CN111821259A - Medicinal composition for eyes - Google Patents
Medicinal composition for eyes Download PDFInfo
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- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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Abstract
The invention discloses an ophthalmic pharmaceutical composition, which comprises 0.01-1 wt% of atropine sulfate, wherein the pH value of the ophthalmic pharmaceutical composition is 3.5-4.0; the osmotic pressure was 180-300 mOsm/kg. The pharmaceutical composition can obviously improve the related substance problem which is not easy to overcome by the prior art; the composition is simple in components, is not easy to form aggregates with the size of more than micron, and is beneficial to improving the corneal penetrability of atropine sulfate molecules.
Description
Technical Field
The invention relates to the technical field of pharmaceutical compositions, in particular to an ophthalmic pharmaceutical composition, and especially relates to an ophthalmic pharmaceutical composition for improving content of substances related to corneal penetration reduction of atropine sulfate.
Background
Atropine sulfate belongs to ester drugs, and is easily decomposed in an aqueous solution to generate belladonnal (Tropine), Tropine (TropicAcid), Scopolamine (Scopolamine) and other related substances, so that the atropine sulfate pharmaceutical composition is easy to hydrolyze and lose efficacy in the storage process. When no element capable of stabilizing hydroxide ions exists in the aqueous solution, atropine sulfate is easily affected by the hydroxide ions, so that bonds are broken and degraded to form related substances such as belladonnal, tropine acid and the like (figure 1/path 1); alternatively, the hydroxyl ion is easily bonded to the chair structure of atropine sulfate to form related substances such as 6-Hydroxyhyoscyamine (6-Hydroxyhyoscyamine) and 7-Hydroxyhyoscyamine (7-Hydroxyhyoscyamine) (FIG. 1/route 2). Therefore, it can be known that atropine sulfate in the aqueous solution is an active ingredient very sensitive to the buffer system, and when the buffer system generates slight difference, it may cause severe degradation of atropine sulfate, resulting in the loss of activity of the drug and failure to exert the therapeutic effect of the drug. In summary, the buffering component of atropine sulfate pharmaceutical composition plays a crucial role.
At present, before the end-of-life period of the conventional commercial atropine sulfate eye drops is reached, a large amount of related substances (tropine, 6-hydroxy scopolamine, any single unknown related substance and the total amount of the related substances and the like) are formed, and the degradation of the atropine sulfate and the generation of the related substances may influence the effectiveness and safety of the drug.
And the buffer component of the atropine sulfate eye drops belongs to the favorable growth environment of strains, and the prior art generally adopts two modes to solve the problem: firstly, adding preservative, and secondly, using a single dose package or a sterile eye drop bottle with an air filtration function. Many of the prior art use preservatives to inhibit bacterial growth of atropine sulfate eye drops, but the preservatives often cause allergic or irritation to the eye and may damage corneal epithelial cells after long-term use. The atropine sulfate eye drops packaged in single dose are used and must be discarded when the eye drops are not used up, otherwise, the problem of bacteria growth still exists; in addition, as in chinese patent No. CN110755377A, atropine sulfate eye drops are separately filled in multi-dose, single-direction, sterile air filtration eye drops bottles, but the eye drops using the above two containers are generally expensive and not easy to be popularized. Therefore, it is desirable in the art to formulate an atropine sulfate ophthalmic solution which can be dispensed in a conventional eye drop bottle without a preservative.
Disclosure of Invention
In view of the above, the present invention provides an ophthalmic pharmaceutical composition (i.e., atropine sulfate eye drops) to solve the problems of atropine sulfate degradation and related substance generation in the prior art, and further improve the corneal penetration of the composition.
In order to achieve the above objects, the present invention provides an ophthalmic pharmaceutical composition comprising 0.01 to 1 wt% of atropine sulfate, the ophthalmic pharmaceutical composition having a pH of 3.5 to 4.0; the osmotic pressure was 180-300 mOsm/kg.
