Nasal composition comprising olopatadine

Abstract

The present invention relates to a composition wherein olopatadine is stably in solution state, and a process for preparing the composition.

Description

[Technical Field]

[0001] This invention relates to a composition of olopatadine that exists stably in a dissolved state and a method for manufacturing the same. This invention can also be used to treat allergic rhinitis. [Previous Technology]

[0002] Europalate is currently used as an antihistamine in the treatment of allergic rhinitis and allergic conjunctivitis. Patent Document 1 discloses a nasal drop of Europalate hydrochloride, specifically an invention for the treatment and / or prevention of allergic rhinitis or inflammatory diseases. It is a formulation of Europalate containing 0.54 to 0.62% (w / v) of Europalate as a free base and with the pH adjusted to 3.6 to 3.8.

[0003] Regarding the product according to the patent document, 0.6% PATANASE (registered trademark) (Europalate nasal solution) is currently the only Europalate nasal drop product commercially available for nasal use. According to the label information, it contains Europalate hydrochloride equivalent to 0.6% Europalate, 0.01% benzyl ammonium chloride, and unspecified amounts of disodium hydrogen phosphate, sodium edetate hydrate, sodium chloride, hydrochloric acid and / or sodium hydroxide (for pH adjustment) and purified water, but the pH is adjusted to approximately 3.7, which is extremely irritating to the nasal mucosa.

[0004] Moreover, an ophthalmic solution product with the same composition as PATANASE (registered trademark) and with pH adjusted to about 7 is also sold as PATANOL (registered trademark). However, since Europalate is difficult to dissolve near neutral, the concentration converted to Europalate free base is an extremely low value of 0.1%.

[0005] Patent Document 1 has already examined the poor solubility of europetrazol in detail. It presents two "pH-solubility curves of europetrazol", both of which show that when the pH exceeds 5, it cannot dissolve europetrazol, which is equivalent to more than 0.2% of europetrazol free base. Therefore, when europetrazol is to be prepared in a dissolved state, if the concentration is more than 0.2%, the pH must be adjusted to 3.6 to 3.8. From the point of view of nasal mucosal irritation, it is physiologically unacceptable not only as an eye drop component but also as a nasal drop component.

[0005] [Previous Technical Documents]

[0005] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent No. 5149308

[0007] In preparing the nasal spray composition of europetrazol, which is poorly soluble in slightly acidic to neutral conditions, the present invention addresses the issue that the pH of the nasal cavity of adults varies between 5.5 and 6.5. Therefore, the object of the present invention is to develop a pharmaceutical composition having a suitable pH range of 4.0 to 7.0, preferably 4.5 to 6.5, and more preferably 5.0 to 6.0, without significantly deviating from this pH range and exhibiting low physiological irritation. In this range, europetrazol remains dissolved even at high concentrations and has excellent retention in the nasal cavity after spraying.

[0008] In view of the above-mentioned problems, the inventors, through dedicated and repeated research, discovered that in a nasal spray composition containing europetidine, which is poorly soluble in water, by containing a carboxyethylene polymer used as a thickener or thickener, rather than using a solvent or cosolvent, europetidine can maintain a high concentration and stable solubility even in the pH range of 5.0 to 6.0, thus completing the present invention.

[0009] The state of the present invention is as follows.

[0010] [Item 1] A nasal drop composition comprising europetidine or a pharmaceutically permissible salt thereof, and a carboxyethylene polymer, wherein the pH is adjusted to 4.0 to 7.0 (preferably 4.5 to 6.5, more preferably 5.0 to 6.0).

[0011] [Item 2] The nasal drop composition as described in Item 1, wherein europetidine or a pharmaceutically permissible salt thereof is a hydrochloride salt, and europetidine hydrochloride salt is present at a concentration of 0.2% (w / w) or higher and is in a dissolved state.

[0012] [Item 3] The nasal drop composition as described in item 1 or 2, wherein the carboxyethylene polymer is present at a concentration of 0.1 to 2% (by weight).

