Fluticasone furoate nasal preparation composition
阅读说明：本技术 糠酸氟替卡松鼻制剂组合物 (Fluticasone furoate nasal preparation composition ) 是由 上下泰造 宫崎隆 于 2019-06-07 设计创作，主要内容包括：本发明涉及包含糠酸氟替卡松和羧基乙烯基聚合物的药物组合物。(The present invention relates to pharmaceutical compositions comprising fluticasone furoate and carboxyvinyl polymers.)
1. A pharmaceutical composition comprising fluticasone furoate and a carboxyvinyl polymer.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is an aqueous suspension.
3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition comprises 0.1% (w/w) to 2% (w/w) carboxyvinyl polymer.
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises 0.005% (w/w) to 1% (w/w) fluticasone furoate.
5. The pharmaceutical composition of any one of claims 1 to 4, wherein the pharmaceutical composition further comprises at least one suspending agent.
6. The pharmaceutical composition of claim 5, wherein the suspending agent comprises polysorbate 80.
7. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition further comprises at least one preservative.
8. The pharmaceutical composition of claim 7, wherein the preservative comprises benzalkonium chloride.
9. The pharmaceutical composition of claim 7 or 8, wherein the preservative comprises disodium edetate.
10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition further comprises at least one tonicity agent.
11. The pharmaceutical composition of claim 10, wherein the tonicity agent comprises sodium chloride and/or glycerin.
12. The pharmaceutical composition of claim 10 or 11, wherein the pharmaceutical composition comprises 0.1% (w/w) to 10% (w/w) tonicity agent.
13. The pharmaceutical composition of any one of claims 1 to 12, wherein the pharmaceutical composition is isotonic.
14. The pharmaceutical composition of any one of claims 1 to 13, wherein the pH is 5 to 7.
15. The pharmaceutical composition of claim 14, wherein the pH is adjusted with sodium hydroxide and/or L-arginine.
16. The pharmaceutical composition of any one of claims 2 to 15, wherein the liquid particle size of the aqueous suspension has an average particle size of 30 to 100 μ ι η.
17. The pharmaceutical composition of claim 15 or 16, wherein the suspending agent comprises polysorbate 80, the preservative comprises disodium edetate and benzalkonium chloride, the tonicity agent comprises glycerin and sodium chloride, and the pH adjusting agent comprises L-arginine and sodium hydroxide.
18. A nasal spray formulation for intranasal administration, comprising the pharmaceutical composition according to any one of claims 1 to 17.
19. A method of stabilizing the suspensibility of an aqueous suspension comprising fluticasone furoate by the addition of carboxyvinyl polymer.
Technical Field
The present invention relates to homogeneous compositions comprising fluticasone furoate and processes for preparing such compositions. The present invention may also be used to treat allergic rhinitis.
Background
Corticosteroids having anti-inflammatory activity are widely used in the treatment of inflammatory diseases such as dermatitis, asthma and rhinitis. Fluticasone furoate is a corticosteroid, a glucocorticoid for topical use for reducing inflammation of the skin or airways, and has been marketed in the open market in the form of nasal drops for the treatment of allergic rhinitis (patent document 1).
Fluticasone furoate is slightly soluble in water. In order to increase the water solubility of fluticasone furoate for the preparation of nasal drops for the treatment of allergic rhinitis, it may be effective to add an organic solvent or additive such as ethanol for increasing the solubility. However, in view of administration to fragile nasal mucosa, it is difficult to use irritant organic solvents such as ethanol in nasal drops, or there is a limit to select safe solubilizers which are less irritating to nasal mucosa. After all, fluticasone furoate nasal drops were developed as aqueous suspensions and the aqueous suspensions were already marketed in the open market (allermist (tm) nasal spray).
When nasal drops are developed as aqueous suspensions, it is important to select the suspending agent to be used therein. The selection should be made in consideration of the characteristics of the formulation. That is, the selection of the suspending agent may greatly affect the suspension characteristics such as suspension stability, redispersibility, spray performance, retentivity on mucous membranes (viscosity) and irritation of nasal mucous membranes, and also have no small influence on the efficacy or stability of the nasal drops (patent document 2).
