JP2008031165A - Aqueous composition containing vitamin a compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aqueous composition with a stabilized vitamin A compound, excellent in viscosity stability with time as well while containing the vitamin A compound and alginic acid and/or its salt. <P>SOLUTION: The aqueous composition is prepared by compounding a combination of (A) the vitamin A compound, (B) alginic acid and/or its salt and (C) a vitamin E compound. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  In the aqueous composition containing vitamin A, the present invention improves the stability of vitamin A by adding alginic acid and / or a salt thereof and vitamin E at the same time, and the viscosity stability of the composition is improved. The present invention relates to an aqueous composition that is improved and at the same time the gelling properties of the composition are kept stable, and thus can effectively enjoy the physiological activity based on vitamins A and E. Furthermore, the present invention relates to a method for stabilizing vitamin A.

  Vitamin A has a recovery action for tired eyes and is used in the ophthalmic field. However, since vitamins A are easily destabilized with respect to ultraviolet rays, oxygen, high temperature, etc., the stability of vitamins A is improved in order to produce vitamin As in an aqueous composition. Is needed. Conventionally, it has been reported that the use of antioxidants such as tocopherol is effective for stabilizing vitamin A (see, for example, Patent Document 1). However, the method of stabilizing vitamin A using only an antioxidant is not sufficiently effective. To develop a product that can stably and effectively acquire the action of vitamin A, vitamin A There is a need to further improve the stability of the class.

Alginic acid, on the other hand, has an action of gelation (high viscosity) by being partially cross-linked by a divalent or higher cation such as Ca ²⁺ ion, and should be a component that can be used in the ophthalmic field. It is already known (see, for example, Patent Document 2). When an aqueous composition containing alginic acid is applied to the eye, Ca ²⁺ ions present on the ocular mucosa come into contact with the alginic acid, causing the composition to gel (high viscosity) on the ocular mucosa, It has also been found useful for enhancing the retention of the composition and for maintaining the effect of the active ingredient. On the other hand, alginic acid tends to decrease in molecular weight over time in an aqueous composition. Therefore, in the aqueous composition containing alginic acid, there is a problem that the viscosity of the composition decreases with time, and the viscosity cannot be stably maintained over a long period of time in the formulation design. On the other hand, alginic acid has a low molecular weight, and the viscosity of the aqueous composition containing the same decreases with time, so that the high viscosity property (gelation property) possessed by alginic acid is impaired, and as a result, at the application site. There was also a problem that stable gelation of the composition could not be achieved, and as a result, desired formulation characteristics could not be exhibited at the application site.

In the prior art, there is no known means for further improving the stability of vitamin A imparted by an antioxidant, and means for stabilizing the viscosity of an aqueous composition containing alginic acid over time. When both vitamin A and alginic acid are contained, no means is known for simultaneously realizing stabilization of vitamin A and stabilization of the viscosity of the composition.
JP-A-5-17350 JP 2002-332248 A

  The present invention provides an aqueous composition containing vitamin A, wherein the vitamin A is stabilized and the viscosity of the composition is excellent in stability over time. Main purpose.

  The inventors of the present invention have made extensive studies to solve the above-mentioned problems. As a result, vitamin (A), vitamin A, (B) alginic acid and / or a salt thereof, and (C) vitamin E are combined and blended. It has been found that the stability over time of class A and the stability over time of the viscosity of the aqueous composition can be combined. The present invention has been completed by making further improvements based on these findings.

That is, this invention provides the composition and method of the aspect hung up below.
Item 1. An aqueous composition comprising the following components (A) to (C):
(A) Vitamin A,
(B) Alginic acid and / or salt thereof,
(C) Vitamin E.
Item 2. Item 2. The aqueous composition according to Item 1, wherein the component (B) is contained in a ratio of 0.00001 to 5 g and the component (C) is contained in a ratio of 0.00001 to 0.5 g with respect to 10,000 units (international units) of the component (A).
Item 3. Item 3. The aqueous composition according to Item 1 or 2, which is an ophthalmic composition.
Item 4. A method for stabilizing vitamin A, comprising (B) alginic acid and / or a salt thereof and (C) vitamin E in an aqueous composition containing (A) vitamin A.
Item 5. (B) A method for stabilizing the viscosity of an aqueous composition, which comprises blending (A) vitamins A and (C) vitamin E with an aqueous composition containing alginic acid and / or a salt thereof.

