RHINENCHYSIS COMPOSITION CONTAINING OLOPATADINE

Abstract

The present invention relates to a composition wherein olopatadine is stably dissolved and a process thereof.

Claims

1. A composition for use in nasal administration comprising olopatadine or a pharmaceutically acceptable salt thereof, and carboxy vinyl polymer, wherein the pH is adjusted to 4.0-7.0.

2. The composition for use in nasal administration of claim 1, wherein the olopatadine or a pharmaceutically acceptable salt thereof is olopatadine hydrochloride, and the olopatadine hydrochloride is in solution state in a concentration of 0.2% (w/w) or more.

3. The composition for use in nasal administration of claim 1, wherein the concentration of the carboxy vinyl polymer is 0.1-2% (w/w).

4. The composition for use in nasal administration of claim 1, wherein the pH is adjusted with L-arginine and/or sodium hydroxide and/or hydrochloric acid as a pH adjuster.

5. The composition for use in nasal administration of claim 1, further comprising one or more preservatives.

6. The composition for use in nasal administration of claim 5, wherein the preservative comprises benzalkonium chloride.

7. The composition for use in nasal administration of claim 5, wherein the preservative comprises disodium edetate hydrate.

8. The composition for use in nasal administration of claim 1, further comprising one or more isotonizing agents.

9. The composition for use in nasal administration of claim 8, wherein the isotonizing agent comprises sodium chloride and/or glycerin.

10. The composition for use in nasal administration of claim 8, wherein the concentration of the isotonizing agent is 0.1-10% (w/w).

11. The composition for use in nasal administration of claim 1, which is isotonic.

12. The composition for use in nasal administration of claim 1, wherein the viscosity is 250-2500 mPa.Math.s.

13. The composition for use in nasal administration of claim 1, whose mean liquid particle size is 30-100 μm when sprayed.

14. The composition for use in nasal administration of claim 11, wherein the pH adjuster is L-arginine and sodium hydroxide, the preservative is disodium edetate hydrate and benzalkonium chloride, and the isotonizing agent is glycerin and sodium chloride.

15. The composition for use in nasal administration of claim 1, wherein the pH is adjusted to 4.5-6.5.

16. The composition for use in nasal administration of claim 1, wherein the pH is adjusted to 5.0-6.0.

17. A formulation for spray-administration to nasal cavity, comprising the composition for use in nasal administration of claim 1.

18. A composition for use in nasal administration which is prepared by adding carboxy vinyl polymer to the composition to dissolve olopatadine at pH 5.0-6.0.

Description

DESCRIPTION OF EMBODIMENTS

[0011] Olopatadine is a compound of formula:

##STR00001##

which has been already used as antihistamine for treating allergic rhinitis or allergic conjunctivitis.

[0012] Olopatadine or a salt thereof is used in the preparation of a composition for use in nasal administration, preferably used as olopatadine hydrochloride. The concentration of olopatadine in the present formulation is 0.2% (w/w) or more, preferably 0.4 -0.8% (w/w), more preferably 0.4-0.7% (w/w) as olopatadine hydrochloride.

[0013] The “pharmaceutically acceptable salt” is not limited to a specific one as long as the salt does not negatively affect humans or animals such as toxicity. It includes hydrochloride, citrate, succinate, hydrobromide, ascorbate, furoate, sulfate, acetate, valerate, oleinate, palmitate, laurate, stearate, bisulfate, borate, benzoate, lactate, phosphate, methanesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, glucoheptonate, lactobionate, and laurylsulfate, as an acid-addition salt; and alkali metal salt such as sodium and potassium, and alkali-earth metal salt such as calcium and magnesium, as a basic salt.

[0014] Carboxy vinyl polymer used herein should not be limited as long as it is what is usually used in a medical formulation. Preferably, it is carboxy vinyl polymer whose viscosity is adjusted by adding an outside shearing force. The method of the adjustment and the effect of the modified carboxy vinyl polymer are disclosed in WO 2007/123193. For example, the outside shearing force may be added with a known device giving a shearing force such as a high-speed spinning-type emulsifying device, a colloidal mill-type emulsifying device, a high-pressure emulsifying device, a roll mill-type emulsifying device, an ultrasonic-type emulsifying device and a membrane-type emulsifying device. Especially, a homo mixer-type, a comb-type, and an intermittently-jet-stream-generating-type, high-speed spinning-type emulsifying devices are preferable. The content of carboxy vinyl polymer is 0.1 to 2% (w/w), preferably 0.25 to 1.0%.

