JP4430616B2 - Aqueous suspension - Google Patents

Description

  The present invention relates to an aqueous suspension excellent in redispersibility of a poorly soluble drug, characterized by blending poly (polar charge side chain amino acid) and a nonionic surfactant.

When an aqueous suspension of a poorly soluble drug is stored for a long period of time, problems arise that the precipitated drug particles cause secondary aggregation such as caking or adhere to or adsorb to a container. For this reason, the drug particles do not easily disperse and need to be shaken for a long time during use.
In general, polymers and / or surfactants are used as suspending agents for poorly soluble drugs. For example, as an aqueous suspension with improved redispersibility, a composition containing a corticosteroid, a nonionic polymer, a nonionic surfactant and a nonionic tonicity agent (US Pat. No. 5,540,930) ), An aqueous suspension containing a water-soluble polymer and a poorly soluble drug in a concentration range in which the surface tension decreases from a concentration at which the surface tension of the liquid begins to decrease (Japanese Patent Laid-Open No. 11-29463), ionic An aqueous suspension type eye drop (JP-A-8-295622) of a poorly soluble drug containing a polymer (carboxyvinyl polymer, carboxymethylcellulose) and a metal ion and having a viscosity of 100 cP or less, a poorly soluble drug, polyvinylpyrrolidone, and Contains water-soluble anionic polymers (anionic polysaccharides, anionic polyvinyl polymers, anionic polymer polypeptides) Aqueous suspensions (WO 2002/15878 pamphlet) and the like.
In addition, as a composition containing an amino acid or a polyamino acid, for example, it contains an aliphatic amino acid having 2 to 7 carbon atoms in loteprednol etabonate. Suspensions (Japanese Patent Laid-Open No. 10-316572), detergent compositions using polyglutamic acid as a dispersant for stain-causing substances (WO 1993/06202), polysulphide as a suspending agent for inorganic and organic particles An aqueous suspension (US Pat. No. 5,284,512) containing aspartic acid is known.
However, by combining poly (polar charge side chain amino acids) and nonionic surfactants, aqueous suspension formulations with good redispersibility, which have improved aggregation suppression of the precipitated drug particles and release from the container Is not yet known.
An object of the present invention is to provide an aqueous suspension excellent in redispersibility of a poorly soluble drug.