By further specifically limiting the pH value and the osmotic pressure, the ophthalmic pharmaceutical composition provided by the invention has the effects of low content of related substances, good corneal penetration and the like, and can effectively solve the problems of the prior art and the medicines sold on the market.
In addition, the ophthalmic pharmaceutical composition of the present invention may also have the effect of "preservative-free composition".
Preferably, the ophthalmic pharmaceutical composition according to the present invention does not comprise a preservative. Wherein the preservative is a preservative commonly found in the art, for example including but not limited to: benzalkonium chloride, benzalkonium bromide, cetrimide, polyquaternium, chlorobutanol, benzyl alcohol, phenylethyl alcohol, phenoxyethanol, methylparaben, ethylparaben, propylparaben, ethylenediaminetetraacetic acid, boric acid, tricerotic acid, stable oxychloro complexes, sodium chlorite, sodium perborate, polyhexamethylene hydrochloride and the like.
The pH ranges proposed in the prior art to date fall between 4.0 and 8.0 (CN 107456440A, CN110917133A and CN 110934816A). However, the present inventors have unexpectedly found that limiting the pH of the ophthalmic pharmaceutical composition to a range of 3.5 to 4.0 is effective in inhibiting the production of related substances, and can optimize the antibacterial preservative effect of the atropine sulfate pharmaceutical composition, as well as increase the stability of the pharmaceutical composition. A further preferable pH range is 3.5 to 3.8, more preferably 3.5 to 3.7, still more preferably 3.55 to 3.65, wherein when the pH is 3.6, an optimum effect of suppressing the production of the substance concerned can be achieved.
Preferably, the pH of the ophthalmic pharmaceutical composition of the present invention is adjusted by a pH adjuster, and the pH adjuster is an organic acid or an inorganic acid.
Preferably, the organic acid is selected from citric acid and acetic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid.
Further preferably, the present inventors found that the effect when an organic acid is used as the pH adjuster is superior to the effect when an inorganic acid is used as the pH adjuster, and wherein, when the pH adjuster is citric acid, the effect of suppressing the generation of the relevant substance is significantly superior to the effect when the pH adjuster is acetic acid, hydrochloric acid, sulfuric acid, or phosphoric acid.
Wherein, the dosage of the pH value regulator is such that the pH value of the ophthalmic medicine composition is 3.5-4.0. For example, the pH adjustor may be used in an amount of 0.001 to 1 wt% based on the total weight of the ophthalmic pharmaceutical composition as 100 wt%.
Further, the inventors of the present application have unexpectedly found that the generation of related substances can be effectively inhibited by adjusting the osmotic pressure of the ophthalmic pharmaceutical composition to 180-300 mOsm/kg. Further preferred osmotic pressure ranges are 220-280 mOsm/kg; more preferably 240-280 mOsm/kg; further preferably 250-270mOsm/kg, and still further preferably 255-265mOsm/kg, wherein when the osmotic pressure is 260mOsm/kg, the optimal effect of inhibiting the generation of the relevant substances can be achieved.
As used herein, unless otherwise specified, the present numerical ranges should be understood to include the values of any integer within the range, and, where appropriate, fractions thereof (e.g., tenths and hundredths of the number). By way of example, the present invention has a pH in the range of 3.5 to 3.8, which is to be understood as including pH 3.51, 3.52, 3.53, 3.54, 3.55, … …, 3.60, 3.61, 3.62, 3.63, 3.64, 3.65, … …, 3.70, 3.71, … …, 3.78, 3.79, and the like. As another example, the present invention has an osmolality in the range of 180-300mOsm/kg, which is to be understood as including osmolality in the range of 181, 182, 183, … …, 255, 256, 257, … …, 261, 262, 263, 264, 265, … …, 298, 299, and the like.
Preferably, the osmotic pressure of the ophthalmic pharmaceutical composition of the present invention is adjusted by an osmotic pressure adjusting agent selected from at least one of an alkali metal halide salt, an alkaline earth halide salt and a polyhydric alcohol.
