done according to the modified Draize scoring method. After the ophthalmic examinations, the rabbits were assigned to one treatment group or one reference group, 6 rabbits in each, by block randomization based on body weights.
Composition of the test product:
Tafluprost 0.0005%-Timolol 0.1% eye drops, preservative-free Drug substance/Excipients Quantity (mg/g)
Tafluprost 0.005
Timolol maleate 1.368
Polysorbate 80 0.05
Disodium phosphate dihydrate 20
Glycerol 1
Carbopol 98 INF 3
pH 6.9-7.2
Composition of the reference product:
Tafluprost 0.0015% - Timolol 0.5% eye drops (brand name Taptiqom), preservative-free solution in a single dose container
Drug substance/Excipients Quantity (mg/ml)
Tafluprost 0.015
Timolol maleate 6.84
(equivalent to timolol) (5.0)
Glycerol q.s.
Disodium phosphate dodecahydrate q.s.
Disodium edetate q.s.
Polysorbate 80 q.s.
Hydrochloric acid/Sodium hydroxide q.s. to 6.4-6.5
Water for injection q.s.
Part I of the study:
Test group: Preservative-free Tafluprost 0.0005% - Timolol 0.1% eye drops, a single instillation during one day
Reference group: Preservative-free Tafluprost 0.0015% - Timolol 0.5% eye drops
(Taptiqom), a single instillation during one day
Administration of the test and reference products:
The upper eyelid of the left/right eye was extended and 30 μΐ of the test product or the reference product was instilled with a micropipette dorsally on the bulbar conjunctiva. Observations, examinations and measurements:
The day of administration was defined as Day 1. The following observation and examination days after Day 1 were Days 2 and 3.
Daily observations of the animals for clinical signs were performed twice daily (a.m and p.m) and abnormal findings were recorded. All ophthalmological observations at specified time points were performed masked so that the observer did not know which product each eye had received. Redness, chemosis and discharge of the conjunctiva of both eyes were examined macro- scopically before the experimental starting date and at 0.5, 1, 2 and 4 hours after the instillation on Day 1 and once a day on Days 2 and 3. Because there were no findings above animal-specific baseline values (animal-specific findings observed prior to experimental part) the study was finished on Day 3.
Part II of the study
There was a wash-out period of at least 5 days between Parts I and II.
Test group: Preservative-free Tafluprost 0.0005% - Timolol 0.1% eye drops, 10 consecutive instillations at 30 minute intervals during one day
Reference group: Preservative-free Tafluprost 0.0015% - Timolol 0.5% eye drops (Taptiqom), 10 times instillation at 30 minute intervals during one day
Administration, observations, examinations and measurements were as defined for Part I.
Results
There were no statistically significant differences in redness, discharge or chemosis between the test and reference groups at any time points, presumably due to small number of animals used. However, a tendency to minor frequency of redness in the test group than in the reference group was observed in Part I of the study (Fig.9). Slightly more score 2 (moderate) redness was observed in the reference group in Part II of the study (Fig.10). There was a slight tendency to more discharge findings in the test group than in the reference group. REFERENCES
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Rouland JF, Morel-Mandrino P, Elena PP, Polzer H, Sunder Raj P (2002). Timolol 0.1% gel (Nyogel 0.1%) once daily versus conventional timolol 0.5% solution twice daily: a comparison of efficacy and safety. Ophthalmologica 216:449-454. Uusitalo H, Kahonen M, Ropo A, Maenpaa J, Bjarnhall G, Hedenstrom H, Turjanmaa V (2006) Improved systemic safety and risk-benefit ratio of topical 0.1% timolol hydrogel compared with 0.5% timolol aqueous solution in the treatment of glaucoma. Graefes Arch. Clin. Exp. Ophthalmol. 244: 1491-1496.
Uusitalo H, Nino J, Tahvanainen K, Turjanmaa V, Ropo A, Tuominen J, Kahonen M (2005) Efficacy and systemic side-effects of topical 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Acta. Ophthalmol. Scand. 83 :723-728.