The present inventor suppresses aggregation of the poorly soluble drug that has settled by blending poly (polar charge side chain amino acid) or a salt thereof and a nonionic surfactant, and prevents the poorly soluble drug from peeling from the container. It was found that the re-dispersibility was improved, and further research was conducted to complete the present invention.
The poly (polar charge side chain amino acid) of the present invention is a polymerized amino acid having a side chain having a polar charge such as an amino group or a carboxyl group in the side chain, and more specifically, an acid that is a monoaminodicarboxylic acid. Examples include polycondensates of amino acids [poly (acidic amino acids)] and polycondensates of basic amino acids that are diaminomonocarboxylic acids [poly (basic amino acids)].
That is, the present invention is as follows.
(1) an aqueous suspension containing a poorly soluble drug, poly (polar charge side chain amino acid) or a salt thereof, and a nonionic surfactant;
(2) The lower limit concentration of poly (polar charge side chain amino acid) or a salt thereof is 0.01 w / v%, the upper limit concentration is 1.0 w / v%, and the lower limit concentration of nonionic surfactant is 0.05 w / v. %, And the upper limit concentration is 1.0 w / v%, the aqueous suspension according to the above (1),
(3) The aqueous suspension according to the above (1), wherein the poorly soluble drug is a steroid,
(4) The aqueous suspension according to (3), wherein the steroid is at least one selected from loteprednol etabonate, prednisolone acetate, difluprednate, and fluorometholone,
(5) The aqueous suspension according to the above (1), wherein the poly (polar charge side chain amino acid) is poly (acidic amino acid),
(6) The aqueous suspension according to the above (5), wherein the poly (acidic amino acid) is polyglutamic acid,
(7) The aqueous suspension according to the above (1), wherein the nonionic surfactant is tyloxapol,
(8) The aqueous liquid preparation according to the above (1) to (7), which is an eye drop,
(9) The aqueous liquid preparation according to the above (1) to (7), which is a nasal drop,
(10) The aqueous liquid preparation according to the above (1) to (7), which is an ear drop,
(11) An aqueous solution containing 0.05 to 2 w / v% loteprednol etabonate, 0.01 to 1.0 w / v% polyglutamic acid or a salt thereof, and 0.05 to 1.0 w / v% tyloxapol. Suspension eye drops,
(12) A method for improving the redispersibility of an aqueous suspension by incorporating poly (polar charge side chain amino acid) or a salt thereof and a nonionic surfactant into an aqueous suspension of a poorly soluble drug. ,
(13) The lower limit concentration of poly (polar charge side chain amino acid) or a salt thereof is 0.01 w / v%, the upper limit concentration is 1.0 w / v%, and the lower limit concentration of the nonionic surfactant is 0.05 w / v. And the upper limit concentration is 1.0 w / v%.
The molecular weight of the poly (polar charge side chain amino acid) of the present invention is usually 500 or more, preferably 1000 or more, more preferably 5000 or more, still more preferably 8000 or more, and usually 1000000 or less, preferably 500000 or less, more preferably 200000 or less. More preferably, it is 150,000 or less.
Examples of the salt of poly (polar charge side chain amino acid) include, but are not limited to, alkali metal salts such as sodium salt and potassium salt, and inorganic acid salts such as hydrochloric acid.
Examples of poly (acidic amino acids) include polyglutamic acid and polyaspartic acid, and examples of poly (basic amino acids) include polylysine. Preferred is poly (acidic amino acid), and more preferred is polyglutamic acid.
As polyglutamic acid, poly-L-glutamic acid sodium salt manufactured by Peptide Institute, Inc. is preferably used.
The lower limit of the concentration of poly (polar charged side chain amino acid) or a salt thereof is usually 0.01 w / v%, preferably 0.025 w / v%, more preferably 0.05 w / v%, still more preferably 0.00%. 075 w / v%, particularly preferably 0.1 w / v%, the upper limit is usually 1.0 w / v%, preferably 0.8 w / v%, more preferably 0.6 w / v%, particularly preferably 0.5 w / v%.
Nonionic surfactants used in the present invention include tyloxapol, polyoxyl myristate, polysorbate 80, poloxamer and polyoxyethylene hydrogenated castor oil. Preferred is tyloxapol.
The lower limit of the concentration of the nonionic surfactant is usually 0.05 w / v%, preferably 0.06 w / v%, more preferably 0.08 w / v%, still more preferably 0.1 w / v%, and the upper limit is usually It is 1.0 w / v%, preferably 0.8 w / v%, more preferably 0.6 w / v%.
The poorly soluble drug used in the present invention is a term indicating the solubility of the 14th revised Japanese Pharmacopoeia, “dissolvable (the amount of solvent required to dissolve 1 g of drug is 100 ml or more and less than 1000 ml)”, “extremely insoluble ( The solubility is either “the amount of solvent required to dissolve 1 g of drug is 1,000 ml or more and less than 10000 ml” or “almost insoluble (the amount of solvent required to dissolve 1 g of drug is 10,000 ml or more)”.
The particle size of the poorly soluble drug suitable for the preparation of the aqueous suspension of the present invention is usually 0.1 to 75 μm, for example, when measured with a laser diffraction particle size distribution analyzer SALD-2100 manufactured by Shimadzu Corporation. Preferably it is 0.5-30 micrometers, More preferably, it is 2-10 micrometers.
