CN111671722A - Eye drops and preparation method thereof - Google Patents
Eye drops and preparation method thereof Download PDFInfo
- Publication number
- CN111671722A CN111671722A CN202010754649.8A CN202010754649A CN111671722A CN 111671722 A CN111671722 A CN 111671722A CN 202010754649 A CN202010754649 A CN 202010754649A CN 111671722 A CN111671722 A CN 111671722A
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- CN
- China
- Prior art keywords
- liposome
- vitamin
- palmitate
- cholesterol
- sodium hyaluronate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000011780 sodium chloride Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- 230000029663 wound healing Effects 0.000 description 1
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Abstract
The invention discloses an eye drop and a preparation method thereof, relating to the field of eye drop manufacturing process, wherein the eye drop comprises the following components: the vitamin A palmitate liposome comprises a vitamin A palmitate liposome and sodium hyaluronate, wherein the vitamin A palmitate liposome is liposome-coated vitamin A palmitate, the amount of the vitamin A palmitate is 0.05 mg/ml-0.4 mg/ml, and the amount of the sodium hyaluronate is 0.5 mg/ml-3 mg/ml. In the eye drops, the synergistic effect of the vitamin A palmitate lipid and the sodium hyaluronate greatly improves the restoration of the cornea and the conjunctiva, and the eye drops are liquid and improve the comfort of users.
Description
Technical Field
The invention relates to the field of eye drop pharmaceutical technology, and in particular relates to eye drops and a preparation method thereof.
Background
Dry Eye Disease (DED) is a common ocular surface disorder with clinical manifestations of ocular discomfort, Dry sensation, eye fatigue, hyperemia, keratoconjunctival epithelial lesions, and vision abnormalities. When the disease deteriorates, it greatly hinders people from performing daily activities such as driving, reading, performing professional work, using a computer, and watching television, thereby deteriorating the quality of life of patients. Dry eye is most common in the elderly population. The incidence of disease is reported to be between 5% and 34% in people over 50 years of age. However, in China, with the popularization of electronic products including electronic screens, such as smart phones, tablet computers, readers and the like, the incidence rate of dry eye diseases tends to rise year by year, and patients are younger and younger. With the increased awareness of the harm of dry eye, dry eye has received more and more attention and has become a social problem to be solved urgently. The dry eye has complex etiology and the pathogenesis of the dry eye is not exactly determined at present, but the reduction of the volume of tears on the surface of the cornea and the conjunctiva caused by the reduction of the secretion of tears or the acceleration of evaporation is the main reason, thereby causing the instability of the tear film on the surface of the eye and the damage of the corneal conjunctiva epithelium. At present, the treatment of dry eye is mainly drug therapy.
The eye drop preparation is the most widely used medicine form for clinical application of medicine treatment, and has convenient administration and good patient compliance. Among the first 10 dry eye drug varieties sold worldwide, 8 are artificial tear eye drop products. In recent years, there have also been studies on the improvement of the therapeutic effect of dry eye by combining two or more pharmacologically active ingredients. And various compound artificial tear products are available on the market, such as 'tear eye drops' containing dextran and hypromellose, 'tear eye drops' containing polyethylene glycol, propylene glycol and guar gum, 'new tear eye drops' containing dextran, glycerol and hypromellose and 'Optive eye drops' containing hyaluronic acid and sodium carboxymethylcellulose. The compound artificial tear eye drops are combined by different high molecular polymers or micromolecular polyols with the functions of moisturizing, and compared with the traditional artificial tears, the compound artificial tear eye drops have the advantages that the effects of lubricating and moisturizing the ocular surface are improved, the medication comfort of patients is greatly improved, but the effect of repairing damaged cornea and conjunctiva is not good, and the clinical treatment effect is not ideal.
In 1984, Ubels and Macrae found retinol, also known as vitamin a (va), in human tears, a factor against dry eye disease. It has the functions of regulating the proliferation and differentiation of corneal epithelial cells and preserving conjunctival goblet cells. Its deficiency can lead to pathological changes in the cornea and conjunctiva. However, VA is very unstable and easily oxidized to lose its efficacy, and thus cannot be directly used for the treatment of eye diseases.
