WO2004073748A1

WO2004073748A1 - Aqueous suspension medicine

Info

Publication number: WO2004073748A1
Application number: PCT/JP2004/001833
Authority: WO
Inventors: Keiichi Matsuhisa
Original assignee: Senju Pharmaceutical Co., Ltd.
Priority date: 2003-02-20
Filing date: 2004-02-18
Publication date: 2004-09-02
Also published as: JP4430616B2; JPWO2004073748A1

Abstract

An aqueous suspension medicine which is prepared from a mixture of a sparingly soluble drug, a polymer of a polar amino acid having a charged side chain or salt thereof, and a nonionic surfactant. In the aqueous suspension medicine obtained, the sparingly soluble drug which has sedimented is prevented from aggregating and readily separates from the container. Consequently, the aqueous suspension medicine is usable as eye drops, nasal drops, ear drops, etc. which are excellent in redispersibility.

Description

Aqueous suspension technology

The present invention relates to an aqueous suspension excellent in redispersibility of a poorly soluble drug, which comprises a poly (polar charged side chain amino acid) and a nonionic surfactant. Background art

When an aqueous suspension of a sparingly soluble drug is stored for a long period of time, problems such as sedimentation of the precipitated drug particles, secondary aggregation such as caching, and adhesion or adsorption to a container arise. As a result, the drug particles are not easily dispersed and need to be shaken for a long time during use.

Polymers and / or surfactants are usually used as suspending agents for poorly soluble drugs. For example, a composition containing corticosteroid, a nonionic polymer, a nonionic surfactant and a nonionic tonicity agent as an aqueous suspension having improved redispersibility (US Pat. An aqueous suspension containing a water-soluble polymer and a sparingly soluble drug in a concentration range from the concentration at which the surface tension of the liquid begins to decrease to the concentration at which the decrease in surface tension stops (Japanese Patent Application Laid-Open No. Aqueous suspension-type ophthalmic solution of a poorly soluble drug that combines an ionic polymer (carboxyvinyl polymer, carboxymethylcellulose) with a metal ion and has a viscosity of 100 cP or less. Agent (JP-A-8-295562) and poorly soluble drug, polyvinylpyrrolidone and water-soluble aionic polymer (anionic polysaccharide, anionic polypinyl polymer, anionic polymeric polypeptide) Aqueous containing Suspensions (International Publication No. WO 02/1587878 pamphlet).

In addition, as a composition containing an amino acid or a polyamino acid, for example, L-predone-l-pentanone is characterized by containing an aliphatic amino acid having 2 to 7 carbon atoms. -Free aqueous suspension (Japanese Unexamined Patent Publication No. Hei 10-3167072), detergent using polyglutamic acid as a dispersant for soil-causing substances Compositions (WO 1993Z06202 pamphlet), aqueous suspensions containing polyaspartic acid as a suspending agent for inorganic and organic particles (US Pat. No. 5,284,512) and the like are known.

However, by blending poly (polar charged side chain amino acid) and a nonionic surfactant, an aqueous suspension formulation with good re-dispersibility, in which aggregation of precipitated drug particles is suppressed and separation from the container is improved. Is not yet known.

An object of the present invention is to provide an aqueous suspension having excellent redispersibility of a poorly soluble drug. Disclosure of the invention

The present inventor has found that, by blending poly (polar charged side chain amino acid) or a salt thereof, and a nonionic surfactant, aggregation of the precipitated poorly soluble drug is suppressed, and the poorly soluble drug from the container is removed. They found that the separation was improved and the redispersibility was improved, and further studied, and completed the present invention.

The poly (polar 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 ゃ carboxyl group in the side chain, and more specifically, an acidic amino acid which is a monoaminodicarboxylic acid. Polycondensates of amino acids [poly (acidic amino acid)] and polycondensates of basic amino acids which are diaminomonocarboxylic acids [poly (basic amino acid)].

That is, the present invention is as follows.

