CN112426405A

CN112426405A - Pharmaceutical composition for preventing and controlling myopia development, eye drops and preparation method and application thereof

Info

Publication number: CN112426405A
Application number: CN202011398555.8A
Authority: CN
Inventors: 权春满
Original assignee: Shandong Zhongguan Mingshi Medical Technology Co ltd
Current assignee: Shandong Zhongguan Mingshi Medical Technology Co ltd
Priority date: 2020-12-04
Filing date: 2020-12-04
Publication date: 2021-03-02

Abstract

The invention discloses a pharmaceutical composition for preventing and controlling myopia development, eye drops and a preparation method and application thereof, wherein the eye drops comprise the following components: 0.001-2% of atropine medicine, 0-2% of thickening agent, acid-base regulator, osmotic pressure buffering agent, 0-2.2% of stabilizing agent, 0-0.05% of bacteriostatic agent and the balance of water, wherein the% is w/v; the pH value of the pharmaceutical composition is 3.0-8.5, and the osmotic pressure is 260-380 m0 sm/L; the stabilizer is one or more selected from sodium pyrosulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, thiourea, vitamin C, cysteine or its hydrochloride, citric acid and tartaric acid. The eye drops can effectively prevent and delay juvenile myopia and have good application prospect.

Description

Pharmaceutical composition for preventing and controlling myopia development, eye drops and preparation method and application thereof

Technical Field

The invention belongs to the technical field of myopia medicines, and particularly relates to a pharmaceutical composition for preventing and controlling myopia development, eye drops, and a preparation method and application thereof.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Currently, myopic diseases become the most common diseases in the young and the young, and are major public health problems faced by countries in the world. In recent years, due to the learning pressure and the influence of electronic products, the situation is particularly severe in China, particularly in China teenagers, the myopia rate of China teenagers is up to 50-60% according to statistics, and the number of myopia people is increased by about 6% every year. The incidence of ametropia diseases such as myopia, hypermetropia and the like of a group before the age of 20 years is high, the myopia of teenagers in China is under the condition of a low-age trend, the prevalence rate is high and is the first in the world, the myopia is already a national disease, the existing means for controlling and treating the myopia is the most common and common means for reducing the eye use time, advocating sanitary eyes and doing eye exercises, and the like, but the reduction of the eye use time is unrealistic along with the continuous improvement of the study pressure of the current teenagers in China, particularly the huge pressure of primary school students, junior middle school students and high school students facing examinations, and the prevention of the myopia by using the methods such as medicines is very important on the premise.

Through years of research of expert scholars in Singapore, America and other countries, the atropic eye drops can effectively delay myopia of children, and through treatment with atropic medicines, original tense ciliary muscles of teenagers and children can be quickly recovered, and the adjusting function of the atropic eye drops is further recovered in the sleeping process. In the clinical research process, it is found that atropine with high concentration is accompanied by a plurality of adverse reactions and side effects, while atropine with low concentration is easy to oxidize, so the stability is not good.

Disclosure of Invention

Aiming at the technical problems in the prior art, the invention provides a pharmaceutical composition for preventing and controlling myopia development, eye drops, and a preparation method and application thereof. Can effectively prevent the myopia of teenagers and has better storage stability.

To solve the above technical problem, one or more of the following embodiments of the present invention provide the following technical solutions:

in a first aspect, the invention provides a pharmaceutical composition for preventing and controlling myopia development, which comprises the following components in parts by weight:

0.001-2 parts of atropine medicine, 0-2 parts of thickening agent, acid-base regulator, osmotic pressure buffering agent, 0-2.2 parts of stabilizing agent and 0-0.05 part of bacteriostatic agent;

the stabilizer is one or more selected from sodium pyrosulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, thiourea, vitamin C, cysteine or its hydrochloride, citric acid and tartaric acid.

In a second aspect, the invention provides an eye drop for preventing and controlling myopia development, which comprises the following components:

0.001-2% of atropine medicine, 0-2% of thickening agent, acid-base regulator, osmotic pressure buffering agent, 0-2.2% of stabilizing agent, 0-0.05% of bacteriostatic agent and the balance of water, wherein the% is w/v;

the pH value of the pharmaceutical composition is 3.0-8.5, and the osmotic pressure is 260-380 m0 sm/L;

In a third aspect, the present invention provides a method for preparing the eye drops, comprising the steps of:

dissolving the stabilizer, the thickening agent, the acid-base regulator, the bacteriostatic agent and the osmotic pressure buffering agent completely by water, adding the atropine medicines, dissolving uniformly, and filtering to obtain the compound preparation;

or dissolving the atropine medicines completely in water, adding the solution of the stabilizing agent, the thickening agent, the acid-base regulator, the bacteriostatic agent and the osmotic pressure buffering agent, mixing uniformly, and filtering to obtain the atropine medicine.

