CN115154483B - Ophthalmic pharmaceutical composition containing sodium hyaluronate and exosomes - Google Patents
Ophthalmic pharmaceutical composition containing sodium hyaluronate and exosomes Download PDFInfo
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- CN115154483B CN115154483B CN202210933576.8A CN202210933576A CN115154483B CN 115154483 B CN115154483 B CN 115154483B CN 202210933576 A CN202210933576 A CN 202210933576A CN 115154483 B CN115154483 B CN 115154483B
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- sodium hyaluronate
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- 210000001808 exosome Anatomy 0.000 title claims abstract description 51
- 229920002385 Sodium hyaluronate Polymers 0.000 title claims abstract description 33
- 229940010747 sodium hyaluronate Drugs 0.000 title claims abstract description 33
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 33
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
Abstract
The invention relates to the technical field of biological medicines, in particular to an ophthalmic pharmaceutical composition containing sodium hyaluronate and exosomes. The ophthalmic pharmaceutical composition comprises 0.04 to 0.06 weight percent of sodium hyaluronate and more than or equal to 1 multiplied by 10 10 The exosomes derived from mesenchymal stem cells and the solvents with indissolvable lipid components. The composition has excellent effect on treating xerophthalmia, and can generate better technical effect when the concentration of exosomes is low, so that the cost can be effectively reduced, and the composition has good application prospect.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to an ophthalmic pharmaceutical composition containing sodium hyaluronate and exosomes.
Background
Ocular surface disease is a disease that causes damage to normal structure and function of the conjunctiva, and dry eye is one of them, and has been receiving increasing attention from ophthalmologists in recent years. The term "dry eye" originates at the earliest from an ophthalmologist Honrid siren, sweden, who presents a triple of dry eye, dry mouth and joint pain. According to the second agreement of the international tear film and the dry eye series published by the working group of the ocular surface society, dry eye is considered to be a multi-factor ocular surface disease, which is characterized by unstable tear film, elevated tear osmotic pressure, ocular surface inflammation and injury, and abnormal nerve sensation. Due to the changes of living environment, living style, working strength and electronic products, the prevalence of dry eye is 21-30%, and the need for treatment is growing year by year.
Recently, a recent study published in 2022 science Advances showed that exosomes were able to ameliorate the adverse effects of dry eye caused by GVHD (graft versus host disease). GVHD is a common postoperative complication, and the survival of patients is affected by light GVHD, and long-term survival of patients is seriously threatened. In a prospective clinical experiment, mesenchymal stem cell exosomes (MSC-exo) can be used for inhibiting inflammatory swedish disease, improving epithelial repair, and has obvious curative effect on mice and people. After the medicine is used, the symptoms of eye stinging, burning, redness and the like are all reduced, and the medicine is more effective than artificial tears.
Sodium hyaluronate is macromolecular mucopolysaccharide, is widely distributed in extracellular matrixes of connective tissues of animals and human bodies, is colorless and transparent, has no heat source, has no antigenicity, is not sensitized, does not generate immune response, and has no colloid permeation effect. Sodium hyaluronate has very good biocompatibility, and also has important physical properties such as high viscoelasticity, pseudoplasticity and the like in solution. The medicine viscosity is increased, and the defect that the eyelid is not easy to blink is overcome, so that the medicine becomes a good carrier of eye drops. Sodium hyaluronate at 0.1% is commonly used in the conventional art for the treatment of dry eye.
Disclosure of Invention
The invention provides an ophthalmic pharmaceutical composition, which comprises 0.04 to 0.06 weight percent of sodium hyaluronate and more than or equal to 1 multiplied by 10 10 The exosomes derived from mesenchymal stem cells and the solvents with indissolvable lipid components.
The invention also relates to the use of an ophthalmic pharmaceutical composition as described above for the preparation of a medicament for the treatment of dry eye.
The novel ophthalmic pharmaceutical composition containing exosomes provided by the invention has excellent effect in the aspect of treating xerophthalmia, and can also generate better technical effect when the exosomes concentration is low, so that the cost can be effectively reduced, and the novel ophthalmic pharmaceutical composition containing exosomes has good application prospect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is an electron microscope image of an exosome according to one embodiment of the present invention;
FIG. 2 is a schematic diagram showing the particle size of exosomes according to one embodiment of the present invention;
FIG. 3 is a graph showing the measurement of the amount of lacrimal secretion provided in one embodiment of the present invention; * p <0.05, vs blank; #p <0.05, vs. control group 2;
FIG. 4 is a graph showing tear film break time measurements according to one embodiment of the present invention; * p <0.05, vs blank; #p <0.05, vs. control group 2;
FIG. 5 is a graph showing the results of a conjunctival goblet cell number test according to one embodiment of the present invention; * p <0.05, vs blank; #p <0.05, vs. control group 2;
FIG. 6 is a representative picture of fluorescent staining of the cornea of each group of mice.