[0013] [Item 4] The nasal drop composition as described in any one of items 1 to 3, wherein L-arginine and / or sodium hydroxide and / or hydrochloric acid are used as pH adjusters for adjusting pH.

[0014] [Item 5] The nasal drop composition described in any one of items 1 to 4 contains one or more preservatives.

[0015] [Item 6] The nasal drop composition as described in Item 5, wherein the preservative comprises benzyl alkyl chloride.

[0016] [Item 7] A nasal drop composition as described in Item 5 or 6, wherein the preservative comprises sodium edetate hydrate.

[0017] [Item 8] The nasal drop composition described in any one of items 1 to 7 further comprises one or more isotonicity agents.

[0018] [Item 9] The nasal drop composition as described in Item 8, wherein the isotonic adjuster comprises sodium chloride and / or glycerin.

[0019] [Item 10] The nasal drop composition as described in Item 8 or 9, wherein the isotonic adjuster is present at a concentration of 0.1 to 10% (by weight).

[0020] [Item 11] The nasal filling composition as described in any one of items 1 to 10 is isotonic.

[0021] [Item 12] A nasal drop composition as described in any one of items 1 to 11, wherein the viscosity is 250 to 2500 mPa·s (preferably 500 to 1500 mPa·s).

[0022] [Item 13] A nasal droplet composition as described in any one of items 1 to 12, which, when sprayed, has an average droplet diameter of 30 to 100 μm.

[0023] [Item 14] A nasal drop composition as described in any one of items 11 to 13, wherein the pH adjuster is L-arginine and sodium hydroxide, the preservative is sodium edetate hydrate and benzyl ammonium chloride, and the isotonic agent is glycerol and sodium chloride.

[0024] [Item 15] A nasal spray formulation comprising the nasal drop composition described in any one of items 1 to 14.

[0025] [Item 16] A nasal drop formulation, which is prepared by means of adding a carboxyethylene polymer to dissolve europetidine in the range of pH 5.0 to 6.0.

[0026] According to the present invention, in a spray-type nasal spray containing an aqueous solution of europetidine or a pharmaceutically permissible salt thereof, the europetidine is in a dissolved state, and the pH is adjusted to 5.0 to 6.0, which is physiologically more acceptable as a nasal spray. After being sprayed into the nasal cavity, the agent is easily retained in the nasal cavity, and a sustained and effective improvement in efficacy can be expected.

Implementation Method

[0027] Europalate is a compound having the structure shown in the following formula, and is currently used as an antihistamine in the treatment of allergic rhinitis and allergic conjunctivitis.

[0027]

[0028] Regarding europetrazol, it is preferable to use europetrazol or its salt to prepare the nasal drop formulation, specifically europetrazol hydrochloride. The concentration of europetrazol contained in the formulation of the present invention, as europetrazol hydrochloride, is preferably 0.2% (by weight) or more, preferably 0.4% to 0.8% (by weight), and more preferably 0.4% to 0.7% (by weight).

[0029] “Pharmaceuticalally permissible salts” are those that will not cause adverse effects such as toxicity when used on humans or animals, and there are no special restrictions. Examples of acid addition salts include: hydrochloride, citrate, succinate, hydrobromide, ascorbate, furoate, sulfate, acetate, valerate, oleate, palmitate, laurate, stearate, hydrogen sulfate, borate, benzoate, lactate, phosphate, methanesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, gluconate, lactobionate, and lauryl sulfate, etc. Examples of salts that react with bases include: alkali metal salts such as sodium and potassium; and alkaline earth metal salts such as calcium and magnesium.