Preferably, the alkali gold halide salt is sodium chloride or potassium chloride; the alkaline earth halogen salt is calcium chloride or magnesium chloride; the polyalcohol is glycerol or propylene glycol.
The inventors of the present application found that the effect of an alkali gold halide salt as an osmolality adjusting agent is superior to the effect of an alkaline earth halide salt and a polyol as osmolality adjusting agents, wherein the effect is optimal when the osmolality adjusting agent is sodium chloride.
Wherein, the dosage of the osmotic pressure regulator is that the osmotic pressure of the ophthalmic drug composition is 180-300 mOsm/kg. For example, the tonicity modifier may be used in an amount of 0.001 to 3 wt% based on the total weight of the ophthalmic pharmaceutical composition being 100 wt%.
In one embodiment of the present invention, the ophthalmic pharmaceutical composition comprises the following components, based on the total weight of the composition being 100 wt%:
0.01-1 wt% atropine sulfate;
a pH adjuster for adjusting the pH of the composition to 3.5 to 4.0;
an osmotic pressure regulator for adjusting the osmotic pressure of the composition to 180-300 mOsm/kg;
and the balance of water.
Preferably, the pH value regulator is selected from one or more of citric acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerol and propylene glycol.
In another embodiment of the present invention, the ophthalmic pharmaceutical composition consists of the following ingredients, based on the total weight of the composition being 100 wt%:
0.01-1 wt% atropine sulfate;
a pH value regulator for regulating the pH value of the composition to 3.5-3.8;
an osmotic pressure regulator for adjusting the osmotic pressure of the composition to 220-280 mOsm/kg;
and the balance of water.
Preferably, the pH value regulator is selected from one or more of citric acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerol and propylene glycol.
In another embodiment of the present invention, the ophthalmic pharmaceutical composition comprises the following components, based on the total weight of the composition being 100 wt%:
0.01-1 wt% atropine sulfate;
0.001-1 wt% of a pH value regulator;
0.001-3 wt% of an osmotic pressure regulator;
and the balance of water.
Preferably, the pH value regulator is selected from one or more of citric acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerol and propylene glycol.
In another embodiment of the present invention, the ophthalmic pharmaceutical composition consists of the following ingredients, based on the total weight of the composition being 100 wt%:
0.01-1 wt% atropine sulfate;
0.001-1 wt% of a pH value regulator;
0.01-1 wt% of an osmotic pressure regulator;
and the balance of water.
Preferably, the pH value regulator is selected from one or more of citric acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerol and propylene glycol.
In another preferred embodiment of the present invention, the ophthalmic pharmaceutical composition consists of the following components, based on the total weight of the ophthalmic pharmaceutical composition being 100 wt%: 0.01 wt% atropine sulfate, 0.003 wt% citric acid, 0.8 wt% sodium chloride, and the balance water;
wherein the pH value of the ophthalmic medicine composition is 3.6, and the osmotic pressure is 260 mOsm/kg.
The ophthalmic pharmaceutical composition of the present invention can be prepared conventionally by methods known to those skilled in the art.
The invention also provides application of the ophthalmic medicine composition in preparing medicines for preventing and treating ophthalmic diseases.
Preferably, the ophthalmic disease is any one of myopic accommodative eye fatigue and mydriasis in ophthalmic examination or ophthalmic surgery.
The ophthalmic medicinal composition can obviously improve the related substance problem of the atropine sulfate medicinal composition; the ophthalmic medicinal composition has simple components, is not easy to form aggregates above micron level, and is beneficial to improving the corneal penetrability of atropine sulfate molecules; the pH value and osmotic pressure of the ophthalmic pharmaceutical composition are controlled within a specific range, and the ophthalmic pharmaceutical composition can be repeatedly used after being unsealed and can be stored for a long time without single-dose packaging even if preservative is not added.