[0015] The preservative herein includes, for example, benzalkonium chloride, benzethonium chloride, chlorobutanol and/or disodium edetate hydrate, preferably benzalkonium chloride and/or disodium edetate hydrate. The content of each preservative is 0.005-1% (w/w), preferably 0.01-0.1%.

[0016] The present aqueous composition for use in nasal administration is isotonic or around isotonic. The isotonicity may be adjusted with an isotonizing agent such as sodium chloride, boric acid, glycerin and/or glucose. The content of each isotonizing agent is 0.1 to 10% (w/w), preferably 0.1 to 1.0%.

[0017] The pH of the present aqueous composition for use in nasal administration needs to be adjusted to 4.0-7.0 (preferably 4.5-6.5, more preferably 5.0-6.0), and the adjustment of pH may be done with a pH adjuster such as sodium hydroxide, potassium hydroxide, L-arginine, and hydrochloric acid, preferably with sodium hydroxide and/or L-arginine.

[0018] The viscosity of the present aqueous composition for use in nasal administration is generally 250-2500 mPa.Math.s, preferably 500-1500 mPa.Math.s.

[0019] The “composition for use in nasal administration” used herein means an aqueous composition in soluble state, i.e., solution.

[0020] The “solution state” in the present invention means a state wherein an objective pharmaceutical ingredient is completely dissolved, and the “dispersion state” means a state wherein an objective pharmaceutical ingredient is homogeneously suspended without depositing crystal.

[0021] The liquid particle size of the present aqueous composition for use in, nasal administration means the particle size of the sprayed liquid particle. The mean liquid particle size is preferably 30-100 μm, more preferably 40-80 μm.

[0022] The “for use in nasal administration” or “as nasal drop” means a subject to be administered into the nasal cavity by dropping or with a device such as a spray device. And, the “composition for use in nasal administration” means a liquid preparation to be administered by dropping or spraying the composition into nasal cavity.

[0023] The nasal-spray preparation for intranasal administration of the present invention is directed to the nasal-spray preparation in a normal nasal spray container, or in an upper-pressure-relief airless-type spray container disclosed in WO 2007/123193 and WO 2007/123207.

EXAMPLES

[0024] Hereinafter, the present invention is illustrated based on Examples, Reference examples, and Solubility test, but are not limited thereto. The evaluations of the Examples and Reference examples prepared below, and the solubility test and stability test were carried out according to Japanese Pharmacopoeia, unless otherwise indicated.

[0025] The viscosity measurement was carried out according to Japanese Pharmacopoeia/General Tests/Viscosity Determination/Viscosity measurement by rotational viscometer, and the details are as follows.

(Measuring Method)

[0026] 1.1 mL of the test sample (test preparation) was charged into a sample cup of a cone-flat plate-type rotational viscometer (cone plate type) which was beforehand set for 20° C., while being careful not to put air bubble. The sample was let stand for 5 minutes, and then subjected to a shearing force for 3 minutes. Subsequently, the viscosity of the sample was measured according to the following condition.

(Measuring Condition)

[0027] Apparatus: TOKI SANGYO CO.,LTD. TVE-25 type viscosity meter
Measuring range: R (full-scale torque 1437.4 μN.Math.m)
Shearing rate: 9.575 s.sup.−1 (2.5 rotations per minute)

Rotor: 1°34′×R24

[0028] The liquid particle size (mean liquid particle size, 10 to 100 μm (%)) was measured with a laser diffraction/scattering particle-size-distribution analyzer.