After all, in the commercial Allermist nasal spray described above, microcrystalline cellulose and sodium carboxymethylcellulose (carmellose sodium) have been used as suspending agents. However, the suspension dispersibility of the formulation is not necessarily stable, and therefore the formulation contains a cue to shake the bottle before use. The fact that the dispersibility of the suspension is unstable means that the stability or sprayability of the pharmaceutical formulation is affected. Also, by shaking the formulation before use, the viscosity of the formulation is reduced, and such low viscosity makes it difficult to keep the formulation in the nasal cavity for a long time. Therefore, adverse effects on drug efficacy have attracted increasing attention.
Prior Art
[ patent document 1] WO 2002/012265
[ patent document 2] JP 4838493B
Disclosure of Invention
(problem of the technology)
One of the objects is to develop a pharmaceutical composition which is a nasal spray formulation as an aqueous suspension comprising fluticasone furoate which is poorly water soluble, which does not require shaking before use because the suspension dispersion state is stable and which has good retention in the nasal cavity after spray administration.
(solution of problem)
As a result of intensive studies on the above problems, it was found that fluticasone furoate can be brought into a very stable, unprecedented suspension-dispersed state by adding carboxyvinyl polymers which are generally used as viscosity agents or thickening agents and which do not belong to general suspending agents. The present invention has been completed based on the new findings.
The present invention can provide the following embodiments.
(item 1) a pharmaceutical composition comprising fluticasone furoate and a carboxyvinyl polymer.
(item 2) the pharmaceutical composition according to item 1, which is an aqueous suspension.
(item 3) the pharmaceutical composition according to item 1 or 2, which comprises 0.1% (w/w) to 2% (w/w) of the carboxyvinyl polymer.
(item 4) the pharmaceutical composition according to any one of items 1 to 3, comprising 0.005% (w/w) to 1% (w/w) fluticasone furoate.
(item 5) the pharmaceutical composition according to any one of items 1 to 4, further comprising at least one suspending agent.
(item 6) the pharmaceutical composition according to item 5, wherein the suspending agent comprises polysorbate 80.
(item 7) the pharmaceutical composition according to any one of items 1 to 6, further comprising at least one preservative.
(item 8) the pharmaceutical composition according to item 7, wherein the preservative comprises benzalkonium chloride.
(item 9) the pharmaceutical composition according to item 7 or 8, wherein the preservative comprises disodium edetate.
(item 10) the pharmaceutical composition according to any one of items 1 to 9, further comprising at least one tonicity agent.
(item 11) the pharmaceutical composition according to item 10, wherein the tonicity agent comprises sodium chloride and/or glycerin.
(item 12) the pharmaceutical composition according to item 10 or 11, which comprises 0.1% (w/w) to 10% (w/w) tonicity agent.
(item 13) the pharmaceutical composition according to any one of items 1 to 12, which is isotonic.
(item 14) the pharmaceutical composition according to any one of items 1 to 13, wherein the pH is 5 to 7.
(item 15) the pharmaceutical composition according to item 14, wherein the pH is adjusted with sodium hydroxide and/or L-arginine.
(item 16) the pharmaceutical composition according to any one of items 2 to 15, wherein the liquid particle size of the aqueous suspension has an average particle size of 30 μm to 100 μm.
(item 17) the pharmaceutical composition according to item 15 or 16, wherein the suspending agent comprises polysorbate 80, the preservative comprises disodium edetate and benzalkonium chloride, the tonicity agent comprises glycerin and sodium chloride, and the pH adjuster comprises L-arginine and sodium hydroxide.
(item 18) a nasal spray formulation for intranasal administration, which comprises the pharmaceutical composition of any one of items 1 to 17.
(item 19) a method for stabilizing the suspensibility of an aqueous suspension comprising fluticasone furoate by adding carboxyvinyl polymer.
(Effect of the invention)
Due to the findings of the present invention, the suspensibility of the nasal spray formulation comprising fluticasone furoate as an aqueous suspension has been largely stabilized and does not require shaking before use. In addition, since shaking is not required before use, the problem of viscosity reduction due to shaking is eliminated. Therefore, it is desirable to keep the drug in the nasal cavity for a long time after it is administered therein, and to improve the drug efficacy so that it is sustainable and effective.