Examples of poorly soluble drugs used in the present invention include steroids, anti-inflammatory analgesics, chemotherapeutic agents, synthetic antibacterial agents, antiviral agents, hormone agents, anti-cataract agents, angiogenesis inhibitors, immunosuppressants, protease inhibitors Steroids, aldose reductase inhibitors, etc. are preferred, and steroids are preferred. Examples of the steroid include loteprednol etabonate, prednisolone acetate, difluprednate, fluorometholone, prednisolone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, fluocinide, cortisone acetate, hydrocortisone acetate, fluticasone propionate, and the like. Preferred are loteprednol etabonate, prednisolone acetate, difluprednate and fluorometholone.
The average particle size of the poorly soluble drug used in the present invention varies depending on the drug used, but the upper limit is usually 75 μm, preferably 40 μm, more preferably 20 μm.
The concentration of the poorly soluble drug used in the present invention in the suspension varies depending on the drug used, but the lower limit is usually 0.001 w / v%, preferably 0.003 w / v%, more preferably 0.005 w / v. It is v%, more preferably 0.01 w / v%, and the upper limit is usually 5 w / v%, 3 w / v%, preferably 2 w / v%.
When a steroid is used, the lower limit is usually 0.003 w / v%, preferably 0.005 w / v%, and the upper limit is 3 w / v%, preferably 2 w / v%.
As the concentration of loteprednol etabonate, the lower limit is 0.05 w / v%, preferably 0.1 w / v%, more preferably 0.2 w / v%, and the upper limit is usually 2 w / v%, 1.5 w / v. %, Preferably 1 w / v%.
As the concentration of fluorometholone, the lower limit is usually 0.01 w / v%, preferably 0.02 w / v%, and the upper limit is usually 0.5 w / v%, preferably 0.2 w / v%.
As for the concentration of prednisolone acetate, the lower limit is usually 0.1 w / v%, preferably 0.5 w / v%, and the upper limit is usually 2 w / v%, preferably 1.5 w / v%.
As for the concentration of difluprednate, the lower limit is usually 0.01 w / v%, preferably 0.02 w / v%, and the upper limit is usually 0.5 w / v%, preferably 0.2 w / v%.
The weight ratio of poly (polar charge amino acid) and nonionic surfactant to steroid in the aqueous suspension of the present invention is usually 1: 0.01-50: 0.01-100, preferably 1: 0. 05-30: 0.02-50.
The weight ratio of poly (polar charge amino acid) and nonionic surfactant to loteprednol etabonate is usually 1: 0.05-5: 0.05-5, preferably 1: 0.1-3: 0.1-3.
The weight ratio of poly (polar charge amino acid) and nonionic surfactant to fluorometholone is usually 1: 0.2-30: 0.3-40, preferably 1: 0.5-25: 0.5. ~ 30.
The weight ratio of poly (polar charge amino acid) and nonionic surfactant to prednisolone acetate is usually 1: 0.03 to 1.5: 0.03 to 2, preferably 1: 0.05 to 1: 0. 0.05 to 1.5.
The weight ratio of poly (polar charged amino acid) and nonionic surfactant to difluprednate is usually 1: 0.25-30: 0.3-40, preferably 1: 0.5-25: 0. 5-30.
For example, when using the above steroid as an aqueous suspension ophthalmic solution, blepharitis, conjunctivitis, keratitis, scleritis, epidural inflammation, iritis, iridocyclitis, uveitis, postoperative inflammation, It can be used for allergic conjunctivitis. The amount of the aqueous suspension ophthalmic solution containing the above-mentioned concentration of steroid can be instilled usually once or twice a day and 2 to 4 times a day. The number of times can be appropriately increased or decreased depending on the age and the degree of symptoms.
In addition to poorly soluble drugs, poly (polar charge side chain amino acids) and nonionic surfactants, the aqueous suspensions of the present invention include buffers, isotonic agents, preservatives, thickeners, chelating agents and the like. In general, additives used in aqueous liquids may be added as appropriate.
Examples of the buffer include phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetic acid buffer, amino acids (epsilonaminocaproic acid, glutamic acid), and the like.
Examples of the isotonic agent include sugars such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin and propylene glycol, salts such as sodium chloride, and boric acid.
Examples of the preservative include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, paraoxybenzoic acid such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate. Examples thereof include esters, benzyl alcohol, sorbic acid, thimerosal, chlorobutanol, and sodium dehydroacetate.
Examples of the thickening agent include polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium alginate and the like.
Examples of chelating agents include sodium edetate and citric acid.
The pH of the eye drop of the present invention is usually adjusted to 4.0 to 8.0, preferably about 5.0 to 7.0.
Since the aqueous suspension of the present invention is excellent in redispersibility, it can be used as a medicine (for example, preventive or therapeutic agent for various diseases), a veterinary drug or the like as a human or a non-human mammal (for example, rat, mouse, Used in guinea pigs, monkeys, dogs, cows, etc.).
The aqueous suspension of the present invention can be suitably used as an eye drop, a nose drop, an ear drop, an injection, an internal preparation, a lotion, etc. Among them, an eye drop, a nose drop, and an ear drop are preferable. .
The aqueous suspension of the present invention can be produced by a method known per se, for example, the method described in the 14th revised Japanese Pharmacopoeia, liquid preparations, suspensions, or eye drops of the General Formulation.

