An ophthalmic composition containing tetraisopalmitate ascorbate and a method of making the same

Abstract

The present application relates to the technical field of ophthalmic drugs, in particular to a vitamin C isopalmitate (VC-IP) eye drop for preventing and treating myopia and a preparation method thereof. In view of the problems of large side effects and poor compliance of the existing myopia prevention means, the present application provides an eye preparation taking tetraisopalmitate ascorbate as the main active ingredient, which improves the drug stability and corneal permeability through the liposolubility thereof. The eye drop can effectively inhibit the growth of the eye axis and improve the accommodation lag, and has no irritation, and is suitable for long-term use.

Description

[0001] This invention relates to the field of ophthalmic pharmaceutical technology, and more specifically, to an ophthalmic composition containing tetraisopalmitate ascorbic acid and a method for its preparation. Background Technology

[0002] Myopia, especially the problem of rapid axial elongation in adolescents, is receiving increasing attention. Current interventions mainly include orthokeratology lenses (OK lenses) and low-concentration atropine eye drops. However, existing technologies have certain limitations in application: for example, some drugs may have side effects such as photophobia and decreased accommodation; or existing antioxidants have a short residence time on the ocular surface and low bioavailability, making it difficult to exert a sustained effect. Therefore, there is an urgent need to develop a novel ophthalmic composition that is highly safe, can effectively inhibit axial elongation, and is well-tolerated by the eye. Summary of the Invention

[0003] The purpose of this invention is to provide an ophthalmic composition containing tetraisopalmitate ascorbic acid to solve the problems existing in the prior art.

[0004] To achieve the above objectives, the present invention provides the following technical solution: An ophthalmic composition containing tetraisopalmitate ascorbic acid, characterized in that it comprises a therapeutically effective amount of tetraisopalmitate ascorbic acid (VC-IP) and a pharmaceutically acceptable carrier.

[0005] Further, the tetraisopalmitate ascorbic acid concentration in the composition is 0.01% to 5% by weight / volume. Further, the pharmaceutically acceptable carrier is selected from one or more of sodium hyaluronate solution or physiological saline. Preferably, the carrier is preservative-free sodium hyaluronate eye drops.

[0006] The beneficial effects of this invention are as follows: 1. This invention uses the fat-soluble tetraisopalmitate ascorbic acid (VC-IP) as the active ingredient. Compared with ordinary vitamin C, it has better transdermal absorption and stability, and can more effectively penetrate into the ocular tissue. 2. It has high safety and good tolerability, and does not contain anticholinergic drugs such as atropine, therefore it will not cause side effects such as photophobia, blurred vision, and decreased accommodation. It is suitable for children and adolescents and other people who require long-term intervention. However, specific use should be in accordance with medical advice and adjusted according to individual reactions. Detailed implementation method: Example x: Progress chart of anti-myopia effect

[0007] Initial state (6-week-old New Zealand rabbits) Rabbit 1 12.70 1.60 4.50 12.70 1.60 4.50 Rabbit 4 12.90 1.80 4.40 13.00 1.80 4.30 Rabbit 5 12.60 1.80 4.30 12.50 1.70 4.20 Rabbit 8 12.60 1.60 4.80 12.70 1.80 4.60 Immediately after myopia induction (before medication) 6-9 weeks old Rabbit 1 14.00 2.00 5.10 13.60 1.50 5.20 Rabbit 4 14.10 1.90 5.20 14.20 2.00 4.90 Rabbit 5 13.90 1.60 5.40 13.80 1.80 5.00 Rabbit 8 14.10 1.80 5.50 14.40 1.60 5.30 Day 14 of medication administration to the left eye Rabbit 1 14.60 1.90 5.90 14.30 1.60 5.90 Rabbit 4 14.60 2.00 5.80 14.60 1.90 5.60 Rabbit 5 14.50 1.70 5.80 14.80 1.80 5.50 Rabbit 8 14.60 2.00 6.00 14.90 1.90 5.90 Comparison of myopia range between left and right eyes Rabbit 1 1.30 0.04 0.60 0.90 0.10 decrease 0.70 Rabbit 4 1.20 0.10 0.80 1.20 0.20 0.60 Rabbit 5 1.30 0.20 decrease 1.10 1.30 0.10 0.80 Rabbit 8 1.50 0.20 0.70 1.40 0.20 decrease 0.70 Comparison of left eye with drug administration and right eye without drug administration Rabbit 1 0.60 0.10 decrease 0.80 0.70 0.10 0.70 Rabbit 4 0.50 0.10 0.60 0.40 0.10 decrease 0.70 Rabbit 5 0.60 0.10 0.40 1.00 0 unchanged 0.50 Rabbit 8 0.50 0.20 0.50 0.80 0.30 0.60 Experimental Methods: Six-week-old New Zealand rabbits were selected for myopia induction. The left eye was the experimental group, and the ophthalmic composition containing 0.5% tetraisopalmitate ascorbic acid prepared according to this invention was applied. The right eye was the control group and was not treated. Detection Indicator: Axial length was measured using ultrasound in a professional veterinary hospital.

