SK500932014U1 - Eye drops for treatment of ocular hypertension and glaucoma comprising derivative of prostaglandin F2-alpha, latanoprost - Google Patents

Abstract

The eye drops contain 0.001 to 0.01 wt. % of latanoprost, 15 to 40 wt. % nonionic surfactant, further 15 to 40 wt. % of the cyclodextrin derivative and the remainder to 100 wt. water for injection.

Description

BACKGROUND OF THE INVENTION

Ophthalmic compositions containing latanoprost - a prostaglandin B derivative? with the chemical name isopropyl- (Z) -7 [(1R, 2R, 3R, 5S) 3,5-dihydroxy-2 - [(3R) -3-hydroxy-5-phenylpentyl] cyclopentyl] -5-heptanoate as active substances are: known and used for the treatment of glaucoma and high ocular pressure. However, latanoprost is readily degradable in water and tends to adsorb to the inner surface of the storage container at room temperature. Usually it is a plastic container and the manufacturer requires storage in a cool place and away from light.

EP1553953 B1 describes the use of latanoprost in admixture with Polysorbate 80, EDTA and benzalkonium chloride for the manufacture of a composition for the treatment of ocular hypertension and glaucoma.

EP2193795 discloses an aqueous pharmaceutical composition of latanoprost filled in a container with a filter that prevents the adsorption of latanoprost.

EP2123278 discloses a mixture of latanoprost in a polypropylene or polyethylene container containing benzalkonium chloride.

Preservatives used in ophthalmic preparations should demonstrate sufficient antimicrobial activity on bacteria, fungi, fungi and yeasts as well as a high level of safety. Despite these requirements, preservatives, such as the widely used benzalkonium chloride, cause allergies or other difficulties for some more sensitive patients.

The packaging material used maintains eye drop sterility even without the use of a preservative by not aspirating the drop back into the vial after application that could be contaminated in air. The necessary air to compensate for the original bottle shape is filtered through a 0.22 µm filter. The packaging material consists of a vial made of polyethylene, a type of sterilizing air filter Emflon® PTFE membrane.

The essence of the technical solution

The prior art ophthalmic formulations based on the prostanglandin derivative F2alpha are extended by the formulation according to the present invention, which consists in that it contains 0.001 to 0.01 wt. Latanoprost, a nonionic surfactant of 15 to 40 wt.%, Further 15 to 40 wt. % cyclodextrin derivative (hydroxypropylbetadex); forms water for injection.

Other pharmaceutical auxiliaries may be from the group of inorganic and organic buffer substances (pH-adjusting solution) 1 to 10% by weight, inorganic and organic salts, substances to adjust the osmolality of the solution from 0.01 to 3% by weight, surfactants 15 to 40% by weight, chelating agents, antioxidants (vitamin E, sodium thiosulfate) 0.01 to 10% by weight; and mixtures thereof.

Excipients that maintain the pH range of 6-7 are boric acid, sodium tertaborate, sodium acetate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, citric acid, tartaric acid, sodium tartrate, trometamol, sulfuric acid, hydrochloric acid, sodium hydroxide individually or in the mixture.

Osmotic pressure adjuvants: sodium chloride, potassium chloride, calcium chloride, sorbitol, mannitol, glycerol, glucose and sucrose individually or in a mixture.

Latanoprost solubilizing surfactants are polyoxyethylene sorbitan monooleate, polyoxyl 35 castor oil, polyethylene glycol individually or in admixture.

Vitamin E or sodium thiosulphate are other adjuvants that maintain antioxidant environmental protection.

Latanoprost preparations can be used in ophthalmology to reduce elevated eye pressure in glaucoma (glaucoma) or ocular hypertension (increased intraocular pressure). It can be used either alone or with other eye drops that reduce intraocular pressure such as beta-blockers.

EXAMPLES

Example 1

Composition 1:

latanoprost

Sodium chloride

Sodium dihydrogen phosphate monohydrate Sodium hydrogen phosphate anhydrous Hydroxypropylbetadex

Polyethylene glycol 400

Sodium hydroxide, acid. Hydrochloric Water for Injection pg / ml (0.005%) 0.7 mg / ml (0.7%) 5.1 mg / ml (5.1%) 4 mg / ml (4%) mg / ml (34%) mg / ml ml (30%) q with pH = 7 and 1 ml

Example 2

Composition of the composition

Latanoprost Potassium chloride Citric acid Sodium citrate Hydroxypropylbetadex pg / ml (0.005%) 0.7 mg / ml (0.7%) 5.1 mg / ml (5.1%) 4 mg / ml (4%) mg / ml (34 %)

Polysorbate 80 Sodium thiosulfate Sodium hydroxide / HCl Water is injected mg / ml (30%) 1 mg / ml (1%) q.s pH = 6.9 and 1 ml

Example 3 - Composition of Composition 3

Latanoprost Tartaric acid Sodium tartrate Hydroxypropylbetadex Polyethylene glycol 400 Vitamin E

Sodium hydroxide / HCl Water I injected

Example 4 - testing pg / ml (0.005%) 5.1 mg / ml (5.1%) 4 mg / ml (4%) mg / ml (34%) mg / ml (30%) mg / ml (10 %) qs ad 1 ml

The ophthalmic composition based on latanoprost, nonionic surfactant, cyclodextrin and preservative free according to Example 1 was compared to the original XALATAN® (Pfizer) eye irritation test after repeated administration for 28 days to NZW x CA rabbits.

The preparations were administered once daily at 50µΙ (male) + 100µl (female).

