CN103919718A - Vitamin A palmitate eye drop, preparation method and use thereof - Google Patents
Vitamin A palmitate eye drop, preparation method and use thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical pharmacy, and relates to a vitamin A palmitate eye drop, a preparation method and a use thereof. Specifically the eye drop contains 0.01-0.2% (w/w) of vitamin A palmitate adopted as a main drug, 0.01-5.0% (w/w) of a solubilizing agent and 0.01-10.0% (w/w) of a co-solvent. According to the present invention, the assisted solubilizing manner is adopted so as to solve problems of solubility and stability of vitamin A palmitate in water; and the eye drop is a light yellow transparent solution, has a characteristic of low eye irritation, and is suitable for eyes.
Description
Technical field
The invention belongs to pharmaceutics field, relate to a kind of vitamin A palmitate eye drop and its production and use.
Background technology
Vitamin A palmitate belongs to vitamin medicaments, and its molecular formula is C
36h
60o
2, molecular weight is 524.5, structural formula is as follows:
Vitamin A comprises that its cetylate can significantly increase Conjunctival Goblet Cells quantity, induction corneal epithelial cell growth factor receptors forms and glycoprotein synthesizes, stimulate glucose and glucosamine to mix corneal epithelium, promote bitot's patches speckle and the damaged healing of cornea point-like, make coarse, granular anterior corneal surface becomes smooth, can be used for a variety of causes (Sjogren's syndrome for example, neuroparalytic keratitis, exposure keratitis etc.) xerophthalmia causing and because tear film protection lacks for example cornea keratinization of the conjunctiva that causes or corneal irritation, corneal epithelial wound etc.In addition, vitamin A palmitate is a medicine that safety is very high, the basic avirulence of local use.
Vitamin A palmitate tool is fat-soluble, and to light, oxygen sensitive, so its raw material and preparation all should be preserved under the condition of airtight, shading.
At present, on market, the preparation of vitamin A palmitate has a lot, but because vitamin A palmitate is a fat-soluble stronger medicine, so be dissolved in to make solution in vegetable oil.But conventionally there are many shortcomings in the preparation that the oil of take is solvent, especially for eye is local, use, unacceptable.
Also have in addition the gel preparation of vitamin A palmitate, it is 10 grams that listing product has " vitamin A palmitate gel for eye use " content of Switzerland Novartis: 10000 units, 1000 units/gram, are about 0.06%.The feature of gel for eye use be can prolong drug in the holdup time of eye table, the release of prolong drug or diffusion, improve the local concentration of medicine; But stability is bad, for example, need low temperature storage or holding time too short; In addition, after a use, sometimes have of short duration slight burn feeling, eyelid adhesion and/or temporary blurred vision.
Eye drop is current most popular eye dosage form, and it uses more comfortable and non-irritating advantage and is more easily accepted.But fat-soluble vitamin A palmitate is prepared into eye drop, has very large difficulty, therefore for a long time, on market, not yet have desirable vitamin A palmitate eye drop.
Summary of the invention
The inventor, through deep research and performing creative labour and a large amount of tests, has obtained being applicable to vitamin A palmitate to make the prescription of eye drop, thereby has made a kind of vitamin A palmitate eye drop; And the inventor is surprised to find, (particularly cosolvent comprises polyoxyethylene hydrogenated Oleum Ricini to this eye drop
40during with propylene glycol) have good stability, little to Ocular irritation, be very suitable for eye and use.Following invention is provided thus:
One aspect of the present invention relates to a kind of eye drop, it comprises vitamin A palmitate, lytic agent and cosolvent as principal agent, wherein, the content of vitamin A palmitate is 0.01%-0.2%(w/w), the content of lytic agent is 0.01%-5.0%(w/w), the content of cosolvent is 0.01%-10.0%(w/w).
Eye drop according to the present invention described in any one, wherein, the content of described vitamin A palmitate is 0.06%-0.2%(w/w), be preferably 0.08%-0.2%(w/w) for example, 0.08%-0.10%(w/w), 0.08%-0.12%(w/w), 0.08%-0.14%(w/w), 0.08%-0.16%(w/w), 0.08%-0.18%(w/w), 0.10%-0.12%(w/w), 0.10%-0.14%(w/w), 0.10%-0.16%(w/w), 0.10%-0.18%(w/w), 0.10%-0.2%(w/w), 0.12%-0.14%(w/w), 0.12%-0.16%(w/w), 0.12%-0.18%(w/w), 0.12%-0.2%(w/w), 0.14%-0.16%(w/w), 0.14%-0.18%(w/w), 0.14%-0.2%(w/w), 0.16%-0.18%(w/w), 0.16%-0.2%(w/w) or 0.18%-0.2%(w/w), be for example again 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%(w/w).