[0008] Example 1: An ophthalmic composition containing 0.5% VC-IP (Preferred Example)

[0009] This embodiment provides an ophthalmic composition with good stability and high bioavailability; Formula: Tetraisopalmitate ascorbic acid (VC-IP) 50mg, anhydrous ethanol 0.1ml, preservative-free sodium hyaluronate solution (0.1% w / v) approximately 9ml; Preparation method: Measure 9 ml of preservative-free sodium hyaluronate solution into a clean container; add 0.1 ml of anhydrous ethanol as a co-solvent; weigh 50 mg of tetraisopalmitate ascorbic acid and add it to the above mixture; add sodium hyaluronate solution to make up to 10 ml, and shake vigorously to evenly disperse the tetraisopalmitate ascorbic acid in the sodium hyaluronate solution; thus, an ophthalmic composition containing 0.5% (w / v) tetraisopalmitate ascorbic acid is obtained. The resulting composition has a pH value that naturally falls within the physiological tolerance range of the eye (e.g., pH 5.0-8.0), eliminating the need for additional acid-base regulators and avoiding the potential irritation risks associated with the introduction of exogenous regulators. Effects and properties: The composition has a uniform, fine, milky-white (or semi-transparent milky) appearance. Observation shows that the system exhibits good redispersibility; even if slight phase separation occurs upon standing, it can be quickly restored to a homogeneous state with simple shaking, without the formation of lumps or hard precipitates. In rabbit eye irritation experiments, despite the microemulsion form of the solution, it exhibited excellent biocompatibility. After 14 days of continuous administration, the rabbits did not show any discomfort symptoms such as nictitating membrane reflex (blinking), tearing, or eye rubbing. This confirms that the microemulsion system has extremely fine particles, causes no mechanical friction to the corneal epithelium, and combines high bioavailability with excellent comfort. This indirectly confirms the good biocompatibility of the composition and solves the problem of making comfortable eye drops from high-concentration, fat-soluble vitamin C derivatives. Example 2: Low-concentration ophthalmic composition containing 0.1% tetraisopalmitate ascorbic acid

[0010] Low-concentration formulas are available for people with low sensitivity or for daily care needs; Preparation method: Sodium solution Take 2 ml of the 0.5% tetraisopalmitate ascorbic acid ophthalmic composition prepared in Example 1, add 8 ml of preservative-free sodium hyaluronate solution and 0.1 ml of anhydrous ethanol, shake vigorously to obtain an ophthalmic composition containing 0.1% tetraisopalmitate ascorbic acid. Note: Since Example 1 has demonstrated the biocompatibility and mildness of this carrier system, the low-concentration composition obtained by simple dilution also exhibits a uniform microemulsion state, has better safety, and maintains the antioxidant activity and easy redispersibility of tetraisopalmitate ascorbic acid. Example 3: A low-concentration ophthalmic composition containing 1.0% tetraisopalmitate ascorbic acid

[0011] Preparation method: Measure 100 mg of tetraisopalmitate ascorbic acid, add 0.2 ml of anhydrous ethanol, and then add preservative-free sodium hyaluronate solution to bring the volume to 10 ml. Shake vigorously to evenly disperse the tetraisopalmitate ascorbic acid in the sodium hyaluronate solution; this yields an ophthalmic composition containing 1.0% (w / v) tetraisopalmitate ascorbic acid. Explanation and effects: As the concentration increases, the viscosity of the system rises slightly, but it still maintains uniform microemulsion kinetics.

[0012] Comparative Example 1: 50 mg of ordinary vitamin C ascorbic acid was dissolved directly in 10 ml of physiological saline;

[0013] Comparative results: The solution turned noticeably yellow within 24 hours under light exposure (oxidative degradation), and because ordinary vitamin C is water-soluble, it has difficulty effectively penetrating the corneal epithelium. After being instilled into the rabbit eye, it had a short retention time on the ocular surface and was easily washed away with tears, resulting in low bioavailability. In contrast, the tetraisopalmitate ascorbic acid composition of this invention showed significant efficacy and no irritation under the same conditions, demonstrating the significant advantages of lipid-soluble derivatives in ocular applications.

[0014] Explanation of Concentration Selection and Safety Evaluation Through experiments, the inventors discovered that although tetraisopalmitate ascorbic acid has good lipid solubility, a balance between solubility and ocular tolerance is still necessary in ophthalmic formulations. High concentration warning (>2.0%): While theoretically highly effective at concentrations exceeding 2.0%, tetraisopalmitate ascorbic acid is acidic and may irritate the ocular surface at concentrations above 2.0%. Therefore, this invention recommends using concentrations below 2.0% to ensure long-term safety.

Claims

1. An ophthalmic composition containing tetraisopalmitate ascorbic acid Its features are, The composition comprises the following weight percentages: Tetraisopalmitate ascorbic acid: 0.1%-2.0% (w / v); Co-solvent: 0.1%-5.0% (w / v); Sodium hyaluronate solution: balance; The pH value of the composition is 5.0-8.

0.

2. The ophthalmic composition according to claim 1 Its features are, The co-solvent is selected from one or more of anhydrous ethanol, propylene glycol, or polysorbate.

3. The ophthalmic composition according to claim 1 Its features are, The concentration of the tetraisopalmitate ascorbic acid is 0.5% (w / v).

4. The ophthalmic composition according to claim 1 Its features are, The pH value of the composition is 6.0-7.

5.

5. The ophthalmic composition according to claim 1 Its features are, The composition is a milky white suspension or microemulsion; phase separation occurs after standing, but it can be restored to a homogeneous state after shaking.

6. A method for preparing the ophthalmic composition according to any one of claims 1-5 Its features are, Includes the following steps: (1) Dissolve tetraisopalmitate ascorbic acid in a solubilizer, add it to sodium hyaluronate solution, and shake vigorously; (2) Adjust the pH value to 5.0-8.0 or not, and you will get the desired result.

7. The use of the ophthalmic composition according to any one of claims 1-5 in the preparation of the following products: (1) Drugs that improve ocular oxidative stress; (2) Drugs that relieve eye fatigue or dry eye; (3) Drugs that delay axial elongation or control myopia progression.