JP2010280722A - Nasal drop - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a nasal drop reduced in stimulation caused at the time of rhinenchysis of steroid. <P>SOLUTION: The nasal drop reduced in stimulation is obtained by bringing the nasal drop to contain (A) one or more selected from the group consisting of beclomethasone, its derivatives, solvates thereof, and salts thereof, (B) one or more selected from the group consisting of menthol, camphor, borneol, and geraniol, and (C) one or more selected from the group consisting of chlorobutanol, lidocaine, dibucaine, procaine, procainamide, methyl aminobenzoate, and salts thereof. In addition, the nasal drop further reduced or eliminated in stimulation is obtained by bringing the nasal drop to contain a viscosifying agent such as propylene glycol alginate. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to steroid nasal drops with reduced irritation.

  In recent years, the number of allergic rhinitis patients caused by pollen, house dust, etc. has been rapidly increasing, and treatments in which antiallergic agents, steroidal agents, leukotriene antagonists, thromboxane A2 antagonists, etc. are administered by oral administration or instillation are performed. It is. Administration of these drugs is a symptomatic treatment. In an environment where antigens such as pollen cannot be removed to an acceptable level or below, symptoms will appear as long as the antigen is present in the patient's area. Cannot be obtained.

Currently used steroidal compounds include flunisolide, beclomethasone propionate, fluticasone propionate, etc., which are known to show excellent medicinal properties against nasal inflammation, but any nasal drops are administered The feeling of irritation at times is a problem. Especially when inflammatory symptoms are present in the nasal cavity, the surface of the nasal mucosa is very sensitive, causing side effects such as further discomfort caused by irritation. This is a very important issue.
As a method for alleviating irritation of steroid nasal drops, an aqueous anti-inflammatory steroid preparation containing propylene glycol, polyethylene glycol 400 and polysorbate 20 suitable for nasal administration without tingling (Patent Document 1: Japanese Patent No. 2521291) However, menthol and chlorobutanol are not mentioned.

  It is also known that menthol and chlorobutanol can improve discomfort such as irritation and stinging with nonsteroidal antiallergic drugs. Specifically, suplatast, pemirolast, ketotifen, levocabastine and their salts, known as non-steroidal antiallergic drugs, cause unpleasant sensations such as irritation due to their chemical composition during nose drops or eye drops However, it is known that the feeling of use is improved by blending menthol, camphor, mint oil, eucalyptus oil, peppermint oil, chlorobutanol and menthyl lactate which are the refreshing agents (Patent Document 2: JP-A-2002). -205942). Moreover, it is known that an ophthalmic solution containing menthol and chlorobutanol mixed with sodium cromoglycate does not cause eye pain and has a feature of suppressing eye itching for a long time (Patent Document 3: JP 2002-128671 A). Publication). However, these all improve the problems of non-steroidal anti-allergic drugs, and no investigation has been made on steroidal compounds such as flunisolide.

Japanese Patent No. 2521291 JP 2002-205942 A JP 2002-128671 A

  An object of the present invention is to provide a nasal drop that is highly safe and has significantly improved irritation in the nasal cavity.

  As a result of intensive studies to solve the above problems, the present inventors have found that at least one or more of flunisolide, beclomethasone and their derivatives, one or two selected from the group consisting of menthol, camphor, borneol and geraniol. It was found that the irritation at the time of administration was remarkably reduced by blending one or two or more selected from the group consisting of the above and chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate. . Furthermore, it discovered that the nasal drop which was further excellent in the usability | use_condition can be obtained by mix | blending a thickener.

That is, the present invention is a nasal drop shown in the following (1) to (4).
(1) (A) one or more selected from the group consisting of flunisolide, beclomethasone and derivatives thereof, (B) one or more selected from the group consisting of menthol, camphor, borneol and geraniol, and (C) A nasal drop containing one or more selected from the group consisting of chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate.
(2) The nasal drop according to (1), further containing a thickening agent.
(3) The nasal preparation according to (1) or (2), wherein the thickening agent is at least one of polyethylene glycol, glycerin, hydroxypropyl cellulose, or propylene glycol alginate.
(4) The nasal drop according to any one of (1) to (3), wherein the pH is in the range of 4.0 to 9.0.
In the present specification, unless otherwise specified,% means w / v%.