(1) an aqueous suspension containing a poorly soluble drug, poly (polarly charged side chain amino acid) or a salt thereof, and a non-ionic surfactant,

(2) The lower limit concentration of poly (polar charged side chain amino acid) or its salt is 0.0 lwZv%, the upper limit concentration is 1.0 OwZv%, and the lower limit concentration of nonionic surfactant is 0.05 w / v%. The aqueous suspension according to the above (1), wherein the upper limit concentration is 1. OwZv%,

(3) The aqueous suspension according to the above (1), wherein the poorly soluble drug is a steroid,

(4) The steroid in which the steroid is at least one selected from oral teprednol etaponate, prednisolone acetate, difurprednate, and fluorometron (3) The aqueous suspension according to,

(5) The aqueous suspension according to the above (1), wherein the poly (polar charged side chain amino acid) is a poly (acid amino acid),

(6) The aqueous suspension according to the above (5), wherein the poly (acid 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 eardrop;

(11) 0.05 to 2 wZv% of mouth teprednole and 0.01 to 1.0 w / v% of polyglutamic acid or its salt, 0.05 to 1.0 w / v% of tyloxabol % Aqueous suspension containing ophthalmic solution.

(12) Improve redispersibility of aqueous suspension by blending poly (polar side chain amino acid) or its salt and nonionic surfactant with aqueous suspension of poorly soluble drug How to make

(13) When the lower concentration of poly (polar charged side chain amino acid) or its salt is 0. 1wZv% and the upper concentration is 1. Ow / v- The lower concentration of nonionic surfactant is 0.05wZv%. The present invention relates to the method described in (12) above, wherein the upper limit concentration is 1. Ow / v%.

The molecular weight of the poly (polar charged 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 1,000,000 or less, preferably 500,000 or less, more preferably 200,000 or less. Or less, more preferably 150,000 or less.

Examples of the poly (polar side chain amino acid) salt include an alkali metal salt such as a sodium salt and a potassium salt, and an inorganic acid salt such as a hydrochloric acid, but are not limited thereto.

Examples of poly (acidic amino acids) include polyglutamic acid and polyaspara Examples of the poly (basic amino acid) include formic acid and the like include polylysine and the like. Preferred is poly (acidic amino acid), and more preferred is polyglutamic acid.

As the polyglutamic acid, sodium poly-L-Dalmonic acid salt manufactured by Beptide Laboratories Inc. is preferably used.

The lower limit of the concentration of poly (polar charged side chain amino acid) or a salt thereof is usually lower than or equal to 0.01w Zv%, preferably 0.025wZv%, more preferably 0.05w / v%, and even more preferably 0.075wZ. / v%, particularly preferably 0.1 wwZv%, and the upper limit is usually 1. OwZv%, preferably 0.8 wZv%, more preferably 0.6 wZv%, particularly preferably 0.5 wZv%.

Examples of the nonionic surfactant used in the present invention include tyloxapol, polyoxyl myristate, polysorbate 8 (poloxamer and polyoxyethylene hydrogenated castor oil, etc. Preferred is tyloxapol.

The lower limit of the concentration of the nonionic surfactant is usually 0.05 wZv%, preferably 0.06 w / v%, more preferably 0.08 w / v%, even more preferably 0.1 w / v%, and the upper limit is usually 1. OwZv%, preferably 0.8 wZv%, more preferably 0.6

W, V% is ₀

The poorly soluble drug used in the present invention is a term indicating solubility according to the 14th revision of the Japanese Pharmacopoeia, "poorly soluble (the amount of solvent required to dissolve 1 g of the drug is 10 Oml or more and less than 1000 m1)", One of the following: "It is extremely hard to dissolve (the amount of solvent required to dissolve 1 g of drug is 100 Om1 or more and less than 1000 Om1)" or "It is hardly soluble (The amount of solvent required to dissolve drug lg is 10,000 ml or more)" It shows solubility.

The particle size of the poorly soluble drug suitable for preparing the aqueous suspension of the present invention is, for example, generally 0.1 to 0.1 when measured with a laser diffraction type particle size distribution analyzer SALD-2100 manufactured by Shimadzu Corporation. 75 m, preferably 0.5 to 30 m, more preferably 2 to 10 m.