[0030] There are no particular restrictions on the use of carboxyethylene polymers in general formulations. Preferably, the viscosity of the carboxyethylene polymer is adjusted by applying an external shear force, the method and effect of which are described in WO 2007 / 123193. Specifically, conventional shear force-applying devices such as high-speed rotary emulsifiers, colloid mill emulsifiers, high-pressure emulsifiers, roller mill emulsifiers, ultrasonic emulsifiers, and film emulsifiers can be used. In particular, high-speed rotary emulsifiers of the homogenizing, comb-type, and intermittent jet generation types are preferred. The concentration of the carboxyethylene polymer is 0.1 to 2% (w / w), preferably 0.25 to 1.0%.

[0031] Examples of preservatives used in this invention include: benzalkonium chloride, benzethonium chloride, chlorobutanol, and / or sodium edetate hydrate, with benzalkonium chloride and / or sodium edetate hydrate being preferred. The concentration of the preservative is 0.005 to 1% (by weight), preferably 0.01 to 0.1%.

[0032] The aqueous nasal drop composition of the present invention is intended to be isotonic or near isotonic. Isotonicity can be adjusted using isotonic adjusters such as sodium chloride, boric acid, glycerin, and / or glucose. Here, the concentration of the isotonic adjuster is 0.1 to 10% (w / w), preferably 0.1 to 1.0%.

[0033] The pH of the aqueous nasal drop composition of the present invention must be adjusted to 4.0 to 7.0 (preferably 4.5 to 6.5, and even more preferably 5.0 to 6.0). In adjusting the pH, sodium hydroxide, potassium hydroxide, L-arginine, hydrochloric acid, etc. are used as pH adjusters, and sodium hydroxide and / or L-arginine are preferred.

[0034] The viscosity of the aqueous nasal drop composition of the present invention is generally 250 to 2500 mPa·s, preferably 500 to 1500 mPa·s.

[0035] The "nasal drop composition" in this invention refers to an aqueous composition in a dissolved state, that is, an aqueous solution.

[0035] In this invention, "dissolved state" refers to the state in which the target pharmaceutical ingredient is completely dissolved, and "dispersed state" refers to the state in which the target pharmaceutical ingredient does not precipitate crystals and is uniformly suspended.

[0036] The droplet diameter of the aqueous nasal droplet composition of the present invention refers to the droplet size during spraying, and the average droplet diameter is preferably 30 to 100 μm, and more preferably 40 to 80 μm.

[0037] "Nasal drops" refers to substances administered into the nasal cavity via droppers or sprays, and "nasal drop ingredients" refers to liquid preparations administered into the nasal cavity via drops or sprays.

[0037] The nasal spray preparation of the present invention is intended to be a nasal preparation filled in a general nasal sprayer, or an airless spray container with exhaust pressure as described in WO 2007 / 123193 and WO 2007 / 123207.

[0037] [Example]

[0038] Hereinafter, examples, comparative examples, and solubility tests are provided to illustrate the present invention in more detail, but the present invention is not limited thereto. Unless otherwise specified, the evaluation of the examples and comparative examples, and the evaluation of the solubility and stability tests conducted below are based on tests performed in accordance with the Japanese Pharmacopoeia.

[0039] The viscosity determination was performed in accordance with the Japanese Pharmacopoeia / General Test Method / Viscosity Determination Method / Rotation Viscometer Method, and the contents of the determination method are as follows.

[0039] [Determination Method]

[0039] To minimize the entry of air bubbles, 1.1 mL of the test sample (test preparation) was placed in the sample cup of a cone-plate type rotational viscometer (cone-plate type) pre-set to 20°C and left for 5 minutes. The viscosity value was then measured under the following conditions when a shear force was applied for 3 minutes.

[0039] [Measurement Conditions]

[0039] Machine used: TVE-25 viscometer from Toki Industrial Co., Ltd.

[0039] Measurement range: R (full-scale torque 1437.4 μN·m)

[0039] Shearing speed: 9.575s-1 (2.5 revolutions per minute)

[0039] Rotor: 1°34'×R24

[0040] The droplet size (average droplet size: 10 to 100 μm (%)) was determined using a laser diffraction particle size distribution measuring device.