Claims

Claims
1. An ophthalmic aqueous solution for treating ocular hypertension and glaucoma compris- ing
(i) tafluprost in an amount of 0.0001 to 0.0010% (w/v);
(ii) polyacrylic acid;
and substantially no preservatives.
2. An ophthalmic aqueous solution according to claim 1 further comprising organic amine.
3. The ophthalmic aqueous solution according to claim 1 or 2, wherein the amount of tafluprost is 0.0003-0.0008%, preferably 0.00075% (w/v).
4. The ophthalmic aqueous solution according to claim 2 or 3, wherein the organic amine is selected from organic amines having a hydroxyl group, such as monoethanolamine, di- ethanolamine, triethanolamine, trometamol and meglumine, preferably trometamol, and wherein the organic amine is present in an amount of 0.02-0.08%, preferably 0.04-0.06% (w/v).
5. The ophthalmic aqueous solution according to any one of claims 2 to 4, wherein the organic amine is trometamol which is present in an amount of approximately 0.05%.
6. The ophthalmic aqueous solution according to any one of the preceding claims wherein the polyacrylic acid is selected from high molecular polyacrylic acid polymers or car- bomers.
7. The ophthalmic aqueous solution according to any one of claims 2 to 6, wherein the polyacrylic acid is present in an amount of from 0.005-0.07%), such as 0.005-0.04%), prefera- bly 0.01-0.03%.
8. The ophthalmic aqueous solution according to any one of claims 2 to 7, wherein the polyacrylic acid is a carbomer which is present in an amount of 0.01-0.03%).
9. The ophthalmic aqueous solution according to claim 8 wherein the polyacrylic acid is a carbomer (Carbopol 981) in an amount of 0.01%.
10. An ophthalmic aqueous solution comprising
0.00075% tafluprost;
0.04-0.06% organic amine;
0.005-0.07% carbomer;
substantially no preservatives;
and optionally buffering agents and pH adjusters conventionally used in ophthalmic solu- tions.
11. An ophthalmic aqueous solution comprising
0.00075% tafluprost;
0.05% trometamol;
0.01% carbomer (Carbopol 981);
substantially no preservatives;
and optionally buffering agents and pH adjusters conventionally used in ophthalmic solutions.
12. An ophthalmic aqueous solution consisting essentially of
0.00075% tafluprost;
0.04-0.06% organic amine;
0.005-0.07% carbomer;
and pH adjusters conventionally used in ophthalmic solutions.
13. A method for improving local tolerability and for reducing unnecessary systemic exposure of an ophthalmic composition comprising tafluprost for treatment of ocular hypertension and glaucoma, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution containing a significantly lower amount of tafluprost than con- ventional formulations comprising tafluprost, the ophthalmic solution further comprising an organic amine and polyacrylic acid, and administering the composition to a subject in need of such treatment.
14. A method for lowering tafluprost concentration dependent conjunctival hyperemia and periorbital skin pigmentation, the method comprising the steps of preparing a preservative- free ophthalmic aqueous solution containing significantly lower amounts of tafluprost than conventional formulations, the solution further comprising an organic amine and a poly- acrylic acid, and administering the composition to a subject in need of such treatment.
15. A method for treating ocular hypertension and glaucoma, which method comprises administering a preservative-free ophthalmic aqueous solution comprising tafluprost as active ingredient thereof to a subject in need of said treatment, wherein the ophthalmic aqueous solution further comprises polyacrylic acid, and substantially no preservatives.
16. The method according to claim 15, wherein the ophthalmic aqueous solution further comprises an organic amine.
17. An ophthalmic aqueous solution according to claim 1 for treating ocular hypertension and glaucoma comprising
