Patent Application
20250195540
The present disclosure relates to the technical field of ophthalmic drugs, specifically to a use of dehydroepiandrosterone (DHEA) in preparation of a drug for preventing and treating ophthalmic myopia, dosage forms of the DHEA, and preparation methods of the dosage forms.
The population suffer from myopia has been increasing and has also become younger and younger. However, there is currently no definite and effective method for preventing and treating myopia. Some researches have shown that increasing the amount of time spent outdoors under sun light, applying atropine eye drops, and wearing orthokeratology lenses are currently promising interventions for myopia control. However, outdoor activities can only slow down the progression of myopia and may require multi-sided coordination from children, parents and schools, and time spent on close reading needs to be reduced, which are challenging for a long time. Additionally, patients using atropine eye drops will undergo a rebound of myopia after discontinuing drugs for a certain period, which is manifested as myopia progression. Moreover, atropine eye drops lead to high incidence rates of systemic and local adverse reactions. Patients who wear orthokeratology lenses is also required to continue the wearing every day, which is difficult to stick to. In addition, patients who wear orthokeratology lenses are prone to the risk of corneal damage, infection, or damage to the ophthalmic surface environment, and easily undergo a rebound of myopia after stopping wearing. Therefore, there is an urgent need to develop appropriate ophthalmic drugs for preventing and treating myopia.
The present disclosure aims to overcome at least one of the defects (deficiencies) of the prior art. In one aspect, the present disclosure provides a use of dehydroepiandrosterone (DHEA) in preparation of a drug for preventing and treating ophthalmic myopia.
A second object of the present disclosure is to provide a DHEA-based eye drop and a preparation method thereof.
A third object of the present disclosure is to provide a DHEA-based eye ointment and a preparation method thereof.
A fourth object of the present disclosure is to provide a DHEA-based gel and a preparation method thereof.
According to the present disclosure, a use of DHEA in preparation of a drug for preventing and treating myopia is provided.
Dehydroepiandrosterone, also known as DHEA, is chemically known as 3-β-hydroxyandrost-5-en-17-one, with a molecular formula of C19H28O2 and a molecular weight of 288.41. DHEA is an adrenal hormone precursor secreted by the zona reticularis of the human adrenal cortex, which exists mostly in the sulphated form (DHEA-s) in the blood, and they are the key precursors for the synthesis of estrogen and testosterone in the human body. Normally, the amount of DHEA secreted in the human body gradually declines with age. Currently, DHEA, as an oral drug and a health care drug, has the effects of regulating obesity, preventing diabetes, resisting carcinogenic and viral infection, improving memory, immune response, and stress response, and alleviating tension. However, there are still few studies on eyes.
Through clinical and animal experimental studies, the present inventor has found that DHEA is involved in the occurrence mechanisms of various ophthalmic lesions, especially myopia, and that DHEA can reduce the growth of axial length (AL) in animal models when applied locally to eyes and thus has the effect of preventing and treating myopia.
The drug using DHEA is preferably for external use.
The topical and external administration to eyes is also a convenient and non-invasive ophthalmic administration route for treating eye diseases, and is more in line with the needs of users.
The dosage form of the drug is preferably an eye drop, an eye ointment, or a gel.
Provided is a DHEA-based eye drop according to the present disclosure, including the following pharmaceutical components in parts by weight: 8 to 10 parts of hydroxypropyl methylcellulose; 24 to 28 parts of boric acid; 1 to 5 parts of borax; 0.05 to 0.1 part of benzalkonium chloride; 0.04 to 8 parts of DHEA; 0.001 to 0.1 part of a pH-adjusting agent; and 0.001 to 0.1 part of an osmolarity adjusting agent.
A preparation method of the DHEA-based eye drop described above including the following steps.
Further, in the step S1, the blank solvent is preferably prepared by the following specific steps.
In the step S2, the DHEA solution is preferably prepared by the following specific step:
A rotational speed of the high-shear emulsifying machine may be 1,000 r/min.
Concentration percentage of the DHEA is calculated by the ratio of the parts by weight of the DHEA to 400 parts by weight of the blank solvent, namely=parts by weight of the DHEA/400 parts by weight of the blank solvent×100%.
