WO2015125921A1 - Composition médicale aqueuse ayant une efficacité de conservation - Google Patents

Composition médicale aqueuse ayant une efficacité de conservation Download PDF

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Publication number
WO2015125921A1
WO2015125921A1 PCT/JP2015/054803 JP2015054803W WO2015125921A1 WO 2015125921 A1 WO2015125921 A1 WO 2015125921A1 JP 2015054803 W JP2015054803 W JP 2015054803W WO 2015125921 A1 WO2015125921 A1 WO 2015125921A1
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Prior art keywords
pharmaceutical composition
aqueous pharmaceutical
cysteine
acid
preservative
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PCT/JP2015/054803
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English (en)
Japanese (ja)
Inventor
恵美 川口
夏子 中林
可奈 高橋
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わかもと製薬株式会社
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Priority to JP2016504187A priority Critical patent/JPWO2015125921A1/ja
Publication of WO2015125921A1 publication Critical patent/WO2015125921A1/fr

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    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention is a pharmaceutical product that has excellent preservative effect even when preservatives such as benzalkonium chloride and parabens are blended at a low concentration or not at all, and is hypoallergenic for diseases and troubled eyes. It relates to an aqueous composition.
  • additives such as buffering agents, isotonic agents, preservatives, stabilizers, pH adjusters and the like are generally blended with eye drops.
  • the eye drops are used up in a single administration, so that it is not necessary to add a preservative.
  • the multi-dose type is used in small amounts over a long period of time. Therefore, a multidose type eye drop that is frequently administered even after opening is often blended with a preservative from the viewpoint of preventing contamination due to contamination with microorganisms.
  • Common preservatives used in eye drops include quaternary ammonium salts such as benzalkonium chloride, paraoxybenzoates, chlorobutanol, etc., of which the most frequently used Is benzalkonium chloride.
  • Benzalkonium chloride denatures the structure of the cell membrane by binding to phospholipids constituting the cell membrane of microorganisms and exerts a strong antibacterial effect.
  • Benzalkonium chloride has not only an excellent antibacterial effect, but also has a feature that it is chemically stable and has a high solubility in water. Such a feature is also preserved in aqueous pharmaceutical compositions. This is the reason why those skilled in the art choose benzalkonium chloride as the agent.
  • benzalkonium chloride is known to act on cells other than microorganisms. That is, it is known that when benzalkonium chloride is added as a preservative in eye drops, it acts on corneal epithelial cells and induces corneal epithelial damage. Therefore, in order to reduce the influence of benzalkonium chloride on corneal epithelial cells, it has been frequently performed to reduce the concentration of benzalkonium chloride to be blended in the ophthalmic aqueous composition.
  • Patent Document 2 As an alternative to benzalkonium chloride, there is an invention that has a preservative effect without combining a preservative in an ophthalmic composition by combining several additives that are not preservatives. Combinations are mentioned (Patent Document 2).
  • cysteine is L-cysteine (also known as 2-amino-3-mercaptopropionic acid) (Non-patent Document 2) or L-cysteine hydrochloride hydrate (Non-patent Document 3).
  • L-cysteine also known as 2-amino-3-mercaptopropionic acid
  • Non-patent Document 3 L-cysteine hydrochloride hydrate
  • it is blended for uses such as a stabilizer of the active ingredient (also referred to as a stabilizer, hereinafter the same) and a solubilizer.
  • malic acid refers to DL-malic acid, and is generally formulated for use as an active ingredient stabilizer, buffering agent, flavoring agent, coating agent, etc. Patent Document 2).
  • the combination of cysteine and malic acid shown in the present invention can be used to add a preservative to an aqueous pharmaceutical composition without adding a preservative. It is not known at all to have the same preservative effect as when blended, and there is no known aqueous pharmaceutical composition formulated in such a combination.
  • the problem to be solved by the present invention is to replace preservatives, particularly benzalkonium chloride, which are currently blended in aqueous pharmaceutical compositions with additives that exhibit preservative effects without causing side effects peculiar to preservatives. And a pharmaceutical aqueous composition containing an additive or a combination of additives and additives that exhibit preservative effects without causing side effects peculiar to preservatives. It is to provide a composition, especially an ophthalmic aqueous composition.
  • the present invention relates to a method for blending cysteine and malic acid, which are additives, in order to obtain an aqueous pharmaceutical composition that is compatible with a storage efficacy test, a combination of additives having storage efficacy, and the aforementioned aqueous pharmaceutical composition Is to provide.
  • an aqueous pharmaceutical composition comprising (A) cysteine and (B) malic acid.
