CN103932983A - Eyedrops containing high-concentration vitamin A - Google Patents

Abstract

The invention discloses an eyedrops composition. The eyedrops composition is characterized by containing over 50,000 unit/100 mL of high-concentration vitamin A, kestose and tear substitute, wherein the tear substitute is selected from one or more of polyhydric alcohols, dextran, water-soluble protein, carbopol, gum and cellulose derivative. The components of the eyedrops are properly proportioned to achieve unexpected effects in relieving asthenopia and treating eye disease.

Description

A kind of collyrium that contains high concentration vitamin A

Technical field

The present invention relates to a kind of collyrium that contains high concentration vitamin A, ketose and tear substitute.

Background technology

Xerophthalmia is a kind of crowd's who affects about 10～20% ocular disease.This sickness influence crowd's ratio is larger with advancing age; in addition; use eye and in dry environment, use the crowd of eye for long-time; easily suffer from xerophthalmia; in the individuality of suffering from xerophthalmia, it is incomplete conventionally protecting the tear protective layer of ocular surface, thereby causes the generation that in tear, more than a kind or a kind composition can not be sufficient or healthy; this can cause the exposure of ocular surface, has finally accelerated the dry and infringement of superficial cell.

The S&S of xerophthalmia includes, but are not limited to keratitis, and in conjunctiva and corneal dyeing, hyperemia, blurred vision, tear thin film break-up time reduce, tear generation reduces, lacrimal secretion volume and tear flow, increase conjunctival congestion, tear film, unnecessary fragment, sears optical, eyes grittiness, eyes are burnt, had foreign body sensation, unnecessary tear, photophobia, eyes to twinge, reflect damage, eyes sensitivity and eye irritation in eyes.

Vitamin A attracts tremendous attention as the active ingredient that prevents and treat above-mentioned xerophthalmia and cornea, conjunctiva, skin mucosa seborrheic keratosis etc.In addition, the vitamin A of fatsoluble vitamin is very responsive, particularly extremely unstable in aqueous solution for air, light, heat, acid, metal ion etc., is therefore extremely difficult for stable being matched with in collyrium.

As by this unsettled vitamin A stable be matched with the prior art in collyrium, the vitamin E class (as: Japanese patent laid-open 6-247853 communique) of Bi pockmarks wet goods non-ionic surfactant (as: Japanese patent laid-open 5-331056 communique) or hydrophobicity antioxidant is added polyethylene and is firmly changed in known having in collyrium.But, in the prior art, but there is no the still method of the vitamin A of (more than 50,000 units) of unresolved cooperation high concentration.

In view of above problem, the inventor is through the discovery of concentrating on studies, in collyrium compositions, sneak into a certain amount of ketose (1-kestose), the vitamin A of high concentration will be contributed to coordinate in collyrium, coordinate appropriate tear substitute simultaneously, played beyond thought effect for treatment xerophthalmia and alleviation eye fatigue.

Therefore, the invention provides a kind of collyrium, it is characterized in that containing more than 50,000 units/100mL vitamin A, ketose and tear substitute.

Collyrium as above, the concentration of preferred contained ketose is 0.4～2.0W/V%.

Collyrium as above, wherein tear substitute is selected from one or more in polyhydric alcohol, dextran, water-solubility protein, carbomer, natural gum and cellulose derivative.

By the suitable proportioning of each component of the present invention, alleviating asthenopia and treatment ophthalmic tool are had an unexpected effect.

Detailed description of the invention

Below, the present invention is described in detail for pin.

Collyrium compositions of the present invention contains vitamin A, ketose and tear substitute component more than 50,000 units/100mL.In addition, the invention provides a kind of collyrium compositions of improving xerophthalmia effect that has, the present invention more has another effect for improving the effect of xerophthalmia.

Vitamin A

As vitamin A, except vitamin A itself, can also be vitamin A wet goods vitamin A derivative such as mixture, vitamin A fatty acid ester of containing vitamin A etc.Specifically comprise: vitamin A palmitate, retinyl acetate, vitamin A, retinoic acid, retinoid (retinoid) etc.Preferred vitamin A cetylate, retinyl acetate, retinoic acid.The vitamin A palmitate conventionally commercially available product that has 1,000,000～180 million international units (hereinafter referred to as unit or I.U.), concrete example is as " Palimitate-A " (1,700,000 I.U./g) that company of Roche Group produces.

Vitamin A composition one kind or two or more being used in combination in above-mentioned that can be used alone, its content, for collyrium total composition, is more than 50,000 units/100mL.Vitamin A has the effect for the treatment of cornea, conjunctival damage, improves xerophthalmia, improves eyestrain, the effect of vision, contains 50,000 units/100mL in collyrium, can obviously give play to better effect.If represent with W (quality)/V (volume) % (g/100mL), preferably 0.03～0.3W/V% of the melting concn of described vitamin A.