Be not limited to theoretical restriction, if surpass 0.2%, likely occur that principal agent becomes to analyze and causes layering, thereby affect other indexs such as clarity, zest.
Eye drop according to the present invention described in any one, wherein, described lytic agent is MCT Oil.Described MCT Oil has the general sense that those skilled in the art know, preferably, is the mixture of any or two kinds in Trivent OCG and tricaprin.
Eye drop according to the present invention described in any one, wherein, the content of described lytic agent is 0.1%-5.0%(w/w); Be preferably 0.1%-4.0%(w/w); 0.1%-3.0%(w/w more preferably) or 0.5%-4.0%(w/w) or 1.0%-2.0%(w/w), for example 1.2%-1.8%, 1.5%-2.0%, 1.0%-1.5%, 1.3%-1.6%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or 2.0%(w/w).
Eye drop according to the present invention described in any one, wherein, described cosolvent is for being selected from polyoxyethylene hydrogenated Oleum Ricini
40, propylene glycol, Polyethylene Glycol
400, in tween 80, poloxamer, glycerol and n-butyl alcohol any or multiple.
Eye drop according to the present invention described in any one, wherein, the content of described cosolvent is 0.1%-10.0%(w/w); Be preferably 0.3%-7.0%(w/w); 0.5%-5.0%(w/w more preferably) or 1.0%-3.0%(w/w), for example 1.0%-2.0%, 1.5%-2.5%, 2.0%-3.0%, 1.5%-3.0%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% or 3.0%(w/w).
Eye drop according to the present invention described in any one, wherein preferably, described cosolvent comprises polyoxyethylene hydrogenated Oleum Ricini
40and propylene glycol.Alternatively, described cosolvent also comprises and is selected from Polyethylene Glycol
400, in tween 80, poloxamer, glycerol and n-butyl alcohol any or multiple.
Eye drop according to the present invention described in any one, wherein particularly preferably, described cosolvent comprises (or being) polyoxyethylene hydrogenated Oleum Ricini
40, propylene glycol and glycerol; Alternatively, also comprise and be selected from Polyethylene Glycol
400, in tween 80, poloxamer and n-butyl alcohol any or multiple.
Eye drop according to the present invention described in any one, wherein, polyoxyethylene hydrogenated Oleum Ricini
40with the ratio of propylene glycol be 5:1 to 1:5; Be preferably 4:1 to 1:4; 3:1 to 1:3 more preferably; 2:1 to 1:2 more preferably; Be particularly preferably 1:1.The consumption of described glycerol is preferably polyoxyethylene hydrogenated Oleum Ricini
4050%-150% or 50%-125%, for example 50%-75%, 50%-100%, 75%-100%, 75%-100%, 75%-150%, 100%-150%, 50%, 75%, 100%, 125% or 150%.
Eye drop according to the present invention described in any one, wherein, described cosolvent comprises cosolvent 1, and it is selected from polyoxyethylene hydrogenated Oleum Ricini
40, in tween 80 and poloxamer any one or multiple; With cosolvent 2, it is selected from propylene glycol, Polyethylene Glycol
400, in glycerol and n-butyl alcohol any one or multiple.
Eye drop according to the present invention described in any one, wherein, the ratio of cosolvent 1 and cosolvent 2 is 5:1 to 1:5; Be preferably 4:1 to 1:4; 3:1 to 1:3 more preferably; 2:1 to 1:2 more preferably; Be particularly preferably 1:1.
Eye drop according to the present invention described in any one, wherein, the ratio of described lytic agent and cosolvent is 10:1 to 1:10; Be preferably 8:1 to 1:8; 4:1 to 1:4 more preferably; For example 4:1,1:4,3:1,1:3,2:1,1:1 or 1:2; Be particularly preferably 1:4.
In a particularly preferred embodiment of the present invention, lytic agent (for example MCT Oil) and polyoxyethylene hydrogenated Oleum Ricini
40with the ratio of propylene glycol be 1:2:2.
Eye drop according to the present invention described in any one, it also comprises one or more in antioxidant, antiseptic and osmotic pressure regulator.
Eye drop according to the present invention described in any one, it meets any one or more in following (1)-(3):
(1) described antioxidant is to be selected from one or more in BHA, BHT and vitamin E, and its content is 0.01%-0.2%(w/w); Particularly, be 0.05%-0.1%(w/w);
(2) described osmotic pressure regulator is to be selected from one or more in glycerol, sodium chloride, mannitol and sorbitol, and the content of described osmotic pressure regulator is 0.1%-5.0%(w/w); Particularly, be 0.5%-3.0%(w/w);
(3) described antiseptic is to be selected from one or more in benzalkonium chloride, benzalkonium bromide, ethyl hydroxybenzoate, chlorobutanol and cetrimonium bromide, and the content of described antiseptic is 0.01%-5.0%(w/w); Particularly, be 0.01%-3.0%(w/w).