Compared with the prior art, one or more technical schemes of the invention have the following beneficial effects:

the eye drops can effectively prevent and delay juvenile myopia and have good application prospect.

Detailed Description

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

In some embodiments, the atropine drug is atropine sulfate, DL-hyoscyamine sulfate, atropine, metaatropine, or a derivative thereof.

Further, the content of the atropine medicine in the eye drops is 0.005-2% w/v; preferably 0.01% to 0.05%, w/v.

In some embodiments, the thickening agent is a mixture of one or more of chondroitin sulfate, methylcellulose, sodium hyaluronate, hyaluronic acid, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), dextran, or chitosan.

Further, the methylcellulose is hydroxypropyl methylcellulose HPMC or carboxymethyl cellulose CMC.

The thickener has lubricating, thickening and moisturizing effects.

Further, the thickening agent is a mixture of hydroxypropyl methylcellulose and sodium hyaluronate.

Tests show that when the thickening agent is a mixture of the two substances, the two components have synergistic effect and have better effect of preventing and treating juvenile myopia.

Furthermore, the mass ratio of the hydroxypropyl methylcellulose to the sodium hyaluronate is 0.02-50, and the content of the thickening agent in the eye drops is 0.01-0.6% by weight and w/v.

In some embodiments, the ph adjusting agent is selected from any one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid salt, boric acid, borate, hydrochloric acid, and sodium hydroxide.

In some embodiments, the osmotic buffering agent is selected from one or more of sodium chloride, mannitol, borax, boric acid, glucose.

Further, the osmotic pressure buffering agent is a mixture of sodium chloride and borax. The mixture of the two can effectively relieve asthenopia.

Still further, the stabilizer is selected from at least two of sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, thiourea, vitamin C, cysteine or a hydrochloride thereof, citric acid and tartaric acid.

Experiments show that when a plurality of thickening agents and osmotic pressure regulators are simultaneously added into the eye drops, better curative effect can be exerted, and the toxic and side effect of the medicine can be reduced.

Furthermore, the dosage of the osmotic pressure regulator is based on the osmotic pressure regulation to 280-360 m0 sm/L.

In some embodiments, the stabilizer is sodium bisulfite, L-cysteine hydrochloride, or a mixture of both.

Further, the content of the stabilizing agent in the eye drops is 0-0.15 percent, w/v.

In some embodiments, the bacteriostatic agent is selected from one or more of benzoic acid and its sodium salt, boric acid, phenylmercuric acetate, sorbic acid, potassium sorbate, chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, parabens.

Further, the paraben is methyl paraben, ethyl paraben, propyl paraben, isopropyl paraben, butyl paraben, isobutyl paraben, heptyl paraben, or the like.

Furthermore, the bacteriostatic agent is benzalkonium chloride or ethylparaben.

Still further, the content of the bacteriostatic agent in the eye drops is 0.01-0.03 percent and w/v.

In some embodiments, the pore size of the filter is 0.22 μm or 0.2 μm.

Example 1

An eye drop capable of preventing and treating myopia development comprises atropine sulfate, an isotonic regulator and a diluent, and is used at night every day, and the ratio of each component is as follows:

the preparation method comprises the following steps: stirring the sodium chloride with the prescription amount by using 90% of water for injection or distilled water until the sodium chloride is completely dissolved, adding the atropine medicine with the prescription amount, stirring the mixture again until the atropine medicine is completely dissolved, filtering the mixture by using a 0.22 mu m (or 0.2 mu m) filter, and filling the mixture under an aseptic condition to obtain the pharmaceutical composition.

Example 2

An eye drop capable of preventing and treating myopia development comprises atropine sulfate, a bacteriostatic agent, an isotonic regulator and a diluent, and is used at night every day, and the ratio of each component is as follows:

the preparation method comprises the following steps: stirring the bacteriostatic agent according to the prescription with a proper amount of water for injection or distilled water until the bacteriostatic agent is completely dissolved, adding the atropine medicine according to the prescription, stirring and dissolving the atropine medicine completely, filtering the mixture by a 0.22 mu m (or 0.2 mu m) filter, and filling the mixture under an aseptic condition to obtain the bacteriostatic agent.