The vitamin A palmitate is a derivative of the vitamin A, can improve the oxidation stability of the vitamin A, and can be applied as a raw material drug of the vitamin A, so that the possibility of using the VA for treating the dry eye syndrome is provided. However, the vitamin A palmitate exists in a free form, and the problems of the common eye drop preparation such as tear washing, tear loss from nasolacrimal ducts, short corneal retention time, insufficient conjunctiva effective absorption, short drug effect maintenance, low bioavailability and the like easily occur after administration. Therefore, there is an ophthalmic drug in which vitamin a palmitate is coated with cationic liposome to form a gel or an in situ gel. Although the vitamin A palmitate coated by the liposome can effectively prolong the time of the drug staying on the cornea, the gel form can cause transient blurred vision and the feeling of covering eyes when in use, and the use comfort is low.
Therefore, it is an urgent technical problem to improve the comfort of the patient in terms of the drug application while improving the effect of the ocular drug on the cornea and conjunctiva repair of the eye.
Disclosure of Invention
Therefore, the invention provides an eye drop which comprises sodium hyaluronate and vitamin A palmitate liposome, is in a liquid state, improves the comfort of a patient during administration, and can greatly improve the repairing effect on damaged cornea and conjunctiva by the mutual synergy of the drug effects of the sodium hyaluronate and the vitamin A palmitate liposome.
The technical scheme of the invention is as follows:
an ophthalmic solution, comprising: the vitamin A palmitate liposome comprises a vitamin A palmitate liposome and sodium hyaluronate, wherein the vitamin A palmitate liposome is liposome-coated vitamin A palmitate, the amount of the vitamin A palmitate is 0.05 mg/ml-0.4 mg/ml, and the amount of the sodium hyaluronate is 0.5 mg/ml-3 mg/ml.
The vitamin A palmitate liposome regulates the proliferation and differentiation of corneal epithelial cells and preserves conjunctival goblet cells, the sodium hyaluronate can not only supplement water and preserve moisture, improve the water-deficient state of the ocular surface and increase the stability of a tear film, but also promote the connection and extension of the corneal epithelial cells, and the vitamin A palmitate liposome and the sodium hyaluronate cooperate to remarkably improve the repairing effect of the cornea and the conjunctiva.
Preferably, the liposome comprises: neutral liposomes, anionic liposomes or cationic liposomes.
Preferably, the neutral liposome comprises a phospholipid and/or cholesterol; the anionic liposome comprises an anionic power supply unit and phospholipid and/or cholesterol, and the cationic liposome comprises a cationic power supply unit and phospholipid and/or cholesterol.
Preferably, the mass ratio of the phospholipid to the vitamin A palmitate in the liposome is 10: 1-50: 1.
Preferably, the mass ratio of cholesterol to phospholipid in the liposome is 0: 1-0.5: 1.
Preferably, the mass ratio of the anionic liposome phospholipid to the anion power supply unit is 5: 1-50: 1, and the mass ratio of the cationic liposome phospholipid to the cation power supply unit is 5: 1-50: 1.
Preferably, the anion power supply unit is one of cis-9-octadecenoic acid, glutamic acid modified cholesterol or aspartic acid modified cholesterol; the cation power supply unit is one of octadecylamine, 9-octadecenylamine, arginine modified cholesterol or lysine modified cholesterol.
Preferably, the eye drops further comprise an antioxidant, such as vitamin E, edetate disodium, vitamin C, and the like.
The invention also provides a preparation method of the eye drops, which is characterized by comprising the following steps:
(1) preparing a vitamin A palmitate carrying liposome solution;
(2) preparing a sodium hyaluronate aqueous solution;
(3) mixing the liposome solution prepared in the step (1) with the solution prepared in the step (2);
(4) phosphate buffer solution or water to constant volume.