Examples of the poorly soluble drug used in the present invention include steroids, anti-inflammatory analgesics, Chemotherapeutic agents, synthetic antibacterial agents, antiviral agents, hormonal agents, anticataract agents, angiogenesis inhibitors, immunosuppressants, protease inhibitors, aldose reductase inhibitors, etc., with steroids being preferred. It is. Examples of steroids include lote prednol etaponone, prednisolone acetate, difluprednate, fluorometron, prednisolone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, cortisone acetate, and hydprocipion acetate. Acid flutizone. Preferred are lote prednol etaponate, prednisolone acetate, difluprednate, and fluorometron.

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 zm, preferably 40 m, more preferably 20; m. 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 to 00 lwZv%, preferably 0.003 wZv%, more preferably 0.005 w / v%. ', More preferably 0.01 w / v, the upper limit is usually 5 w / v%, 3 w / v%, preferably 2 wv%.

When steroids are used, the lower limit is usually 0.003 w / v%, preferably 0.005 w / V% _{¾ the} upper limit is 3 wZ V%, preferably 2-w / v%.

The lower limit of the concentration of oral prepredanol ethabonate is 0.05 wZv%, preferably 0.1 w / v%, more preferably 0.2 w / v%, and the upper limit is usually 2 wZv%, 1.5 w / v%, preferably lw / v%.

The lower limit of the concentration of fluorometron is usually 0.0 lwZv%, preferably 0.02 w / V%, and the upper limit is usually 0-5 wZv%, preferably 0.2 w / v%. The lower limit of the concentration of prednisolone acetate is usually 0.1 w / v%, preferably 0.5 w / v%, and the upper limit is usually 2 w / v%, preferably 1.5 wZv%.

The lower limit of the concentration of difluprednate is usually 0.01 wZv%, preferably 0.02 wZv%, and the upper limit is usually 0.5 wZv%, preferably 0.2 w / v%.

Poly (polar charged amino acids) for steroids in the aqueous suspensions of the invention, The weight ratio of the nonionic surfactant used is generally 1: 0.01 to 50: 0.01 to 100, preferably 1: 0.05 to 30: 0.02 to 50.

The weight ratio of poly (polar charged amino acid) and nonionic surfactant to loteprednol etaponate is usually 1: 0.05-5: 0.05-5, preferably 1: 0.1-3. : 0.1 to 3.

The weight ratio of poly (polar charged amino acid) to non-ionic surfactant to fluorometholone is usually 1: 0.2 to 30: 0.3 to 40, preferably 1: 0.5 to 25: 0.5 to 0.5. 30.

The weight ratio of poly (polar charged 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. 05 to 1.5.

The weight ratio of the poly (polar amino acid) and the nonionic surfactant to difluprednate is usually 1: 0.25-30: 0.3-40, preferably 1: 0.5-25: 0. 5-30.

For example, when the above steroids are used as aqueous suspension eye drops, blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, iritis, iridocyclitis, uveitis, postoperative Inflammation Can be used for allergic conjunctivitis and the like. The dosage is usually 1 to 1 times after shaking the aqueous suspension ophthalmic solution containing the steroid at the above concentration well before use.

2 drops, 2 to 4 times a day. The frequency can be increased or decreased as appropriate depending on the age and degree of symptoms.

The aqueous suspension of the present invention may be a buffer, an isotonic agent, a preservative, a thickener, a chelating agent, etc., in addition to the poorly soluble drug, poly (polar charged side chain amino acid) and a nonionic surfactant. Note that additives usually used in aqueous liquid preparations may be appropriately added.

Examples of the buffer include a phosphate buffer, a borate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, and an amino acid (ipsilonaminocaproic acid, glutamic acid).

Examples of the tonicity agent include sugars such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin and propylene glycol, and sodium chloride. Salts, such as lime, and boric acid.

As preservatives, for example, quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, paraoxymethyl benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl paraoxybenzoate and propyl parabutyl butyl butyl Benzoic acid esters, benzyl alcohol, sorbic acid, thimerosal, chlorobutanol, sodium dehydroacetate and the like. Examples of the thickening agent include polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium and sodium alginate.

