JP2006176457A - Aqueous liquid composition for medicinal use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To prevent the precipitation of foreign materials in the long-term storage of an aqueous liquid preparation for medicinal use. <P>SOLUTION: The aqueous liquid composition for medicinal use effective for preventing the precipitation of foreign materials in long-term storage to improve the stability of the properties is produced by incorporating an aqueous liquid composition for medicinal use with a medicine and one or more additives selected from hyaluronic acid and its pharmacologically permissible salt. The composition is effective for preventing the precipitation of foreign materials feared to be caused in the case of using a plastic container and provides an aqueous liquid preparation having excellent stability of properties. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a pharmaceutical aqueous liquid composition and a pharmaceutical aqueous liquid preparation which have improved the problems related to the precipitation of foreign substances during storage.

In aqueous pharmaceutical liquid preparations such as injections, nasal drops and eye drops, it is caused by the interaction between the drug and additives mixed, the substance eluted from the storage container, the interaction between the substance and the ingredients, etc. Precipitation of insoluble foreign matter can be a problem in long-term storage. When preparing and storing an aqueous pharmaceutical liquid formulation using a glass container such as a glass ampoule, if the storage period is long, aluminum ions etc. in the glass composition will elute due to the erosion of the glass ampoule over time. Foreign matter may precipitate, and even when prepared using a plastic container, elution of a small amount of low-molecular compounds such as plasticizers, residual monomers, and other additives contained in the container material may occur. Interaction with drugs and additives in a single substance or solution may cause foreign matter precipitation and become a problem.

In order to ensure the property and quality standards during storage of an aqueous pharmaceutical liquid pharmaceutical preparation, appropriate additives are blended as necessary in preparation of the preparation. Additives such as solubilizers and solubilizers may be used to prevent the precipitation of foreign substances in the aqueous pharmaceutical liquid formulation and maintain the stability of properties. These additives have a high solubilizing ability and preferably have a high concentration in the preparation, but there is a concern of causing damage at the administration site. The use of solubilizers and solubilizers requires consideration from the viewpoint of safety, and the type and amount of addition are limited.

As a technique for suppressing the precipitation of foreign substances in a pharmaceutical aqueous liquid preparation, it contains bisphosphonic acid or a derivative thereof, and an organic acid buffer component, and further contains an isotonic agent and / or an amino alcohol as desired. An injection solution is disclosed (Patent Document 1). In addition, an injection solution containing ozagrel sodium and a polyhydric alcohol (Patent Document 2), ozagrel sodium, and one or more selected from organic acids, amino acids and polyaminocarboxylic acids, and pharmaceutically acceptable salts thereof An injection solution (Patent Document 3) is disclosed, which describes that the formation of foreign matter in the injection solution can be suppressed.

As a technique for maintaining a poorly water-soluble drug in a stable dissolved state in an aqueous solution, an aqueous pharmaceutical preparation comprising a poorly water-soluble drug and one or more of a polyhydric alcohol, a water-soluble polysaccharide or a derivative thereof ( Patent document 4) is disclosed. Although hyaluronic acid is described in the examples of the water-soluble polysaccharide used, there is no specific description about the effect when hyaluronic acid is used.

Hyaluronic acid is used as an additive for cosmetics and quasi-drugs for the purpose of moisturizing, and for pharmaceuticals, additives (wetting agents and thickeners), joint function improving agents, ophthalmic surgical aids, and eye drops for treating corneal epithelial disorders It is used as the drug substance of the drug. However, it has not been known so far that hyaluronic acid suppresses the precipitation of foreign substances in a pharmaceutical aqueous liquid preparation.
JP-A-8-92102 JP 2001-316265 A JP 2003-63963 A JP 2002-284704 A

An object of the present invention is to prevent precipitation of foreign substances during long-term storage of an aqueous pharmaceutical liquid composition or an aqueous pharmaceutical liquid formulation.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained a pharmaceutical aqueous solution containing one or more selected from hyaluronic acid and pharmaceutically acceptable salts thereof as drugs and additives. The liquid composition was found to improve the stability of properties by improving the precipitation of foreign matters during long-term storage. Furthermore, the present inventors have found that precipitation of foreign matters is remarkably improved when the above composition is filled in a plastic container and stored as a preparation for a long period of time, thereby completing the present invention.