[0040] [Measurement Conditions]

[0040] Machine used: Atomized particle size analyzer (Malvern Spraytech)

[0040] Reading distance: 30mm

[0040] Spray angle: 40°

[0040] Extrusion speed: 100mm / s

[0041] Example 1:

[0041] (Formula)

[0041]

[0041] (Manufacturing Method)

[0041] After dissolving L-arginine, sodium edetate hydrate, concentrated glycerol, and europetrazol hydrochloride in purified water, the mixture is added to a vacuum stirring apparatus. A liquid containing dissolved benzyl alkylate chloride is then added to the purified water, and the mixture is stirred. A liquid pre-dissolved in purified water with carboxyethylene polymer is added. These are then mixed and stirred in a vacuum stirring apparatus. If necessary, the pH is adjusted to 5.5 with sodium hydroxide solution or dilute hydrochloric acid, and then the mixture is stirred at high speed with additional shear until the viscosity reaches 1150 mPa·s, thus preparing a homogeneous nasal dot formulation.

[0042] (Assessment)

[0042] The evaluation results of the contents of the obtained nasal spray are presented below.

[0042]

[0043] Example 2:

[0043] (Formula)

[0043]

[0043] (Manufacturing Method)

[0043] After dissolving L-arginine, sodium edetate hydrate, concentrated glycerol, and europetrazol hydrochloride in purified water, the mixture is placed in a vacuum stirring apparatus. A liquid containing dissolved benzyl alkylate chloride is then added to the purified water, and the mixture is stirred. A liquid pre-dissolved in purified water with carboxyethylene polymer is added. These are then mixed and stirred in a vacuum stirring apparatus. If necessary, the pH is adjusted to 5.5 with sodium hydroxide solution or dilute hydrochloric acid, and then the mixture is stirred at high speed with additional shear until the viscosity reaches 1000 mPa·s. Finally, ethanol is added and the mixture is stirred to form a homogeneous nasal spray composition.

[0044] (Assessment)

[0044] The evaluation results of the contents of the obtained nasal spray are presented below.

[0044]

[0045] Comparative Example 1:

[0045] [Example 1 as described in Japanese Patent No. 5149308]

[0045] (Formula)

[0045]

[0045] (Manufacturing Method)

[0045] While stirring the purified water, add disodium hydrogen phosphate (anhydrous), sodium chloride, sodium edetate hydrate, benzyl ammonium chloride, and europetrazol hydrochloride. To dissolve each component, add an appropriate amount of dilute hydrochloric acid at appropriate times. Add purified water, measure the pH, and adjust it to 3.7 with hydrochloric acid and sodium hydroxide as needed, then add purified water to correct the weight.

[0046] (Assessment)

[0046] The evaluation results of the contents of the obtained nasal spray are presented below.

[0046]

[0047] Comparative Example 2:

[0047] (Formula)

[0047]

[0047] (Manufacturing Method)

[0047] While stirring purified water, add disodium hydrogen phosphate (anhydrous), sodium chloride, sodium edetate hydrate, benzyl ammonium chloride, and europetidine hydrochloride. To dissolve the components, heat to approximately 60°C and stir for an appropriate time to dissolve them. Add purified water, measure the pH, adjust to 5.0 with sodium hydroxide, and then add purified water to correct the weight.

[0048] (Assessment)

[0048] The evaluation results of the contents of the obtained nasal spray are presented below.

[0048]

[0049] [Europalate Indole Dissolution Stability Test]

[0049] Comparison test solution sample:

[0049] (1) Patanase™ (Batch No.: 7FPS1A) [Concentration pH 3.8]

[0049] The contents of the product container are removed and transferred to a glass container as a sample.

[0049] (2) To make the concentration of europetrazine 0.6% (w / w), europetrazine hydrochloride is dissolved in purified water and then prepared into a liquid with pH 3.8 using L-arginine (stored in a glass container).