Chelating agents include sodium edetate, citric acid and the like.

The pH of the eye drops of the present invention is usually 4.0 to 8.0, preferably about 5.0 to 7.0.

Adjusted to 0.

Since the aqueous suspension of the present invention is excellent in redispersibility, it can be used as a pharmaceutical (eg, a prophylactic or therapeutic agent for various diseases), an animal drug, and the like in mammals other than humans and humans (eg, rats). , Mouse, guinea pig, monkey, dog, dog, etc.).

The aqueous suspension of the present invention can be suitably used as an eye drop, a drop, an ear drop, an injection, an oral preparation, a lotion, etc., and among them, an eye drop, a nasal 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, a method described in Japanese Pharmacopoeia 14th Edition, Liquid, Suspension or Eye Drops of the General Rules for Preparation. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described specifically with reference to Examples and Test Examples, but the present invention is not limited thereto.

The sodium poly (L-glutamate) salt shown in the examples used had a molecular weight of 800 to 150,000, manufactured by Beptide Laboratories. Example 1

An eye drop having the following formulation was prepared according to a conventional method.

Mouth teprednol etaponate 0.5 g glycerin 2.6 g

O.lg Poly-L-glutamate sodium salt 0.3 g tyloxapol 0.3 g disodium edetate O.OOlg Shiodii benzalkonium 0.005 g Total amount 100 ml H 5.5 Example 2

Mouth Teprednol Etaponate 0.5g

2.6g

L-glutamic acid O.lg Poly-L-glutamic acid 0.3 g tyloxapol 0.3 g edetate disodium O.OOlg benzalkonium chloride 0.005 g

100 ml

PH 5.5 Example 3 A nasal drop having the following formulation was prepared according to a conventional method.

Mouth Teprednol Etaponet 0.5g Mannitol 5.0g

O.lg Poly-L-glutamic acid 0.3 g Tyloxapol 0.3 g disodium edetate O.OOlg Benzalkonium chloride 0.005 g Sterilized purified water Total volume 100 ml pH 5.5 Example 4

According to a conventional method, eardrops having the following formulation were prepared.

Mouth teprednol etabonone 0.5g Sodium chloride 0.9g Epsilon aminocaproic acid O.lg Poly-L-dalnamate sodium salt 0.3g Tyloxapol 0.3g Disodium edetate O.OOlg Benzalkonium chloride 0.005 g Sterile purified water Total volume 100 ml pH 5.5 Example 5

Prednisolone acetate O.llg 2.6g

O.lg Poly-L-sodium glutamate 0.3g Tyloxapol 0.3g Disodium edetate O.OOlg Benzalkonium chloride 0.005g Total sterilized water 100 ml pH 5.5 Example 6

According to the usual method, eye drops of the following formulation were prepared

Prednisolone acetate l.lg Glycerin 2.6 g

O.lg Poly-L-glutamate sodium salt 0.3 g Tyloxapol 0.3 g disodium edetate O.OOlg Benzalkonium chloride 0.005 g Sterile purified water Total volume 100 ml pH 5.5 Example 7

Difluprednate 0.05 g Glycerin 2.6 g

O.lg Poly L sodium glutamate 0.3 g Tyloxapol 0.3 g disodium edetate O.OOlg Benzalkonium chloride 0.005 g Sterile purified water Total volume 100 ml PH 5.5 Example 8

Fluorometron O.lg Glycerin 2.6 g Epsilon aminocaproic acid O.lg Poly-L-daltamic acid sodium salt 0.3 g Tyloxapol 0.3 g Edetate disodium O.OOlg Benzalkonium chloride 0.005 g Sterile purified water 100 ml pH 5.5 Comparative Example 1

According to a conventional method, an aqueous suspension having the following formulation was prepared.

