JP5977919B2 - Pharmaceutical composition - Google Patents

Description

The present invention relates to a pharmaceutical composition used for ophthalmic agents and the like.

In recent years, the number of people who complain of eye strain has increased with changes in lifestyle such as the increase in VDT work due to the spread of personal computers. Eye strain is an unpleasant symptom associated with eye symptoms such as eye pain, blurred vision, dazzling, and redness, and systemic symptoms such as headache, stiff shoulders, and nausea due to visual work. Various causes have been reported. However, many are caused by overuse of the eyes.

A wide range of products have been developed as countermeasures for eye strain, including ophthalmic preparations such as internal medicines, eye drops, and eyewashes, massage machines around the eyes, etc. Eye drops include vitamins, taurine, menthol, caffeine, etc. Eye drops for eye strain blended with are commercially available.

For example, Patent Documents 1 and 2 disclose that vitamins cyanocobalamin has an effect of improving eye strain and can be used for eye drops. However, even when such an eye drop is used, the improvement effect is insufficient and the immediate effect is not particularly satisfactory.

JP-A-56-75438 Japanese Patent Laid-Open No. 3-145421

The present invention solves the above-mentioned problems and provides a pharmaceutical composition such as an ophthalmic agent (eyewash, eye drop, etc.) having an excellent effect on improving eye strain and having an excellent immediate effect. Objective.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained berberine or a salt thereof, which has been conventionally known only to have antibacterial and anti-inflammatory effects in a pharmaceutical composition, as a vitamin. When used in combination with B12, the present inventors have found that the eye fatigue improvement effect is synergistically exhibited and is excellent in immediate effect. Furthermore, it discovered that a higher improvement effect was exhibited by adjusting the viscosity of the pharmaceutical composition which used both these components together to 1-60 cp. The present invention has been completed based on the above findings.

The present invention is a pharmaceutical composition comprising vitamin B12 and berberine and / or a salt thereof.
The pharmaceutical composition preferably has a viscosity of 1 to 60 cp at 25 ° C.
The pharmaceutical composition is preferably an ophthalmic agent. Moreover, it is preferable that the said pharmaceutical composition is an eye strain improvement agent.

Since the pharmaceutical composition of the present invention uses vitamin B12 in combination with berberine and / or a salt thereof, the effect of improving eyestrain synergistically is exhibited, and the composition is adjusted to a specific viscosity. In this way, a higher improvement effect can be exhibited. Furthermore, the immediate effect of the improvement effect is also excellent. Therefore, particularly when used as an ophthalmic agent such as eye drops and eye wash, it is possible to obtain an eye strain improvement effect that is remarkable and excellent in immediate effect.

The pharmaceutical composition of the present invention contains vitamin B12 and berberine and / or a salt thereof.
In the present invention, vitamin B12 is a water-soluble vitamin having a structure containing cobalt ions in the choline ring. As vitamin B12, cyanocobalamin, hydroxocobalamin, adenosylcobalamin, methylcobalamin, acocobalamin, nitritocobalamin, sulfitocobalamin, etc. are known to exist depending on the type of ligand for cobalt ions. In the invention, any form can be used. In addition, organic salts or inorganic salts of these compounds can also be used as vitamin B12 (hereinafter collectively referred to as “vitamin B12s”). Of these, cyanocobalamin, methylcobalamin (mecobalamin), hydroxocobalamin acetate, and hydroxocobalamin hydrochloride are preferred from the viewpoint of excellent eye strain improvement effect. These vitamin B12s may be used alone or in combination of two or more.

In the pharmaceutical composition of the present invention, the concentration of vitamin B12 is not particularly limited as long as the effects of the present invention can be obtained, but preferably 0.02 mg or more, more preferably 0.1 in 100 g of the entire composition. -50 mg, more preferably 0.2-20 mg. In the case of liquid ophthalmic preparations such as eye drops and eyewashes, the total composition is preferably 0.2 mg or more, more preferably 0.2 to 20 mg, and in the case of eye drops 5 to 20 mg. More preferably, in the case of eyewash, 0.5 to 2 mg is more preferable. Within this range, a particularly excellent eye strain improvement effect can be obtained by combining with berberine and / or a salt thereof.