  The aqueous composition of the present invention contains (A) vitamin A, (B) alginic acid and / or a salt thereof, and (C) vitamin E in combination, thereby stabilizing the stability of vitamin A and the aqueous composition. Both the viscosities over time are improved. Therefore, according to the aqueous composition of the present invention, the component concentration and physical properties immediately after production can be stably maintained even when stored for a long period of time, and the effect and feeling of use of the active ingredient can be stably maintained.

Furthermore, since the aqueous composition of the present invention contains alginic acid and / or a salt thereof, and the molecular weight of the component is suppressed, it is present at an application site such as an ocular mucosa based on the component. It has a more stable property of gelling in contact with Ca ²⁺ ions. Such gelation characteristics of the aqueous composition of the present invention improve the retention at the application site, and consequently improve the persistence of the bioactive action based on vitamins A and E. Furthermore, in addition to being stabilized, vitamin A in the aqueous composition of the present invention has improved retention at the application site due to the stable gelation characteristics of the composition. Based on this useful action, according to the aqueous composition of the present invention, it is possible to more effectively enjoy the physiological activity of vitamins A.

  Therefore, according to the aqueous composition of the present invention, the stability of vitamin A and the viscosity of the composition are improved, the gelation characteristics of the composition are kept stable, and thus the vitamin A and vitamin It is possible to effectively enjoy the physiologically active action based on E.

  Hereinafter, the present invention will be described in detail. In addition, in this specification, an aqueous composition is a composition containing water. The aqueous composition is, for example, 1 part by weight or more, preferably 5 parts by weight or more, more preferably 20 parts by weight or more, still more preferably 50 parts by weight or more, particularly preferably 80 parts by weight per 100 parts by weight of the composition. Examples are those containing at least 90 parts by weight, more preferably 90 parts by weight.

(I) Aqueous Composition The aqueous composition of the present invention contains (A) vitamins A (sometimes referred to simply as “component (A)” in this specification).

  The vitamin A used in the present invention is not particularly limited as long as it is pharmacologically or physiologically acceptable, and specific examples include retinol (vitamin A1); 3-dehydroretinol (vitamin A2). These derivatives (for example, retinol acetate, retinol palmitate, etc.) and the like. Among these, retinol acetate and retinol palmitate are preferable. In the present invention, the vitamin A may be used alone or in combination of two or more.

  The blending ratio of the component (A) in the aqueous composition of the present invention is not particularly limited, and can be appropriately set according to the type of the component (A), the use and form of the composition, and the like. As an example of the blending ratio of the component (A), in the aqueous composition, the total amount of the component (A) is 50 to 500,000 units / 100 mL, preferably 100 to 200,000 units / 100 mL with respect to the total amount of the composition. For example, if the aqueous composition is an eye drop, more preferably 1000 to 100,000 units / 100 mL, particularly preferably 5000 to 50000 units / 100 mL; for example, if the aqueous composition is an eye wash, more preferably 100 to 10,000 units. / 100 mL, particularly preferably a ratio of 500 to 5000 units / 100 mL is exemplified. In the present specification, the “unit” relating to the component (A) is an international unit (I.U.).

  The aqueous composition of the present invention further contains (B) alginic acid and / or a salt thereof (sometimes referred to simply as “component (B)” herein).

  Alginic acid is a polysaccharide composed of mannuronic acid (hereinafter sometimes simply referred to as “M”) and guluronic acid (hereinafter sometimes simply denoted as “G”). A block copolymer in which a polymer fraction (MM fraction), a homopolymer fraction of guluronic acid (GG fraction), and a fraction in which mannuronic acid and guluronic acid are randomly arranged (MG fraction) are arbitrarily combined. is there.

  The origin of alginic acid used in the present invention is not particularly limited, and for example, those derived from algae such as Lessonia (Lessonia nigrescens, etc.) and Kombu (Laminaria Japonica, etc.) are used.