Prednisolone acetate 0.1 lg Glycerin 2.6 g Tyloxapol 0.3 g Polyvinylpyrrolidone 0.6 g Disodium edetate O.OOlg

Benzalkonium chloride 0.005g Total volume 100 ml

H 5.5 Comparative Example 2

Fluorometron O.lg

Glycerin 2.6g

Epsilon aminocaproic acid O.lg

Tyloxapol 0.3g

0.6 g of polypinyl pyrrolidone

Disodium edetate O.OOlg

Benzalkonium chloride 0.005g Total volume 100 ml

pH 5.5 Test Example 1

Redispersibility test

The eye drops of Examples 5 and 8 described above were prepared and filled in a 5 ml polypropylene container. After storage at 40 ° C for 2 weeks, the drug was sedimented. 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 times of shaking until the adhered drug was peeled was measured. As controls, the aqueous suspensions of Comparative Examples 1 and 2 were similarly operated.

Prednisolone acetate ophthalmic solution (Example 5) and fluorometron ophthalmic solution (Example 8) containing sodium polyglutamate glutamate and tyloxabol were The drug was peeled from the container after 3 and 4 shakings, respectively. On the other hand, the aqueous solution of prednisolone acetate containing polyvinylpyrrolidone and tyloxapol as a control (Comparative Example 1) exfoliated the drug from the container after four shakings, but fine aggregates were observed. In the case of the aqueous fluorometron suspension (Comparative Example 2), the drug peeled off from the container after shaking 43 times, and fine cohesive souls were observed.

The same operation was performed for loteprednol etaponate ophthalmic solution (Example 1) and difluprednate ophthalmic solution (Example 7) containing poly (L-glutamic acid sodium salt and tyloxapol). At 7 times, difluprednate ophthalmic solution was shaken 3 times, and the drug peeled off from the container. No change in particle size was observed.

This result indicates that when poly (polar charged side chain amino acid) and a nonionic surfactant are blended, the precipitated poorly soluble drug is easily peeled off the container and aggregation is suppressed. Industrial potential

ADVANTAGE OF THE INVENTION The aqueous suspension of this invention is easy to peel the settled drug particle from the container, and can also suppress aggregation. Therefore, the aqueous suspension having good redispersibility according to the present invention can be very advantageously used for eye drops, drops, and ear drops.

Claims

The scope of the claims

1. An aqueous suspension containing a poorly soluble drug, poly (polar charged side chain amino acid) or a salt thereof, and a non-ionic surfactant.

2. The lower limit concentration of poly (polar charged side chain amino acid) or its salt is 0. O lwZ v%, the upper limit concentration is 1. Ow / v%, and the lower limit concentration of nonionic surfactant is 0.05 wZv%. 2. The aqueous suspension according to claim 1, wherein the upper limit concentration is 1.0 w / V%.

3. The aqueous suspension according to claim 1, wherein the poorly soluble drug is a steroid.

4. The aqueous suspension according to claim 3, wherein the steroid is at least one selected from loteprednol ponate, prednisolone acetate, difluprednate, and fluorometron.

5. The aqueous suspension according to claim 1, wherein the poly (polar charged side chain amino acid) is a poly (acid amino acid).

6. The aqueous suspension according to claim 5, wherein the poly (acid amino acid) is polyglutamic acid.

7. The aqueous suspension according to claim 1, wherein the nonionic surfactant is tyloxapol.

8. The aqueous liquid preparation according to any one of claims 1 to 7, which is an eye drop.

9. The aqueous liquid preparation according to any one of claims 1 to 7, which is a nasal drop.

10. The aqueous liquid preparation according to any one of claims 1 to 7, which is an eardrop.

11. Contains 0.05 to 2 w / v% of teprednole oretabone, 0.01 to 1. Ow / v% of polyglutamic acid or a salt thereof, and 0.05 to 1. Ow / v% of tyloxapol. Aqueous suspension eye drops.

12. Redispersibility of K-type suspension is improved by blending poly (polar charged side chain amino acid) or its salt and nonionic surfactant with aqueous suspension of poorly soluble drug. How to let.

13. The lower limit concentration of poly (polar charged side chain amino acid) or its salt is 0.0 OlwZ v%, the upper limit concentration is 1. OwZv%, and the lower limit concentration of nonionic surfactant is 0.0. 13. The method according to claim 12, wherein the content is 5 v% and the upper limit concentration is 1.0 wZ v%.