In the present invention, berberine and / or a salt thereof (hereinafter collectively referred to as “berberine”) are used. Berberine is a known compound having benzylisoquinoline as a skeleton. The salt of berberine is a pharmacologically or physiologically acceptable salt, and is not particularly limited. Examples thereof include berberine chloride, berberine sulfate, berberine tannate, berberine benzoate, berberine bromide, and berberine iodide. Etc. Furthermore, a herbal extract or extract containing berberine such as duck or auren can be used. Of these, berberine chloride, berberine sulfate, and berberine tannate are preferable from the viewpoint of excellent eye strain improvement effect. These berberines may be used alone or in combination of two or more.

In the pharmaceutical composition of the present invention, the concentration of berberine is not particularly limited as long as the effects of the present invention can be obtained, but in 100 g of the entire composition, preferably 0.05 mg or more, more preferably 0.25 to 0.25. 25 mg, more preferably 0.5 to 25 mg. In the case of liquid ophthalmic preparations such as eye drops and eyewashes, the total composition is preferably 0.5 mg or more, more preferably 0.5 to 25 mg, and in the case of eye drops 5 to 10 mg. More preferably, in the case of eyewash, 0.5 to 2.5 mg is more preferable. When it is within this range, a particularly excellent eye strain improvement effect can be obtained by combining with vitamin B12.

In the pharmaceutical composition of the present invention, the content ratio of vitamin B12 and berberine is preferably 0.05 to 10 parts by weight of berberine with respect to 1 part by weight of vitamin B12. The amount is more preferably 1 to 5 parts by weight, further preferably 0.2 to 3 parts by weight, and particularly preferably 0.5 to 1.8 parts by weight. With this content, the effect of improving eye strain per berberine compounding amount is excellent. Moreover, when a pharmaceutical composition is made into a liquid state, the color tone of the liquid becomes light orange to deep orange, and a preparation having excellent light stability of vitamin B12 can be obtained.

The pharmaceutical composition of the present invention can be used, for example, in an internal or external form depending on the purpose. As an internal use form, it can be provided as a topical preparation for various uses, for example, for internal medicine, and as an external form, for ophthalmology or dermatology.
The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include liquids, gels, ointments (greasy ointments, emulsion ointments, water-soluble ointments), powders, granules, tablets and the like. And may be appropriately selected depending on the application.

In particular, the ophthalmic agent is not limited to a pharmaceutical preparation, and can be used as a non-pharmaceutical preparation such as a contact lens preparation. Specific examples of ophthalmic agents include eye drops (including eye drops that can also be used while wearing contact lenses), eye wash (including eye drops that can also be used while wearing contact lenses), eye ointments, and contact lens mounting solutions. And contact lens agents (cleaning solution, preserving solution, rinsing solution, disinfecting solution, multi-purpose solution, etc.) and the like. In the present specification, the contact lens means any type of contact lens such as a hard contact lens (including an oxygen permeable hard contact lens) and a soft contact lens. Moreover, the pharmaceutical composition of the present invention can be suitably used as an eye strain improving agent.

Since the pharmaceutical composition of the present invention has high stability of the active ingredient, it is packaged in a form to be administered multiple times, and is a multi-dose aqueous solution that is continuously used by the user, for example, eye drops, eye wash It is also useful as a liquid oral medicine (liquid gastrointestinal medicine, liquid cold medicine, etc.), and a skin external medicine.