Compared with the prior art, the invention has the following advantages:
(1) in the eye drops, the vitamin A palmitate is encapsulated by the liposome, and the liposome has the characteristic of slow release, so that the corneal penetration of the drug is improved, and the retention time of the vitamin A palmitate on the ocular surface is prolonged;
(2) the vitamin A palmitate liposome is prepared into a liquid form, so that the vitamin A palmitate liposome is convenient for a patient to use, does not generate gel when being dripped into the eyes of the patient, has no irritation, and can improve the using comfort of the patient;
(3) the sodium hyaluronate and the vitamin A palmitate liposome act synergistically, so that the corneal and conjunctival epithelial cell repairing speed is greatly improved, and the drug effect of the ophthalmic drug is remarkably improved compared with that of a single sodium hyaluronate eye drop and a single vitamin A palmitate liposome.
Drawings
The accompanying drawings, which are included to provide a further understanding of the embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention. In the drawings:
FIG. 1 is a graph showing a distribution of particle diameters in example 1 of the present invention;
FIG. 2 is a graph showing a distribution of particle diameters in example 2 of the present invention;
FIG. 3 is a graph showing a distribution of particle diameters in example 3 of the present invention;
FIG. 4 is a comparison graph of the density of PAS positive cells of the lower eyelid and conjunctiva of a rabbit under different sample test conditions;
FIG. 5 is a graph comparing the concentration of MMP 9 expressed by rat cornea in the case of different sample experiments.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
Example 1
The prescription composition is as follows: (in 10ml eye drops)
The preparation method comprises the following steps:
(1) dissolving soybean lecithin and cholesterol with diethyl ether to obtain a mixed solution I;
(2) dissolving vitamin A palmitate and vitamin E in dichloromethane to obtain a mixed solution II;
(3) carrying out ultrasonic mixing on the mixed solution I and the mixed solution II, and carrying out ultrasonic treatment to obtain a mixed solution III;
(4) carrying out rotary evaporation and reduced pressure distillation on the prepared mixed solution (c) in a water bath at 40 ℃ to form a lipoid film; adding PBS buffer solution into the lipoid film, shaking and eluting the film to obtain liposome suspension, and carrying out ultrasonic treatment on the liposome suspension for 5 min;
(5) preparing a sodium hyaluronate aqueous solution;
(6) mixing the sodium hyaluronate aqueous solution with the liposome suspension, and magnetically stirring and mixing for 5 min;
(7) water for injection was added to the final volume.
Example 2
The prescription composition is as follows: (in 10ml eye drops)
The preparation method comprises the following steps:
(1) dissolving egg yolk lecithin, cholesterol and cis-9-octadecenoic acid with diethyl ether to obtain a mixed solution I;
(2) dissolving vitamin A palmitate and vitamin E in dichloromethane to obtain a mixed solution II;
(3) carrying out ultrasonic mixing on the mixed solution I and the mixed solution II, and carrying out ultrasonic treatment to obtain a mixed solution III;
(4) carrying out rotary evaporation and reduced pressure distillation on the prepared mixed solution (c) in a water bath at 40 ℃ to form a lipoid film; adding PBS buffer solution into the lipoid film, shaking and eluting the film to obtain liposome suspension, and carrying out ultrasonic treatment on the liposome suspension for 5 min;
(5) preparing a sodium hyaluronate aqueous solution;
(6) mixing the sodium hyaluronate aqueous solution with the liposome suspension, and magnetically stirring and mixing for 5 min;
(7) water for injection was added to the final volume.
Example 3
The prescription composition is as follows: (in 10ml eye drops)
The preparation method comprises the following steps:
(1) dissolving egg yolk lecithin and octadecylamine in diethyl ether to obtain a mixed solution I;
(2) dissolving vitamin A palmitate and vitamin E in dichloromethane to obtain a mixed solution II;
(3) carrying out ultrasonic mixing on the mixed solution I and the mixed solution II, and carrying out ultrasonic treatment to obtain a mixed solution III;
(4) carrying out rotary evaporation and reduced pressure distillation on the prepared mixed solution (c) in a water bath at 40 ℃ to form a lipoid film; adding PBS buffer solution into the lipoid film, shaking and eluting the film to obtain liposome suspension, and carrying out ultrasonic treatment on the liposome suspension for 5 min;
(5) preparing a sodium hyaluronate aqueous solution;
(6) mixing the sodium hyaluronate aqueous solution with the liposome suspension, and magnetically stirring and mixing for 5 min;
(7) water for injection was added to the final volume.