Example 3

An eye drop capable of preventing and treating myopia development comprises atropine sulfate, a stabilizing agent, a bacteriostatic agent, a pH regulator, an isotonic regulator, a thickening agent and a diluent, is used every night, and comprises the following components in percentage by weight:

the preparation method comprises the following steps:

1) stirring and dissolving prescribed amount of atropine medicaments by using 10 percent of water for injection or distilled water to completely form a medicament solution I;

2) dissolving the formula amount of the auxiliary materials such as the stabilizing agent, the bacteriostatic agent, the pH regulator, the isotonic regulator, the thickening agent and the like in 10 percent of water for injection or distilled water by stirring to form an auxiliary material solution II;

3) adding the medicinal solution I into the adjuvant solution II, stirring, filtering with 0.22 μm (or 0.2 μm) filter, and packaging under aseptic condition.

Example 4

the preparation method comprises the following steps:

Example 5

An eye drop capable of preventing and treating myopia development comprises atropine sulfate, a stabilizing agent, a bacteriostatic agent, a pH regulator, a thickening agent and a diluent, and is used at night every day, and the ratio of each component is as follows:

the preparation method comprises the following steps:

Example 6

the preparation method comprises the following steps:

Example 7

the preparation method comprises the following steps:

Example 8

the preparation method comprises the following steps:

Examples 1 to 8: stability study of atropine sulfate eye drops with different prescriptions

The prepared atropine sulfate eye drop is filled with 5ml in an eye drop bottle, stability study is carried out at 40 ℃, samples are taken at 0 month, 1 month, 3 months and 6 months for detecting the content of the sample (ultraviolet-visible spectrophotometry), and the results are shown in table 1:

table 1: stability research result of atropine sulfate eye drops with different prescriptions

Group of	0 month	1 month	3 month	6 month
					Example 1	99.8％	95.1％	90.4％	90.4％
Example 2	100.5％	96.3％	88.6％	80.2％
					Example 3	100.2％	99.6％	98.7％	98.0％
Example 4	99.6％	99.4％	98.5％	98.3％
					Example 5	100.3％	99.9％	99.5％	99.2％
Example 6	100.1％	99.7％	99.4％	98.9％
					Example 7	99.8％	99.6％	99.3％	99.0％
Example 8	100.2％	99.9％	99.4％	99.2％

As can be seen from the data in Table 1, the stability of the atropine sulfate eye drop is obviously improved after the product is added with the stabilizer, so that the formula suggests that the product is kept stable for a long time by adding a proper amount of the stabilizer.

Examples 1 to 8: research on effect of atropine sulfate eye drops with different prescriptions on treatment of myopia

1. Experimental methods

135 myopic patients aged 8-16 are selected. The diopter of the selected eye is-0.50 DS-5.00 DS; the initial near vision value is more than or equal to-0.25D; normal intraocular pressure, not more than 21mmHg. The groups were randomized into 8 groups of 15 cases. Atropine eye drops (prepared in examples 1-8) were added to 6 test groups, and 0.9% physiological saline was added to the control group; each group is administered 1 time per day, 1 drop per eye each time, and dropped into conjunctival sac before sleep for 20 days. Myopia tests were performed on days 0, 10, and 20, and initial myopia values and decay times were recorded.

The comprehensive optometry instrument has the advantages that the optometry (non-cycloplegia) is performed, and according to the optometry result, the full-correction frame glasses are worn to correct the far vision to the optimal vision, so that the equivalent sphere power is obtained. Rest for 10 minutes in a complete dark room to relax possible adjustments. The data was then recorded using an autorefractor, with both eyes looking at a 5m distance target, measuring the right eye distance power. Then, the short-distance work is started, the short-distance work adopts double-eye reading, the reading content is a simplified Chinese 12pt font, the reading distance is 35-40cm, and the reading time lh is set. The subjects should pay attention to the words, and keep the words clear and not distracted in the middle. After completing the near work, the subject quickly (within 2 s) fixates on the far sighting target. And the distance diopter of the full-corrective frame glasses worn by the right eye is measured again, and the initial near vision is recorded.