In the pharmaceutical composition of the present invention, when the dosage form is liquid, the viscosity is not particularly limited. However, in the ophthalmic preparation, the viscosity at 25 ° C. is preferable from the viewpoint that the effect of improving eye strain is excellent. It is 1-60 cp, More preferably, it is 1-50 cp, More preferably, it is 2-50 cp. In particular, in the case of an eye wash, the viscosity (25 ° C.) is preferably 2 to 20 cp, more preferably 2 to 15 cp, and even more preferably 2 to 10 cp. Moreover, 2-50 cp is preferable, as for the viscosity (25 degreeC) in the case of an eye drop, 5-50 cp is more preferable, and 10-50 cp is still more preferable.
In the present invention, as described in Examples, the viscosity of the pharmaceutical composition is a digital viscometer (model name: DV-II +, manufactured by Brookfield), which is a B-type viscometer, and the spindle is ULA. Was performed under the conditions of a rotation speed of 6 to 30 rpm and a liquid temperature of 25 ° C.

The pH of the pharmaceutical composition of the present invention is preferably 2.0 to 10.0, more preferably 4.0 to 9.0, more preferably 4.0 to 9.0, in terms of ingestion and stability of the active ingredient in the liquid for internal use. Preferably it is 6.0-8.0. In the outer skin composition, the pH is preferably 3.0 to 10.0, more preferably 3.0 to 9.9, from the viewpoints of low irritation to the skin, good usability and stability of the active ingredient. 0, more preferably 4.0 to 9.0. In particular, in the case of ophthalmic preparations such as eyewashes and eye drops, the pH is preferably 5.0 to 9.5, more preferably 5.5 from the viewpoints of low irritation to mucous membranes and stability of active ingredients. To 9.0, more preferably 5.5 to 8.0.

The pharmaceutical composition of the present invention may further contain other components that are usually used in the art as necessary. However, this is not the case when it overlaps with the already described components. Other components include, for example, decongesting components, eye conditioning components, anti-inflammatory components, astringent components, antihistamine components, antiallergic components, vitamins, amino acids, antibacterial components, bactericidal components, saccharides, polysaccharides and their derivatives. , Cellulose and its derivatives, water-soluble polymers, local anesthetic components, steroid components, glaucoma therapeutic components, and cataract therapeutic components. Examples of other components preferable in the present invention include the following.

Decongestants: for example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, methylephedrine hydrochloride, hydrogen tartrate Epinephrine and the like. These may be d-form, l-form or dl-form.

Eye muscle modulator component: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically, quaternary ammonium compounds such as neostigmine methyl sulfate and pharmacologically acceptable salts thereof.

Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, dipotassium glycyrrhizinate, diclofenac sodium, bromfenac sodium, methyl salicylate Etc.

Vitamins: for example, at least one vitamin selected from the group consisting of vitamin A, vitamin B (other than vitamin B12), vitamin C, vitamin D, vitamin E, and other vitamins Can be contained. Examples of vitamin A include retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof. Examples of vitamin Bs include thiamine, thiamine disulfide, dicetiamine, octothiamine, chicotiamine, bisibhiamine, bisbenchamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal Folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, panthenol, biotin, choline, inositol and pharmacologically acceptable salts thereof. Examples of vitamin C include ascorbic acid and derivatives thereof, erythorbic acid and derivatives thereof, and pharmacologically acceptable salts thereof. Examples of vitamin D include ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol and pharmacologically acceptable salts thereof. Examples of vitamin E include tocopherol and its derivatives, ubiquinone derivatives and pharmacologically acceptable salts thereof. Examples of other vitamins include carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperidin and pharmacologically acceptable salts thereof.

Amino acids: for example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, sodium glutamate, sodium chondroitin sulfate, aspartic acid, potassium aspartate, magnesium aspartate and the like. These may be d-form, l-form or dl-form.