  In the present invention, the nasal drops containing any one or more of flunisolide and beclomethasone, one or more of menthol, camphor, borneol or geraniol, chlorobutanol, lidocaine, dibucaine, procaine, procainamide or aminobenzoic acid By containing any one or more of methyl, unpleasant sensation accompanied by irritation to the nasal mucosa caused by these steroid compounds is improved. Furthermore, when a thickening agent such as polyethylene glycol, glycerin, hydroxypropyl cellulose, propylene glycol alginate or the like is contained, this discomfort can be further reduced, and a more suitable nasal agent can be obtained.

  Flunisolide, beclomethasone and derivatives thereof used in the present invention are known compounds, and may be synthesized by a known method or obtained as a commercial product. These flunisolide, beclomethasone and derivatives thereof can be used alone or in combination of two or more.

As derivatives of flunisolide and beclomethasone used in the present invention, ester derivatives [eg, monocarboxylic acid esters (such as acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, furancarboxylic acid, pivalic acid, etc.), polyvalent carboxylic acids Esters (fumaric acid, maleic acid, etc.), oxycarboxylic acid esters (lactic acid, tartaric acid, citric acid, succinic acid, malonic acid, etc.), organic sulfonic acid esters (methanesulfonic acid, tosylic acid ester, etc.)], ether derivatives [ For example, methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, etc.] can be exemplified.
Flunisolide, beclomethasone and derivatives thereof used in the present invention can also be used in the form of solvates such as hydrates.
Of the flunisolide, beclomethasone and derivatives thereof used in the present invention, flunisolide, flunisolide hemihydrate, and beclomethasone propionate are particularly preferred.

  In the present invention, flunisolide, beclomethasone and derivatives thereof may be pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate). Acid salt), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.) Etc.], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, Salts with organic amines such as pyrrolidine, tripyridine, picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), Alkaline earth metals (calcium, magnesium etc.) and salts with metals such as aluminum or the like].

  The blending amount of flunisolide in the nasal drops of the present invention is usually 0.001 to 0.05%, preferably 0.003 to 0.03%, more preferably 0.005 to the total amount of flunisolide and flunisolide derivatives. 0.015%. The amount of beclomethasone is generally 0.006 to 0.3%, preferably 0.015 to 0.15%, and more preferably 0.03 to 0.1% as the total amount of beclomethasone and beclomethasone derivatives. .

  The dose of flunasolide, beclomethasone and derivatives thereof of the nasal preparation of the present invention to each nasal cavity per one time is the total amount of each component (from the viewpoint of avoiding the occurrence of side effects while sufficiently exerting the effect) For example, the total amount of flunisolide and flunisolide derivatives) is preferably 1 to 100 μg, more preferably 5 to 50 μg, and even more preferably 10 to 25 μg. Further, the daily dose to each nasal cavity is preferably 10 to 1000 μg, more preferably 50 to 800 μg, and even more preferably 100 to 400 μg, but is not limited thereto.

Menthol or camphor used in the present invention is a compound described in the Japanese Pharmacopoeia, and borneol or geraniol is a compound described in the Pharmaceutical Additives Dictionary and can be obtained as a commercial product. In addition, menthol, camphor, borneol and geraniol may be derived from natural products or synthetic products, and may be any of d-form, l-form and dl-form. Furthermore, it may be used as an essential oil containing menthol, camphor, borneol and geraniol such as mint oil, spearmint oil, peppermint oil and mint oil without isolation and purification from plants.
The blending amount of menthol, camphor, borneol and geraniol in the nasal drops of the present invention is preferably 0.0001 to 0.5%, more preferably 0.001 to 0.1% as the total amount of each component, 0 0.003 to 0.05% is more preferable.

Chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate used in the present invention are compounds described in the Japanese Pharmacopoeia, and may be synthesized by known methods or obtained as commercial products. be able to.
In the present invention, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate may be pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), preferably hydrochloride, sulfate, nitrate, Hydrochloride is preferable, and specific examples include lidocaine hydrochloride.
The amount of chlorobutanol, lidocaine, dibucaine, procaine, procainamide and methyl aminobenzoate in the nasal drops of the present invention is preferably 0.01 to 5.0%, more preferably 0.05 to 1%. 0.1 to 0.5% is more preferable.