  In the alginic acid used in the present invention, the constituent ratio (M / G ratio; molar ratio) of mannuronic acid to guluronic acid is not particularly limited. For example, the M / G ratio is in the range of 0.4 to 4.0. What is included in is widely used. The smaller the M / G ratio, the easier the gelation of the composition tends to start. From the viewpoint of improving the retention at the application site of other pharmacologically active ingredients to be blended, the M / G ratio is 2. It is desirable that it is 5 or less, preferably 2.0 or less, more preferably 1.6 or less. In particular, the M / G ratio is preferably 0.4 to 2.0, more preferably 0.5 to 1.6, and particularly preferably 1.0 to 1.6. desirable. In the present invention, the M / G ratio is a value calculated by fractionating alginic acid decomposed in block units and quantifying each, and specifically, A. Haug et al., Carbohyd. Res. 32 (1974), p.217-225.

  In the alginic acid used in the present invention, the ratio of the MM fraction, the GG fraction and the MG fraction is not particularly limited, and can be appropriately selected according to the use and shape of the aqueous composition.

  Moreover, the alginic acid used in the present invention can be suitably used from a low molecular weight to a high molecular weight.

  Furthermore, the salt of alginic acid is not particularly limited as long as it is pharmacologically or physiologically acceptable. Specific examples of the alginic acid salt include sodium salt, potassium salt, triethanolamine salt, ammonium salt and the like. These alginic acid salts may be used alone or in any combination of two or more.

  In the aqueous composition of the present invention, one type may be selected from these alginic acids and salts thereof, or two or more types may be used in any combination. In particular, alginic acid, sodium alginate, and potassium alginate are water-soluble and are preferably used in the present invention.

  Alginic acid and its salts are commercially available from Kibun Food Chemifa Co., Ltd., Kimika Co., Ltd., Fuji Chemical Industry Co., Ltd., Kelco (UK), Sigma (US), PRONOVA biopolymer (NO), etc. These commercially available products can be used.

  The blending ratio of the component (B) in the aqueous composition of the present invention is not particularly limited, and can be appropriately set according to the type of the component (B), the use and form of the composition, and the like. As an example of the blending ratio of the component (B), in the aqueous composition, the total amount of the component (B) is 0.001 to 5 w / v%, preferably 0.001 to 1 w / v with respect to the total amount of the composition. %; For example, if the aqueous composition is an eye drop, more preferably 0.001 to 0.5 w / v%, particularly preferably 0.005 to 0.2 w / v%; for example, if the aqueous composition is an eye wash, more preferably 0.001. A ratio of ˜0.2 w / v%, particularly preferably 0.005 to 0.1 w / v% is exemplified.

  Furthermore, the aqueous composition of the present invention contains (C) vitamin E in addition to the components (A) and (B). In the aqueous composition, by containing the components (A) to (C) as inseparable components, the stabilization of vitamin A is further improved, and the stability of the viscosity of the aqueous composition with time is also improved. It becomes possible.

  Vitamin E used in the present invention is not particularly limited as long as it is pharmacologically or physiologically acceptable. Specific examples include α-, β-, γ-, and δ-tocopherol. Α-, β-, γ-, or δ-tocotrienol; derivatives thereof (for example, tocopherol acetate, tocopherol nicotinate, tocopherol succinate); vitamin E linoleate and the like. The tocopherol and tocotrienol can be used regardless of whether they are d-form (natural vitamin E or the like) or dl-form. Of these, tocopherol acetate is preferred. In the present invention, the vitamin Es may be used singly or in combination of two or more.

  The blending ratio of the component (C) in the aqueous composition of the present invention is not particularly limited, and can be appropriately set according to the type of the component (C), the use and form of the composition, and the like. As an example of the blending ratio of the component (C), in the aqueous composition, the total amount of the component (C) is 0.00005 to 1 w / v%, preferably 0.0001 to 0.5 w / v based on the total amount of the composition. %; For example, if the aqueous composition is an eye drop, more preferably 0.001 to 0.1 w / v%, particularly preferably 0.005 to 0.05 w / v%; for example, if the aqueous composition is an eye wash, more preferably 0.0001. A ratio of ˜0.01 w / v%, particularly preferably 0.0005 to 0.005 w / v% is exemplified.

In the aqueous composition of the present invention, the stability of vitamin A and the stability of the viscosity of the aqueous composition over time can be more effectively obtained, and the gelation characteristics of the composition can be kept stable. In order to more effectively enjoy the physiologically active action based on vitamin E, it is desirable that the components (A) to (C) satisfy the following compounding ratio.
(A) component 10,000 units, (B) component 0.00001-5g and (C) component 0.00001-0.5g, preferably (B) component 0.0001-5g and (C) component 0.0001-0.5g More preferably, the component (B) is 0.001 to 5 g and the component (C) is 0.001 to 0.5 g, and particularly preferably the component (B) is 0.001 to 2 g and the component (C) is 0.001 to 0.1 g.