Example 4
The prescription composition is as follows: (in 10ml eye drops)
The preparation method comprises the following steps:
(1) dissolving hydrogenated lecithin, cholesterol and octadecylamine in diethyl ether to obtain a mixed solution I;
(2) dissolving vitamin A palmitate and vitamin E in dichloromethane to obtain a mixed solution II;
(3) carrying out ultrasonic mixing on the mixed solution I and the mixed solution II, and carrying out ultrasonic treatment to obtain a mixed solution III;
(4) carrying out rotary evaporation and reduced pressure distillation on the prepared mixed solution (c) in a water bath at 40 ℃ to form a lipoid film; adding PBS buffer solution into the lipoid film, shaking and eluting the film to obtain liposome suspension, and carrying out ultrasonic treatment on the liposome suspension for 5 min;
(5) preparing a sodium hyaluronate aqueous solution;
(6) mixing the sodium hyaluronate aqueous solution with the liposome suspension, and magnetically stirring and mixing for 5 min;
(7) water for injection was added to the final volume.
Example 5
The prescription composition is as follows: (in 10ml eye drops)
The preparation method comprises the following steps:
(1) dissolving soybean lecithin, cholesterol and octadecylamine in diethyl ether to obtain a mixed solution I;
(2) dissolving vitamin A palmitate and vitamin E in dichloromethane to obtain a mixed solution II;
(3) carrying out ultrasonic mixing on the mixed solution I and the mixed solution II, and carrying out ultrasonic treatment to obtain a mixed solution III;
(4) carrying out rotary evaporation and reduced pressure distillation on the prepared mixed solution (c) in a water bath at 40 ℃ to form a lipoid film; adding PBS buffer solution into the lipoid film, shaking and eluting the film to obtain liposome suspension, and carrying out ultrasonic treatment on the liposome suspension for 5 min;
(5) preparing a sodium hyaluronate aqueous solution;
(6) mixing the sodium hyaluronate aqueous solution with the liposome suspension, and magnetically stirring and mixing for 5 min;
(7) water for injection was added to the final volume.
Example 6
This example differs from example 5 only in that 9-octadecenylamine is used instead of octadecylamine.
Example 7
This example differs from example 5 only in that arginine-modified cholesterol was used instead of octadecylamine;
the preparation method of the arginine-modified cholesterol comprises the following steps: cholesterol and arginine (such as arginine with alpha amino protected by tert-butyloxycarbonyl and guanidino amino protected by 2,3, 6-trimethyl-4-methoxybenzenesulfonyl, Boc-Arg (mtr) -OH) are used as raw materials, 4-dimethylaminopyridine is used as a catalyst and dicyclohexylcarbodiimide is used as a dehydrating agent, the arginine-modified cholesterol with protective groups is generated under the protection of nitrogen, and the protective groups on the alpha amino and the guanidino amino are removed under the action of trifluoroacetic acid to obtain the arginine-modified cholesterol.
Example 8
This example differs from example 7 only in that lysine-modified cholesterol was used instead of arginine-modified cholesterol.
Example 9
This example differs from example 7 only in that the arginine-modified cholesterol was replaced with glutamic acid-modified cholesterol.
Example 10
This example differs from example 7 only in that aspartate-modified cholesterol is used instead of arginine-modified cholesterol.
It should be noted that, although vitamin E is used as the antioxidant in the examples of the present invention, it is known to those skilled in the art that disodium edetate, vitamin C, and the like, which can achieve an antioxidant effect, can achieve the same technical effect, and the kind of the antioxidant described in the examples is not intended to limit the present invention.
The beneficial effects of the eye drops of the present invention are demonstrated by particle size test, irritation test and conjunctival and corneal repair test, respectively.
Particle size testing
Particle Size distribution charts of eye drops obtained in examples 1 to 3 are shown in FIGS. 1 to 3, wherein the abscissa Size (d.nm) represents the particle Size (nm) of the eye drops, and the ordinate intensity (percentage) represents the laser intensity (%);
examples 1-3 average particle size and polydispersity index (PDI) of eye drops are shown in Table 1, the particle size distribution of the eye drops obtained by the present invention is between 100 and 200nm, the PDI of the eye drops is small, the particle size distribution is narrow, the particle size is uniform, and the use standard of the eye drops can be reached.