Drawings
FIG. 1 is a schematic diagram showing the reaction of the precipitation of atropine sulfate-related substance (including pathway 1 and pathway 2).
FIG. 2a is a graph showing the results of the hydration diameter evaluation test prescribed for control group A.
FIG. 2B is a graph showing the results of the hydration diameter evaluation test prescribed for control group B.
FIG. 2c is a graph showing the results of the hydration diameter evaluation test of the ophthalmic pharmaceutical composition (atropine sulfate eye drops) [ example 3] of the present application.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The starting materials used in the following examples are all conventional commercially available products or can be prepared by conventional methods known in the art. Coli, pseudomonas aeruginosa, staphylococcus aureus, candida albicans, aspergillus niger, all of which are common in the art, were commercially available in the following test examples. The compositions of the following examples and comparative examples can be prepared by conventional methods in the art.
Examples 1 to 7
Examples 1 to 12 of the present invention provide an ophthalmic pharmaceutical composition, which comprises: atropine sulfate, citric acid as a pH value regulator, sodium chloride as an osmotic pressure regulator and water; and the ophthalmic pharmaceutical composition is preservative-free. Wherein, the contents of the components of the ophthalmic medicine composition and the pH value and osmotic pressure parameters thereof are shown in the following table 1.
TABLE 1
Comparative examples 1 to 5
Comparative examples 1 to 5 of the present invention provide an ophthalmic pharmaceutical composition, the formulation of which comprises: atropine sulfate, a pH regulator, an osmotic pressure regulator, water, and/or a preservative. Wherein the contents of the components of the ophthalmic pharmaceutical composition are shown in the following table 2.
TABLE 2
Test example 1: evaluation of the Total amount of related substances
In order to confirm the stability of the ophthalmic pharmaceutical composition, the present invention observes the change of the total amount (weight) of the relevant substances through a destructive test (65 ℃), evaluatesThe ophthalmic pharmaceutical composition is based on whether the total amount of relevant substances meets the United states pharmacopoeia Specification (USP40-NF35) and thus serves as an accelerated stability (40 ℃. sup. based on ℃. based on-<25% RH) and long term stability (25 ℃/40% RH) for sample storage. The total amount of related substances of the ophthalmic pharmaceutical composition of the invention is measured by Hitachi CM5000 series HPLC high performance liquid chromatography,
c18 HPLC Column. Specifically, the substances of interest are determined by the following method:
the content of related substances is determined by referring to United states pharmacopoeia (USP40-NF35) and British pharmacopoeia (BP2019), and parameters such as flow rate, ultraviolet wavelength and column temperature are set to be 2.0mL/min, 210nm and 50 ℃; the buffers, solution A and solution B were prepared as shown in Table 3 below.
TABLE 3
| Time (minutes) | Solution A (percent) [ b ]] | Solution B (percent) [ c ]] |
| 0 | 92 | 8 |
| 11 | 79 | 21 |
| 15 | 46 | 54 |
| 15.1 | 92 | 8 |
| 20 | 92 | 8 |
[a] Buffer solution: weighing 1.8 g of monopotassium phosphate and 2.5 g of 1-pentane sodium sulfonate, adding 900mL of water, shaking and mixing uniformly, adjusting the pH value to 2.5 by using phosphoric acid, and adding water to quantify to 1000 mL;
[b] solution a was filtered through 0.45 μm filter paper (Nylon) with acetonitrile and 5:95 buffer;
[c] solution B was filtered through 0.45 μm filter paper (Nylon) with acetonitrile and 80:20 buffer;
after the HPLC baseline is stable, respectively injecting 40 mu L of system applicability solution (1)5 needles, system applicability solution (2)1 needle, tropine acid solution 1 needle, standard solution 1 needle and test solution 1 needle, comparing the wave front areas, and calculating the content percentage of each related substance through the following formula.