2. Results of the experiment

As shown in tables 2-3 below.

Table 2: effect of atropine sulfate eye drops of different prescriptions on initial myopia number of eyes (x + -S, n 15)

Table 3: effect of atropine sulfate eye drops of different prescriptions on the decay time of myopia (x + -S, n 15)

As can be seen from the data in tables 3 and 4, the concentration of the atropine in the eye drops is 0.01 percent to 0.05 percent after the atropine is prepared into the eye drops, and the atropine eye drops have a dose-effect relationship when used for treating myopia. After hypromellose and sodium hyaluronate are added into the prescription, the treatment effect tends to be enhanced, particularly in a high-concentration preparation, the trend is more obvious, and researches show that the prescription simultaneously containing two components, namely hypromellose and sodium hyaluronate has a more obvious synergistic enhancement treatment effect compared with one component containing the two components, particularly, a plurality of thickening agents and osmotic pressure regulators can be used in an atropine low-concentration group (such as example 8) to exert a better curative effect, and the toxic and side effects of the medicine can be predictably reduced.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition for preventing and controlling myopia progression, comprising: the composition comprises the following components in parts by weight:

2. An eye drop for preventing and controlling myopia development is characterized in that: the composition consists of the following components:

3. The pharmaceutical composition for preventing and controlling the progression of myopia according to claim 1 or the ophthalmic solution for preventing and controlling the progression of myopia according to claim 2, wherein: the atropine medicines are atropine sulfate, DL-hyoscyamine sulfate, atropine, post-atropine or derivatives thereof;

4. The pharmaceutical composition for preventing and controlling the progression of myopia according to claim 1 or the ophthalmic solution for preventing and controlling the progression of myopia according to claim 2, wherein: the thickening agent is one or a mixture of chondroitin sulfate, methylcellulose, sodium hyaluronate, hyaluronic acid, polyvinyl pyrrolidone, polyvinyl alcohol, dextran or chitosan;

further, the methylcellulose is hydroxypropyl methylcellulose or carboxymethyl cellulose;

further, the thickening agent is a mixture of hydroxypropyl methylcellulose and sodium hyaluronate;

furthermore, the mass ratio of the hydroxypropyl cellulose to the sodium hyaluronate is 0.02-50, and the content of the thickening agent in the eye drops is 0.01-0.6% w/v.

5. The pharmaceutical composition for preventing and controlling the progression of myopia according to claim 1 or the ophthalmic solution for preventing and controlling the progression of myopia according to claim 2, wherein: the acid-base regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid salt, boric acid, borate, hydrochloric acid and sodium hydroxide.

6. The pharmaceutical composition for preventing and controlling the progression of myopia according to claim 1 or the ophthalmic solution for preventing and controlling the progression of myopia according to claim 2, wherein: the osmotic pressure buffering agent is selected from one or more of sodium chloride, mannitol, borax and glucose;

further, the osmotic pressure buffering agent is a mixture of sodium chloride, boric acid and borax;

further, the stabilizer is selected from at least two of sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, thiourea, vitamin C, cysteine or a hydrochloride thereof, citric acid and tartaric acid;

7. The pharmaceutical composition for preventing and controlling the progression of myopia according to claim 1 or the ophthalmic solution for preventing and controlling the progression of myopia according to claim 2, wherein: the stabilizer is one of sodium bisulfite and L-cysteine hydrochloride, or a mixture of sodium bisulfite and L-cysteine hydrochloride;

8. The pharmaceutical composition for preventing and controlling the progression of myopia according to claim 1 or the ophthalmic solution for preventing and controlling the progression of myopia according to claim 2, wherein: the bacteriostatic agent is selected from one or more of benzoic acid and sodium salt thereof, boric acid, phenylmercuric acetate, sorbic acid, potassium sorbate, chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide and parabens;

further, the parabens are methyl paraben, ethyl paraben, propyl paraben, isopropyl paraben, butyl paraben, isobutyl paraben or heptyl paraben;

furthermore, the bacteriostatic agent is benzalkonium chloride or ethylparaben;

9. A process for the preparation of an ophthalmic solution as claimed in any of claims 2 to 8, which comprises: the method comprises the following steps:

10. A method for producing an ophthalmic solution according to claim 9, wherein: the pore size of the filter is 0.22 μm or 0.2. mu.m.