When a thickening agent is added to the nasal drop of the present invention, flunisolide and beclomethasone can further improve irritation to the nasal mucosa and prevent dripping after nasal drop, thus providing a more preferable nasal drop. can do. Examples of thickening agents include polyethylene glycol, polyoxyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, cellulose derivatives (cellulose ethers such as hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose or the like. Salt, etc.), propylene glycol alginate, gum arabic powder, carmellose sodium, xanthan gum, glycerin, magnesium aluminum silicate, sodium chondroitin sulfate, cyclodextrin, tragacanth powder, macrogol 4000, etc., polyethylene glycol, polyoxyethylene Glycol, hydroxypropylcellulose, alginic acid B propylene glycol, and glycerin are preferable.
0.001 to 20% is preferable, as for the compounding quantity of the thickener in the nasal drop of this invention, 0.005 to 18% is more preferable, and 0.01 to 15% is further more preferable.

  The nasal drops of the present invention can take various forms such as a drop type, a coating type, and a spray type. In the case of the spray type, manual pump type nasal drops with a mechanism for ejecting liquid by manually moving the pump attached to the container, compressed gas (air, oxygen, nitrogen, carbonic acid, mixed gas), etc. In addition, an aerosol type nasal spray having a mechanism in which a liquid agent is automatically ejected by moving a valve attached to the container and filling the container with the propellant is automatically included.

When applied to the nasal mucosa, the nasal drops of the present invention can be adjusted in pH so that unpleasant irritation is less likely to occur, and is usually 4.0 to 9.0, preferably 4.0 to 7 0.5, more preferably 4.5 to 7.0, and particularly preferably 4.5 to 6.5. As pH adjusters, boric acid, borax, phosphoric acid, acetic acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, citric acid, succinic acid, tartaric acid, malic acid, gluconolactone, ammonium acetate, hydrochloric acid , Sulfuric acid, polyphosphoric acid, potassium carbonate, sodium bicarbonate, sodium carbonate, ammonium bicarbonate, potassium hydrogen phosphate, sodium lactate, sodium citrate, potassium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine, diisopropanol Examples thereof include amines and triisopropanolamine.
Moreover, you may use a buffer agent for pH adjustment of the nasal drop of this invention. Examples of the buffer include known borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Good buffer, etc., preferably Good buffer, borate buffer, Phosphate buffer, carbonate buffer or citrate buffer, particularly preferably Good buffer, borate buffer, phosphate buffer or citrate buffer. “Good buffering agent” is a general term for aminoethanesulfonic acid derivatives and aminopropanesulfonic acid derivatives having a zwitterionic structure having buffering ability, and is a buffering agent devised by Good et al. Good buffering agents include MES, MOPS (3-morpholinopropanesulfonic acid), PIPES, HEPES (2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid), BES, TES and the like. . Examples of the boric acid buffer include boric acid, boric acid salts such as alkali metal borate salts and alkaline earth metal borate salts, and combinations of boric acid and boric acid salts. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates. Examples of the citrate buffer include citrates such as citric acid, alkali metal citrate salts, and alkaline earth metal citrate salts, and combinations of citric acid and citrate salts. Further, borate, phosphate or citrate hydrate may be used as borate buffer, phosphate buffer or citrate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium hydrogencarbonate, sodium carbonate, etc.), citric acid or a salt thereof (monosodium citrate, trisodium citrate, etc.).

  Furthermore, the nasal drops of the present invention include one or more active ingredients, preservatives, nonionic surfactants, fragrances and the like used in the nasal drops as needed, as long as the effects of the present invention are not hindered. Two or more types can be used in combination.