That is, the present invention provides an aqueous pharmaceutical liquid composition containing one or more selected from hyaluronic acid and pharmaceutically acceptable salts thereof as drugs and additives. One or more selected from hyaluronic acid used as an additive and pharmaceutically acceptable salts thereof are preferably used as a stabilizer, more preferably as a foreign matter precipitation inhibitor. The present invention also provides a pharmaceutical aqueous liquid preparation having an improved precipitation of foreign substances filled in a plastic container with the above composition.

According to the aqueous pharmaceutical liquid composition of the present invention, the composition contains one or more kinds selected from hyaluronic acid and pharmaceutically acceptable salts thereof as a drug and an additive, so that it can be stored for a long time. It is possible to improve the stability of properties by improving the problem of foreign matter precipitation inside. Furthermore, according to the pharmaceutical aqueous liquid preparation of the present invention, it is possible to remarkably improve foreign matter precipitation which is a concern when stored for a long time using a plastic container, and to maintain the stability of properties. As a result, it is possible to provide a pharmaceutical having excellent property stability in which precipitation of foreign substances during storage is suppressed.

The aqueous pharmaceutical liquid composition of the present invention is prepared by blending one or more selected from hyaluronic acid and pharmaceutically acceptable salts thereof as a drug and an additive, and an appropriate amount of water. . The aqueous pharmaceutical liquid formulation of the present invention is prepared by filling a plastic container with the aqueous pharmaceutical liquid composition.

Hyaluronic acid and pharmaceutically acceptable salts thereof used in the present invention are not particularly limited, and examples thereof include sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, and calcium hyaluronate, preferably sodium hyaluronate. Can be mentioned. There is no restriction | limiting in particular in the weight average molecular weight of hyaluronic acid and its pharmacologically acceptable salt, A low molecular weight and high molecular weight thing can be used. The weight average molecular weight of hyaluronic acid and pharmaceutically acceptable salts thereof is usually about 1,600 to about 3,900,000, preferably about 600,000 to about 1,200,000. These hyaluronic acid and pharmaceutically acceptable salts thereof are sold under trade names such as hyaluronic acid HA-AM and HA-Q (Cuppy), biohyaluronic acid sodium HA9 (Shiseido). And easily available. Usually used at 0.0005 to 5 w / v%.

There is no particular limitation on the drug used in the present invention, for example, diclofenac, bromfenac, pranoprofen, parecoxib and pharmaceutically acceptable salts thereof, aspirin, indomethacin, ibuprofen, flurbiprofen, piroxicam, Non-steroidal anti-inflammatory agents such as acetaminophen, pyrophenone, zaltoprofen, celecoxib, etodolag, rofecoxib, lumiracoxib and valdecoxib, tacrolimus and its hydrate, cyclosporin A, infliximab, gusperimus hydrochloride, anisperimus, tresperimus trifluteate and rituximab Such as immunosuppressive agents such as alefacept, fluorometholone, clobetasone butyrate, clobetasol propionate and difluprednate Ido, atopic dermatitis treatments such as pimecrolimus and NFκB decoiolide, hormones such as ghrelin, pralmorelin hydrochloride and 20KDa human growth hormone (MS-706), antivirals such as acyclovir, oseltamivir phosphate, zanamivir hydrate Influenza virus infections such as amantadine hydrochloride, respiratory infections such as pleconaril, antibacterial agents, vitamins such as retinol palmitate, etretinate, calcitriol, alfacalcidol and menatetrenone, tafluprost, bimatoprost, travoprost , Lomelidine hydrochloride, olmesartan monohydrate, iganidipine hydrochloride and brimonidine tartrate, anti-glaucoma agents, olopatadine hydrochloride, bepotastine besylate, Montelocast sodium, epinephrine, omalizumab, Nlucast hydrate, epinastine hydrochloride, fexofenadine hydrochloride, mizolastine, anti-allergic agents such as T cell epitope peptide and anti-T cell receptor antibody, antihistamine, zoledronic acid, minodronic acid, ibandronic acid, basedoxifen and lasofoxifene tartrate Osteoporosis treatment agents such as zolmitriptan, migraine treatment agents such as naratriptan hydrochloride and almotriptan, neuralgia treatment agents such as pregabalin and sarpogrelate hydrochloride, neurodegenerative disease agents such as edaravone and natalizumab, and cerebral blood vessels such as alteplase and nicarabene Disability treatment agent, analgesic agent such as fentanyl citrate, tramadol hydrochloride, nalflaphine hydrochloride and indislam, local anesthetic, anticholinergic agent, sympathomimetic agent, sympathetic nerve blocker, sympathetic nerve inhibitor, parasympathomimetic agent, Sympathetic nerve suppressant, parasympathetic blocker, antitussive, prostatic hypertrophy, ulcer, diabetes, insulin, insulin detemia, and liraglutide, prostaglandin, liver ameliorator, central nervous system, calcium Antagonists, antitumor agents, chemotherapeutic agents, therapeutic agents for asthma / chronic obstructive pulmonary disease such as silomilast and roflumilast, bronchodilators, vasodilators such as vintoperol and beraprost sodium, antihypertensive agents, Antihyperglycemic, Hyperlipidemia, Diuretic, Heart failure, Anti-arteriosclerosis, Muscle relaxant, Side effect, Parkinson, Antirheumatic, Antimalarial, Antimuscarinic, Serotonin antagonist , Radical scavengers, vaccines, diagnostic agents, appetite suppressants, dry mouth symptom improving agents and the like. The amount of the drug used is usually 0.001 to 5 w / v%. Among these drugs, diclofenac, bromfenac, pranoprofen, parecoxib and their pharmaceutically acceptable salts, aspirin, indomethacin, ibuprofen, flurbiprofen, piroxicam, acetaminophen, pyrophenone, zaltoprofen, celecoxib Non-steroidal anti-inflammatory agents such as etodolag, rofecoxib, lumiracoxib and valdecoxib are preferred, and pranoprofen and their pharmaceutically acceptable salts are more preferred.