(Measuring Condition)

Apparatus: Malvern SprayTec

[0029] Reading distance: 30 mm
Spray angle: 40°
Extrusion speed: 100 mm/s

Example 1

(Production Composition)

[0030]

TABLE-US-00001 Ingredients Amount (% by weight) olopatadine hydrochloride 0.443 carboxy vinyl polymer 0.50 L-arginine 0.73 disodium edetate hydrate 0.05 benzalkonium chloride 0.02 concentrated glycerin 0.50 sodium hydroxide q.s. hydrochloric acid q.s. purified water q.s. (until reaching 100%) Total 100.0

(Production Method)

[0031] A solution of L-arginine, disodium edatate hydrate, concentrated glycerin, and olopatadine hydrochloride in purified water was charged into a vacuum mixer, then a solution of benzalkonium chloride in purified water was added thereto, and the mixture was stirred. Separately, carboxy vinyl polymer was dissolved in purified water with stirring and the solution was added to the mixture in the vacuum mixer. The mixture was stirred in the vacuum mixer. The pH of the mixture was adjusted to pH 5.5 optionally by adding aqueous sodium hydroxide or diluted hydrochloric acid, and then the mixture was subjected to a high-speed shearing force to adjust the viscosity to 1150 mPa.Math.s with stirring.

(Evaluation Result)

[0032] The evaluation results of the obtained nasal composition are shown below.

TABLE-US-00002 Aspect A clear, colorless, viscous liquid, which is practically odorless pH 5.5 viscosity (mPa .Math. s) 1150 osmolality (mOs/L) 276 Mean liquid particle 69.4 size (μm) Liquid particle size of 86.5 10 to 100 μm (%)

Example 2

(Production Composition)

[0033]

TABLE-US-00003 Ingredients Amount (% by weight) olopatadine hydrochloride 0.665 carboxy vinyl polymer 0.50 L-arginine 0.84 disodium edetate hydrate 0.05 benzalkonium chloride 0.01 concentrated glycerin 0.35 ethanol 0.8 sodium hydroxide q.s. hydrochloric acid q.s. purified water q.s. (until reaching 100%) Total 100.0

(Production Method)

[0034] A solution of L-arginine, disodium edatate hydrate, concentrated glycerin, and olopatadine hydrochloride in purified water was charged into a vacuum mixer, then a solution of benzalkonium chloride in purified water was added thereto, and the mixture was stirred. Separately, carboxy vinyl polymer was dissolved in purified water with stirring and the solution was added to the mixture in the vacuum mixer. The mixture was stirred in the vacuum mixer. The pH of the mixture was adjusted to pH 5.5 optionally by adding aqueous sodium hydroxide or diluted hydrochloric acid, and then the mixture was subjected to a high-speed shearing force to adjust the viscosity to 1000 mPa.Math.s with stirring. Finally, ethanol was added to the mixture and the mixture was stirred to give a uniform nasal composition.

(Evaluation Result)

[0035] The evaluation results of the obtained nasal composition are shown below.

TABLE-US-00004 Aspect A clear, colorless, viscous liquid, which is practically odorless pH 5.5 viscosity (mPa .Math. s) 1000 osmolality (mOs/L) 281 Mean liquid particle 62.2 size (μm) Liquid particle size of 89.7 10 to 100 μm (%)

Reference Example 1

(According to Example 1 in JP 5149308 B)

(Production Composition)

[0036]

TABLE-US-00005 Ingredients Amount (% by weight) olopatadine hydrochloride 0.665 benzalkonium chloride 0.01 disodium edetate hydrate 0.01 sodium chloride 0.41 disodium hydrogen phosphate 0.5 anhydrous sodium hydroxide q.s. hydrochloric acid q.s. purified water q.s. (until reaching 100%) Total 100.0

(Production Method)

[0037] To purified water were added disodium hydrogen phosphate anhydrous, sodium chloride, disodium edetate hydrate, benzalkonium chloride, and olopatadine hydrochloride, while stirring. In order to dissolve each ingredient, appropriate quantities of diluted hydrochloric acid were added thereto with a moderate time interval. Purified water was added thereto, the pH was measured, the pH was adjusted to pH 3.7 optionally by adding hydrochloric acid or sodium hydroxide, and then purified water was added thereto to adjust the total weight.

(Evaluation Result)

[0038] The evaluation results of the obtained nasal preparation are shown below.