When the DHEA is of 8 parts, the concentration of the DHEA solution obtained is 2%.
When the DHEA is of 4 parts, the concentration of the DHEA solution obtained is 1%.
When the DHEA is of 2 parts, the concentration of the DHEA solution obtained is 0.5%.
When the DHEA is of 0.4 part, the concentration of the DHEA solution obtained is 0.1%.
When the DHEA is of 0.2 part, the concentration of the DHEA solution obtained is 0.05%.
When the DHEA is of 0.04 part, the concentration of the DHEA solution obtained is 0.01%.
According to the above preparation relationship:
When a DHEA solution with a concentration of 1% is prepared from a DHEA solution with a concentration of 2%, 1 part by weight of the blank solvent is added to each 1 part by weight of the DHEA solution with the concentration of 2%.
When a DHEA solution with a concentration of 0.5% is prepared from a DHEA solution with a concentration of 1%, 1 part by weight of the blank solvent is added to each 1 part by weight of the DHEA solution with the concentration of 1%.
When a DHEA solution with a concentration of 0.1% is prepared from a DHEA solution with a concentration of 0.5%, 4 parts by weight of the blank solvent are added to each 1 part by weight of the DHEA solution with the concentration of 0.5%.
When a DHEA solution with a concentration of 0.05% is prepared from a DHEA solution with a concentration of 0.1%, 1 part by weight of the blank solvent is added to each 1 part by weight of the DHEA solution with the concentration of 0.1%.
When a DHEA solution with a concentration of 0.01% is prepared from a DHEA solution with a concentration of 0.05%, 4 parts by weight of the blank solvent are added to each 1 part by weight of the DHEA solution with the concentration of 0.05%.
In the S3, the pH-adjusting agent is added to adjust a pH of the eye drop to 6.2 to 7.2. The pH-adjusting agent may be disodium phosphate, or monosodium phosphate, or a mixture of disodium phosphate and monosodium phosphate. The osmolarity adjusting agent is added to adjust an osmolarity to 280 mOsm/L to 310 mOsm/L. The osmolarity adjusting agent may be sodium chloride.
A DHEA-based eye ointment is provided according to the present disclosure, including the following pharmaceutical components in parts by weight: 5 to 10 parts of DHEA; 25 to 50 parts of lanolin; 12 to 25 parts of sterile liquid paraffin; and 850 to 1,000 parts of yellow Vaseline.
A preparation method of the DHEA-based eye ointment described above is provided, including the following steps.
A DHEA-based gel is provided according to the present disclosure, including the following pharmaceutical components in parts by weight: 0.5 to 2 parts of DHEA; 1 to 5 parts of a thickening agent; 0.8 to 1.5 part of an isotonic agent; 0.001 to 0.05 part of a bacteriostatic agent; 0.001 to 0.005 part of a pH-adjusting agent; and 0.2 to 1 part of a humectant.
A preparation method of the DHEA-based gel described above is provided, including the following steps.
In the present disclosure, the thickening agent may be carbomer, the isotonic agent may be sodium chloride, the bacteriostatic agent may be benzalkonium bromide, the pH-adjusting agent may be phosphoric acid, and the humectant may be sodium hyaluronate. Specifically, the pH-adjusting agent is used to adjust the pH of the DHEA-based gel to 7.
Further, a use of the DHEA-based eye drop described above, the DHEA-based eye ointment described above, and/or the DHEA-based gel described above in preparation of a drug for preventing and treating ophthalmic myopia is provided. The ophthalmic myopia includes true myopia and pseudomyopia.
Compared with the prior art, the present disclosure has the following beneficial effects.
The present disclosure discloses a use of DHEA in preparation of a drug for preventing and treating ophthalmic myopia. The existing drugs for treating ophthalmic myopia are mainly atropine. Compared with the existing ophthalmic formulations, the present application innovatively adopts DHEA to prepare a drug for ophthalmic myopia. Moreover, a large number of experimental results have shown that the ophthalmic formulations prepared in the present application have the beneficial effects of safety, economy, effectiveness, and small irritation, and are more in line with the needs of users. The present disclosure also provides preparation methods of a DHEA-based eye drop, a DHEA-based eye ointment, a DHEA-based gel, and a DHEA-based liquid temperature-sensitive gel. It has been proved through experimental results that the DHEA-based ophthalmic formulations exhibit a significant therapeutic effect in the prevention and treatment of ophthalmic myopia, and have strong practical performance.