In the present invention, if necessary, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan tristearate, Solubilizers and solubilizers such as polyoxyl 40 stearate, sucrose stearate, decaglyceryl monostearate, lauryl glucoside, macrogol 4000, acetic acid, phosphoric acid and their pharmaceutically acceptable salts, monoethanol Buffers such as amine, triethanolamine, boric acid, borax, sodium carbonate, sodium bicarbonate, aminoethylsulfonic acid, L-glutamic acid, ε-aminocaproic acid, sodium chloride, potassium chloride, xylitol, mannitol, sorbitol, Sugars such as sucrose, polyhydric alcohols such as propylene glycol and glycerin, and isotonic agents such as sodium chloride, polyvinylpyrrolidone, polyvinyl alcohol, sodium polyacrylate synthetic polymer, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, Water-soluble cellulose derivatives such as hydroxyethyl cellulose and hydroxyethyl methyl cellulose, protein polymers such as gelatin, dextran, carrageenan, sodium chondroitin sulfate, xanthan gum, gum arabic, caraya gum, locust bean gum and other thickening agents such as polysaccharides Thickening agents, pH regulators such as sodium hydroxide and hydrochloric acid, parabens such as methyl parahydroxybenzoate and propyl parahydroxybenzoate, sorbic acid and its Pharmaceutically acceptable salts, benzyl alcohol, phenylethyl alcohol, benzethonium chloride, benzalkonium chloride, benzododecinium bromide, chlorhexidine gluconate, oxyquinoline sulfate, chlorobutanol, thimerosal, etc., histidine, arginine , Amino acids such as cysteine, methionine, phenylalanine and serine and pharmaceutically acceptable salts thereof, tocopherol and derivatives thereof, ethylenediaminetetraacetic acid and pharmaceutically acceptable salts thereof, citric acid and pharmaceutically acceptable salts thereof One or more additives selected from stabilizers such as polyethylene glycol, antioxidants or preservatives such as ascorbic acid, sodium hydrogen sulfite, sodium thioglycolate and α-thioglycerin are used in the present invention. Does not spoil the effect It can be added in circumference.

The present invention is usually prepared at a pH of 4.5 to 8.5. When used in the ophthalmological region, pH 5.5 to 8.0 is preferable from the viewpoint of eye irritation.

The present invention can be sterilized by membrane filtration sterilization, heat sterilization, or the like.

The present invention fills various containers such as plastic containers such as eye drops bottles, nasal bottles and infusion bags, or glass containers such as glass ampoules, transdermal, oral, vaginal, enteral, injection, Aqueous liquid pharmaceutical preparations for use in eye drops, nose drops, ear drops, inhalation administration, etc. can be constituted, mouthwash, oral liquid, injection, intraocular injection, eye drops, nasal drops, ear drops, Contrast agent, vaginal agent, enteral agent, aerosol agent, capsule agent, lotion agent, liquid agent, syrup agent, jelly agent and the like can be used. It is particularly suitable for injections, intraocular injections and eye drops.