The content percentage of the related substances is (rU/rT) x (1/F) x 100
The peak response of various related substances in the sample solution
rT is the sum of all peak responses in the sample solution
F is the relative response factor of various related substances (as shown in the following table)
The total amount of the related substances is not higher than 0.5% according to the acceptance standard of the atropine raw material in the United states pharmacopoeia, and the results of the total amount of the related substances of each example and each comparative example are shown in tables 4 and 5.
TABLE 4
Failure test: 65 ℃/1 day is equivalent to 25 ℃/81 days
TABLE 5
Failure test: 65 ℃/1 day is equivalent to 25 ℃/81 days
First, in example 1, when the pH was 3.6 and the osmotic pressure was 180mOsm/kg, the total amount of the relevant substances increased to 0.90% with time (day 14), and in example 2, the osmotic pressure was increased to 220mOsm/kg, and the total amount of the relevant substances was slightly decreased to 0.84% (day 14); example 3 is to increase the osmotic pressure to 260mOsm/kg and to reduce the total amount of related substances to 0.21% by a large margin (day 14). The total amount of the related substances rose significantly to 0.80% with the increase of the osmotic pressure to 280mOsm/kg (day 14); and the total amount of related substances has not been greatly different with the increase of osmotic pressure to 300 mOsm/kg. From the above experiments, it is clear that when the pH value of the atropine sulfate eye drops is 3.6 and the osmotic pressure is 260mOsm/kg, the best value of the total amount of the related substances is obtained. In order to confirm whether the pH value is within the range of 3.5-4.0, the invention can have better related substance total amount value; in examples 6 and 7, it was found that when the pH was 4.0 and the osmotic pressures were 220 and 280mOsm/kg, the total amount of the substances was 0.93% (day 14) and 0.97% (day 14), and that the total amount of the substances could not be more preferably obtained as the pH increased, as shown in Table 4.
Through the above experimental observation, the optimum total amount of the relevant substances was obtained at an osmotic pressure of 260mOsm/kg, and comparative example 1 is described to further confirm whether the optimum total amount of the relevant substances can be obtained outside the pH range set in the present invention. When the pH value is 4.5 and the osmotic pressure is 260mOsm/kg, the total amount of related substances is increased to 1.19 percent (day 14), and the pH value of 3.5-4.0 is proved to be the optimal range of the atropine sulfate eye drops. In comparative examples 2 to 5, acetic acid, hydrochloric acid, sulfuric acid, and phosphoric acid were used as pH regulators, and the total amount of the substances was increased to 1.46%, 1.12%, 2.62%, and 1.75% on day 14, as compared with example 3, showing that acetic acid, hydrochloric acid, sulfuric acid, and phosphoric acid were used as pH regulators, and the substances were more easily produced, as shown in table 5.
Test example 2: evaluation of hydration diameter
From the above description, it can be seen that when the pH value is 3.6 and the osmotic pressure is 260mOsm/kg, the atropine sulfate eye drops have the best total amount of related substances. To confirm whether the atropine sulfate eye drops of example 3 have better corneal penetration, a comparison of hydration diameters was made with control a and control B prescriptions (as shown in table 6). The hydration diameter of the aggregate of the atropine sulfate eye drops is measured by loading a sample to be measured in a particle size sample chamber _ DTS0012(100ea/Box-PS) through a MalvernZetasizer Nano ZS Nano particle size and potential analyzer.