About (2) above, be not limited to theoretical restriction, the osmotic pressure of tear equates with serum, the osmotic pressure that is equivalent to 0.9% sodium chloride (286mOsm), eyes can tolerate the osmotic pressure scope (about 200-450mOsm) that is equivalent to 0.6-1.5% sodium chloride, best osmotic pressure scope is 260-310mOsm, the osmotic pressure corneal permeability of eye drop has certain influence, when eye drop and normal saline osmotic pressure differ greatly, because the effect stimulating impels lacrimal secretion dilution medicine, reduce cornea permeability, therefore eye drop should be made into and equate with tear osmotic pressure or close solution.The eye drop Ke Shiwai ocular tissue that height oozes loses moisture content, and tissue is dried and the sense of generation discomfort, and hypotonic eye drop can make external eyes histiocyte swell, and produces excitement, so eye drop should be made into isosmotic solution.In the present invention, preferably osmotic pressure is controlled between 260-310mOsm.
Eye drop according to the present invention described in any one, its pH is 5.0-7.0; Be preferably 5.5-6.5.The present invention is without adding pH adjusting agent, and the pH of the eye drop obtaining is in above-mentioned pH scope.
Eye drop according to the present invention described in any one, it comprises any a group in the group of following (1)-(9):
（1）
（2）
（3）
（4）
（5）
（6）
（7）
（8）
（9）
Wherein, preferably above (4), (5), (6), (8) or (9) group.
An object of the present invention is vitamin A palmitate to make solution-type eye drop.Be not limited to theoretical restriction, solution is directed to gel, oil preparation has multiple advantage, and solution is not only conducive to release and the absorption of medicine, and the feature such as it is good to have comfortableness, and toleration is strong.The present invention adopts the method for hydrotropy, chooses lytic agent main component is dissolved in wherein, utilizes hydrophilic-close oil properties of this lytic agent, fat-soluble medicine is dissolved and be distributed in the middle of aqueous solution, forms water soluble preparation.Preferably, also need to add cosolvent, antioxidant, antiseptic, osmotic pressure regulator, thereby make the stable clinical eye drop that can be used for.
Eye drop of the present invention in eye Local irritation study, show this product through single-dose, multiple dosing to rabbit all without eye irritation, prove that the comfortableness of eye drop of the present invention is better.
Three batch samples of the present invention are through the investigation of accelerated test (6 months) and long term test (24 months), and result, for all to meet the requirement of eye drop, illustrates that eye drop stability of the present invention is better.The prescription of simultaneously determining this product rationally, technical maturity, steady quality, standard be controlled, and meet the demand that industrialization is produced and declared.
Another aspect of the present invention relates to the preparation method of the eye drop described in any one in the present invention, comprises the following steps:
1) vitamin A palmitate and optional antioxidant are added in lytic agent, make it to dissolve, obtain lytic agent solution;
2) in water, add cosolvent and optional antiseptic and osmotic pressure regulator, stir and make it to dissolve, obtain aqueous solution;
3) under stirring, lytic agent solution is added in aqueous solution to mix homogeneously;
4) water is supplemented to full dose, filters and get final product.
Of the present inventionly relate in one aspect to again the eye drop described in any one in the present invention and treat and/or prevent and/or auxiliary treatment xerophthalmia or the protection of tear film lack the purposes in the medicine of the conjunctiva that causes or corneal irritation in preparation.Particularly, described xerophthalmia is caused by one or more in Sjogren's syndrome, neuroparalytic keratitis, exposure keratitis.Particularly, described tear film protection shortage causes conjunctiva or corneal irritation are cornea keratinization or corneal epithelial wound.
In the present invention, if not otherwise specified, the content of each component or composition be all weight percentage (w/w).
In the present invention, if not otherwise specified, described ratio or consumption are weight ratio.
The beneficial effect of the invention
The present invention has adopted the hydrotropy formula of optimizing, and has solved the dissolubility of vitamin A palmitate in water and the problem of stability.The present invention has realized local use and vitimin supplement A, and the eye local irritation of eye drop is little, and comfort level is good; In addition, eye drop of the present invention has been realized higher vitamin A palmitate drug loading, has kept good stability simultaneously.
The specific embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
embodiment 1: the preparation of vitamin A palmitate eye drop 1
1) prescription:
2) preparation method:
(1) vitamin A palmitate and BHA are added in MCT Oil, mixed dissolution is standby;
(2) poloxamer is dissolved with Sq water soaking, standby;
(3) ethyl hydroxybenzoate is added in the water of Sq to heating for dissolving.