The present invention is suitable for suppressing foreign matter precipitation when a plastic container is used. The material of the plastic container used in the present invention is not particularly limited, and various plastics and plastics having various polymerization degrees and densities can be used. For example, vinyl chloride, polypropylene, high density polyethylene, low density polyethylene, polyethylene terephthalate , Polystyrene, and ethylene / vinyl acetate copolymer.

EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these Examples.

Example 1: An appropriate amount of water was added to 2 g of polysorbate 80 and dissolved by stirring to prepare a polysorbate 80 preliminarily prepared solution. An appropriate amount of water was added to a beaker, 5.7 g of borax was added and dissolved, and further, the entire amount of polysorbate 80 preparatory solution was added and dissolved. To this solution, 0.05 g of sodium edetate, 0.05 g of benzalkonium chloride, 1.5 g of sodium chloride, 1 g of pranoprofen, 12.5 g of boric acid and 0.05 g of sodium hyaluronate were added and dissolved in this order. Water was added thereto to make up to 1 L, and the mixture was stirred to obtain a uniform solution. This solution was filtered under pressure with a 0.22 μm membrane filter and aseptically filled in 5 mL of a white polypropylene bottle to give an eye drop.

Comparative Example 1: A suitable amount of water was added to 2 g of polysorbate 80 and dissolved by stirring to prepare a polysorbate 80 preliminarily prepared solution. An appropriate amount of water was added to a beaker, 5.7 g of borax was added and dissolved, and further, the entire amount of polysorbate 80 preparatory solution was added and dissolved. To this solution, 0.05 g of sodium edetate, 0.05 g of benzalkonium chloride, 1.5 g of sodium chloride, 1 g of pranoprofen and 12.5 g of boric acid were added and dissolved in this order. Water was added thereto, and the volume was adjusted to 1 L and stirred to obtain a uniform solution. This solution was filtered under pressure with a 0.22 μm membrane filter and aseptically filled in 5 mL of a white polypropylene bottle to give an eye drop.

Test Example 1: 50 samples each of Example 1 and Comparative Example 1 were stored for 6 months in an environment of 40 ° C. and 75% RH, and precipitation of foreign matters was observed.

Test Example 2: Samples of Example 1 and Comparative Example 1 50 containers were stored for 4 months in an environment of 5 ° C., and precipitation of foreign matters was observed.

As shown in Table 2, in Example 1, the rate of foreign matter precipitation is clearly lower in Comparative Example 1 not containing sodium hyaluronate when stored at 40 ° C. and 75% RH for 6 months and at 5 ° C. for 4 months. It was shown that the precipitation of foreign matter was improved by the addition of sodium hyaluronate.

Claims (10)

An aqueous pharmaceutical liquid composition comprising one or more selected from hyaluronic acid and pharmaceutically acceptable salts thereof as a drug and an additive. An aqueous pharmaceutical liquid composition comprising one or more selected from hyaluronic acid and a pharmaceutically acceptable salt thereof as a drug and a stabilizer. An aqueous pharmaceutical liquid composition comprising one or more selected from hyaluronic acid and pharmaceutically acceptable salts thereof as a drug and a foreign matter precipitation inhibitor. The pharmaceutical aqueous liquid composition according to any one of claims 1 to 3, wherein the drug is a poorly water-soluble drug. The aqueous pharmaceutical liquid composition according to any one of claims 1 to 3, wherein the drug is a non-steroidal anti-inflammatory agent. The aqueous pharmaceutical liquid composition according to claim 5, wherein the non-steroidal anti-inflammatory agent is pranoprofen or a pharmaceutically acceptable salt thereof. A pharmaceutical aqueous liquid preparation comprising a plastic container filled with the pharmaceutical aqueous liquid composition according to any one of claims 1 to 6. Precipitation of foreign matter that occurs during long-term storage of an aqueous pharmaceutical liquid composition or an aqueous pharmaceutical liquid formulation is formulated with one or more selected from hyaluronic acid and pharmaceutically acceptable salts thereof in the composition How to prevent in. Precipitation of foreign substances that occur during long-term storage of aqueous pharmaceutical liquid preparations prepared by filling containers is formulated with one or more selected from hyaluronic acid and pharmaceutically acceptable salts in the formulation composition How to prevent it. Precipitation of foreign matter that occurs when a pharmaceutical aqueous liquid preparation using a plastic container is stored for a long period of time is formulated with one or more selected from hyaluronic acid and pharmaceutically acceptable salts thereof in the preparation composition. How to prevent it.