Detailed Description
Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.
Unless otherwise defined, all terms (including technical and scientific terms) used to describe the invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By way of further guidance, the following definitions are used to better understand the teachings of the present invention. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising," "including," and "comprising," as used herein, are synonymous, inclusive or open-ended, and do not exclude additional, unrecited members, elements, or method steps.
The recitation of numerical ranges by endpoints of the present invention includes all numbers and fractions subsumed within that range, as well as the recited endpoint. Concentration values are referred to in this invention, the meaning of which includes fluctuations within a certain range. For example, it may fluctuate within a corresponding accuracy range. For example, 2%, may allow fluctuations within + -0.1%. For values that are larger or do not require finer control, it is also permissible for the meaning to include larger fluctuations. For example, 100mM, fluctuations in the range of.+ -. 1%,.+ -. 2%,.+ -. 5%, etc. can be tolerated.
Ophthalmic pharmaceutical composition comprising 0.04 to 0.06% by weight of sodium hyaluronate and ≡1X10 10 The exosomes derived from mesenchymal stem cells and the solvents with indissolvable lipid components.
The content of the sodium hyaluronate can also be selected to be 0.05wt%.
The content of exosomes derived from mesenchymal stem cells can be 2×10 10 particles/mL、3×10 10 particles/mL、4×10 10 particles/mL、5×10 10 particles/mL、6×10 10 particles/mL、7×10 10 Particles/mL or higher, preferably (2-3). Times.10 10 particles/mL。
The invention discovers that the low-concentration sodium hyaluronate can effectively promote the curative effect of the exosome from mesenchymal stem cells, reduce the dosage of the exosome, on the one hand, reduce the drug cost, and on the other hand, also reduce the possible side effects of the exosome administration (the exosome contains a large amount of exogenous components with complex compositions, and can induce inflammation after long-term use). This is probably because sodium hyaluronate can bind to the hyaluronate receptor on the surface of cornea, and thus the active ingredients such as nucleic acid and active protein in the exosomes act more.
The term "mesenchymal stem cells" includes bone marrow-derived mesenchymal stem cells as well as non-bone marrow-derived mesenchymal stem cells, such as placenta, umbilical cord blood, adipose tissue, adult muscle, cornea stroma, deciduous tooth pulp.
In some embodiments, the poorly soluble solvent of the lipid component is water. Preferably, the water is present in the composition in an amount of not less than 50wt%, for example 60wt%, 70wt%, 80wt%, 90wt%, 95wt%, 96wt%, 97wt% or more. The poorly soluble solvent of the lipid component may also be other solvents that are pharmaceutically acceptable, such as ethanol, t-butanol, ethylene glycol, etc.
In some embodiments, the anti-settling agent is a sugar.
In some embodiments, the sugar is sucrose.
Sucrose can increase the stability of ophthalmic pharmaceutical compositions.
In some embodiments, the ophthalmic pharmaceutical composition further comprises a buffer.
In some embodiments, the buffering agent is selected from one or more of boric acid and salts thereof, phosphoric acid and salts thereof, acetic acid and salts thereof, citric acid and salts thereof. Preferably citric acid and its salts.
In some embodiments, the ophthalmically acceptable preservative is selected from at least one of thimerosal, benzalkonium chloride, benzalkonium bromide, POLYQUAD, chlorobutanol, methylparaben, ethylparaben, sodium perborate, and sorbic acid.
In some embodiments, the concentration of the ophthalmically acceptable preservative is from 0.001% to 0.05%, e.g., 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04% by weight.
The invention also relates to the use of an ophthalmic pharmaceutical composition as described above for the preparation of a medicament for the treatment of dry eye.
In some embodiments, the drug is an artificial tear.
Embodiments of the present invention will be described in detail below with reference to examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are preferably referred to in the guidelines given in the present invention, and may be according to the experimental manuals or conventional conditions in the art, and may be referred to other experimental methods known in the art, or according to the conditions suggested by the manufacturer.
In the specific examples described below, the measurement parameters relating to the raw material components, unless otherwise specified, may have fine deviations within the accuracy of weighing. Temperature and time parameters are involved, allowing acceptable deviations from instrument testing accuracy or operational accuracy.