(4) poloxamer soak is added in above-mentioned solution to mix homogeneously;
(5) Polyethylene Glycol is added in above-mentioned solution to heating for dissolving; And add respectively sorbitol, glycerol stirring and dissolving, mix homogeneously;
(6) vitamin A palmitate solution is added in above-mentioned solution,
(7) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 2: the preparation of vitamin A palmitate eye drop 2
1) prescription:
2) preparation method:
(1) vitamin A palmitate and BHA are added to stirring and dissolving in MCT Oil, standby;
(2) benzalkonium bromide is added in the water of Sq to stirring and dissolving;
(3) respectively tween 80, glycerol, sorbitol are added in above-mentioned solution to stirring and dissolving;
(4) vitamin A palmitate solution is added in above-mentioned solution to mix homogeneously;
(5) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 3: the preparation of vitamin A palmitate eye drop 3
1) prescription:
2) preparation method:
(1) vitamin A palmitate and BHT are added in MCT Oil, mixed dissolution is standby;
(2) poloxamer is dissolved with Sq water soaking, standby;
(3) cetrimonium bromide is added in the water of Sq to heating for dissolving;
(4) poloxamer soak is added in above-mentioned solution to mix homogeneously;
(5) propylene glycol is added in above-mentioned solution to heating for dissolving; And add respectively mannitol, glycerol stirring and dissolving, mix homogeneously; Mix homogeneously;
(6) vitamin A palmitate solution is added in above-mentioned solution,
(7) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 4: the preparation of vitamin A palmitate 4
1) prescription:
2) preparation method:
(1) vitamin A palmitate and vitamin E are added to stirring and dissolving in MCT Oil, standby;
(2) benzalkonium chloride is added in the water of Sq to stirring and dissolving;
(3) respectively by polyoxyethylene hydrogenated Oleum Ricini
40, propylene glycol adds in above-mentioned solution, stirring and dissolving;
(4) respectively mannitol, glycerol are added in above-mentioned solution to stirring and dissolving;
(5) vitamin A palmitate solution is added in above-mentioned solution to mix homogeneously;
(6) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 5: the preparation of vitamin A palmitate eye drop 5
1) prescription:
2) preparation method:
(1) vitamin A palmitate and vitamin E are added to stirring and dissolving in MCT Oil, standby;
(2) cetrimonium bromide is added in the water of Sq to stirring and dissolving;
(3) respectively by polyoxyethylene hydrogenated Oleum Ricini
40, n-butyl alcohol adds in above-mentioned solution, stirring and dissolving;
(4) respectively propylene glycol, glycerol are added in above-mentioned solution to stirring and dissolving;
(5) vitamin A palmitate solution is added in above-mentioned solution to mix homogeneously;
(6) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 6: the preparation of vitamin A palmitate eye drop 6
1) prescription:
2) preparation method:
(1) vitamin A palmitate and BHA are added to stirring and dissolving in MCT Oil, standby;
(2) benzalkonium chloride is added in the water of Sq to stirring and dissolving;
(3) respectively by polyoxyethylene hydrogenated Oleum Ricini
40, propylene glycol adds in above-mentioned solution, stirring and dissolving;
(4) respectively mannitol, glycerol are added in above-mentioned solution to stirring and dissolving;
(5) vitamin A palmitate solution is added in above-mentioned solution to mix homogeneously;
(6) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 7: the preparation of vitamin A palmitate eye drop 7
1) prescription:
2) preparation method:
(1) vitamin A palmitate and BHT are added in MCT Oil, mixed dissolution is standby;
(2) poloxamer is dissolved with Sq water soaking, standby;
(3) chlorobutanol is added in the water of Sq to heating for dissolving;
(4) poloxamer soak is added in above-mentioned solution to mix homogeneously;
(5) Polyethylene Glycol is added in above-mentioned solution to heating for dissolving; And add respectively mannitol, glycerol stirring and dissolving, mix homogeneously;
(6) vitamin A palmitate solution is added in above-mentioned solution,
(7) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 8: the preparation of vitamin A palmitate eye drop 8
1) prescription:
2) preparation method:
(1) vitamin A palmitate and BHA are added to stirring and dissolving in MCT Oil, standby;
(2) cetrimonium bromide is added in the water of Sq to stirring and dissolving;
(3) respectively by polyoxyethylene hydrogenated Oleum Ricini
40, propylene glycol adds in above-mentioned solution, stirring and dissolving;
(4) respectively mannitol, glycerol are added in above-mentioned solution to stirring and dissolving;
(5) vitamin A palmitate solution is added in above-mentioned solution to mix homogeneously;
(6) supplementing water is to full dose, and mix homogeneously filters and get final product.