  The viscosity of the aqueous composition of the present invention is not particularly limited, but the retention of the aqueous composition on the skin, nasal mucosa, ocular mucosa, etc., ease of eye drops in the case of eye drops, etc. From the viewpoint of improving, it is 1.2 to 100 mPa · s, preferably 1.3 to 50 mPa · s, more preferably 1.4 to 30 mPa · s, particularly preferably 1.5 to 15 mPa · s, and still more preferably 1.6 to 10 mPa · s. It is desirable to satisfy the range. The above viscosity is based on the 14th revised Japanese Pharmacy Law General Test Method, 45. Viscosity measurement method, second method rotational viscometer method, measured according to the method described in the section “(3) Cone-Plate type rotational viscometer”. More specific measurement conditions for the viscosity are as follows.

  In measuring the viscosity, commercially available viscometers, for example, E type viscometer [manufactured by TOKIMEC, sold by Toki Sangyo (Japan)], E type viscometer “DIGITAL VISCOMETER DVM-E” (manufactured by Tokyo Keiki) , Synchroelectric PC type (Brookfield, USA), Ferranti Shirley (Feranti, UK), Rot Bisco R (Haake, Germany), IGK Hischer Rheometer (Ishida Giken, Japan), Shimadzu Rheometer R (Shimadzu) Manufactory, Japan), Weissenberg Greogoniometer (Sangamo, UK), mechanical spectrometer (Rheometrics, USA), etc. can be used. Then, by appropriately selecting these commercially available viscometers and rotors, and appropriately adjusting the petroleum-based hydrocarbon oil (Newtonian fluid) defined by JIS Z8809 as a calibration standard solution for each test sample measurement, The viscosity at 20 ° C. can be measured.

More specifically, as shown in FIG. 1, a sample is put into a gap having an angle α between the cone 1 and the flat disk 2, and the cone 1 or the flat disk 2 is rotated at a constant angular velocity ω or torque T. Then, the torque or angular velocity received by the flat disk 2 or the cone 1 when reaching a steady state was measured, and the viscosity was measured by calculating the viscosity η of the sample by the following equation.
η = 100 × (3α / 2πR ³ ) · (T / ω)
η: Viscosity of sample (mPa · s) (Pa · s = 10 ³ mPa · s)
α: angle formed by the flat disk 2 and the cone 1 (rad)
π: Circumference ratio R: Radius of cone 1 (cm)
T: Torque (10 ⁻⁷ N · m) acting on the flat disk 2 or the conical surface
ω: Angular velocity (rad / s).

  Moreover, it is preferable to mix | blend a buffering agent with the aqueous composition of this invention further. The buffer that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmacologically or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, and the like. These buffering agents may be used in combination. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer. In order to make the effect of the present invention more remarkable, a particularly preferable buffer is a borate buffer, a citrate buffer, or a phosphate buffer. Examples of the borate buffer include borates such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the citrate buffer include citrates such as alkali metal citrate and alkaline earth metal citrate. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) or a hydrate thereof, phosphoric acid or a salt thereof (dihydrogen phosphate) Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.) or hydrates thereof, carbonic acid or a salt thereof (carbonic acid) Sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.) or hydrates thereof, citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, citric acid) Sodium dihydrogen, disodium citrate, etc.) or their hydrates, acetic acid or its Examples thereof include salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) or hydrates thereof. These buffering agents may be used alone or in any combination of two or more.

  When blending a buffering agent in the aqueous composition of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used and the expected effect, and cannot be defined uniformly, for example, The ratio of the buffer to the total weight of the composition is 0.001 to 10 w / v%, preferably about 0.1 to 5 w / v%. More specifically, when the ratio of the buffer in the aqueous composition is a borate buffer or a phosphate buffer, for example, 0.001 to 10 w / v%, preferably 0.01 to 5 w. When a carbonate buffer is used, for example, 0.001 to 5 w / v%, preferably about 0.005 to 3 w / v%; when a citrate buffer is used, for example, 0 0.001 to 5 w / v%, preferably about 0.005 to 3 w / v%; if an acetate buffer is used, for example 0.001 to 5 w / v%, preferably 0.005 to 3 w / v% In the case of using epsilon-aminocaproic acid, the ratio is, for example, about 0.005 to 10 w / v%, preferably about 0.01 to 5 w / v%.