Ketose

The molecular formula of ketose involved in the present invention is

Preferably 0.4～2.0W/V% of the content of described ketose; More select 0.6～1.8W/V%; Further preferred 0.8～1.6W/V%; Most preferably 1.0～1.4W/V%.

Tear substitute

Tear substitute is selected from one or more in polyhydric alcohol, dextran, water-solubility protein, carbomer, natural gum and cellulose derivative.Tear substitute can also be artificial tears, classifies according to chemical composition or biological effect.Following component is for artificial tears (about the component in the different tear substitutes being obtained commercially): 1) water; 2) saline solution; 3) glycerol, monosaccharide and disaccharides (for example glycerol, sucrose, glucose (dextrose), sorbitol, mannitol); 4) polysaccharide (for example mucus [colloid], glucosan and mucopolysaccharide [hyaluronate sodium, sodium chondroitin sulfate]); 5) synthetic polymer (for example ethenyl derivatives, ethylene glycol derivative, other synthetic polymer [Polysorbate]); 6) gelatin; 7) biofluid (for example serum, colostrum, saliva, ovalbumin and mucin); With 8) lipid.

Antioxidant

In collyrium of the present invention, for improving the stability of vitamin A composition, can add antioxidant.As antioxidant, can enumerate d-á-tocopherol, tocopherol, tocopherol, tocopherol, dl-á-tocopherol, acetic acid d-á-tocopherol, acetic acid dl-á-tocopherol, acetic acid tocopherol, acetic acid tocopherol, acetic acid the vitamin E classes such as tocopherol, niacin dl-á-tocopherol; The fat-soluble antioxidant such as dibenzylatiooluene, Butylated hydroxyanisole; The water soluble antioxidants such as vitamin C, hydrogen roller, cysteine, glutathion etc.

Above antioxidant can be used alone a kind, can also combine in 2 above use, its content for collyrium total composition, preferably 0.005～5W/V%; More preferably 0.005～1W/V%; Further preferred 0.005～0.2W/V%.

In the present invention's collyrium compositions, not undermining under the scope of effect of the present invention, except above-mentioned composition, can coordinate the various compositions that make an addition in collyrium compositions.The examples such as such as polyhydric alcohol, interfacial agent, buffer agent, sticky dose, saccharide, pH adjusting agent, antiseptic, isotonization agent, stabilization agent, refrigerant agent, medicine, water.

As coordinated active drug composition, can enumerate as: congested remover (as: naphazoline hydrochloride, hydrochloric acid tetrahydro naphazoline, hydrochloric acid dehydrogenation epinephrine, epinephrine, ephedrine hydrochloride, dl-hydrochloride methyl ephedrine, nitric acid tetrahydro naphazoline, Naphazoline Nitrate etc.), antiinflammatory, astringent (as: neostigmine methylsulfate, amidcaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysozyme chloride, glycyrrhizic acid dipotassium, ammonium glycyrrhizinate, glycyrrhizic acid, methyl salicylate, azulenes sodium sulfonate etc.), (as: the hydrochloric acid 2-bis-benzyloxies-N of antihistaminic, N-dimethyl amine, 2-benzhydryl-N, N-dimethyl amine, the different dibenzyl ester of hydrochloric acid, maleic acid Pre-Sate etc.), water soluble vitamins (activated form vitamin B2, vitamin B6, vitamin B12 etc.), amino acid (as: L-Radix Asparagi amino acid potassium, L-Radix Asparagi amino acid magnesium, amido ethylsulfonic acid, sodium chondroitin sulfate etc.), vulcanizing agent, antibacterial (as: sulfur, isopropyl cresol, thujaplicin etc.), anti-allergic agent, local anesthetic (as: lignocaine, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride etc.), San Rising-moon agent, agent for treating cataract (pirenoxine, the sweet phthalein of paddy Guang etc.).

The present invention's collyrium compositions can directly make liquor, also can be modulated into suspending agent, gel etc.As using form person, concrete example (is generally used collyrium as: drop (as: use drop, contact lens drop etc.), collyrium, take out the collyrium that used after hidden glasses etc.), load the loadings liquid of contact lens, the taking-up liquid of taking-up contact lens etc.

Collyrium compositions of the present invention is aqueous, preferably 1～100mPas of its viscosity; More preferably 1～50mPas; Further preferred 1～30mPss.

Collyrium compositions of the present invention, relevant its compound method is restriction especially not, general as: make vitamin A in aseptic RO water, carry out solubilization by polyethylene glycol oxide polyoxypropyleneglycol, then, add trometamol, respectively coordinate composition, can obtain after adjusting pH.Afterwards, in suitable container, as: in the container of polyethylene terephthalate system etc., carry out aseptic filling.