In this example, a DHEA-based eye drop was disclosed, including the following pharmaceutical components: DHEA, a pH-adjusting agent, an osmolarity adjusting agent, and a blank solvent. Specifically, a preparation method of the DHEA-based eye drop in this example was as follows.
In step S1, a blank solvent was prepared. Specifically, 9 parts by weight of hydroxypropyl methylcellulose were weighed and dissolved in 400 parts by weight of purified water to produce a first solution; then 26 parts by weight of boric acid and 3 parts by weight of borax were weighed and added to the first solution, and stirring was conducted for complete dissolution to produce a second solution; 0.075 part by weight of benzalkonium chloride was weighed and added to the second solution, stirring was conducted for complete dissolution, and finally 1,500 parts by weight of purified water were added for diluting to a specified volume or concentration to produce the blank solvent.
In step S2, DHEA solutions with concentrations of 0.01% to 2% were prepared. Specific preparation processes were as follows:
In step S3, the pH-adjusting agent and the osmolarity adjusting agent were added to each DHEA solution prepared to adjust a pH and an osmolarity of the DHEA solution to 6.2 to 7.2 and 280 to 310 mOsm/L respectively to produce the DHEA-based eye drop.
Specifically, in this example, pH values and osmolarity of DHEA-based eye drops with different concentrations were shown in Table 1 below.
Specifically, in this example, a main function of the pH-adjusting agent added is to keep a pH of an eye drop basically consistent with the pH of the human tears, which allows little irritation. A main function of the osmolarity adjusting agent added is to keep an osmolarity of an eye drop close to the osmolarity of the human tears.
This example was different from Example 1 in that: in the step S2, according to the following relationship: concentration percentage of DHEA=parts by weight of a DHEA/400 parts by weight of a blank solvent×100%, required parts by weight of the DHEA and the blank solvent were weighed, and then the DHEA was dispersed evenly in the blank solvent with a high-shear emulsifying machine to prepare a DHEA solution with a concentration of 0.01% to 2%.
Specifically, in this example, preparation parameters for DHEA-based eye drops with different concentrations were shown in Table 2 below.
In this example, a DHEA-based eye ointment was disclosed, including the following pharmaceutical components in parts by weight: 5 parts by weight of DHEA; 25 parts by weight of lanolin; 12.5 parts by weight of sterile liquid paraffin; 953.5 parts by weight of yellow Vaseline; and 4 parts by weight of sterile water for injection, with 1,000 parts in total.
The DHEA-based eye ointment was prepared through the following method.
A preparation method of the DHEA-based eye ointment included the following steps.
In step S1, an eye ointment matrix is prepared. Specifically, 25 parts by weight of lanolin and 953.5 parts by weight of yellow Vaseline were weighed, mixed, and heated for melting. Then 12.5 parts by weight of sterile liquid paraffin were added, and then thorough mixing and cooling were conducted to produce the eye ointment matrix.
In step S2, 5 parts by weight of a DHEA were weighed and dissolved in 4 parts by weight of sterile water for injection to produce a mixed solution.
In step S3, the mixed solution obtained in the step S2 was added to the eye ointment matrix obtained in the step S1 to produce a mixture. The mixture was thoroughly stirred and aseptically dispensed to produce the DHEA-based eye ointment.
Specifically, in the step S1, the lanolin and the yellow Vaseline were heated at 100° C. to achieve the purpose of sterilization, and the cooling was conducted to 80° C. In the step S3, the mixed solution was added to the eye ointment matrix under vigorous stirring.
A mass percentage of DHEA in the DHEA-based eye ointment obtained in this example was 0.5%.