Antibacterial component or bactericidal component: For example, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, alkylpolyaminoethylglycine, chloramphenicol, tetracycline hydrochloride, oxytetracycline hydrochloride Ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, sulbenicin sodium, cefmenoxime hydrochloride, benzylpenicillin potassium, colistin metasulfonate sodium, erythromycin, erythromycin lactobionate, kitasamycin, spiramycin, fradiomycin sulfate, polymyxin sulfate, dibekacin, amikacin, Amikacin sulfate, acyclovir, iododeoxysi Gin, idoxuridine, cyclocytidine, cytosine arabinoside, trifluorothymidine, bromodeoxyuridine, polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, miconazole Can be mentioned.

Saccharides: Examples include monosaccharides and disaccharides, specifically glucose, trehalose, lactose, fructose and the like.

Polysaccharides or derivatives thereof: for example, sodium hyaluronate, sodium chondroitin sulfate and the like.

Cellulose or a derivative thereof or a salt thereof: Examples thereof include sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like.

Water-soluble polymers other than those mentioned above include, for example, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, dextrin, polyethylene glycol and the like.

Local anesthetic component: For example, lidocaine, oxybuprocaine, dibucaine, procaine, ethyl aminobenzoate, meprilucaine, and salts thereof.

Steroid component: Examples thereof include hydrocortisone, prednisolone, and salts thereof.

Glaucoma treatment component: for example, levobunolol, timolol, and salts thereof.

Cataract treatment component: For example, pirenoxine and the like.

In the pharmaceutical composition of the present invention, the content ratio of these components is appropriately determined according to the use, the kind of the contained component, and the like. For example, in the case of a liquid ophthalmic preparation, it is preferably 0.0001 to 50 w / v%, more preferably 0.0001 to 25 w / v%, still more preferably 0.001 to 10 w / v%, based on the entire composition. It is.

In addition, the pharmaceutical composition of the present invention can further contain additives that are usually used in the art as long as they do not impair the effect of improving eye strain. However, this is not the case when it overlaps with the already described components. Examples of such components include preservatives, bactericides or antibacterial agents, thickeners, solubilizers or solubilizers, pH adjusters, isotonic agents, fragrances, cooling agents, chelating agents, and buffering agents. , Stabilizers, bases and the like. Examples of preferable additives in the present invention include the following additives.

Preservatives, bactericides or antibacterials: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid Examples include propyl, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds, and acrinol.

Thickener: For example, sodium carboxymethylcellulose, dextran, polyethylene glycol, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, chondroitin sulfate, etc. Can be mentioned.

Solubilizers or solubilizers: for example, glycine-type amphoteric surfactants such as alkyldiaminoethylglycine, alkyl ether carboxylates, sulfonates such as sodium tetradecenesulfonate, alkyl sulfates such as sodium lauryl sulfate, N N-acyl taurine salts such as sodium cocoylmethyl taurine, POE alkyl ether phosphoric acid and salts thereof such as POE (10) sodium lauryl ether phosphate, N-acyl amino acid salts such as sodium lauroylmethylalanine, POE (3) lauryl Examples include POE alkyl ether sulfates such as sodium ether sulfate and anionic surfactants such as α-olefin sulfonate. Specifically, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20 ) Sorbitan oleate, polyoxyl 40 stearate, sucrose stearate, decaglyceryl monostearate, lauryl glucoside, macrogol 4000. The numbers in parentheses indicate the number of added moles.

pH adjuster: For example, hydrochloric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, triethanolamine, monoethanolamine and the like can be mentioned.

Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol Etc.

Perfume or refreshing agent: for example, terpenes (specifically, anethole, eugenol, camphor, geraniol, cineol, borneol, menthol, limonene, rhubarb, etc. These may be any of d-form, l-form or dl-form. Good oil) (specifically, fennel oil, cool mint oil, cinnamon oil, spearmint pond, mint water, mint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.).

Chelating agent: for example, ascorbic acid, tetrasodium edetate, sodium edetate, citric acid and the like.

Buffering agents: For example, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, boric acid, borax and the like can be mentioned.

Stabilizer: For example, cyclodextrin, dibutylhydroxytoluene, trometamol, tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate and the like can be mentioned.

Base: for example, octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum, etc. .