Collyrium of the present invention is applicable to corneal injury treatment collyrium compositions, dry eye treatment agent.In addition, xerophthalmia is abnormal via the matter of tear or amount, the state that the angle conjunctiva on eyeball surface is hindered.Tear is made up of oil reservoir, water layer and mucoprotein layer, and matter, the amount equilibrium of this three-layer structure are damaged, and cause tear unstable, and obstacle appears in corneal, causes xerophthalmia.In dry eye treatment, it focuses on making the oil reservoir, water layer of this tear, the three-layer structure of mucoprotein layer to recover, and treatment cornea obstacle.In addition, contact lens user, easily causes xerophthalmia, thereby collyrium, contact lens that collyrium compositions of the present invention is applicable to after drop for contact lens, taking-up contact lens load liquid, contact lens taking fluid etc.While being applicable to dry eye treatment agent, after 1 30～60 ì L of eye dripping, 3～6 times on the 1st, can further bring into play its effect.

Embodiment

Below show embodiment and comparative example, carry out specific description of the present invention, but the present invention is not limited to following embodiment.

At 85 DEG C, make vitamin A and antioxidant preparation dissolve the collyrium compositions (drop) of composition shown in table 1.This preparation solute is joined in the aseptic RO water of 85 DEG C of heating and is dissolved, cooling after, add mixing composition, adjust pH (20 DEG C) to 7.0, obtain collyrium compositions.15mL is obtained to collyrium compositions and be filled in eye drop container for 15mL (polyethylene terephthalate system).

< vitamin A palmitate residual rate (%) >

After preparing above-mentioned collyrium, be preserved in 40 DEG C, 75% humidity lower 6 months, then measure the content of vitamin A palmitate in collyrium compositions.Specifically use high-speed liquid chromatography method to measure.By the vitamin A palmitate content obtaining, calculate vitamin A palmitate residual rate (%) according to calculating formula below.

Vitamin A palmitate content × 100 after vitamin A palmitate content/manufacture after vitamin A palmitate residual rate (%)=preservation

The therapeutic effect > of < cornea, conjunctival damage

The cornea that uses enanthol to process the cornea of rabbit, conjunctival epithelium Disorder Model carries out the therapeutic effect test of conjunctival damage.

The eyes of rabbit are processed to (making enanthol/ethanol=8: 2 mixed liquors splash into simple eye 200 ì L) with enanthol, make rabbit cornea, the impaired model of conjunctival epithelium.Then, use sample of the present invention to carry out continuously eye dripping 11 days in (6 times (100 ì L/ time)/sky).During eye dripping, regularly carry out fluorescent staining (the simple eye 50 ì L that splash into of 2% fluorescein), according to Lenp determinating reference, with 15 points of full marks (mark after treatment enanthol is made to 15 points, according to its effectively degree of improvement fall point) evaluate.Show the evaluation result of the 5th day.

< eye irritation >

With 50 ì L/ time, interval 5 minutes, rabbit is carried out to overclockings time some eye test 15 times.

After eye dripping 15 times, carry out fluorescent staining (the simple eye 50 ì L that splash into of 2% fluorescein), according to following benchmark evaluation corneal injury scope.

Scoring 4: the more than 2/3 appearance dyeing of all areas of cornea

Scoring 3: 2/3 appearance that more than 1/3 do not reach of all areas of cornea is dyeed

Scoring 2: the dyeing of all area appearance of cornea does not reach 1/3

Scoring 1: slightly dyeing

Scoring 0: do not occur dyeing

Table 1. experimental result and evaluation

Table 1 has shown therapeutic effect and the eye irritation of evaluating according to the method described above vitamin A palmitate residual rate, corneal, conjunctival damage.As shown in Table 1, collyrium compositions of the present invention all has the vitamin A palmitate residual rate of telling somebody what one's real intentions are, and the therapeutic effect of corneal, conjunctival damage is remarkable, and eyes are not stimulated.

Raw material reagent shown in table 1 is all purchased from commercially available chemical reagent, and wherein ketose is purchased from Sigma company, and other is the pure level of general analysis reagent.

Claims (6)

1. a collyrium compositions, is characterized in that, contains more than 50,000 units/100mL vitamin A, ketose and tear substitute.

2. collyrium compositions as claimed in claim 1, wherein, the concentration of described ketose is 0.4～2.0W/V%.

3. collyrium compositions as claimed in claim 1, wherein, the concentration of described ketose is 0.6～1.8W/V%.

4. collyrium compositions as claimed in claim 1, wherein, the concentration of described ketose is 0.8～1.6W/V%.

5. collyrium compositions as claimed in claim 1, wherein, the concentration of described ketose is 1.0～1.4W/V%.

6. the collyrium compositions as described in claim 1～5 any one, wherein, described tear substitute is selected from one or more in polyhydric alcohol, dextran, water-solubility protein, carbomer, natural gum and cellulose derivative.