  • aqueous pharmaceutical composition according to ⁇ 1> wherein (A) cysteine / (B) malic acid (concentration ratio) in the composition is 0.001 to 300.
  • concentration ratio concentration ratio
  • B The aqueous pharmaceutical composition according to any one of ⁇ 1> to ⁇ 3>, wherein the malic acid concentration is 0.01 to 1.0 (w / v%).
  • ⁇ 5> The aqueous pharmaceutical composition according to any one of ⁇ 1> to ⁇ 4>, wherein the pH is 3.0 to 9.0.
  • ⁇ 6> The aqueous pharmaceutical composition according to any one of ⁇ 1> to ⁇ 5>, which does not contain a preservative.
  • the buffer is selected from the group consisting of boric acid, phosphoric acid, citric acid, ⁇ -aminocaproic acid, acetic acid, tartaric acid, trometamol and pharmaceutically acceptable salts thereof or hydrates thereof.
  • the aqueous pharmaceutical composition according to any one of ⁇ 1> to ⁇ 6> comprising at least one kind.
  • aqueous pharmaceutical composition according to any one of ⁇ 1> to ⁇ 7>, which is in the form of an aqueous ophthalmic composition.
  • a method of imparting storage efficacy to an aqueous pharmaceutical composition comprising adding (A) cysteine and (B) malic acid to the aqueous pharmaceutical composition.
  • a preservative for an aqueous pharmaceutical composition comprising (A) cysteine and (B) malic acid.
  • the aqueous pharmaceutical composition of the present invention has a preservative effect even if it does not contain a preservative that causes factors such as corneal damage, particularly benzalkonium chloride, and therefore, for example, a drug is administered over a long period of time such as glaucoma or allergy. It hardly affects the cornea etc. of patients with the necessary symptoms.
  • the aqueous pharmaceutical composition of the present invention can be used as an ophthalmic composition such as artificial tears, contact lens mounting liquids, and eye drops by taking advantage of its characteristics, and can also be used as injections, oral preparations, ear drops. It can also be used in the form of agents, nasal drops, coating agents and the like.
  • the preservative is added to a multi-dose type pharmaceutical product for the purpose of preventing microbial contamination, and has a sufficient bactericidal action against bacteria and fungi. It refers to those that show side effects by increasing permeability, causing membrane disruption and cytoplasmic degeneration, leading to inhibition of cell proliferation, decreased cell adhesion, and the development of hypersensitivity.
  • the preservative causes a change in formulation with the main agent and other additives, or the preservative itself is not stable against heating and long-term storage.
  • the preservative include parabens such as quaternary ammonium salts and paraoxybenzoic acid esters such as benzalkonium chloride and benzethonium chloride, and chlorobutanol.
  • the preservative refers to a substance different from the preservative.
  • the preservative in the present specification has a broad antibacterial spectrum against gram-negative bacteria, gram-positive bacteria, fungi, etc. without causing problems in side effects and pharmaceutical stability like the above-mentioned preservatives, and promotes the growth of microorganisms. It refers to those that can be blocked and are water-soluble and exhibit the storage stability of pharmaceuticals.
  • the preservative is less irritating at the time of administration, does not cause damage to the administered tissue, and does not cause an allergic reaction due to long-term use.
  • a preservative refers to a combination of cysteine and malic acid.
  • Cysteine used in the present invention is L-cysteine and pharmaceutically acceptable salts.
  • examples of the pharmaceutically acceptable salt of L-cysteine include L-cysteine hydrochloride.
  • the concentration of cysteine is usually 0.001 to 3.0 (w / v%), and is preferably 0.001 to 1.0 (w / v) because cysteine is completely dissolved and stable in an aqueous solution. v%), more preferably 0.001 to 0.3 (w / v%).
  • the malic acid used in the present invention is DL-malic acid.
  • the concentration of malic acid is usually 0.01 to 1.0 (w / v%), preferably 0.05 to 1.0 (w / v%), more preferably 0.1 to 1.0 (w / v%). w / v%).
  • the ratio of (A) cysteine concentration and (B) malic acid concentration used in the present invention is expressed as (A) / (B).
  • (A) / (B) is not particularly limited as long as the effect of the present invention can be obtained, but is usually 0.001 to 300, and cysteine and malic acid are completely dissolved in an aqueous solution. In order to achieve this, it is preferably 0.001 to 20, more preferably 0.001 to 3.
  • the buffer used in the present invention is not particularly limited as long as the effects of the present invention are obtained, but boric acid, phosphoric acid, citric acid, ⁇ -aminocaproic acid, acetic acid, tartaric acid, trometamol, and pharmaceutically acceptable salts thereof. Or at least one selected from the group consisting of hydrates thereof.
  • the pH of the aqueous pharmaceutical composition in the present invention is usually 3.0 to 9.0, preferably 5.0 to 8.0, more preferably 5.5 to 8. .0.
  • various pH adjusting agents that are usually added can be used.
  • the acids include ascorbic acid, hydrochloric acid, glucuronic acid, gluconic acid, acetic acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, sulfuric acid, citric acid, malic acid, tartaric acid and the like.