The pharmaceutical composition of the present invention is adjusted to an osmotic pressure ratio within a range that is acceptable to a living body, if necessary. The osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.0, preferably 0.5 to 2.0, more preferably 0.5 to 1.4. The osmotic pressure ratio can be adjusted by appropriately using a buffer, an isotonic agent, salts, and the like in addition to the pH adjuster.

The pharmaceutical composition of the present invention can be produced by a known method. For example, in the case of eye drops, eye wash, etc., it can be prepared by first mixing the respective components, further subjecting to filtration sterilization treatment if necessary, and finally filling the container.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Formulation Examples, but the present invention is not limited to these.

Examples and Comparative Examples Test Example 1 Evaluation of Eye Fatigue (1)
(Preparation of pharmaceutical composition (eyewash))
According to the formulation shown in Table 1, to dissolve the components in sterile purified water to prepare a pharmaceutical composition of Example 1及 beauty Comparative Examples 1-3 and 6-7. The pH was adjusted to 6.0. In Example 1, an appropriate amount of HPMC (hydroxypropylmethylcellulose) (“Metrozu 60SH-4000” manufactured by Shin-Etsu Chemical Co., Ltd.) was added to the composition of Comparative Example 6 to prepare a viscosity of 3 cp.

The viscosity of the composition is measured using a digital viscometer (model name: DV-II +, manufactured by Brookfield), which is a B-type viscometer, the spindle is ULA, the rotational speed is 6-30 rpm, and the liquid temperature is 25 ° C. It went on condition of.

(Evaluation method)
The eye strain improvement effect of the prepared eye wash was evaluated by the following measuring equipment, measurement index, method, and judgment criteria.
measuring equipment:
Adjustable tremor analysis device MF-1 (manufactured by Light Manufacturing Co., Ltd.)
Measurement index:
The degree of eye strain is evaluated by HFC (High Frequency Component) (the higher the HFC value, the higher the fatigue level). Note that a value of a focal length of 40 cm is adopted.
Method:
(1) The degree of eye strain of the subject is measured (initial value).
(2) Applying eye strain (VDT work for 15 minutes).
(3) Perform eyewash using 5 mL of each composition.
(4) The degree of eye strain of the subject is measured (measured value after eye washing).
The eye wash cup used for eye washing was the eye wash cup attached to "Ivon" (manufactured by Kobayashi Pharmaceutical Co., Ltd.). In addition, the evaluation when the eye wash is not performed in (3) is also performed (no treatment).
Judgment criteria:
The difference between the time of no treatment (measured value after initial treatment of VDT / initial value) × 100 and the time when each composition was used (measured value / initial value after eye washing of each composition) × 100 was calculated. Find the effect of improving fine fatigue.
The value of the eye strain improvement effect of Comparative Example 3 was set to 100% (reference), and the value of each example (relative improvement effect (%)) was calculated.

Test example 2 Evaluation of eye strain (2)
Preparation of pharmaceutical composition (eyewash and eye drops) (preparation of eyewash)
In Examples 4 to 14, an appropriate amount of HPMC (hydroxypropylmethylcellulose) (“Metroze 60SH-4000” manufactured by Shin-Etsu Chemical Co., Ltd.) was added to the composition of Comparative Example 6 in Table 1 so that the viscosity shown in Table 2 was obtained. Prepared. Comparative Examples 4 and 5 were prepared in the same manner as in Example 5 except that cyanocobalamin or berberine chloride was not blended.
(Preparation of eye drops)
It was prepared in the same manner as the above eyewash except that the components shown in Table 2 (cyanocobalamin and berberine chloride) were adjusted to a 10-fold concentration.