  Active ingredients: Vasoconstrictors such as epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, pseudoephedrine, antihistamines such as iproheptin, diphenhydramine, chlorpheniramine, acrinol, cetylpyridinium, benzalkonium, benzethonium, chlorhexidine Agents, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, glycol salicylate, allantoin, azulene, azulenesulfonic acid, guaiazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice and other anti-inflammatory agents, zinc white, zinc lactate, zinc sulfate Astringents such as indomethacin, ibuprofen, ibuprofen piconol, bufexamac, flufenamic acid Le, bendazac, piroxicam, ketoprofen, felbinac, lithospermi radix, horse chestnut, and the like salts thereof

  Preservatives: sodium benzoate, paraoxybenzoate ester, potassium sorbate, phenoxyethanol, hexanediol, boric acid, borax, etc.

  Nonionic surfactant: polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (eg, poloxamer 407, poloxamer 235, poloxamer 188, poloxamine, etc.); monolauric acid POE (20) sorbitan (polysorbate 20), POE sorbitan fatty acid esters such as monooleic acid POE (20) sorbitan (polysorbate 80); POE castor oil such as POE (60) castor oil, POE (60) hydrogenated castor oil or hydrogenated castor oil; POE (9) lauryl ether POE alkyl ethers such as POE (20) POP (4) POE alkyl ethers such as POP (4) cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether

  Fragrance: Terpineol, Cadinene, Anesol, Ferrandrene, Safrole, Eugenol, Linalol, Cinnamaldehyde, Citronellol, Limonene, Nerol, Estragol, Patchol Alcohol, Thymol, Benzyl Acetate, Linalyl Acetate, Jasmon, Indole, Mint Lactone, Piperidone, Octanol , Miltenol, Carvacrol, Ethylfuran, Ocymen, Cineol, Farnesol, Guaiol, Santalol, Cuminaldehyde, Cedrol, Santalol, Tsuyopsen, Globulol, Cedrene, Epiglobulol, Essential Oil, etc.

  The method for producing the nasal drops of the present invention is not particularly limited and can be produced by a known method. For example, after dissolving and suspending each of the above components in water or warm water in a conventional manner in an oily base as necessary, adjusting the pH, osmotic pressure, etc., to prepare a liquid, and further necessary Aseptic filtration is performed according to the above, and a nasal container is filled and manufactured.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

Example 1
Flunisolide 1/2 hydrate 0.0255g
l-Menthol 0.03g
Chlorobutanol 0.2g
Polyethylene glycol 10g
Benzalkonium chloride 0.01g
20g propylene glycol
Polysorbate 80 0.2g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.

Example 2
Flunisolide 0.02g
l-Menthol 0.02g
Chlorobutanol 0.3g
Lidocaine 0.1g
Glycerin 5g
Benzalkonium chloride 0.01g
10g of propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.

Example 3
Flunisolide 0.0125g
l-Menthol 0.01g
Chlorobutanol 0.1g
Propylene glycol alginate 0.1g
Naphazoline hydrochloride 0.05g
Benzethonium chloride 0.01g
15g propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.

Example 4
Flunisolide 0.0125g
d-Camphor 0.01g
Dibucaine hydrochloride 0.5g
Propylene glycol alginate 0.1g
Tetrahydrozoline hydrochloride 0.05g
Cetylpyridinium chloride 0.025g
15g propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.

Example 5
Flunisolide 0.0125g
d-borneol 0.03g
Procaine hydrochloride 0.5g
Propylene glycol alginate 0.1g
Pseudoephedrine hydrochloride 0.03g
Acrinol 0.05g
15g propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 5.5, and then filled into a nasal drop container to obtain a nasal drop.

Example 6
0.05 g beclomethasone propionate
Fluticasone propionate 0.026g
l-Menthol 0.03g
Chlorobutanol 0.2g
Hydroxypropylcellulose 0.1g
Benzalkonium chloride 0.01g
10g of propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.

Example 7
Flunisolide 0.0063g
Fluticasone propionate 0.013g
dl-Camphor 0.01g
Lidocaine hydrochloride 0.3g
Hydroxypropylcellulose 0.1g
Benzalkonium chloride 0.01g
10g of propylene glycol
Polysorbate 80 0.1g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.

Example 8
0.1 g of beclomethasone propionate
l-Menthol 0.01g
Chlorobutanol 0.1g
Propylene glycol alginate 0.1g
Benzethonium chloride 0.01g
8g propylene glycol
Polysorbate 80 0.2g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.