In this example, a DHEA-based gel was disclosed, including the following pharmaceutical components in parts by weight: 0.5 to 2 parts by weight of DHEA; 1 to 5 parts by weight of a thickening agent; 0.8 to 1.5 part by weight of an isotonic agent; 0.001 to 0.05 part by weight of a bacteriostatic agent; 0.001 to 0.005 part by weight of a pH-adjusting agent; and 0.2 to 1 part by weight of a humectant.
The DHEA-based gel was prepared through the following method.
In step S1, 1 part by weight of the thickening agent was weighed and dissolved in 5 parts by weight of sterile water for injection, and then a pH was adjusted with the pH-adjusting agent to 6.5 to 8.0 to produce a first solution.
In step S2, 0.5 part by weight of a DHEA, 0.8 part by weight of the isotonic agent, 0.001 part by weight of the bacteriostatic agent, and 0.2 part by weight of the humectant were weighed and added to the solution 1, and sterile water for injection was supplemented until a resulting solution was of 100 parts by weight in total. The solution was thoroughly mixed, adjusted to a pH of 7, and filtered through a 0.22 μm microporous filter membrane for sterilization to produce the DHEA-based gel.
In this example, the thickening agent was carbomer, the isotonic agent was sodium chloride, the bacteriostatic agent was benzalkonium bromide, the pH-adjusting agent was phosphoric acid, and the humectant was sodium hyaluronate.
A mass percentage of DHEA in the DHEA-based gel obtained in this example was 0.5%.
In order to investigate the stability of the DHEA-based eye drop, eye ointment, and gel formulations of the present disclosure, 10 samples were collected through random sampling from each of the DHEA-based eye drops, the DHEA-based eye ointment, and the DHEA-based gel obtained in Examples 1, 3, and 4. Contents of DHEA in the eye drops, eye ointment, and gel were tracked and detected by the high-performance liquid chromatography-external standard method to investigate the stability. Specifically, experimental investigation conditions were as follows: temperature: 40° C.±2° C., and relative humidity: 75%+5%. Concentrations of the DHEA-based eye drops in Example 1 were 0.01%, 0.05%, 0.1%, 0.5%, 1%, and 2%, respectively.
The stability of the DHEA-based ophthalmic formulations was investigated by detecting changes in DHEA contents. When a DHEA content changed by 5% or more, it indicated the start of a change. When a DHEA content changed by 10% or more, it indicated the ineffectiveness.
As a result, after 3 months of an accelerated test at 40° C., the DHEA-based eye drops, the DHEA-based eye ointment, and the DHEA-based gel in Examples 1, 3, and 4 all did not change significantly during an experimental cycle, and the appearances, labeled amounts, pH values, and sterility test results of the drugs all were qualified. Therefore, the DHEA-based eye drops, the DHEA-based eye ointment, and the DHEA-based gel of the present disclosure exhibited qualified stability.
New Zealand white rabbits were selected as test subjects and randomly divided into 8 groups with 3 rabbits in each group. There were no significant differences in the age and body weight among rabbits in the groups. There was no abnormality in the ophthalmic examination under a slit lamp before administration.
0.01%, 0.05%, 0.1%, 0.5%, 1%, and 2% DHEA-based eye drops were dropped to the conjunctival sacs of the left eyes of white rabbits in groups 1 to 6 at an amount of 0.05 mL, respectively. 0.1 g of the DHEA-based eye ointment in Example 3 was dropped to the conjunctival sac of the left eye of each white rabbit in group 7. 0.1 g of the DHEA-based gel in Example 4 was dropped to the conjunctival sac of the left eye of each white rabbit in group 8. The right eye of each white rabbit was taken as a control group thereof, and the same amount of a 0.9% sodium chloride solution was dropped to the right eye.
In the groups 1 to 6, the DHEA-based eye drops each were dropped 4 times a day consecutively for 7 days. In the group 7, the DHEA-based eye ointment was dropped once a day consecutively for 7 days. In the group 8, the DHEA-based gel was dropped twice a day consecutively for 7 days. Local reactions were observed and recorded 1 hour after the first eye drop administration and before each administration. The blind trial was adopted, that is, observers did not know the grouping of the observed animals.
Results were scored based on the evaluation criteria for ophthalmic irritation responses in the Guidelines for Preclinical Research of New Drugs (Western Medicines) (Table 3 below).
