WO2004073748A1 - 水性懸濁液剤 - Google Patents
水性懸濁液剤 Download PDFInfo
- Publication number
- WO2004073748A1 WO2004073748A1 PCT/JP2004/001833 JP2004001833W WO2004073748A1 WO 2004073748 A1 WO2004073748 A1 WO 2004073748A1 JP 2004001833 W JP2004001833 W JP 2004001833W WO 2004073748 A1 WO2004073748 A1 WO 2004073748A1
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- WO
- WIPO (PCT)
- Prior art keywords
- aqueous suspension
- poly
- amino acid
- acid
- salt
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0046—Ear
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- 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.
- Polymers and / or surfactants are usually used as suspending agents for poorly soluble drugs.
- 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.
- Agent JP-A-8-295562
- poorly soluble drug polyvinylpyrrolidone
- water-soluble aionic polymer anionic polysaccharide, anionic polypinyl polymer, anionic polymeric polypeptide
- Aqueous containing Suspensions International Publication No. WO 02/1587878 pamphlet.
- compositions 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.
- 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.
- 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 ⁇ 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)].
- the present invention is as follows.
- 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 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,
- 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.
- poly (polar side chain amino acid) salt examples 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.
- poly (acidic amino acids) examples 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.
- 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.
- nonionic surfactant used in the present invention examples 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.
- 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.
- 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%.
- the lower limit is usually 0.003 w / v%, preferably 0.005 w / V% 3 ⁇ 4 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%.
- 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.
- blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, ulceris, 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.
- 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.
- the buffer examples include a phosphate buffer, a borate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, and an amino acid (ipsilonaminocaproic acid, glutamic acid).
- tonicity agent examples 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.
- 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.
- 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.
- 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
- 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 The sodium poly (L-glutamate) salt shown in the examples used had a molecular weight of 800 to 150,000, manufactured by Beptide Laboratories.
- An eye drop having the following formulation was prepared according to a conventional method.
- An eye drop having the following formulation was prepared according to a conventional method.
- Example 3 A nasal drop having the following formulation was prepared 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
- An eye drop having the following formulation was prepared according to a conventional method.
- An eye drop having the following formulation was prepared according to a conventional method.
- An eye drop having the following formulation was prepared according to a conventional method.
- an aqueous suspension having the following formulation was prepared.
- an aqueous suspension having the following formulation was prepared.
- 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.
- 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.
- 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.
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005502746A JP4430616B2 (ja) | 2003-02-20 | 2004-02-18 | 水性懸濁液剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003042714 | 2003-02-20 | ||
JP2003-042714 | 2003-02-20 |
Publications (1)
Publication Number | Publication Date |
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WO2004073748A1 true WO2004073748A1 (ja) | 2004-09-02 |
Family
ID=32905363
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2004/001833 WO2004073748A1 (ja) | 2003-02-20 | 2004-02-18 | 水性懸濁液剤 |
Country Status (2)
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JP (1) | JP4430616B2 (ja) |
WO (1) | WO2004073748A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005094836A2 (en) * | 2004-03-25 | 2005-10-13 | Bausch & Lomb Incorporated | Use of loteprednol etabonate for the treatment of dry eye |
JP2006327949A (ja) * | 2005-05-23 | 2006-12-07 | Hiroshi Takeda | 眼薬用組成物 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5470510A (en) * | 1991-09-27 | 1995-11-28 | The Procter & Gamble Company | Dispersing agent |
US5741478A (en) * | 1994-11-19 | 1998-04-21 | Andaris Limited | Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent |
EP0868919A2 (en) * | 1997-03-14 | 1998-10-07 | Senju Pharmaceutical Co., Ltd. | Aqueous suspension of loteprednol etabonate |
JP2000192015A (ja) * | 1998-12-25 | 2000-07-11 | Hitachi Chem Co Ltd | Cmp研磨剤及び基板の研磨方法 |
US6274634B1 (en) * | 1997-05-14 | 2001-08-14 | Senju Pharmaceutical Co., Ltd. | Aqueous suspension preparations with excellent redispersibility |
-
2004
- 2004-02-18 JP JP2005502746A patent/JP4430616B2/ja not_active Expired - Fee Related
- 2004-02-18 WO PCT/JP2004/001833 patent/WO2004073748A1/ja active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5470510A (en) * | 1991-09-27 | 1995-11-28 | The Procter & Gamble Company | Dispersing agent |
US5741478A (en) * | 1994-11-19 | 1998-04-21 | Andaris Limited | Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent |
EP0868919A2 (en) * | 1997-03-14 | 1998-10-07 | Senju Pharmaceutical Co., Ltd. | Aqueous suspension of loteprednol etabonate |
US6274634B1 (en) * | 1997-05-14 | 2001-08-14 | Senju Pharmaceutical Co., Ltd. | Aqueous suspension preparations with excellent redispersibility |
JP2000192015A (ja) * | 1998-12-25 | 2000-07-11 | Hitachi Chem Co Ltd | Cmp研磨剤及び基板の研磨方法 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005094836A2 (en) * | 2004-03-25 | 2005-10-13 | Bausch & Lomb Incorporated | Use of loteprednol etabonate for the treatment of dry eye |
WO2005094836A3 (en) * | 2004-03-25 | 2006-01-26 | Bausch & Lomb | Use of loteprednol etabonate for the treatment of dry eye |
JP2006327949A (ja) * | 2005-05-23 | 2006-12-07 | Hiroshi Takeda | 眼薬用組成物 |
Also Published As
Publication number | Publication date |
---|---|
JP4430616B2 (ja) | 2010-03-10 |
JPWO2004073748A1 (ja) | 2006-06-01 |
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