Example 9
0.1 g of beclomethasone propionate
dl-Camphor 0.01g
Lidocaine 0.5g
Propylene glycol alginate 0.1g
Benzethonium chloride 0.01g
8g propylene glycol
Polysorbate 80 0.2g
pH adjuster
Purified water
100ml
Each of the above components was weighed and dissolved in an appropriate amount of purified water, adjusted to pH 6.0, and then filled into a nasal drop container to obtain a nasal drop.

Test Example 1 Evaluation of irritation According to the formulation described in Table 1, each component was dissolved in purified water and adjusted to pH, and the total amount was adjusted to 100 mL and filled into a nasal spray container to prepare a nasal drop. 100 μl of this was sprayed once to 6 panelists, and the feeling of irritation immediately after nasal drop was evaluated. Evaluation was scored according to the following four-level evaluation criteria, and the average value was calculated as a score.
3: Very painful, 2: Painful, 1: Slightly painful, 0: Painless results are shown in Table 1.

From Comparative Examples 1 and 2, flunisolide is very irritating, and from Comparative Example 3 it can be seen that the irritation is moderated somewhat when chlorobutanol is added. Moreover, from the comparative example 4, when irritation | stimulation was mix | blended only with menthol, the irritation | stimulation became still stronger, but the degree of irritation | stimulation of Example 10 which mix | blended chlorobutanol and menthol simultaneously with the steroid was comparable as the comparative example 1. It was suppressed to.
Therefore, it has been clarified that the steroid compound alone has a problem in the feeling of use, and the menthol compound alone exhibits a behavior different from that of the nonsteroidal antiallergic agent, such as increasing irritation.

Test Example 2 Evaluation of irritation: Effect of thickening agent The irritation feeling when various thickening agents were added to Example 10 was further evaluated. In accordance with the formulation described in Table 2, nasal drops were prepared in the same manner as in Test Example 1, and 100 μl was sprayed once on 6 panelists, and evaluated according to the same criteria as in Test Example 1. Furthermore, the duration of stimulation was also measured, and the average value of 6 people was calculated as the average duration. The results are shown in Table 2.

  From Examples 11 and 12, when polyethylene glycol and glycerin were blended, the irritation score did not change, but the irritation duration was shortened, and the evaluation as a nasal spray with a better feeling of use than in Example 10 was obtained. It was. Further, from Examples 13 and 14, when hydroxypropylcellulose and propylene glycol alginate were blended, the irritation disappeared completely, and the evaluation was made as a nasal preparation with excellent usability.

Test Example 3 Evaluation of irritation According to the formulation described in Table 3, a nasal drop was prepared in the same manner as in Test Example 1, and 100 μl was dripped once into 6 panelists. Evaluated.
In addition, the duration of stimulation was also measured, and the average value of 6 people was calculated as the average duration.
The results are shown in Table 3.

From Comparative Examples 5 and 6, it can be seen that beclomethasone propionate is much more irritating than flunisolide, and from Comparative Examples 7 and 8, the addition of lidocaine, menthol or camphor reduces the irritation somewhat. On the other hand, in Example 15, in which lidocaine, menthol, and camphor were simultaneously added to the steroid, the irritation was surprisingly lost.
In addition, beclomethasone propionate has a unique odor, but the odor of the preparation could be improved by adding menthol and camphor.

From the above results, it was found that the irritating sensation produced upon administration of a nasal preparation containing a specific steroid compound can be alleviated by adding chlorobutanol, lidocaine or dibucaine, and menthol or camphor.
Furthermore, it was confirmed that a nasal agent having a better feeling of use can be obtained by blending a thickening agent such as polyethylene glycol, glycerin, hydroxypropyl cellulose, propylene glycol alginate.

Claims (1)

(A) One or more selected from the group consisting of beclomethasone, derivatives thereof, solvates thereof, and salts thereof, (B) one selected from the group consisting of menthol, camphor, borneol, and geraniol, or A nose preparation containing two or more, and (C) one or more selected from the group consisting of chlorobutanol, lidocaine, dibucaine, procaine, procainamide, methyl aminobenzoate and salts thereof.