[0049] (3) To make the concentration of europetrazine 0.6% (w / w), europetrazine hydrochloride is dissolved in purified water and then prepared into a liquid with a pH of 3.8 using sodium hydroxide (stored in a glass container).

[0049] (4) To make the concentration of europetrazine 0.6% (w / w), europetrazine hydrochloride is dissolved in purified water and then prepared into a liquid with pH 5.5 using L-arginine (stored in a glass container).

[0049] (5) To make the concentration of europetrazine 0.6% (w / w), europetrazine hydrochloride is dissolved in purified water and then prepared into a liquid with a pH of 5.5 using sodium hydroxide (stored in a glass container).

[0050] (Assessment Method)

[0050] Except for (1) to (5), the preparations of Examples 1 to 2 and Comparative Example 1 were filled into glass containers to prepare specimens for the dissolution stability test and observed by the naked eye.

[0050] ○: Confirmed to be in a dissolved state (transparent).

[0050] ×: Crystallization has been confirmed.

[0051] (Experimental Results)

[0051]

[0051] [Industrial Applicability]

[0052] According to the present invention, an aqueous nasal spray composition is prepared with a physiologically acceptable pH to form a free base of eurapate or an equal amount of pharmaceutically permissible salt of eurapate. This composition stably dissolves eurapate and is at a high concentration. Therefore, after the drug is sprayed into the nasal cavity, it is easy to remain in the nasal cavity, and a sustained and effective improvement in efficacy can be expected.

Claims

1. A nasal drop formulation comprising europetidine or a pharmaceutically permissible salt thereof, and a carboxyethylene polymer, wherein the pH is adjusted to 4.0 to 7.

0.

2. The nasal drop composition as described in claim 1, wherein, Europalate or its pharmaceutically permissible salts are hydrochloride salts, with a concentration of 0.2% (w / w) or higher and in a dissolved state.

3. The nasal filling composition as described in claim 1 or 2, wherein, The carboxyethylene polymer system exists at a concentration of 0.1% to 2% (by weight).

4. The nasal filling composition as described in any one of claims 1 to 3, wherein, To adjust the pH, L-arginine and / or sodium hydroxide and / or hydrochloric acid are used as pH adjusters.

5. The nasal drop composition described in any one of claims 1 to 4 contains one or more preservatives.

6. The nasal drop composition as described in claim 5, wherein, The preservative contains benzyl alkyl ammonium chloride.

7. The nasal drop composition as described in claim 5 or 6, wherein, The preservative contains sodium edetate hydrate.

8. The nasal drop composition described in any one of claims 1 to 7 further comprises one or more isotonic adjusters.

9. The nasal drop composition as described in claim 8, wherein, Isotonic modifiers contain sodium chloride and / or glycerin.

10. The nasal filling composition as described in claim 8 or 9, wherein, The isotropic modifier is present at a concentration of 0.1% to 10% (by weight).

11. The nasal filling composition as described in any of claims 1 to 10 is isotropic.

12. The nasal filling composition as described in any one of claims 1 to 11, wherein, The viscosity ranges from 250 to 2500 mPa·s.

13. The nasal droplet composition as described in any one of claims 1 to 12 has an average droplet diameter of 30 to 100 μm when sprayed.

14. A nasal filling composition as described in any one of claims 11 to 13, wherein, The pH adjuster is L-arginine and sodium hydroxide, the preservatives are sodium edetate hydrate and benzyl ammonium chloride, and the isotonic agent is glycerol and sodium chloride.

15. A nasal filling composition as described in any one of claims 1 to 14, wherein, Adjust the pH to 4.5 to 6.

5.

16. A nasal filling composition as described in any one of claims 1 to 14, wherein, Adjust the pH to 5.0 to 6.

0.

17. A nasal spray formulation comprising the nasal drop composition described in any one of claims 1 to 16.

18. A nasal drop formulation comprising using europetidine at pH 5.0 to [a specific pH value is missing here]. It is prepared by dissolving within the range of 6.0.