  • the base include borax, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide and the like.
  • examples of other pH adjusters include amino acids such as glycine, histidine, and epsilon aminocaproic acid.
  • aqueous pharmaceutical composition of the present invention In preparing the aqueous pharmaceutical composition of the present invention, pharmaceutically acceptable isotonic agents, solubilizers, thickeners, stabilizers, etc., if necessary, do not impair the effects of the present invention. It can be added to the aqueous pharmaceutical composition of the present invention within a range.
  • the isotonic agent include sugars such as glucose, sugar alcohols such as mannitol, sorbitol, and xylitol, propylene glycol, glycerin, sodium chloride, potassium chloride and the like. Sodium chloride and propylene glycol are preferred.
  • solubilizer examples include polysorbate (for example, polysorbate 80), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyl stearate (for example, polyoxyl 40 stearate), tyloxapol, polyethylene glycol and the like. You may use these solubilization individually or in combination of 2 or more types.
  • Other additives include water-soluble polymers (eg, viscous agents such as methylcellulose and povidone K25), ethylenediaminetetraacetic acid and their pharmaceutically acceptable salts, tocopherol and its derivatives, taurine, epsilon aminocaproic acid, sulfite. Stabilizers such as sodium can be mentioned.
  • the osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention is not particularly limited as long as the effects of the present invention are obtained, but is usually 0.5 to 2.0, preferably 0.7 to 1.6, more preferably Is 0.8 to 1.3, most preferably 0.9 to 1.2.
  • the aqueous pharmaceutical composition of the present invention includes a dry eye therapeutic agent, a corneal injury healing agent, a glaucoma therapeutic agent, an anti-inflammatory agent, an allergy therapeutic agent, a mydriatic agent, an ophthalmic surface anesthetic agent, a cataract therapeutic agent or an antibacterial agent
  • a dry eye therapeutic agent a corneal injury healing agent, a glaucoma therapeutic agent, an anti-inflammatory agent, an allergy therapeutic agent, a mydriatic agent, an ophthalmic surface anesthetic agent, a cataract therapeutic agent or an antibacterial agent
  • a variety of drugs can be indicated.
  • the aqueous pharmaceutical composition of the present invention preferably contains no preservative. If the concentration is as low as about 0.001 to 0.003 w / v%, the side effects caused by the preservatives can be significantly reduced, and may be included. Since the aqueous pharmaceutical composition of the present invention exhibits a preservative effect without containing a preservative, it can be used as a multi-dose type or a mono-dose type. For the same reason, the container for storing the aqueous pharmaceutical composition of the present invention is not particularly limited.
  • an aqueous pharmaceutical composition of the present invention was prepared and a storage efficacy test was conducted.
  • the storage efficacy was confirmed by a storage efficacy test.
  • the test procedure for the preservation efficacy test was based on the 16th revised Japanese Pharmacopoeia Manual, reference information, and the preservation efficacy test method.
  • Three kinds of bacteria Esscherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus
  • two kinds of fungi Candida albicans, Aspergillus brasiliensis
  • These cultured cells were collected aseptically, and a suspension containing about 10 8 cells / mL viable bacteria or spores was used as each inoculum.
  • Comparative Example 1 is a composition containing cysteine but not malic acid. Comparative Example 1 met the 7th day in the storage efficacy test, but failed on the 14th day. From the determination on the 7th day, it was shown that the boric acid formulation of Comparative Example 1 had a storage effect, albeit slightly. Comparative Example 2 contains cysteine but does not contain malic acid, and is further added with EDTA (sodium edetate hydrate), which is used as a stabilizer. However, even in Comparative Example 2 to which EDTA was added, in the storage efficacy test, it matched on the 7th day, but it showed non-conformity on the 14th day. From the above, it was found that, in the formulation containing cysteine as in Comparative Examples 1 and 2, but not containing malic acid, it was necessary to add a preservative or the like in order to have sufficient storage efficacy.
  • EDTA sodium edetate hydrate
  • Examples 1 to 8 which are the compositions of the present invention, have a preservative effect without adding a preservative such as benzalkonium chloride.
  • Example 2 According to Table 2, arbitrary components were added to 80 mL of purified water and dissolved. After adjusting this solution to a predetermined pH, purified water was added to make up the volume to make 100 mL of a colorless and clear solution. Subsequently, Examples 9 to 21 were prepared by filtration sterilization with a membrane filter.
  • composition of the present invention was optimal over a wide pH range from basic to acidic.
  • Example 3 According to Table 3, each component was added to 80 mL of purified water and dissolved. After adjusting the pH of this liquid appropriately, purified water was added to make up the volume to make 100 mL of a colorless and clear solution. Then, Examples 22 to 26 were obtained by sterilizing by filtration with a membrane filter.