TABLE 1 EXAMPLES 1-3 average particle size and polydispersity of eye drops
Second, cornea and conjunctival repair experiment
(1) Evaluation of conjunctival repair Effect by Rabbit eye conjunctival goblet cell Density
The test method comprises the following steps: 32 rabbits were subjected to general anesthesia by intraperitoneal injection of 10% chloral hydrate (4ml/kg) 4 weeks after the lacrimal gland resection. A piece of saturated filter paper (circular, 5mm in diameter) soaked with 0.5% sodium hydroxide was placed in the center of the conjunctiva of the lower eyelid on both sides for 30s to cause alkaline injury. The palpebral conjunctiva was washed with 0.9% sodium chloride solution.
The experimental animals were randomly divided into 8 groups. On day 1 after the alkaline injury of the lower eyelid of the rabbit, example formula 1, example formula 2, example formula 3, liposome 1 (example formula 1 does not contain sodium hyaluronate), liposome 2 (example formula 2 does not contain sodium hyaluronate), liposome 3 (example formula 3 does not contain sodium hyaluronate), and 0.3% sodium hyaluronate eye drop were respectively usedAnd 0.9% physiological saline, were applied to 8 groups of experimental animals by eye drop 4 times a day in an amount of 100. mu.l per eye. The conjunctival goblet cell density in the lower eyelid area was assessed using blot cytology before alkaline injury to the lower eyelid and 5 and 10 days after treatment in rabbits. Rabbits were anesthetized systemically by intraperitoneal injection (3.5ml/kg) with 10% chloral hydrate and then locally anesthetized to the lower palpebral conjunctiva with 0.4% oxybutynin hydrochloride. The lower eyelid was stained with PAS reagent, and goblet cells of the lower eyelid were visualized. After obtaining the light mirror image, the number of PAS positive spots was calculated using Scion image software. Randomly selecting 3 visual fields, and determining PAS positive point density. The average is then calculated and converted to cell density per unit area.
As a result: as can be seen from fig. 4, in the group with vitamin a palmitate-loaded drugs (including liposome 1, liposome 2, liposome 3, example 1, example 2 and example 3), the number of PAS positive goblet cells in the palpebral conjunctiva was significantly increased compared to the 0.9% saline group and the 0.3% sodium hyaluronate eye drop group at 10 days of administration, indicating that the disease was accelerated. This is because vitamin a palmitate can promote the differentiation of conjunctival goblet cells, restore goblet cell populations, improve goblet cells damaged by conjunctival epithelium, promote the production of tear mucus layer, and stabilize tear film. At 10 days of administration, the number of PAS positive goblet cells in the palpebral conjunctiva of the lower eyelid(s) in 3 groups of vitamin a palmitate liposomes containing sodium hyaluronate (examples 1, 2 and 3) reached 350 cells/mm2Above, the number of goblet cells (about 516 cells/mm) before conjunctival alkaline damage can be recovered2) 67.8% of. Description of the use of the sodium hyaluronate-containing vitamin A palmitate ester of the present inventionCompared with simple sodium hyaluronate eye drops and vitamin A palmitate eye medicaments, the plastid eye drops have better effect of promoting conjunctiva repair.
(2) Evaluation of corneal repair Effect by quantifying matrix metalloproteinase 9(MMP-9) protein in rat cornea
The test method comprises the following steps: 168 male SD rats (weighing 220 g. + -.20 g) were anesthetized by intraperitoneal injection of 10% chloral hydrate (4 ml/kg). A piece of filter paper (circular, 3mm in diameter) saturated with 0.04% sodium hydroxide was placed in the center of the cornea of the right eye of each rat, and left for 45 seconds to perform central corneal alkali lesion molding of the right eye. The wound was then rinsed with 0.9% normal saline. The experimental animals were randomly divided into 8 groups, and the examples formula 1, formula 2, formula 3, liposome 1 (formula 1 did not contain sodium hyaluronate), liposome 2 (formula 2 did not contain sodium hyaluronate), liposome 3 (formula 3 did not contain sodium hyaluronate), and 0.3% sodium hyaluronate eye drops were usedAnd 0.9% physiological saline, were applied to 8 groups of experimental animals in the form of eye drops 4 times a day, in an amount of 50. mu.l per eye.