(Evaluation method)
About the eye strain improvement effect of the prepared eye wash and eye drops, 10 panelists who have subjective symptoms of eye strain are instilled (one use amount: 2 drops) and eye wash (one use amount: 5 mL). The test was carried out 3 times every 3 hours and evaluated according to the following methods and criteria.
Method:
The degree of improvement in eyestrain after using each composition (instillation or eyewash) is compared with that before use, and each of the following five levels is evaluated.
5 points: Improved.
4 points: Slightly improved.
3 points: Neither can be said.
2 points: Not much improved.
1 point: Not improved.
Judgment criteria:
A total score of 10 people is calculated for each of eye drops and eyewashes, and determined according to the following criteria.
◎: 41-50 points ○: 31-40 points Δ: 30 points or less

According to Table 1, in comparison with Comparative Example 3 in which neither berberine chloride nor cyanocobalamin is used , Example 1 and Comparative Examples 6 to 7 using these together have about 3.6 to 8.1 times as much eye strain improvement effect. Was seen. In particular, in Example 1 prepared to have a viscosity of 3 cp, an extremely large improvement effect was observed. In Comparative Example 1 in which only cyanocobalamin was used and in Comparative Example 2 in which only berberine chloride was blended, an improvement effect was not seen as compared with Comparative Example 3, so that a large synergistic effect was obtained by using berberine chloride and cyanocobalamin together. It was revealed that a significant eye strain improvement effect was obtained. Further, such an effect was seen immediately after eye washing, and the immediate effect was excellent.

According to Table 2 which investigated the influence of viscosity, about the eye fatigue improvement effect by eye washing, the sum total of the composition of 2-20 cp is high, Among them, the composition of 2-15 cp is high, The composition of 2-10 cp Was extremely high. Regarding the effect of improving eye strain by instillation, the total score of the 2-50 cp compositions was high, among which the 5-50 cp compositions were high, and the 10-50 cp compositions were extremely high. Moreover, when comparing the results of eyewashing and eyedropping with the same viscosity, eyewashing was more effective at 2 to 20 cp.

Formulation Example According to the formulations shown in Tables 3 to 11, a pharmaceutical composition (eyewash) was prepared by a conventional method (pH was adjusted to 6.0), filtered and sterilized in an aseptic environment, and washed and sterilized. A transparent container (polyethylene terephthalate) was filled and manufactured.
In addition, a pharmaceutical composition (ophthalmic solution) containing 10 times the amount of vitamin B12 and berberine in the formulations shown in Tables 3 to 9 is prepared, filtered and sterilized in an aseptic environment, and transparent and washed and sterilized. A container (polyethylene terephthalate) was filled and manufactured.

About the manufactured pharmaceutical composition, when the eye fatigue improvement effect was evaluated, the synergistic effect was seen like the Example. In particular, the effect of improving eye strain when using an eyewash containing 0.5 to 2.0 mg / 100 ml of vitamin B12 and 0.5 to 2.5 mg / 100 ml of berberine was more excellent. In particular, when the compounding amount of berberine with respect to 1 part by weight of vitamin B12 is 0.5 to 1.8 parts by weight, the effect of improving eye strain per berberine compounding amount was excellent. Moreover, the light stability of vitamin B12 was also excellent.

Claims (5)

Vitamin B12, berberine and / or a salt thereof, contain a thickening agent, trometamol, a pharmaceuticals group formed of eyewash or eye drops, wherein the free of tranilast or azulenes,
Pharmaceuticals group composition as eyewash or eye drops viscosity of 2~50cp at 25 ° C.. Berberine and / or the content of a salt thereof, a pharmaceutical group composition as eyewash or eye drops of claim 1 wherein 0.05 to 10 parts by weight relative to vitamin B12 1 part by weight. Pharmaceuticals group composition as eyewash or eye drops according to claim 1 or 2 containing concentration is 0.2~20mg in the overall composition 100g of vitamin B12. Berberine and / or eye washes or pharmaceuticals sets composition as ophthalmic according to claim 1 which is 0.5 to 25 mg to content concentration in the entire 100 ml composition a salt thereof. Pharmaceuticals group composition as eyewash or eye drops according to any one of claims 1 to 4 which is eyestrain improving agent.