Detailed Description
Fluticasone furoate is the generic name for 6 α, 9-difluoro-17 β - [ (fluoromethylthio) carbonyl ] -11 β -hydroxy-16 α -methyl-3-oxoandrosta-1, 4-dien-17 α -ylfuran-2-carboxylate, the chemical structure of which is shown below, which has been widely used in the treatment of allergic rhinitis. The content of fluticasone furoate in the formulation of the present invention is 0.005% (w/w) to 1% (w/w), preferably 0.025 to 0.1%.
The carboxyvinyl polymer used herein should not be limited as long as it is generally used in medical preparations. Preferably, it is a carboxyvinyl polymer whose viscosity is adjusted by the addition of external shear force. The conditioning methods and effects of modified carboxyvinyl polymers are disclosed in WO 2007/123193. For example, the external shearing force may be added by a known device that provides a shearing force, such as a high-speed rotary type emulsifying device, a colloid mill type emulsifying device, a high-pressure emulsifying device, a roll mill type emulsifying device, an ultrasonic type emulsifying device, and a film type emulsifying device. In particular, a homomixer type, a comb-tooth type, an intermittent jet flow generation type, and a high-speed rotary type emulsification apparatus are preferable. The content of the carboxyvinyl polymer is 0.1% (w/w) to 2% (w/w), preferably 0.25% to 1.0%.
Suspending agents for use herein include, for example, polysorbate 80, polyethylene glycol 40 stearate and/or polyoxyethylene hydrogenated castor oil 60, preferably polysorbate 80. The content of the suspending agent is 0.01% (w/w) to 1% (w/w), preferably 0.025% to 0.5%.
Preservatives useful herein include, for example, benzalkonium chloride, benzethonium chloride, chlorobutanol, and/or disodium edetate, with benzalkonium chloride and/or disodium edetate being preferred. The content of each preservative is 0.005% (w/w) to 1% (w/w), preferably 0.01% to 0.02%.
Preferably, the aqueous suspensions of the invention are isotonic or approximately isotonic. Isotonicity can be adjusted with tonicity agents such as sodium chloride, boric acid, glycerol and/or glucose. The content of each tonicity agent is 0.1% (w/w) to 10% (w/w), preferably 0.1% to 1.0%.
The aqueous suspensions of the present invention preferably have a moderately acidic to about neutral pH, more particularly a pH of 5 to 7. The pH can be adjusted with sodium hydroxide, potassium hydroxide, L-arginine, etc., preferably sodium hydroxide and/or L-arginine.
The liquid particle diameter of the spray aqueous suspension of the present invention is preferably an average particle diameter of 30 μm to 100 μm, more preferably 40 μm to 80 μm.
The nasal spray formulation for intranasal administration of the present invention relates to a nasal spray formulation in a general nasal spray container or in a high-pressure release airless type spray container disclosed in WO2007/123193 and WO 2007/123207.
Examples
Hereinafter, the present invention is illustrated based on examples, reference examples and stability tests, but is not limited thereto. Unless otherwise stated, evaluation and stability test of examples and reference examples prepared below were performed according to "japanese pharmacopoeia".
The viscosity measurement was carried out by a cone-plate type rotational viscometer (20 ℃, 2.5 rpm) according to Japanese pharmacopoeia/general test/viscosity measurement method II rotational viscometer method 2.1.3, as described in detail below.
(measurement method)
1.1mL of the test sample (test preparation) was charged into a sample cup of a cone-plate type rotational viscometer (cone plate type) set at 20 ℃ in advance while taking care not to put air bubbles. The sample was allowed to stand for 5 minutes and then subjected to shear force for 3 minutes. Subsequently, the viscosity of the sample was measured according to the following conditions.
(measurement conditions)
The instrument comprises the following steps: toyobo industries Co Ltd TVE-25 type viscometer
Measurement range: r (full range torque 1437.4 μ N m)
Shear rate: 9.575s-1(2.5 revolutions per minute)
A rotor: 1 ℃ 34' XR 24
The liquid particle diameter (average liquid particle diameter 10 μm to 100 μm (%)) was measured by filling the prepared formulation into a nasal spray device having a 55mg (═ 50 μ L) spray-able pump, spraying the formulation, and analyzing the sprayed liquid particles with a laser diffraction/scattering particle diameter distribution analyzer according to the following conditions.