EXAMPLE 1 preparation of MSC exosomes
MSC culture
C57BL/6J mice, 4 to 6 weeks old, were sacrificed, their tibia/fibula and femur were collected, and bone marrow was extruded with a 22 gauge needle. The bone marrow cells were resuspended in DMEM/F-12 medium containing 10% FBS, penicillin (100U/ml) and streptomycin (100 mg/ml) at 1X 10 6 The density of individual cells/ml. The medium was changed after 24 hours, after which it was changed twice weekly. The expanded cells were sorted by flow cytometry, negative markers for CD11b-FTIC (553310,BD Pharmingen), CD45-APC (559864,BD Pharmingen) and CD34-BV421 (562608,BD Pharmingen) and positive markers for CD44-PE (559864,BD Pharmingen) 553134,BD Pharmingen), CD29-FITC (11-0291-82, eBioscience) and SCA-1-BV421 (108128, bioLegend). Cells were expanded for three to five generations for use.
2. Preparation of exosomes
The common low-temperature centrifuge and the ultracentrifuge are opened in advance, and precooled to 4 ℃.2000g, centrifuged for 10min to remove dead cells and debris. The larger vesicles were removed by filtration through a 0.22 μm filter. The supernatant was transferred to an ultracentrifuge tube, trimmed with PBS, 120000g, and centrifuged for 3h. The supernatant was discarded, the residual liquid on the vessel wall was removed by suction with sterile filter paper, and the vessel bottom was the MSC exosomes. The exosomes prepared were stored at-80 ℃ until use.
3. Exosome detection
3.1 transmission electron microscope observation of exosome samples
1) The exosomes were removed by 10 μl.
2) 10 mu L of the sample is sucked and dripped on a copper net to be precipitated for 1min, and the floating liquid is sucked by filter paper.
3) The uranyl acetate 10 mu L is dripped on a copper net to be precipitated for 1min, and the filter paper is used for sucking off the floating liquid.
4) Drying at normal temperature for several minutes.
5) And (5) performing electron microscope detection imaging at 100 kV.
6) And obtaining a transmission electron microscope imaging result.
An electron microscope of the exosome is shown in figure 1.
3.2 analysis of exosome sample particle size
1) The exosomes were removed by 10 μl and diluted to 30 μl.
2) The exosome sample can be loaded after the instrument performance test is qualified by using the standard substance, and the sample is required to be subjected to gradient dilution to avoid the sample blocking the sampling needle.
3) And obtaining the information of the particle size and concentration of the exosomes detected by the instrument after the sample is detected.
The results of the exosome particle size analysis are shown in the following table:
the particle size of exosomes is schematically shown in fig. 2.
EXAMPLE 2 preparation of Artificial tear
1. At room temperature, adding 0.005g sodium hyaluronate and 0.5g sucrose into 8ml sterile 1 Xcitric acid buffer solution, and mixing;
2. cooling the solution to 4-6 ℃ under stirring;
3. the exosomes prepared in example 1 were added dropwise at low temperature and rotational speed, and the final volume was made up to 10ml with 1×citric acid buffer, wherein the final concentration of exosomes was 2.5x10 10 particles/mL；
4. The solution is stored temporarily at 4-6 ℃, and 0.004-0.025% benzalkonium chloride (which is not added in the embodiment) can be added during long-term storage.
Sodium hyaluronate tablet used in the inventionHas a molecular weight of 2.0 to 3.0X10 6 Viscosity of 2.4-3.2 m 3 The preparation method of the 1 Xcitric acid buffer solution comprises the following steps:
and (3) storing liquid:
a.0.1m citric acid solution: 21.01g of citric acid (C) 6 H 8 O 7 ·H 2 O) was dissolved in 1000ml of distilled water.
B.0.1m sodium citrate solution: 29.41g of sodium citrate (C) 6 H 5 Na 3 O 7 ·2H 2 O) was dissolved in 1000ml of distilled water.
3.2 working solution:
9ml of A solution and 41ml of B solution are added into 450ml of distilled water, and the pH value of the solution is 6.0+/-0.1.
EXAMPLE 3 preparation of Artificial tear
As in example 2, the difference is only that the final exosome concentration is 5X 10 10 particles/mL。
Comparative example 1
The difference from example 2 is that the composition contains only 0.005g of sodium hyaluronate and no exosomes.
Comparative example 2
The difference is that the final concentration of exosomes is 5×10, as in example 2, except that sodium hyaluronate is not included 10 particles/mL。
Example 4 Low temperature stability of Artificial tear
Sodium hyaluronate has good water retention, but has certain viscosity at the same time, and the embodiment is used for testing the stability of a mixed system of sodium hyaluronate and exosomes. The appearance of the sample was observed after 5 days of the experiment at 4 ℃. The results are shown in Table 1.