Clinical observations focused on the detection of organ and tissue damage, including measurement of eye tolerance, to compare the rate of damage to the original benzalkonium chloride preservative drug with the formulation of the present solution without preservative.

Table 1: The severity of the damage was evaluated according to the scale of the following criteria

Part of the eye Observing the eye degree cornea Turbidity: degree of turbidity 0-4 iris Normal - overload - swelling - hyperaemia - reaction to the light 0-2 conjunctiva Redness (refers to ocular and conjunctival disorders) 0-3 chemosis Swelling (covers eyelids) 0-4

Compare results:

Table 2: Eye reaction in rabbits administered the ophthalmic composition of Example 1 without BAC and XALATAN® after repeated administration after 28 days.

Group Animal number No. Parts of the eye cornea iris conjunctiva lids composition on basis latanoprost without BAC males 550/1 0 0 0-1 0 550/2 0 0 0-1 0 550/3 0 0 0-1 0 550/4 0 0 0-1 0 550/5 0 0 0-1 0 composition on basis latanoprost without BAC female 551/1 0 0 0-1 0 551/2 0 0 0-1 0 551/3 0 0 0-1 0 551/4 0 0 0-1 0 551/5 0 0 0-1 0 Xalatan males 552/1 0 0 0-1 0 552/2 0 0 0-1 0 552/3 0 0 0-1 0 552/4 0 0 0-1 0 552/5 0 0 0-1 0 Xalatan female 553/1 0 0 0-1 0 553/2 0 0 0-1 0 553/3 0 0 0-1 0 552/4 0 0 0-1 0 552/5 0 0 0-1 0

Histopathological findings in ocular structures were negative, no significant morphological tissue changes were observed.

Only one sign of eye reaction was observed, it was conjunctival hyperaemia (Table 2). This hyperaemia was observed in all animals in the study.

The test formulation of the present invention is non-irritating, non-corrosive and nontoxic after repeated ocular administration to laboratory rabbits, at the doses described without statistical difference.

Example 5 - stability monitoring

The ophthalmic composition based on latanoprost, nonionic surfactant, cyclodextrin and preservative free according to Example 1 was tested for stability at 25 ° C.

Stable follow-up of UNILAT Preservative Free formulation at 25 ° C ± 2 ° C

Batch number 570101 specification limits entry 3 months 6 months Current acidity [pH] 6.2 to 6.9 6.72 6.80 6.67 Osmolality [mOsm / kg] 270-330 303 315 312 Latanoprost content [pg / ml] 45.0-55.0 47,78 48,63 47,93 Latanoprost acid impurity content [%] <0.4 N D * N D * ND * Impurity content 5,6-trans-latanoprost [%] <0.5 ND * ND * ND * Contaminant content 15 (S) -latanoprost [%] <0.5 ND * ND * ND * Contents of unidentified impurities individually [%] <0.5 N D * ND * ND * Sum of impurities [%] <1.0 ND * ND * ND * sterility sterile complies - complies

ND * = below detection limit

Stability testing results confirm the stability of the ophthalmic composition at 25 ° C.

Γαι /

Claims (6)

PROTECTION REQUIREMENTS Eye drops for the treatment of ocular hypertension and glaucoma comprising a prostaglandin derivative of F2-alpha, latanoprost, characterized in that they contain 0.001 to 0.01% by weight. % latanoprost, 15 to 40 wt. % of a nonionic surfactant; % cyclodextrin derivative, 0.01 to 10 wt. % of excipients to adjust the pH of the solution in the range of 6-7 and the remainder to 100 wt. forms water for injection. Eye drops for the treatment of ocular hypertension and glaucoma according to claim 1, characterized in that the pH-adjusting agents in the range of 6-7 are boric acid, sodium tertaborate, sodium acetate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, citric acid. , tartaric acid, sodium tartrate, trometamol, sulfuric acid, hydrochloric acid, sodium hydroxide individually or in admixture. Eye drops for the treatment of ocular hypertension and glaucoma according to claim 1, characterized in that it contains 0.01 to 3% by weight, of a solution for adjusting the osmolality of the solution, which are sodium chloride, potassium chloride, calcium chloride, sorbitol, mannitol, glycerol. , glucose and sucrose individually or in admixture. Eye drops for the treatment of ocular hypertension and glaucoma according to claim 1, characterized in that the nonionic surfactant for the solubilization of latanoprost is selected from the group of polyoxyethylene sorbitan monooleate, polyoxyl 35 castor oil, polyethylene glycol individually or in a mixture. Eye drops for the treatment of ocular hypertension and glaucoma according to claim 1, characterized in that it comprises from 0.01 to 10% by weight. antioxidants such as vitamin E, sodium thiosulphate or a mixture thereof. Eye drops for the treatment of ocular hypertension and glaucoma according to claim 1, characterized in that it comprises: Latanoprost 50 pg / ml (0.005%) Sodium chloride Sodium dihydrogen phosphate monohydrate Sodium hydrogen phosphate anhydrous Hydroxypropylbetadex Polyethylene glycol 400 Sodium hydroxide, acid. Hydrochloric Water for Injection 0.7 mg / ml (0.7%) 5.1 mg / ml (5.1%) 4 mg / ml (4%) 34 mg / ml (34%) 30 mg / ml (30%) q.s to pH 7 and 1 ml INDUSTRIAL PROPERTY OFFICE OF THE SLOVAK REPUBLIC Svermova 43,974 04 Banska Bystrica 4