(measurement conditions)
The instrument comprises the following steps: malvern SprayTec
Reading distance: 30mm
Spraying angle: 40 degree
Extrusion speed: 100mm/s
Example 1
(production method)
Composition (I)
Amount (wt%)
Fluticasone furoate
0.05
Carboxyvinyl polymer
0.56
L-arginine
0.98
Polysorbate 80
0.1
Disodium edetate hydrate
0.05
Benzalkonium chloride
0.01
Concentrated glycerin
1.0
Sodium chloride
0.5
Purified water
Amount (96.75)
Total of
100.0
The carboxyvinyl polymer was dispersed, mixed and dissolved in purified water. To this solution was added a solution of L-arginine, disodium edetate hydrate and sodium chloride in purified water, and the mixture was stirred. A solution of benzalkonium chloride in purified water was added to the mixture, and the mixture was stirred. Separately, fluticasone furoate was wetted with concentrated glycerin, and polysorbate 80 and purified water were then added thereto. The mixture was uniformly dispersed to prepare a uniform wet solution of fluticasone furoate. A wet solution of fluticasone furoate was added to the solution containing carboxyvinyl polymer prepared above and the mixture was stirred to give a homogeneous nasal formulation.
(evaluation results)
The evaluation results of the obtained nasal preparation are shown below.
Example 2
(production method)
Composition (I)
Amount (wt%)
Fluticasone furoate
0.0275
Carboxyvinyl polymer
0.52
L-arginine
0.91
Polysorbate 80
0.1
Disodium edetate hydrate
0.05
Benzalkonium chloride
0.01
Sodium chloride
0.25
Ethanol
1.0
Purified water
Amount (97.1325)
Total of
100.0
A solution of L-arginine, disodium edetate hydrate, and sodium chloride in purified water was added to a vacuum mixer, then a solution of benzalkonium chloride and polysorbate 80 in purified water was added thereto, and the mixture was stirred. Separately, the carboxyvinyl 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 a vacuum mixer. Separately, fluticasone furoate was wetted with concentrated glycerin, and polysorbate 80 and purified water were then added thereto. After wetting the mixture, a wet solution of fluticasone furoate was added to the stirred mixture prepared above. The mixture was stirred in a vacuum mixer. Further, the mixture was subjected to a high-speed shearing force with stirring to adjust the viscosity to 1250mPa · s.
(evaluation results)
The evaluation results of the obtained nasal preparation are shown below.
Example 3
(production method)
Composition (I)
Amount (wt%)
Fluticasone furoate
0.0275
Carboxyvinyl polymer
0.53
L-arginine
0.95
Polysorbate 80
0.1
Disodium edetate hydrate
0.05
Benzalkonium chloride
0.01
Concentrated glycerin
1.0
Sodium chloride
0.5
Purified water
Amount (96.8325)
Total of
100.0
The carboxyvinyl polymer was dispersed, mixed and dissolved in purified water. To this solution was added a solution of L-arginine, disodium edetate hydrate and sodium chloride in purified water, and the mixture was stirred. A solution of benzalkonium chloride in purified water was added to the mixture, and the mixture was stirred. Separately, fluticasone furoate was wetted with concentrated glycerin, and polysorbate 80 and purified water were then added thereto. The mixture was thoroughly wetted. A wet mixture of fluticasone furoate was added to the mixture containing carboxyvinyl polymer prepared above and the resulting mixture was stirred in a vacuum mixer.
(evaluation results)
The evaluation results of the obtained nasal preparation are shown below.
Example 4
(production method)
Composition (I)
Amount (wt%)
Furoic acidFluticasone
0.05
Carboxyvinyl polymer
0.53
L-arginine
0.2
Polysorbate 80
0.1
Disodium edetate hydrate
0.05
Benzalkonium chloride
0.01
Sodium chloride
0.035
Concentrated glycerin
0.875
Ethanol
0.8
Purified water
Amount (97.1325)
Total of
100.0
A solution of L-arginine, disodium edetate hydrate, and sodium chloride in purified water was added to a vacuum mixer, then a solution of benzalkonium chloride and polysorbate 80 in purified water was added thereto, and the mixture was stirred. Separately, the carboxyvinyl 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 a vacuum mixer. Separately, fluticasone furoate was wetted with concentrated glycerin, and polysorbate 80 and purified water were then added thereto. After wetting the mixture, a wet solution of fluticasone furoate was added to the stirred mixture prepared above. The mixture was stirred in a vacuum mixer. Further, the mixture was subjected to a high-speed shearing force under stirring to adjust the viscosity to 1000mPa · s.