embodiment 9: the preparation of vitamin A palmitate eye drop 9
1) prescription:
2) preparation method:
(1) vitamin A palmitate and BHA are added to stirring and dissolving in MCT Oil, standby;
(2) benzalkonium bromide is added in the water of Sq to stirring and dissolving;
(3) respectively by polyoxyethylene hydrogenated Oleum Ricini
40, propylene glycol adds in above-mentioned solution, stirring and dissolving;
(4) respectively sorbitol, glycerol are added in above-mentioned solution to stirring and dissolving;
(5) vitamin A palmitate solution is added in above-mentioned solution to mix homogeneously;
(6) supplementing water is to full dose, and mix homogeneously filters and get final product.
Although it will be appreciated by those skilled in the art that the unit of weight of each component in embodiment 1-9 is above g, also can be understood as weight portion or other unit of weight.
experimental example 1: stability experiment
1. laboratory sample
By embodiment 1-9 formulation and technology, prepare sample, carry out stability experiment.The vitamin A palmitate gel for eye use (promise abundant, Switzerland Novartis Co.,Ltd produce) of control sample for having gone on the market.
2. experimental technique
This experimentation is according to two appendix I G ophthalmic preparation general rules of < < Chinese Pharmacopoeia > > version in 2010, and the requirement of < < Chinese Pharmacopoeia > > two appendix XI X C crude drug of version in 2010 and pharmaceutical preparation stability test guideline, this prescription is carried out to the investigation of accelerated test (6 months) and long term test (24 months), the results are shown in Table 1-3.
Testing index and method are:
（1）pH：
According to two appendix VI H pH algoscopys of Chinese Pharmacopoeia version in 2010.
(2) related substance (impurity):
Vitamin A palmitate catabolite is comparatively complicated, and conventional normalization method is controlled the total amount of impurity below 1.5%.
With reference to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure.
Chromatographic column: 4.5mm * 30cm silicagel column;
Mobile phase: normal hexane: ethyl acetate: isopropyl alcohol (85: 14.92: 0.08)
Detect wavelength: UV-detector 325nm;
Flow velocity: 2.0ml/min;
Column temperature: 25 ℃ of room temperatures.
Determination step is as follows:
Sample thief is appropriate, accurately weighed, and operation is in accordance with the law diluted to every 1ml containing the solution of the about 30IU of vitamin A by mobile phase, with 0.45 μ m microporous filter membrane, filters, and getting subsequent filtrate is need testing solution.Separately get need testing solution 1.5ml, put in the brown measuring bottle of 100ml, add mobile phase and be diluted to scale, shake up, in contrast solution.Get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, the 10%-20% that the peak height that makes main constituent chromatographic peak is full scale, precision measures need testing solution 20 μ l injection liquid chromatographies again, record chromatogram to 2 times of main composition retention time, with relative retention time, be about 0.30,0.37,0.40 and 0.47 peak area summation (normalization method) calculating vitamin A palmitate related substance, total impurities should be greater than 1.5%.
(3) assay:
With reference to the chromatographic condition under related substance check item, and high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010) is measured.
3. experimental result
As shown in table 1-3 below.
Table 1: the check situation of embodiment 1-9 sample (0 o'clock)
| Embodiment numbering | Character | PH value | Related substance % | Content IU/g | Relative amount % |
| Embodiment 1 | Micro-yellow transparent solution | 5.78 | 0.56 | 1085 | 103.3 |
| Embodiment 2 | Micro-yellow transparent solution | 6.12 | 0.88 | 2076 | 98.9 |
| Embodiment 3 | Micro-yellow transparent solution | 6.07 | 1.27 | 3475 | 99.3 |
| Embodiment 4 | Micro-yellow transparent solution | 5.88 | 0.82 | 2114 | 100.7 |
| Embodiment 5 | Micro-yellow transparent solution | 5.53 | 0.63 | 1380 | 98.6 |
| Embodiment 6 | Micro-yellow transparent solution | 6.45 | 0.67 | 1755 | 100.3 |
| Embodiment 7 | Micro-yellow transparent solution | 6.22 | 0.94 | 2812 | 100.4 |
| Embodiment 8 | Micro-yellow transparent solution | 5.94 | 0.75 | 2435 | 99.4 |
| Embodiment 9 | Micro-yellow transparent solution | 6.15 | 0.84 | 3138 | 99.6 |
| Control sample | Micro-yellow gel | 5.91 | 0.73 | 1227 | - |
Table 2: embodiment 1-9 sample accelerated test result (6 months)
| Embodiment numbering | Character | PH value | Related substance % | Content IU/g | Relative amount % |
| Embodiment 1 | Micro-yellow transparent solution | 5.68 | 2.24 | 838 | 79.8 |
| Embodiment 2 | Micro-yellow transparent solution | 6.09 | 1.53 | 1764 | 84.0 |
| Embodiment 3 | Micro-yellow transparent solution | 6.03 | 1.71 | 2852 | 81.5 |
| Embodiment 4 | Micro-yellow transparent solution | 5.77 | 0.89 | 2092 | 99.6 |
| Embodiment 5 | Micro-yellow transparent solution | 5.50 | 0.74 | 1356 | 96.9 |
| Embodiment 6 | Micro-yellow transparent solution | 6.43 | 0.81 | 1738 | 99.3 |
| Embodiment 7 | Micro-yellow transparent solution | 6.15 | 1.92 | 2560 | 80.7 |
| Embodiment 8 | Micro-yellow transparent solution | 5.91 | 0.88 | 2404 | 98.1 |
| Embodiment 9 | Micro-yellow transparent solution | 6.10 | 1.06 | 3113 | 98.8 |
| Control sample | Micro-yellow gel | 5.06 | 3.56 | 842 | 68.6 |
Note: the investigation condition in table 2 is, 40 ℃ ± 2 ℃ of temperature, relative humidity 25% ± 5%.