(i) tafluprost in an amount of 0.0001 to 0.0010% (w/v);
(ii) timolol in an amount of 0.075 to 0.15%;
(iii) polyacrylic acid;
(iv) nonionic surfactant;
(v) tonicity agent;
and substantially no preservatives.
18. The ophthalmic aqueous solution according to claim 17, wherein the amount of tafluprost is 0.0003-0.00075%, such as 0.0005%.
19. The ophthalmic aqueous solution according to claim 17 or 18, wherein the amount of timolol is 0.1%.
20. The ophthalmic aqueous solution according to any one of claims 17 to 19, wherein polyacrylic acid is present in an amount of from 0.1-0.5%), preferably 0.2-0.4%) (w/v).
21. The ophthalmic aqueous solution according to any one of claims 17 to 20, wherein the nonionic surfactant is selected from the group of polysorbates and the nonionic surfactant is present in an amount of from 0.001 to 0.01%, preferably 0.002 to 0.006%.
22. The ophthalmic aqueous solution according to any one of claims 17 to 21 wherein the tonicity agent is glycerol.
23. The ophthalmic aqueous solution according to any one of claims 17 to 22 wherein timolol is in the form of timolol maleate.
24. An ophthalmic aqueous solution comprising
0.0005% tafluprost;
0.1% timolol;
0.2-0.4% carbomer;
0.002-0.006% nonionic surfactant;
tonicity agent;
and optionally buffering agents and pH adjusters conventionally used in ophthalmic solutions.
25. An ophthalmic aqueous solution comprising
0.0005% tafluprost;
0.1% timolol;
0.3% carbomer (Carbomer 98 INF);
0.005%) nonionic surfactant (Polysorbate 80);
0.1%) tonicity agent (glycerol);
and optionally buffering agents and pH adjusters conventionally used in ophthalmic solutions.
26. The ophthalmic aqueous solution according to any one of claims 1 to 12 or claims 17 to 25 for use in the treatment of ocular hypertension and glaucoma.
27. A method for improving local tolerability and for lowering systemic adverse effects of an ophthalmic composition for treatment of ocular hypertension and glaucoma, the method comprising the steps of preparing a preservative-free ophthalmic aqueous solution contain- ing significantly lower amounts of tafluprost and timolol than conventional fixed dose combinations comprising tafluprost and timolol, the ophthalmic solution further comprising polyacrylic acid, nonionic surfactant and tonicity agent(s), and administering the composition to a subject in need of such treatment.
28. A method for treating ocular hypertension and glaucoma, which method comprises administering an ophthalmic aqueous solution comprising tafluprost and timolol as active ingredients thereof to a subject in need of said treatment, wherein the ophthalmic aqueous solution further comprises polyacrylic acid, nonionic surfactant, tonicity agent(s) and sub- stantially no preservatives.
PCT/IB2017/054963 2016-08-15 2017-08-15 Ophthalmic composition and a method for treating ocular hypertension and glaucoma WO2018033854A1 (en)

Applications Claiming Priority (4)

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WO2019206956A1 (en) 2018-04-27 2019-10-31 Novaliq Gmbh Ophthalmic compositions comprising tafluprost for the treatment of glaucoma
RU2761625C2 (en) * 2021-02-11 2021-12-13 Общество с ограниченной ответственностью "Гротекс" (ООО "Гротекс") Pharmaceutical composition of tafluprost
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019206956A1 (en) 2018-04-27 2019-10-31 Novaliq Gmbh Ophthalmic compositions comprising tafluprost for the treatment of glaucoma
RU2761625C2 (en) * 2021-02-11 2021-12-13 Общество с ограниченной ответственностью "Гротекс" (ООО "Гротекс") Pharmaceutical composition of tafluprost
CN116124936A (en) * 2023-01-03 2023-05-16 苏州欧康维视生物科技有限公司 Detection method for related substances of tafluprost
CN116124936B (en) * 2023-01-03 2024-01-30 苏州欧康维视生物科技有限公司 Detection method for related substances of tafluprost

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