(evaluation results)
The evaluation results of the obtained nasal preparation are shown below.
Example 5
(production method)
Composition (I)
Amount (wt%)
Fluticasone furoate
0.05
Carboxyvinyl polymer
0.35
L-arginine
0.50
Polysorbate 80
0.025
Disodium edetate hydrate
0.015
Benzalkonium chloride
0.01
Sodium chloride
0.035
Concentrated glycerin
0.875
Ethanol
0.5
Purified water
Amount (97.64)
Total of
100.0
A solution of L-arginine, disodium edetate hydrate, and sodium chloride in purified water was added to a vacuum mixer, then a solution of benzalkonium chloride and polysorbate 80 in purified water was added thereto, and the mixture was stirred. Separately, the carboxyvinyl 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 a vacuum mixer. Separately, fluticasone furoate was wetted with concentrated glycerin, and polysorbate 80 and purified water were then added thereto. After wetting the mixture, a wet solution of fluticasone furoate was added to the stirred mixture prepared above. The mixture was stirred in a vacuum mixer. Further, the mixture was subjected to a high-speed shearing force under stirring to adjust the viscosity to 1000m Pa · s.
(evaluation results)
The evaluation results of the obtained nasal preparation are shown below.
Reference example 1(example 1 according to JP 4838493B)
(production method)
Glucose was dissolved in purified water to prepare a glucose solution, and disodium ethylenediaminetetraacetate hydrate was added thereto and dissolved. Avicel RC591 was added to the solution under stirring to prepare hydrated suspension a. Separately, polysorbate 80 was dissolved in purified water at 50 ℃ to 60 ℃, and fluticasone furoate was added thereto to prepare suspension B. Suspension a and suspension B were mixed and stirred. To the suspension mixture was added a solution of benzalkonium chloride in purified water, and the resulting mixture was stirred. To the mixture was added 1N hydrochloric acid to adjust the pH to 6.0. As shown in the above table, purified water was added thereto to adjust the total weight.
(evaluation results)
The evaluation results of the obtained nasal preparation are shown below.
Appearance of the product
White opaque suspension
pH
6.0
Viscosity (mPa. s)
38
Osmolarity (mOs/L)
278
Average liquid particle diameter (μm)
67
Liquid particle diameter of 10 to 100 μm (%)
84.4
Reference examples 2 to 6
In the same manner, each of the reference examples was prepared using each of the suspending agents shown in the following table.
1 to 5: each indicated amount is the amount of each suspending agent added to obtain sufficient viscosity.
(evaluation results)
The evaluation results of the obtained nasal preparation are shown below.
Stability test 1
The following tests were carried out using example 5, reference example 1 and the commercial product Allermeist 27.5. mu.g 56 metered dose nasal spray (hereinafter referred to as "Allermeist nasal spray").
(test method)
The test sample (test formulation) was sufficiently stirred, and then the test sample was taken out from the test sample in a homogeneous state. The content of fluticasone furoate in the test sample was determined by high performance liquid chromatography to obtain each initial content (content a) in a homogeneous state.
Then, 12g of each test sample in a homogeneous state was put into a 13.5mL glass screw cap bottle, and sufficiently shaken again to be in a homogeneous state. The bottled test specimen is left at ambient temperature for 24 hours or a week. Separately, freshly prepared test samples were centrifuged (5000rpm, 10 minutes).
The samples were evaluated for appearance and content of fluticasone furoate in each state before, after placing the samples in screw-cap vials and shaking, after standing for 24 hours and one week, and after centrifuging the samples. In determining the content, each test sample was divided into an upper layer (3g), a middle layer (4g) and the remaining lower layer (3 g). The upper and lower layers were weighed at 2g each as a test sample, and the respective content of fluticasone furoate (content B) was determined by high performance liquid chromatography. Suspension stability was evaluated according to a suspension stability ratio that can be given by the following formula.
Suspension stability ratio (%) - (content B)/(content a) x 100
(test results)
Change in appearance
Suspension stability
Stability test 2
The same test as stability test 1 was carried out using example 4 and reference examples 2 to 6, in which the measurement frequency was higher than that of stability test 1. The results are shown below.
Change in appearance
Suspension stability
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