TABLE 1
Note that: the turbidity degree is judged in an auxiliary way by absorbance, and a system with poor stability can be deteriorated due to the increase of content release caused by exosome aggregation.
It can be seen from table 1 that 5wt% sucrose has a better stabilizing effect on the drug system. The inventors have further verified on the basis of this, and the results are shown in table 2.
TABLE 2
As can be seen, 0.05% sodium hyaluronate, 2.5 to 5X 10 10 The mixed system of the particles/mL exosomes and 5wt% of sucrose has better low-temperature stability.
EXAMPLE 5 efficacy verification of Artificial tear
1. Establishment of mechanical prevention transient preparation mouse dry eye model
Mechanical arrest transient methods can result in tear failure to reach the ocular surface and increased evaporation of water from the tear film, increased osmotic pressure of the tear film and dehydration of corneal tissue, and desiccation and inactivation of the ocular surface epithelium.
75 SPF-class C57BL/6 male mice (15 mice in each group) are selected in the experiment, 22-25 g are selected, the age of the mice is 8 weeks, and the mice are routinely bred under the environment of constant temperature 22 ℃ and humidity 55%. The experiment strictly follows the requirements of animal protection and ethics in animal experiments.
Mice were intraperitoneally injected with 10% chloral hydrate (3 mL kg) -1 ) After anesthesia, the mice are fixed on a fixed plate, skin around eyes is disinfected, no. 1 black silk threads are respectively used for mattress stitching of upper and lower eyelids and fixed on corresponding skin around the orbit, transient eyes of the mice are prevented through mechanical property, keratoconjunctiva is continuously exposed for 24 hours, and a dry eye model of the mice can be prepared successfully. The model lasts no less than 14d.
The environmental humidity, the temperature and the gas flow are effectively controlled, and the damage condition of the ocular surface of the mice is detected in 1 day, 7 days, 10 days and 14 days after the molding is finished.
2. Group setting
Blank control: only 1 Xcitrate buffer was applied;
experiment group 1:0.05% sodium hyaluronate+2.5X10 10 particles/mL (example 2);
experiment group 2:0.05% sodium hyaluronate+5×10 10 particles/mL (example 3);
comparative group 1:0.05% sodium hyaluronate (comparative example 1).
Comparative group 2: 5X 10 10 particles/mL (comparative example 2).
Wherein, the administration method of the comparison group 1 and the comparison group 2 is as follows: administration was continued for 14d from day 0. Each eye was dosed 5 μl of drug twice daily.
The administration methods of the blank control, the experimental group 1 and the experimental group 2 are as follows: once every other day, i.e. 0d, 2d, 4d, 6d … …, for a total of 7d. Each eye was dosed 5 μl of drug twice daily.
3. Detection method
3.1 lacrimal secretion
The secretion of tears was measured in 5 groups of mice by phenol red cotton test, and was measured 1 day, 7 days, 10 days, and 14 days after molding. Under the slit lamp, the phenol red cotton thread is clamped by a microscopic tweezer, is placed in the lower conjunctival sac of a mouse, is taken out after 1/3 of the time of 60 seconds, and the wet length of the cotton thread is observed by a microscope by adopting a vernier caliper in units of: millimeter (mm), readings were accurate to 0.2mm, tear secretion < 5.0mm was low secretion. Data were recorded after each set of examinations.
3.2 tear film rupture time
Tear film stability was assessed according to tear film break time (BUT) and was measured on day 14 after molding. 1% sodium fluorescein 1 μL is dripped into conjunctival sac of a mouse, the eye is transiently observed 3 times after 10 seconds, and the time from the last eye to the 1 st black spot is taken as tear film rupture time when the eye is observed under cobalt blue light of a slit lamp: units: second(s). Screening conditions: BUT (2.5±0.5 s) was repeated 3 times per eye and averaged.
3.3 conjunctival goblet cell number
The measurement was carried out on day 14 after molding. Mice were sacrificed by cervical dislocation, and after complete removal of bulbar conjunctiva, vault conjunctiva and palpebral conjunctiva under a microscope, they were fixed in 4% paraformaldehyde solution, which was dehydrated with alcohol, diffusedly wax, embedded and sectioned at normal temperature. The sections were stained with periodic acid-Schiff (PAS), and the conjunctival epithelial cells and goblet cells were observed under a microscope after staining, and the number of goblet cells per high-power field was counted.