Hereinafter, the present invention will be specifically described with reference to Examples and Test Examples, but the present invention is not limited thereto.
In addition, the poly-L-glutamic acid sodium salt shown in an Example used the thing of the molecular weight 8000 or more and 150,000 or less by the peptide laboratory.

According to a conventional method, an eye drop of the following formulation was prepared.
Loteprednol etabonate 0.5g
Glycerin 2.6g
Epsilon aminocaproic acid 0.1g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5

According to a conventional method, an eye drop of the following formulation was prepared.
Loteprednol etabonate 0.5g
Glycerin 2.6g
L-glutamic acid 0.1 g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5

A nasal drop of the following formulation was prepared according to a conventional method.
Loteprednol etabonate 0.5g
Mannitol 5.0g
Sodium acetate 0.1g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5

According to a conventional method, an ear drop of the following formulation was prepared.
Loteprednol etabonate 0.5g
Sodium chloride 0.9g
Epsilon aminocaproic acid 0.1g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5

According to a conventional method, an eye drop of the following formulation was prepared.
0.11 g of prednisolone acetate
Glycerin 2.6g
Epsilon aminocaproic acid 0.1g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5

According to a conventional method, an eye drop of the following formulation was prepared.
1.1 g prednisolone acetate
Glycerin 2.6g
Epsilon aminocaproic acid 0.1g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5

According to a conventional method, an eye drop of the following formulation was prepared.
Difluprednate 0.05g
Glycerin 2.6g
Epsilon aminocaproic acid 0.1g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5

According to a conventional method, an eye drop of the following formulation was prepared.
Fluorometron 0.1g
Glycerin 2.6g
Epsilon aminocaproic acid 0.1g
Poly-L-glutamic acid sodium salt 0.3 g
Tyloxapol 0.3g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5
Comparative Example 1
In accordance with a conventional method, an aqueous suspension having the following formulation was prepared.
0.11 g of prednisolone acetate
Glycerin 2.6g
Epsilon aminocaproic acid 0.1g
Tyloxapol 0.3g
Polyvinylpyrrolidone 0.6g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5
Comparative Example 2
In accordance with a conventional method, an aqueous suspension having the following formulation was prepared.
Fluorometron 0.1g
Glycerin 2.6g
Epsilon aminocaproic acid 0.1g
Tyloxapol 0.3g
Polyvinylpyrrolidone 0.6g
Edetate disodium 0.001g
Benzalkonium chloride 0.005g
Hydrochloric acid appropriate amount Sterile purified water Total amount 100ml
pH 5.5
Test example 1
Redispersibility test The eye drops of Examples 5 and 8 above were prepared and filled into 5 ml polypropylene containers. Stored at 40 ° C. for 2 weeks to allow the drug to settle. Thereafter, the container was inverted and stored at 40 ° C. for 2 weeks to allow the drug to adhere to the container. The container was shaken, and the number of shakes until the adhered drug was peeled was measured. As a control, the aqueous suspensions of Comparative Examples 1 and 2 were similarly operated.
The prednisolone acetate-containing ophthalmic solution (Example 5) and fluorometholone ophthalmic solution (Example 8) containing poly-L-glutamic acid sodium salt and tyloxapol were shaken 3 times and 4 times, respectively, and the drug was peeled from the container. On the other hand, a prednisolone acetate aqueous suspension (Comparative Example 1) containing polyvinylpyrrolidone and tyloxapol as a control was peeled from the container four times with shaking, but fine aggregates were observed. Further, the fluorometholone aqueous suspension (Comparative Example 2) was shaken 43 times, and the drug was peeled from the container, and a fine agglomerated soul was observed.
As a result of the same operation of loteprednol etabonate ophthalmic solution (Example 1) and difluprednate ophthalmic solution (Example 7) containing poly-L-glutamic acid sodium salt and tyloxapol, loteprednol etabonate ophthalmic solution was With seven shakings, the difluprednate ophthalmic solution was shaken three times and the drug was peeled from the container. Moreover, the change of the particle diameter was not recognized.
This result shows that when poly (polar charge side chain amino acid) and a nonionic surfactant are blended, the precipitated poorly soluble drug easily peels from the container and aggregation is also suppressed.

Industrial applicability

  The aqueous suspension of the present invention can easily separate the precipitated drug particles from the container, and can also suppress aggregation. Therefore, the aqueous suspension having good redispersibility according to the present invention can be used very advantageously for eye drops, nasal drops and ear drops.

Claims (5)

0.05-2.0 w / v% of poorly soluble drug selected from loteprednol etabonate, prednisolone acetate, difluprednate and fluorometholone, 0.01-1.0 w / v% of polyglutamic acid or its salt And an aqueous suspension containing 0.05 to 1.0 w / v% of a nonionic surfactant consisting of tyloxapol. The aqueous liquid preparation according to claim 1, which is an eye drop. The aqueous liquid preparation according to claim 1, which is a nasal drop. The aqueous liquid preparation according to claim 1, which is an ear drop. In an aqueous suspension containing 0.05 to 2.0 w / v% of a poorly soluble drug selected from loteprednol etabonate, prednisolone acetate, diflupredonate and fluorometholone, 0.01 g of polyglutamic acid or a salt thereof is added. A method for improving the redispersibility of a poorly soluble aqueous drug suspension containing 0.05 to 1.0 w / v% of a nonionic surfactant comprising -1.0 w / v% and tyloxapol.