  Furthermore, in order to make the effects of the present invention more remarkable, the aqueous composition of the present invention preferably contains a nonionic surfactant.

  Examples of nonionic surfactants include POE / POP block copolymers such as Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer 124; monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80), etc. POE sorbitan fatty acid esters; POE hydrogenated castor oil such as POE (60) hydrogenated castor oil; POE alkyl ethers such as POE (9) lauryl ether; POE and POP alkyl ethers such as POE (20) POP (4) cetyl ether Class: POE (10) Nonylph POE alkylphenyl ethers such as vinyl ether and the like. Preferred are poloxamer 407, polysorbate 80, POE (60) hydrogenated castor oil, and among these, polysorbate 80 is particularly preferred. POE is an abbreviation for polyoxyethylene and POP is an abbreviation for polyoxypropylene. The number in parentheses indicates the number of added moles.

  In the aqueous composition of the present invention, the nonionic surfactant may be used alone or in combination of two or more.

  The mixing ratio of the nonionic surfactant in the aqueous composition of the present invention is not particularly limited, and can be appropriately set according to the type of the agent, the use and form of the composition, and the like. As an example of the blending ratio of the nonionic surfactant, 0.0001 to 1.0 w / v%, preferably 0.0005 to 1.0 w / v%, more preferably 0.001 to 0.5 w / v% per total amount of the aqueous composition is exemplified. Is done. More specifically, when the aqueous composition is an eye drop, the blending ratio of the nonionic surfactant is particularly preferably 0.01 to 0.5 w / v%, and still more preferably 0.05 to 0.3 w / v%; When the aqueous composition is an eye wash, the blending ratio of the nonionic surfactant is particularly preferably 0.001 to 0.05 w / v%, more preferably 0.005 to 0.03 w / v%.

  The aqueous composition of the present invention is liquid or gel, preferably liquid, and ophthalmically acceptable water, preferably purified water or ultrapure water is used as the base of the composition.

  The pH of the aqueous composition of the present invention is not particularly limited as long as it is within a pharmacologically or physiologically acceptable range. Examples of the pH of the aqueous composition of the present invention include 5 to 9, preferably 5.5 to 8.5, and more preferably 6 to 8. Moreover, if it is in the said pH range, it is safe even if it applies to an eye or a lens, and it is useful as an aqueous composition for ophthalmology.

  If necessary, the aqueous composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable for a living body. The appropriate osmotic pressure ratio varies depending on the use and form of the composition, but is usually 0.2 to 2.5, preferably 0.3 to 1.7, more preferably 0.4 to 1.6, more preferably 0.5 to 1.5, and particularly preferably about 0.6 to 1.4. is there.

  In the aqueous composition of the present invention, the osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of the 0.9 w / v% aqueous sodium chloride solution based on the 14th revised Japanese pharmacopoeia, and the osmotic pressure is the osmotic pressure described in the Japanese pharmacopoeia. Measure according to the pressure measurement method (freezing point depression method). The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500 to 650 ° C. for 40 to 50 minutes, then allowed to cool in a desiccator (silica gel), and 0.900 g was accurately weighed. Dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (aqueous solution containing 0.9 w / v% sodium chloride).

  The pH and osmotic pressure ratio can be adjusted by a method known in the art using inorganic salts and polyhydric alcohols, sugar alcohols, saccharides, and the like.

  The aqueous composition of the present invention can contain various components (including pharmacologically active components and physiologically active components) in combination with the above components, as long as the effects of the present invention are not hindered. As described above, since the gelation characteristics of the aqueous composition of the present invention are stably maintained at the application site, when the pharmacologically active component and the physiologically active component are blended in the ophthalmic composition of the present invention, these components are added. It can be expected that the retention at the application site is improved, and that the pharmacological activity and physiological activity of these components can be enjoyed effectively. The kind of such an ingredient is not particularly limited, and examples thereof include active ingredients in various medicines described in the over-the-counter drug manufacturing (import) approval standard 2000 version (supervised by the Pharmaceutical Affairs Research Committee). Specific examples of components used in ophthalmic drugs include the following components.

  Epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, naphazoline nitrate, neostigmine methyl sulfate, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, lysozyme chloride, sodium azulene sulfonate, glycyrrhizin Dipotassium acid, berberine chloride, berberine sulfate, diphenhydramine hydrochloride, chlorpheniramine maleate, pyridoxine hydrochloride, sodium flavin adenine dinucleotide, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, potassium aspartate, magnesium aspartate, asparagine Magnesium / potassium acid, aminoethylsulfonic acid, chondro Sodium tin sulfate, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisomidine sodium, glucose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol (fully or partially saponified), Polyvinylpyrrolidone and the like.

  Furthermore, in order to prepare the aqueous composition of the present invention in various desired forms, various components and additives are appropriately selected according to conventional methods within a range not impairing the effects of the present invention, and one or more are used in combination. Can be blended. Examples of these components or additives include various additives described in Pharmaceutical Additives Encyclopedia 2005 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.

  Macrogol, alkyldiaminoethylglycine, benzalkonium chloride, parabens, potassium sorbate, polyhexamethylene biguanide, potassium chloride, sodium chloride, calcium chloride, magnesium sulfate, glycerin, propylene glycol, camphor, geraniol, borneol, menthol, Fennel oil, cool mint oil, spearmint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, sodium edetate, citric acid, trometamol, etc.

  The aqueous composition of the present invention can be formulated as a nasal drop or a nasal rinse, but is preferably used as an ophthalmic composition. Specific examples of ophthalmic compositions include eye drops (including eye drops that can be used while wearing contact lenses), eye wash (including eye drops that can be used while wearing contact lenses), and contact lens care. It is used in the form of a liquid preparation (contact lens disinfectant, contact lens storage solution, contact lens cleaning solution, and contact lens cleaning storage solution). Among these forms, eye drops and eye wash are preferable, and eye drops are particularly preferable.

  The aqueous composition of the present invention is produced according to a known method. For example, the above components (A) to (C), and other components as necessary may be added to an aqueous solvent such as purified water and physiological saline, etc. so as to obtain a desired concentration, and prepared according to a conventional method. That's fine.

(II) Method for Stabilizing Vitamin A In addition, as described above, by blending alginic acid and / or a salt thereof with vitamin E in an aqueous composition containing vitamin A, Stabilization is possible. Accordingly, the present invention further provides (A) an aqueous composition containing vitamin A, (B) alginic acid and / or a salt thereof, and (C) vitamin E, A stabilization method is also provided. In this method, the types and blending ratios of components (A) to (C), other blending components, and the like are as described in the column of the aqueous composition of (I) above.

(III) Method for stabilizing viscosity of aqueous composition containing alginic acid and / or salt thereof Further, as described above, blending vitamin A and vitamin E with the aqueous composition containing alginic acid and / or salt thereof By this, it becomes possible to improve the temporal stability of the viscosity of the aqueous composition. Therefore, the present invention further provides (A) vitamin A and (C) vitamin E in an aqueous composition containing (B) alginic acid and / or a salt thereof. Also provided is a method for stabilizing the viscosity. Also in this method, the contents of the aqueous composition column of (I) can be used for the types and blending ratios of components (A) to (C), other blending components, and the like.

  Hereinafter, the present invention will be described in detail based on test examples, examples, and the like, but the present invention is not limited thereto. In addition, the alginic acid used below is derived from Lessonia nigrescens having a standard of M / G ratio of 1.0 to 1.6.

Test Example 1 Evaluation of Stability of Retinol Palmitate-1
In accordance with the formulation shown in Table 1, retinol palmitate-containing aqueous solutions (Example 1 and Comparative Example 1-3) were prepared. Each retinol palmitate-containing aqueous solution was filtered, filled into glass ampoules (capacity 10 mL) by 8 mL, and stored in the dark at 60 ° C. for 1 day (n = 2). Before the start of storage and 1 day after storage, the retinol palmitate concentration in the retinol palmitate-containing aqueous solution was measured by HPLC, and the retinol palmitate residual ratio was calculated according to the following formula.