From FIG. 2a, it can be observed that the "control group A prescription" has three peaks, respectively 19.4nm, 727.2nm and 4363.0nm, and a peak with a hydrated diameter of 19.4nm, which is an ethylenediaminetetraacetic acid (EDTA) molecule or boric acid (B (OH))3) An agglomerate of molecules; the hydration peak diameters are 727.2nm and 4363.0nm, because the 'control group A prescription' contains thickening agent (hydroxypropyl methylcellulose), which is an agglomerate formed by the extrusion of polymer segments in solution, the agglomerate is easy to embed atropine sulfate molecules, and the cornea penetrability is poor. FIG. 2B shows that the "prescription B" of the control group also has three peaks, which are 83.0nm, 446.4nm and 5084.0nm, and two peaks with hydration diameters of 83.0nm and 446.4nm, which are connected with each other, and are agglomerates formed by ethylene diamine tetraacetic acid molecules or atropine sulfate molecules, and charges of the two peaks attract each other; the peak with the hydration diameter of 5084.0nm is a 'control group B prescription' containing more electrolytes (borax and benzalkonium chloride), and mutually attracting to form a large-scale agglomerate. As can be seen from FIG. 2c, the atropine sulfate eye drops (example 3) of the present invention have only one peak, and the hydrated diameter is 151.1nm (standard deviation is only 11.1nm), thus confirming that the prescription of the present invention (example 3) is more favorable for corneal penetration than the "prescription of control group A" and the "prescription of control group B" because the ingredients are simple and do not easily attract charged ions to form larger aggregates.
TABLE 6 parameters and hydration diameter values for each formulation in test example 2
Test example 3: evaluation of antimicrobial efficacy test
Through the < evaluation of total amount of substances > and the < evaluation of hydration diameter >, the atropine sulfate eye drops (example 3) of the present invention are proved to be superior to the prior art and the control prescription, and in order to further find out that the atropine sulfate eye drops (example 3) of the present invention have more potential advantages, the present invention (example 3) is subjected to an antimicrobial efficacy test to observe whether the problem of bacteria growth exists under the condition of no preservative. The operation mode is to test the strain (1X 10)8cfu/ml) dilution to 1X 106cfu/ml, which was used as a inoculum (1X 10)6cfu/mL), 1mL of the inoculum was added to 20mL of the sample to be tested (example 3) and incubated at 22.5 ℃ C. Procedure for determination of antimicrobial efficacy test, from day 0 to day 7, colony count needs to be reduced by one power (1X 10)6cfu/ml is reduced to 1X 105cfu/ml); from day 7 to day 14, the colony count needs to be reduced by three powers (1X 10)5cfu/ml is reduced to 1X 102cfu/ml); from day 14 to day 28, the number of colonies did not increase any more and the antimicrobial efficacy test was judged to be acceptable.
Table 7 shows that the concentration of five test strains (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, Aspergillus niger) is reduced by two powers from 0 th to 7 th (1 × 10)6cfu/ml is reduced to 1X 104cfu/ml); from day 7 to day 14, the number of colonies was reduced by two more powers (1X 10)4cfu/ml is reduced to 1X 102cfu/ml); from day 14 to day 28, there were no colonies. It was confirmed that the ophthalmic pharmaceutical composition (example 3) of the present invention effectively inhibits the growth of the bacterial species without adding a preservative (to avoid corneal damage).
TABLE 7 antimicrobial efficacy test of atropine sulfate eye drops [ example 3]
In conclusion, it is found that the atropine sulfate eye drops (example 3) of the present invention are excellent in the resistance to the formation of the relevant substances, corneal penetration and long-term storage, and superior to the prior art and the control prescription, through the "evaluation of the total amount of the relevant substances", "evaluation of the hydration diameter" and "evaluation of the antimicrobial efficacy test".
Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. An ophthalmic pharmaceutical composition comprising 0.01 to 1 wt% atropine sulfate, characterized in that the ophthalmic pharmaceutical composition has a pH of 3.5 to 4.0; the osmotic pressure was 180-300 mOsm/kg.
2. The ophthalmic pharmaceutical composition according to claim 1, wherein the pH of the ophthalmic pharmaceutical composition is 3.5 to 3.8, preferably 3.5 to 3.7.
3. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition has an osmotic pressure of 220-280 mOsm/kg; preferably 240-280 mOsm/kg; more preferably 250-270 mOsm/kg.
4. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the osmotic pressure is adjusted by an osmotic pressure adjusting agent selected from at least one of an alkali metal halide salt, an alkaline earth halide salt and a polyhydric alcohol;
preferably, the alkali gold halide salt is sodium chloride or potassium chloride; the alkaline earth halogen salt is calcium chloride or magnesium chloride; the polyalcohol is glycerol or propylene glycol;
more preferably, the osmolality adjusting agent is sodium chloride.
5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the pH is adjusted by a pH adjusting agent which is an organic acid or an inorganic acid;
preferably, the organic acid is selected from citric acid and acetic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid;
more preferably, the pH adjusting agent is citric acid.
6. An ophthalmic pharmaceutical composition, characterized in that the composition comprises the following components, based on the total weight of the composition being 100 wt%:
0.01-1 wt% atropine sulfate;
a pH adjuster for adjusting the pH of the composition to 3.5 to 4.0;
an osmotic pressure regulator for adjusting the osmotic pressure of the composition to 180-300 mOsm/kg;
and the balance water;
preferably, the composition consists of the following ingredients, based on the total weight of the composition taken as 100 wt%:
0.01-1 wt% atropine sulfate;
a pH value regulator for regulating the pH value of the composition to 3.5-3.8;
an osmotic pressure regulator for adjusting the osmotic pressure of the composition to 220-280 mOsm/kg;
and the balance of water.
7. The ophthalmic pharmaceutical composition of claim 6, wherein the pH regulator is selected from one or more of citric acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerol and propylene glycol.
8. An ophthalmic pharmaceutical composition, comprising the following components by weight, based on the total weight of the composition being 100 wt%:
0.01-1 wt% atropine sulfate;
0.001-1 wt% of a pH value regulator;
0.001-3 wt% of an osmotic pressure regulator;
and the balance water;
preferably, the composition consists of the following ingredients, based on the total weight of the composition taken as 100 wt%:
0.01-1 wt% atropine sulfate;
0.001-1 wt% of a pH value regulator;
0.1-1 wt% of an osmotic pressure regulator;
and the balance of water.
9. The ophthalmic pharmaceutical composition of claim 8, wherein the pH regulator is selected from one or more of citric acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerol and propylene glycol.
10. Use of the ophthalmic pharmaceutical composition of any one of claims 1 to 9 for the preparation of a medicament for the prevention and treatment of ophthalmic diseases;
preferably, the ophthalmic disease is any one of myopic accommodative eye fatigue and mydriasis in ophthalmic examination or ophthalmic surgery.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010677253.8A CN111821259A (en) | 2020-07-14 | 2020-07-14 | Medicinal composition for eyes |
| CN202311180612.9A CN117379367A (en) | 2020-07-14 | 2021-06-15 | Ophthalmic pharmaceutical composition |
| CN202110662618.4A CN113662915B (en) | 2020-07-14 | 2021-06-15 | Ophthalmic pharmaceutical composition |
| PCT/CN2021/102444 WO2022012304A1 (en) | 2020-07-14 | 2021-06-25 | Ophthalmic pharmaceutical composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010677253.8A CN111821259A (en) | 2020-07-14 | 2020-07-14 | Medicinal composition for eyes |
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| CN111821259A true CN111821259A (en) | 2020-10-27 |
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| CN202010677253.8A Pending CN111821259A (en) | 2020-07-14 | 2020-07-14 | Medicinal composition for eyes |