  • the present invention can also be effective when a solubilizer such as polysorbate 80 or polyoxyl 40 stearate, a stabilizer such as EDTA, or a thickener such as methylcellulose or povidone is further added. Indicated.
  • a solubilizer to the present invention even when a poorly soluble active ingredient is selected as a drug to be included in the composition of the present invention. It can be dispersed evenly, suggesting that it can have excellent storage stability.
  • a thickening agent to the present invention means that in the composition of the present invention, the increase in the retention at the administration site increases the sustainability and migration of the active ingredient, and the bioactivity of the active ingredient. This suggests that it is possible to improve availability. From the above, it was found that the composition of the present invention can be provided as a highly versatile base.
  • Example 4 According to Table 4, each component was added to 80 mL of purified water and dissolved, and then any amount of purified sodium hyaluronate, travoprost, timolol maleate, diclofenac sodium, acitazanolast hydrate or moxifloxacin hydrochloride Salt was added to dissolve. After adjusting the pH of this liquid appropriately, purified water was added to make up the volume to make 100 mL of a colorless and clear solution. Then, Examples 27-32 were those sterilized by filtration with a membrane filter.
  • the composition of the present invention did not show a phenomenon that the storage efficacy was lowered due to the change in the composition in an aqueous solution even when a drug selected as an active ingredient of a pharmaceutical was added. It has been found that the present invention can be widely used as pharmaceutical preparations.
  • Examples 33 and 34 were prepared according to Table 5. As Comparative Examples 3 and 4, 0.002% and 0.005% benzalkonium chloride aqueous solutions were selected, respectively.
  • Human corneal epithelial cells (product name: Human Corneal Epithelial Cell (HCE-T), RIKEN BioResource Center) were used as test materials. In addition, a total of five drug solutions were used: Examples 33 and 34, Comparative Examples 3 and 4, and phosphate buffered saline (PBS) as a negative control.
  • SHEM modified medium DMEM / F-12 (1: 1) + 1% PS + 10 ng / mL EGF + 5 ⁇ g / mL insulin + 0.5% DMSO containing 5% FBS
  • each drug solution had a total of 6 wells.
  • the contact time is 1, 2, 5 or 10 minutes.
  • the wells are washed with PBS, and each well has a reagent for measuring the cell number (Product name: Cell counting kit-8, Dojin Chemical Research Co., Ltd.). 10 ⁇ L each) was added.
  • the absorbance at 450 nm was measured using a microplate reader (device name: Infinite M200 PRO, manufactured by TECAN).
  • the cell viability (%) was calculated from the absorbances of Examples 33 and 34 and Comparative Examples 3 and 4 with the absorbance of the negative control as 100. The test results are shown in FIG.
  • Comparative Examples 3 and 4 cell viability decreased with increasing contact time. Further, even when the contact time was the same, Comparative Example 4 having a higher concentration of the preservative showed lower cell viability than Comparative Example 3. On the other hand, in Examples 33 and 34 of the present invention, the cell viability was higher than in Comparative Examples 3 and 4, and the cell viability was not significantly reduced with the increase in contact time.
  • Example 35 was prepared according to Table 6. As Comparative Example 5, a 0.01% benzalkonium chloride aqueous solution was selected.
  • Example 35 For Example 35 and Comparative Example 5, corneal epithelial disorder in white rabbits was confirmed.
  • Example 35 and Comparative Example 5 Male Japanese white rabbits were used as test animals. A total of two chemical solutions of Example 35 and Comparative Example 5 were used. Example 35 and Comparative Example 5 were instilled into 4 eyes of each test animal at 50 ⁇ L, 3 times a day, 4 hours apart for 15 days. After instillation for 15 days, the corneas of the test animals were stained with fluorescein, and excess fluorescein was washed away with physiological saline. The stained spots of the cornea were observed, and photographs were taken in the dark state (under blue light irradiation). A photograph is shown in FIG.
  • Example 35 of the present invention no staining spots were observed in all four eyes, and no corneal epithelial disorder was observed.
  • Example 35 which did not contain a general preservative showed no corneal epithelial disorder. Thus, it was speculated that Example 35 had a lower risk of developing corneal epithelial disorder during clinical use than Comparative Example 5. From the above, it was shown that the composition of the present invention has a preservative effect without adding a preservative, and thus is a highly safe aqueous pharmaceutical composition with reduced side effects.
  • aqueous medicinal composition having a preservative effect without adding a preservative such as benzalkonium chloride or parabens.
  • the aqueous pharmaceutical composition provided by the present invention can reduce corneal damage caused by preservatives by adapting it to a liquid preparation such as an eye wash or eye drops.