After 24, 48 and 72 hours of base injury molding, rat corneas were harvested with 4.0 mm diameter trephines (n-7 at each time point). The excised cornea was frozen at 80 ℃ and thawed and frozen three times in lysis buffer (lysis buffer containing 50mM pegs/KOH (pH 6.5), 2mM EDTA, 0.1% Chaps, 20mg/ml leupeptin, 10mg/ml pepsin inhibitor, 10mg/ml aprotinin, 5mM DTT, and protease inhibitor). The homogenate was centrifuged at 14000g for 30 minutes and the supernatant thus obtained was used for MMP-9 assay. Corneal MMP-9 levels were measured using a rat-specific ELISA assay kit at 24, 48, and 72 hours post-alkaline injury, respectively.
As a result: as shown in fig. 5, since increased expression and activity of MMP 9 resulted in delayed healing of corneal wound, MMP-9 expression was down-regulated in the cornea at each time point in the group loaded with vitamin a palmitate drug (including liposome 1, liposome 2, liposome 3, example 1, example 2, and example 3) compared to the 0.9% saline group and the 0.3% sodium hyaluronate eye drop group; and the groups of example 1, example 2 and example 3 have more obvious inhibition on MMP-9 expression, which shows that the sodium hyaluronate-containing vitamin A palmitate liposome eye drops have better effect of promoting corneal wound healing.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. An ophthalmic solution, comprising: the vitamin A palmitate liposome comprises a vitamin A palmitate liposome and sodium hyaluronate, wherein the vitamin A palmitate liposome is liposome-coated vitamin A palmitate, the amount of the vitamin A palmitate is 0.05 mg/ml-0.4 mg/ml, and the amount of the sodium hyaluronate is 0.5 mg/ml-3 mg/ml.
2. An ophthalmic solution as claimed in claim 1 wherein the liposomes comprise: neutral liposomes, anionic liposomes or cationic liposomes.
3. An ophthalmic solution according to claim 2 wherein the neutral liposomes comprise a phospholipid and/or cholesterol; the anionic liposome comprises an anionic power supply unit and phospholipid and/or cholesterol, and the cationic liposome comprises a cationic power supply unit and phospholipid and/or cholesterol.
4. An ophthalmic solution as claimed in claim 3, wherein the mass ratio of phospholipid to vitamin A palmitate in the liposome is 10: 1-50: 1.
5. An ophthalmic solution as claimed in claim 3, wherein the ratio of cholesterol to phospholipid in the liposome is 0:1 to 0.5:1 by mass.
6. An ophthalmic solution according to claim 3, wherein the mass ratio of the anionic liposome phospholipid to the anion-donating unit is 5:1 to 50:1, and the mass ratio of the cationic liposome phospholipid to the cation-donating unit is 5:1 to 50: 1.
7. An ophthalmic solution according to claim 3, wherein the anion-donating unit is one of cis-9-octadecenoic acid, glutamic acid-modified cholesterol, or aspartic acid-modified cholesterol; the cation power supply unit is one of octadecylamine, 9-octadecenylamine, arginine modified cholesterol or lysine modified cholesterol.
8. An ophthalmic solution according to claim 1 further comprising an antioxidant.
9. A process for the preparation of an ophthalmic solution according to any of claims 1 to 8, characterized in that it comprises the following steps:
(1) preparing a vitamin A palmitate liposome solution;
(2) preparing a sodium hyaluronate aqueous solution;
(3) mixing the liposome solution prepared in the step (1) with the solution prepared in the step (2);
(4) phosphate buffer solution or water for injection to constant volume.
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EP3673896A1 (en) * | 2018-12-28 | 2020-07-01 | Dr. Rolf Lambert Pharma-Consulting GmbH | Liposomial eye drops solution and uses thereof for the treatment of dry eye syndrome |
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Application publication date: 20200918 |