  The results are also shown in Table 1. In the aqueous solution of Comparative Example 2 containing a combination of retinol palmitate and alginic acid, the residual ratio of retinol palmitate was reduced compared to the aqueous solution of Comparative Example 1 alone containing retinol palmitate. It was suggested that the stability of retinol palmitate is impaired when blended alone. On the other hand, in the aqueous solution of Example 1 containing retinol palmitate, alginic acid, and tocopherol acetate, retinol palmitate is stably retained, and although it contains alginic acid, palmitic acid in Example 1 is used. The residual ratio of retinol was higher than that of the aqueous solution of Comparative Example 3 containing retinol palmitate and tocopherol acetate.

Test Example 2 Evaluation of Viscosity Stability of Aqueous Composition According to the formulation described in Table 2, aqueous compositions (Example 2 and Comparative Example 4) were prepared. Immediately after preparation, the viscosity was measured according to the following method. 10 mL of each aqueous composition is filled into a colorless transparent glass screw vial (capacity: 10 mL) and sealed, and stored in a 60 ° C. incubator for 7 days under light-shielding conditions. Measured by the method. From the measured viscosity, the viscosity reduction rate (%) was calculated according to the following formula.

<Measurement method of viscosity>
Viscosity was measured using an E-type viscometer “DIGITAL VISCOMETER DVM-E” (manufactured by Tokyo Keiki Co., Ltd.) according to the following procedure. First, 1 mL of the aqueous composition was placed in a predetermined plate, placed in a predetermined position of a standard cone rotor (1 ° 34 ′, radius 24 mm), and allowed to stand until the temperature reached 20 ° C. Subsequently, it was rotated at 100 rpm, and after 4 minutes, the displayed viscosity was read and used as a measured value. In order to obtain a highly accurate measurement result, a petroleum hydrocarbon oil (Newtonian fluid) defined by JIS Z 8809 is used as a calibration standard solution before measuring the viscosity of the aqueous composition, and the measured value is a standard solution. It was adjusted to match the viscosity of

  The results are also shown in Table 2. From this result, it was revealed that the viscosity reduction rate was large in the aqueous composition of Comparative Example 4, but the viscosity reduction was suppressed to about half of that in Comparative Example 4 in the aqueous composition of Example 2. . Further, from this result, it was revealed that the molecular weight reduction of alginic acid was suppressed, and the gelation characteristics of the aqueous composition of Example 2 were hardly impaired and kept stable.

Test Example 3 Evaluation of Stability of Retinol Palmitate-2
An aqueous composition (Example 3-7) was prepared according to the formulation described in Table 3. About each aqueous composition, when the stability of retinol palmitate was evaluated by the same method as in Test Example 1, it was confirmed that retinol palmitate was stably held in any aqueous composition.

Formulation Example 1-3
An eye drop (Prescription Example 1-3) was prepared according to the formulation shown in Table 4 below. Moreover, the viscosity immediately after preparation for each eye drop was measured according to the method described in Test Example 2 above. In Table 4, the unit of the blending ratio of components other than retinol palmitate is “w / v%”, and the unit of the blending ratio of retinol palmitate is “international unit / 100 mL”.

Formulation Example 4-40
In the formulations described in Table 5-9 below, eye drops (Prescription Examples 4-11 and 25-30), eyewashes (Prescription Examples 12-18 and 31-36), nasal drops (Prescription Examples 19-24 and 37) -39) and a nasal rinse (Formulation Example 40) were prepared. In addition, about these formulations, it adjusted so that the osmotic pressure ratio might be in the range of 0.6-1.4. In Table 5-9, the unit of the blending ratio of components other than retinol palmitate and retinol acetate is “w / v%”, and the unit of blending ratio of retinol palmitate and retinol acetate is “international unit / 100 mL”. is there.

It is a figure which shows the schematic diagram of the measuring apparatus by the cone-plate type rotational viscometer used in Test Example 2. FIG.

Claims (4)

An aqueous composition comprising the following components (A) to (C):
(A) Vitamin A,
(B) Alginic acid and / or salt thereof,
(C) Vitamin E.   The aqueous composition according to claim 1, wherein the component (B) is contained in a ratio of 0.00001 to 5 g and the component (C) is contained in a ratio of 0.00001 to 0.5 g with respect to 10,000 units (international units) of the component (A).   The aqueous composition according to claim 1 or 2, which is an ophthalmic composition.   A method for stabilizing vitamin A, comprising (B) alginic acid and / or a salt thereof and (C) vitamin E in an aqueous composition containing (A) vitamin A.

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