3.4 corneal fluorescein staining
The measurement was carried out on day 14 after molding. After 1uL of liquid sodium fluorescein (10 mg/ml) was instilled into conjunctival sac and the mice were helped several times, corneal epithelial integrity and sodium fluorescein staining were observed under slit-lamp microscope blue light.
3.5 statistical methods
All data were entered into the SPSS21.0 statistical software and statistical analysis was performed using single-factor, multi-factor analysis of variance of the metering data. All data are expressed as mean and standard deviation, with P <0.05 as the difference being statistically significant.
4. Experimental results
4.1 lacrimal secretion
The experimental results are shown in table 3 and fig. 3.
The experimental groups 1 and 2, and the comparative group 2 each produced a significant increase relative to the blank control group, and the comparative group 1 had a significant increase on days 1 and 7 of the test.
Compared with the comparison group 2, the experimental groups 1 and 2 are obviously improved, which shows that the sodium hyaluronate and exosome combination group still achieve the best technical effect under the premise of obviously reducing the dosage. Control 1 was significantly less effective than control 2 at 7 and 10 days of the test, indicating that low concentrations of sodium hyaluronate alone were not as effective as exosomes.
The experimental groups 1 and 2 did not produce significant differences, demonstrating that low concentrations of exosomes could also achieve good therapeutic effects when used in combination with sodium hyaluronate.
TABLE 2 tear secretion
4.2 alterations in tear film stability
The tear film break time results for each group detected on day 14 are shown in figure 4.
Tear film break times were significantly increased for both experimental groups 1 and 2, and for comparative groups 1 and 2 relative to the blank.
The tear film break up time was significantly increased for both experimental groups 1 and 2 relative to control group 2, and significantly decreased for control group 1.
There was no significant difference between experimental group 1 and experimental group 2.
4.3 conjunctival goblet cell count
The numbers of conjunctival goblet cells detected by each group on day 14 are shown in fig. 5.
The numbers of conjunctival goblet cells of experimental groups 1 and 2 and comparative group 2 were all significantly increased relative to the blank control group, but the low concentration of sodium hyaluronate did not significantly increase the numbers of conjunctival goblet cells.
The conjunctival goblet cell numbers of both experimental groups 1 and 2 were significantly increased relative to control group 2, and control group 1 was significantly decreased.
Likewise, there was no significant difference between experimental group 1 and experimental group 2.
4.4 sodium corneal fluorescein staining
The staining of Pi Yingguang sodium on rat cornea was observed under blue light with a slit-lamp microscope. Representative results are shown in fig. 6. As can be seen from the figures, the cornea surfaces of experimental group 1 and experimental group 2 were smooth with little apparent staining, and the comparison groups 1 and 2 also had a clear improvement over the blank, but still had radial punctiform staining.
In summary, the effect of the low-concentration sodium hyaluronate is limited when the sodium hyaluronate is used alone, the low-concentration sodium hyaluronate can increase the secretion amount of tears and prolong the rupture time of tear films, but the quantity of conjunctival goblet cells cannot be obviously increased; the exosomes derived from the mesenchymal cells alone all have better effects, but the improvement compared to sodium hyaluronate is still limited. The mixed system of the low-concentration sodium hyaluronate and the exosome has better low-temperature stability, and the effect is still optimal on the premise of reducing the administration times, but the effect does not change obviously along with the improvement of the exosome concentration.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. The scope of the invention is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted in accordance with the contents of the claims.
Claims (4)
1. An ophthalmic pharmaceutical composition, characterized by comprising the following components:
0.04-0.06 wt% of sodium hyaluronate, exosomes derived from mesenchymal stem cells and a solvent with indissolvable lipid components, wherein the solvent with indissolvable lipid components is water;
the mesenchymal stem cells are bone marrow-derived mesenchymal stem cells; the content of the exosomes derived from the mesenchymal stem cells is (2-3) x 10 10 particles/mL；
The ophthalmic pharmaceutical composition further comprises 4wt% to 6wt% of an anti-settling agent, a buffer, and an ophthalmically acceptable preservative; the anti-settling agent is sucrose;
the ophthalmic pharmaceutical composition is administered by means of eye drops.
2. The ophthalmic pharmaceutical composition according to claim 1, wherein the buffering agent is selected from one or more of boric acid and its salts, phosphoric acid and its salts, acetic acid and its salts, citric acid and its salts.
3. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmically acceptable preservative is selected from at least one of thimerosal, benzalkonium chloride, benzalkonium bromide, POLYQUAD, chlorobutanol, methylparaben, ethylparaben, sodium perborate, and sorbic acid.
4. Use of an ophthalmic pharmaceutical composition according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of dry eye.
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