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WO2018033854A1 - Composition ophtalmique et procédé de traitement de l'hypertension oculaire et du glaucome - Google Patents

Composition ophtalmique et procédé de traitement de l'hypertension oculaire et du glaucome 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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WIPO (PCT)
Prior art keywords
tafluprost
aqueous solution
ophthalmic
ophthalmic aqueous
timolol
Prior art date
Application number
PCT/IB2017/054963
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English (en)
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/fr

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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

La présente invention concerne une composition aqueuse ophtalmique améliorée contenant du tafluprost, une composition aqueuse ophtalmique améliorée contenant du tafluprost et du timolol, et un procédé pour traiter l'hypertension oculaire et le glaucome par administration desdites compositions à des sujets ayant besoin d'un tel traitement. Un autre objet de l'invention est un procédé permettant d'améliorer la tolérabilité locale et de réduire l'exposition systémique inutile d'une composition ophtalmique comprenant du tafluprost. Un autre objet de l'invention est un procédé permettant d'améliorer la tolérabilité locale et d'abaisser les effets secondaires systémiques d'une composition ophtalmique comprenant du tafluprost et du timolol.
PCT/IB2017/054963 2016-08-15 2017-08-15 Composition ophtalmique et procédé de traitement de l'hypertension oculaire et du glaucome WO2018033854A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019206956A1 (fr) 2018-04-27 2019-10-31 Novaliq Gmbh Compositions ophtalmiques comprenant du tafluprost pour le traitement du glaucome
RU2761625C2 (ru) * 2021-02-11 2021-12-13 Общество с ограниченной ответственностью "Гротекс" (ООО "Гротекс") Фармацевтическая композиция тафлупроста
CN116124936A (zh) * 2023-01-03 2023-05-16 苏州欧康维视生物科技有限公司 一种他氟前列素的有关物质检测方法
US20250041219A1 (en) * 2017-12-19 2025-02-06 University Of Tennessee Research Foundation W/o/w microemulsions for ocular administration

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20250041219A1 (en) * 2017-12-19 2025-02-06 University Of Tennessee Research Foundation W/o/w microemulsions for ocular administration
WO2019206956A1 (fr) 2018-04-27 2019-10-31 Novaliq Gmbh Compositions ophtalmiques comprenant du tafluprost pour le traitement du glaucome
RU2761625C2 (ru) * 2021-02-11 2021-12-13 Общество с ограниченной ответственностью "Гротекс" (ООО "Гротекс") Фармацевтическая композиция тафлупроста
CN116124936A (zh) * 2023-01-03 2023-05-16 苏州欧康维视生物科技有限公司 一种他氟前列素的有关物质检测方法
CN116124936B (zh) * 2023-01-03 2024-01-30 苏州欧康维视生物科技有限公司 一种他氟前列素的有关物质检测方法

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