Table 3: embodiment 1-9 sample long-term test results (24 months)
| Embodiment numbering | Character | PH value | Related substance % | Content IU/g | Relative amount % |
| Embodiment 1 | Micro-yellow transparent solution | 5.71 | 1.03 | 947 | 90.2 |
| Embodiment 2 | Micro-yellow transparent solution | 6.06 | 1.84 | 1770 | 84.3 |
| Embodiment 3 | Micro-yellow transparent solution | 6.01 | 1.39 | 2871 | 82.0 |
| Embodiment 4 | Micro-yellow transparent solution | 5.84 | 0.87 | 2102 | 100.1 |
| Embodiment 5 | Micro-yellow transparent solution | 5.50 | 0.72 | 1364 | 97.4 |
| Embodiment 6 | Micro-yellow transparent solution | 6.40 | 0.77 | 1731 | 98.9 |
| Embodiment 7 | Micro-yellow transparent solution | 6.14 | 1.99 | 2242 | 80.1 |
| Embodiment 8 | Micro-yellow transparent solution | 5.83 | 0.85 | 2414 | 98.5 |
| Embodiment 9 | Micro-yellow transparent solution | 6.11 | 1.02 | 3118 | 99.0 |
| Control sample | Micro-yellow gel | 5.14 | 3.42 | 861 | 70.2 |
Note: the investigation condition in table 3 is, 25 ℃ ± 2 ℃ of temperature, relative humidity 65% ± 10%.
Result demonstration, vitamin A palmitate gel for eye use (promise is abundant) is in the process of accelerated test (6 months) and long term test (24 months), and related substance and assay are all undesirable.Check vitamin A palmitate gel for eye use (promise is abundant) operation instructions, determine that its holding conditions is: " before Kaifeng, this product must be preserved (2 ℃-8 ℃) in refrigerator for the first time.Behind Kaifeng, this product can be stablized 30 days at room temperature (15 ℃-25 ℃) for the first time ".This product, because of stability problem, is not suitable for room temperature and places.
And press the product accelerated tests (6 months) of this patent embodiment 4,5,6,8 and 9 preparations and long term test (24 months) indices and 0 month more all without significant change, illustrate that this eye drop formulation and technology is reasonable, stability is better than the product that goes on the market, and product can be preserved at normal temperatures, meet clinical actual requirement.
experimental example 2: eye irritation test
1. laboratory sample
Vitamin A palmitate eye drop: press the preparation of embodiment 1-9 formulation and technology.
Blank: do not press the preparation of embodiment 1-9 formulation and technology containing all the other components of vitamin A palmitate.
2. laboratory animal
Rabbit, the large ear white race of Japan, body weight 2.3-2.5kg, male and female dual-purpose.By ambisense institute of lab animals, Shenyang City, provided, laboratory animal production licence number is respectively SCXK(the Liao Dynasty) 2003-0012, SYXK(the Liao Dynasty) 2003-0024.
3. experimental technique
(1) adopt single-dose eye irritant test method
(2) adopt multiple dosing eye irritant test method
(3) test scores standard and method: in Table 4, table 5.