| CN202311180612.9A Pending CN117379367A (en) | 2020-07-14 | 2021-06-15 | Ophthalmic pharmaceutical composition |
| CN202110662618.4A Active CN113662915B (en) | 2020-07-14 | 2021-06-15 | Ophthalmic pharmaceutical composition |
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| CN202110662618.4A Active CN113662915B (en) | 2020-07-14 | 2021-06-15 | Ophthalmic pharmaceutical composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022012304A1 (en) * | 2020-07-14 | 2022-01-20 | 艾尔健康医药(辽宁)有限公司 | Ophthalmic pharmaceutical composition |
| EP4088714A1 (en) * | 2021-05-10 | 2022-11-16 | Warszawskie Zaklady Farmaceutyczne Polfa S.A. | Ophthalmic pharmaceutical composition comprising atropine |
| EP4088713A1 (en) * | 2021-05-10 | 2022-11-16 | Warszawskie Zaklady Farmaceutyczne Polfa S.A. | Ophthalmic pharmaceutical composition comprising atropine |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9421199B2 (en) * | 2014-06-24 | 2016-08-23 | Sydnexis, Inc. | Ophthalmic composition |
| CA3063228C (en) * | 2017-05-11 | 2022-06-28 | Nevakar Inc. | Atropine pharmaceutical compositions |
| CN107456440A (en) * | 2017-08-07 | 2017-12-12 | 杭州赫尔斯科技有限公司 | A kind of low concentration atropic category medicament dropping ocular fluid and preparation method thereof |
| CN108338969A (en) * | 2018-02-08 | 2018-07-31 | 胡敏 | A kind of low concentration tropane class drug eye drops and preparation method thereof |
| CN114533652A (en) * | 2018-09-25 | 2022-05-27 | 沈阳兴齐眼科医院有限公司 | Pharmaceutical composition, preparation method and application thereof |
| CN109157503B (en) * | 2018-09-25 | 2019-08-16 | 沈阳兴齐眼药股份有限公司 | The pharmaceutical composition and its medical usage for preventing and treating NITM |
| CN110755377A (en) * | 2019-12-19 | 2020-02-07 | 李善学 | Low-concentration atropine sulfate eye drops and preparation method thereof |
| CN111821259A (en) * | 2020-07-14 | 2020-10-27 | 艾尔健康眼药(辽宁)有限公司 | Medicinal composition for eyes |
| CN112426405A (en) * | 2020-12-04 | 2021-03-02 | 山东中观明视医药科技有限公司 | Pharmaceutical composition for preventing and controlling myopia development, eye drops and preparation method and application thereof |
-
2020
- 2020-07-14 CN CN202010677253.8A patent/CN111821259A/en active Pending
-
2021
- 2021-06-15 CN CN202311180612.9A patent/CN117379367A/en active Pending
- 2021-06-15 CN CN202110662618.4A patent/CN113662915B/en active Active
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022012304A1 (en) * | 2020-07-14 | 2022-01-20 | 艾尔健康医药(辽宁)有限公司 | Ophthalmic pharmaceutical composition |
| EP4088714A1 (en) * | 2021-05-10 | 2022-11-16 | Warszawskie Zaklady Farmaceutyczne Polfa S.A. | Ophthalmic pharmaceutical composition comprising atropine |
| EP4088713A1 (en) * | 2021-05-10 | 2022-11-16 | Warszawskie Zaklady Farmaceutyczne Polfa S.A. | Ophthalmic pharmaceutical composition comprising atropine |
| WO2022238250A1 (en) * | 2021-05-10 | 2022-11-17 | Warszawskie Zakłady Farmaceutyczne Polfa S.A. | Ophthalmic pharmaceutical composition comprising atropine |
| WO2022238251A3 (en) * | 2021-05-10 | 2023-01-26 | Warszawskie Zakłady Farmaceutyczne Polfa S.A. | Ophthalmic pharmaceutical composition comprising atropine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113662915B (en) | 2023-11-28 |
| WO2022012304A1 (en) | 2022-01-20 |
| CN117379367A (en) | 2024-01-12 |
| CN113662915A (en) | 2021-11-19 |
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Address after: 110136 No.40, West No.5 District, 888 Puhe Avenue, Shenbei New District, Shenyang City, Liaoning Province Applicant after: Al health medicine (Liaoning) Co.,Ltd. Address before: 110136 No.40, West No.5 District, 888 Puhe Avenue, Shenbei New District, Shenyang City, Liaoning Province Applicant before: Al health eye medicine (Liaoning) Co.,Ltd. |
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Application publication date: 20201027 |