According to a total score, a corresponding irritation degree was determined. Evaluation criteria for eye irritation were shown in Table 4 below.
Test results: Observation results of ophthalmic irritation in each group 1 hour and 7 days after the first eye drop administration were shown in Table 5.
The results showed that the DHEA-based eye drops of different concentrations, the DHEA-based eye ointment, and the DHEA-based gel in the experimental groups exhibited comparable irritation to the normal saline group, indicating that the DHEA-based eye drops of the technical solution have small ophthalmic irritation and excellent tolerance.
Acute toxicity test is as follows. Healthy New Zealand white rabbits of half male and half female were selected with the inclusion criteria: no external eye diseases and normal reflection of pupils in both eyes to light. The white rabbits were randomly divided into 4 groups with 6 animals in each group, with groups 1 to 3 being the administration groups, and a group 4 being a blank control group. In the blank control group, normal saline was applied. In the administration groups, the 2% DHEA-based eye drop in Example 1, the DHEA-based eye ointment in Example 3, and the DHEA-based gel in Example 4 of the present disclosure were applied, respectively. A dose was 25 times an intended daily dose for adults. When observed for 7 days, the animals did not undergo abnormal changes, indicating that the administration of the drugs was safe.
(1) A total of 40 healthy three-week-old colored guinea pigs were randomly selected and randomly divided into 8 groups with 5 guinea pigs in each group. The 8 guinea pig groups includes a first group: a normal control group, a second group: a myopia model-alone group, a third group: a myopia model+0.01% DHEA-based eye drop group, a fourth group: a myopia model+0.1% DHEA-based eye drop group, a fifth group: myopia model+1% DHEA-based eye drop group, a sixth group: a myopia model+2% DHEA-based eye drop group, a seventh group: a myopia model+DHEA-based eye ointment group, and an eighth group: a myopia model+DHEA-based gel group. There were no statistically-significant differences in the baseline diopter and AL of the right eye among the groups.
(2) Establishment of a form deprivation myopia (FDM) model: the right eye was covered and the left eye was normally opened. The daily observation was conducted to ensure the covering effect for the right eye until the experiment was completed 4 weeks later. For guinea pigs in the third to eighth groups, the left eye was normally opened and the right eye was covered (FDM).
(3) Administration scheme: for guinea pigs in the third to sixth groups, 0.01%, 0.1%, 1%, and 2% DHEA-based eye drops were applied to the right eye at a dose of 50 μL four times a day consecutively for 7 days, respectively; for guinea pigs in the seventh group, the DHEA-based eye ointment in Example 3 was applied to the right eye at a dose of 0.1 g once a day consecutively for 7 days; and for guinea pigs in the eighth group, the DHEA-based gel in Example 4 was applied to the right eye at a dose of 0.1 g twice a day consecutively for 7 days.
(4) Measurement of myopia parameters:
A) Diopter measurement: the optometry was conducted with a streak retinoscope and lenses of different diopters, and an average of diopters in horizontal and vertical meridians was taken. The optometry was conducted 3 times, and an average was taken and recorded as a result.
B) AL measurement: ALs of both eyes were measured by an A-mode ultrasound instrument. Results of 6 measurements under waveform standards were selected, and an average was taken and recorded as a result, which was accurate to 0.01 mm.
(5) Results: the experimental results were shown in
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Therefore, the DHEA-based eye drop, the DHEA-based gel, and the DHEA-based eye ointment of the present disclosure all have the beneficial effect of preventing and controlling myopia.
Apparently, the above embodiments of the present disclosure are merely examples listed to clearly illustrate the technical solutions of the present disclosure, and are not intended to limit the specific implementations of the present disclosure. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the claims of the present disclosure should be included within the protection scope of the claims of the present disclosure.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202211038346.1 | Aug 2022 | CN | national |
The present application is a continuation of International Application No. PCT/CN2023/110037, filed on Jul. 28, 2023, which claims priority from Chinese Application No. 202211038346.1 filed on Aug. 29, 2022, all of which are hereby incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/CN2023/110037 | Jul 2023 | WO |
| Child | 19066888 | US |