Table 4: eye irritant reaction standards of grading
Table 5: result criterion
| Stimulation levels | Total points | Criterion |
| 1 | 0-3 divides | Nonirritant |
| 2 | 4-8 divides | Slight stimulation |
| 3 | 9-12 divides | Moderate stimulates |
| 4 | 13-16 divides | Intensity stimulates |
Specific experiment step is as follows:
(1) single-dose eye irritant test
Get 4 of healthy rabbits, male and female dual-purpose, body weight 2.2-2.8kg, every rabbit left eye drips vitamin A palmitate eye drop 0.1ml, right eye is given corresponding blank 0.1ml, all drops in conjunctival sac passive closed about 10 seconds of upper palpebra inferior, observe after administration the local response situation of 6,24,48,72 hours rabbit corneas, iris, conjunctiva, calculate total points.The zest score of blank is 0 minute, and administration group scores is in Table 6.
(2) multiple dosing eye irritant test
Test: get 4 of healthy rabbits, male and female dual-purpose, body weight 2.2-2.8kg, press single-dose method and dosed administration, administration every day 4 times, successive administration 7 days, observe in 7 days and after last administration the local response situation of 24,48,72,168 hours rabbit corneas, iris, conjunctiva, calculate total points.The zest score of blank is 0 minute, and administration group scores is in Table 6.
Table 6: each embodiment single, multiple dosing group eye irritant test result
| Prescription | Single-dose total points | Multiple dosing total points | Result |
| Embodiment 1 | 0 | 0 | Non-stimulated |
| Embodiment 2 | 0 | 0 | Non-stimulated |
| Embodiment 3 | 0 | 0 | Non-stimulated |
| Embodiment 4 | 0 | 0 | Non-stimulated |
| Embodiment 5 | 0 | 0 | Non-stimulated |
| Embodiment 6 | 0 | 0 | Non-stimulated |
| Embodiment 7 | 0 | 0 | Non-stimulated |
| Embodiment 8 | 0 | 0 | Non-stimulated |
| Embodiment 9 | 0 | 0 | Non-stimulated |
4. experimental result
Through observing, the sample that shows embodiment of the present invention 1-9 once and multiple dosing to lagophthalmos all without obvious stimulation effect, meet clinical requirement completely.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (16)
1. an eye drop, it comprises vitamin A palmitate, lytic agent and cosolvent as principal agent, and wherein, the content of vitamin A palmitate is 0.01%-0.2%(w/w), the content of lytic agent is 0.01%-5.0%(w/w), the content of cosolvent is 0.01%-10.0%(w/w).
2. eye drop according to claim 1, wherein, the content of described vitamin A palmitate is 0.06%-0.2%(w/w); Be preferably 0.08%-0.2%(w/w) for example, 0.10%-0.2%(w/w), 0.10%-0.16%(w/w), 0.08%-0.12%(w/w), 0.10%-0.12%(w/w) or 0.12%-0.16%(w/w).
3. eye drop according to claim 1, wherein, described lytic agent is MCT Oil.
4. eye drop according to claim 1, wherein, the content of described lytic agent is 0.1%-5.0%(w/w); Be preferably 0.1%-4.0%(w/w); 0.1%-3.0%(w/w more preferably) or 0.5%-4.0%(w/w) or 1.0%-2.0%(w/w).
5. eye drop according to claim 1, wherein, described cosolvent is for being selected from polyoxyethylene hydrogenated Oleum Ricini
40, propylene glycol, Polyethylene Glycol
400, in tween 80, poloxamer, glycerol and n-butyl alcohol any or multiple; Particularly, described cosolvent comprises cosolvent 1, and it is selected from polyoxyethylene hydrogenated Oleum Ricini
40, in tween 80 and poloxamer any one or multiple; With cosolvent 2, it is selected from propylene glycol, Polyethylene Glycol
400, in glycerol and n-butyl alcohol any one or multiple.
6. eye drop according to claim 1, wherein, the content of described cosolvent is 0.1%-10.0%(w/w); Be preferably 0.3%-7.0%(w/w); 0.5%-5.0%(w/w more preferably) or be 1.0%-3.0%(w/w).
7. eye drop according to claim 1, wherein, the ratio of described lytic agent and cosolvent is 10:1 to 1:10; Be preferably 8:1 to 1:8; 4:1 to 1:4 more preferably; Be particularly preferably 1:4.
8. eye drop according to claim 5, wherein, the ratio of cosolvent 1 and cosolvent 2 is 5:1 to 1:5; Be preferably 4:1 to 1:4; 3:1 to 1:3 more preferably; 2:1 to 1:2 more preferably; Be particularly preferably 1:1.
9. eye drop according to claim 1, wherein, described cosolvent comprises polyoxyethylene hydrogenated Oleum Ricini
40and propylene glycol; Alternatively, described cosolvent also comprises and is selected from Polyethylene Glycol
400, in tween 80, poloxamer, glycerol and n-butyl alcohol any or multiple.