TABLE-US-00006 Aspect A clear, colorless liquid pH 3.7 viscosity (mPa .Math. s) 3 osmolality (mOs/L) 278 Mean liquid particle size (μm) 51.8 Liquid particle size of 10 to 91.4 100 μm (%)

REFERENCE EXAMPLE 2

(Production Composition)

[0039]

TABLE-US-00007 Ingredients Amount (% by weight) olopatadine hydrochloride 0.665 benzalkonium chloride 0.01 disodium edetate hydrate 0.01 sodium chloride 0.41 disodium hydrogen phosphate 0.5 anhydrous sodium hydroxide q.s. purified water q.s. (until reaching 100%) Total 100.0

(Production Method)

[0040] To purified water were added disodium hydrogen phosphate anhydrous, sodium chloride, disodium edetate hydrate, benzalkonium chloride, and olopatadine hydrochloride, while stirring. In order to dissolve each ingredient, the mixture was warmed to about 60° C. and stirred for an adequate time. Purified water was added thereto, the pH was measured, the pH was adjusted to pH 5.0 by adding sodium hydroxide, and then purified water was added thereto to adjust the total weight.

(Evaluation Result)

[0041] The evaluation results of the obtained nasal preparation are shown below.

TABLE-US-00008 Aspect A clear, colorless liquid pH 5.5 viscosity (mPa .Math. s) 3 osmolality (mOs/L) 279 Mean liquid particle size (μm) 60.4 Liquid particle size of 10 to 88.1 100 μm (%)

Solubility-Stability Test of Olopatadine

Liquid Sample for Comparative Test

(1) Patanase™ (Lot No.: 7FPS1A) (Concentration pH 3.8)

[0042] The content liquid was taken out of the product container, and put into a glass container to be a sample.

[0043] (2) A liquid prepared by dissolving olopatadine hydrochloride in purified water, adjusting the concentration of olopatadine to 0.6% (w/w), and then adjusting pH to 3.8 with L-arginine (stored in a glass container)

(3) A liquid prepared by dissolving olopatadine hydrochloride in purified water, adjusting the concentration of olopatadine to 0.6% (w/w), and then adjusting pH to 3.8 with sodium hydroxide (stored in a glass container)
(4) A liquid prepared by dissolving olopatadine hydrochloride in purified water, adjusting the concentration of olopatadine to 0.6% (w/w), and then adjusting pH to 5.5 with L-arginine (stored in a glass container)
(5) A liquid prepared by dissolving olopatadine hydrochloride in purified water, adjusting the concentration of olopatadine to 0.6% (w/w), and then adjusting pH to 5.5 with sodium hydroxide (stored in a glass container)

(Evaluation Method)

[0044] Each sample of (1)-(5), as well as Examples 1 and 2, and Reference example 1 were put into a glass container to be each sample for solubility stability test. The observation was done grossly.

o: confirmed to be in soluble state (clear).
x: confirmed that a crystal was precipitated.

(Result)

[0045]

TABLE-US-00009 Storage condition 1 month later 3 months later 1 month 3 months Concentration Shortly after 1 day after at room at room later later of olopatadine pH preparation preparation temperature temperature at 5-10° C. at 5-10° C. (1) 0.6% 3.8 ∘ shortly ∘ ∘ ∘ ∘ ∘ after taking out (2) 0.6% 3.8 ∘ ∘ ∘ ∘ ∘ ∘ (3) 0.6% 3.8 ∘ ∘ ∘ ∘ ∘ ∘ (4) 0.6% 5.5 ∘ x x x x x (5) 0.6% 5.5 ∘ x x x x x Example 1 0.4% 5.5 ∘ ∘ ∘ ∘ ∘ ∘ Example 2 0.6% 5.5 ∘ ∘ ∘ ∘ ∘ ∘ Reference 0.6% 3.8 ∘ ∘ ∘ ∘ ∘ ∘ example 1 Reference 0.6% 5.5 ∘ x x x x x example 2

INDUSTRIAL APPLICABILITY

[0046] The present invention is expected to be an aqueous spray-type nasal drop composition comprising olopatadine free base or an equivalent pharmaceutically acceptable salt thereof, wherein olopatadine is stably dissolved at physiologically-acceptable pH, which has a high viscocity and thus has a good retention in the nasal cavity after spray-administration, and thereby also has suspended pharmacological effect.