Abstract

La présente invention concerne une composition médicale aqueuse qui contient de la cystéine et de l'acide malique et possède par conséquent une efficacité de conservation, et qui est faiblement irritante. La composition médicale aqueuse selon la présente invention peut en outre contenir un additif qui peut être ajouté à une composition médicale aqueuse, tel qu'un agent tampon et un agent de tonicité, et peut éventuellement contenir un agent médicinal.
PCT/JP2015/054803 2014-02-20 2015-02-20 Composition médicale aqueuse ayant une efficacité de conservation WO2015125921A1 (fr)

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JP2016504187A JPWO2015125921A1 (ja) 2014-02-20 2015-02-20 保存効力を有する医薬用水性組成物

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JP2014030371 2014-02-20
JP2014-030371 2014-02-20

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JP6134853B1 (ja) * 2016-10-28 2017-05-24 参天製薬株式会社 エピナスチン含有点眼液
JP2018070582A (ja) * 2017-04-24 2018-05-10 参天製薬株式会社 エピナスチン含有点眼液
JP2020059747A (ja) * 2019-12-17 2020-04-16 参天製薬株式会社 エピナスチン含有点眼液
JP2020169213A (ja) * 2020-07-15 2020-10-15 参天製薬株式会社 エピナスチン含有点眼液

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6134853B1 (ja) * 2016-10-28 2017-05-24 参天製薬株式会社 エピナスチン含有点眼液
WO2018079721A1 (fr) * 2016-10-28 2018-05-03 参天製薬株式会社 Gouttes ophtalmiques contenant de l'épinastine
JP2018070500A (ja) * 2016-10-28 2018-05-10 参天製薬株式会社 エピナスチン含有点眼液
JP2018070582A (ja) * 2017-04-24 2018-05-10 参天製薬株式会社 エピナスチン含有点眼液
JP2020059747A (ja) * 2019-12-17 2020-04-16 参天製薬株式会社 エピナスチン含有点眼液
JP2020169213A (ja) * 2020-07-15 2020-10-15 参天製薬株式会社 エピナスチン含有点眼液
JP2021152068A (ja) * 2020-07-15 2021-09-30 参天製薬株式会社 エピナスチン含有点眼液

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