10. eye drop according to claim 9, wherein, polyoxyethylene hydrogenated Oleum Ricini
40with the ratio of propylene glycol be 5:1 to 1:5; Be preferably 4:1 to 1:4; 3:1 to 1:3 more preferably; 2:1 to 1:2 more preferably; Be particularly preferably 1:1.
11. eye drop according to claim 1, it also comprises one or more in antioxidant, antiseptic and osmotic pressure regulator.
12. eye drop according to claim 11, it meets any one or more in following (1)-(3):
(1) described antioxidant is to be selected from one or more in BHA, BHT and vitamin E, and its content is 0.01%-0.2%(w/w); Particularly, be 0.05%-0.1%(w/w);
(2) described osmotic pressure regulator is to be selected from one or more in glycerol, sodium chloride, mannitol and sorbitol, and the content of described osmotic pressure regulator is 0.1%-5.0%(w/w); Particularly, be 0.5%-3.0%(w/w);
(3) described antiseptic is to be selected from one or more in benzalkonium chloride, benzalkonium bromide, ethyl hydroxybenzoate, chlorobutanol and cetrimonium bromide, and the content of described antiseptic is 0.01%-5.0%(w/w); Particularly, be 0.01%-3.0%(w/w).
13. according to the eye drop described in any one in claim 1 to 12, and its pH is 5.0-7.0; Be preferably 5.5-6.5.
14. eye drop according to claim 1, it comprises any a group in the group of following (1)-(9):
（1）
（2）
（3）
（4）
（5）
（6）
（7）
（8）
（9）
The preparation method of the eye drop in 15. claim 1 to 14 described in any one, comprises the following steps:
1) vitamin A palmitate and optional antioxidant are added in lytic agent, make it to dissolve, obtain lytic agent solution;
2) in water, add cosolvent and optional antiseptic and osmotic pressure regulator, stir and make it to dissolve, obtain aqueous solution;
3) under stirring, lytic agent solution is added in aqueous solution to mix homogeneously;
4) water is supplemented to full dose, filters and get final product.
Eye drop in 16. claim 1 to 14 described in any one treats and/or prevents and/or the protection of auxiliary treatment xerophthalmia or tear film lacks the purposes in the medicine of the conjunctiva that causes or corneal irritation in preparation; Particularly, described xerophthalmia is caused by one or more in Sjogren's syndrome, neuroparalytic keratitis, exposure keratitis; Particularly, described tear film protection shortage causes conjunctiva or corneal irritation are cornea keratinization or corneal epithelial wound.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018024662A (en) * | 2016-08-05 | 2018-02-15 | ロート製薬株式会社 | Ophthalmic composition |
| CN112336870A (en) * | 2020-12-03 | 2021-02-09 | 温州医科大学 | Sustained-release system with synergistic effect of various vitamins in eyes and preparation method thereof |
| CN113304069A (en) * | 2021-06-01 | 2021-08-27 | 栈秋(上海)化妆品有限公司 | Retinol nanocrystalline wrap and preparation method thereof |
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|---|---|---|---|---|
| CN1200926A (en) * | 1997-05-14 | 1998-12-09 | 千寿制药株式会社 | Composition containing diflucortolone acetate butyrate |
| CN101912404A (en) * | 2010-01-30 | 2010-12-15 | 湖北天药药业股份有限公司 | Small-capacity injection containing four vitamins and preparation method thereof |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1200926A (en) * | 1997-05-14 | 1998-12-09 | 千寿制药株式会社 | Composition containing diflucortolone acetate butyrate |
| CN101912404A (en) * | 2010-01-30 | 2010-12-15 | 湖北天药药业股份有限公司 | Small-capacity injection containing four vitamins and preparation method thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018024662A (en) * | 2016-08-05 | 2018-02-15 | ロート製薬株式会社 | Ophthalmic composition |
| JP2022082779A (en) * | 2016-08-05 | 2022-06-02 | ロート製薬株式会社 | Ophthalmic composition |
| JP7081909B2 (en) | 2016-08-05 | 2022-06-07 | ロート製薬株式会社 | Ophthalmic composition |
| JP7348347B2 (en) | 2016-08-05 | 2023-09-20 | ロート製薬株式会社 | Ophthalmic composition |
| CN112336870A (en) * | 2020-12-03 | 2021-02-09 | 温州医科大学 | Sustained-release system with synergistic effect of various vitamins in eyes and preparation method thereof |
| CN113304069A (en) * | 2021-06-01 | 2021-08-27 | 栈秋(上海)化妆品有限公司 | Retinol nanocrystalline wrap and preparation method thereof |
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