An aqueous ophthalmic temperature-sensitive gel for treating myopia and a preparation method thereof
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NANJING ZEQING PHARM TECH CO LTD
- Filing Date
- 2026-04-09
- Publication Date
- 2026-06-05
AI Technical Summary
Existing pirenzepine eye drops have problems such as low bioavailability, poor medication adherence, and insufficient safety and comfort in the treatment of myopia in children. In particular, traditional gel formulations have defects in terms of difficulty in instillation, blurred vision, and preservative toxicity. Furthermore, there are no reports on the application of thermosensitive gel technology in pirenzepine.
To develop an aqueous ophthalmic thermosensitive gel containing pirenzepine, a thermosensitive gel matrix, an osmotic pressure regulator, and a pH regulator, designed as a low-viscosity liquid at room temperature and rapidly forming a high-viscosity gel at ocular temperature, using poloxamer 407 and poloxamer 188 as the thermosensitive gel matrix, and adding sodium chloride and other substances to adjust the osmotic pressure and pH value to ensure the stability and safety of the formulation at body temperature.
It achieves smooth eye drops, accurate dosage, long-lasting retention time, reduced dosing frequency, improved bioavailability, avoidance of preservative toxicity, improved medication compliance and comfort, and enhanced myopia treatment efficacy.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention relates to the technical field of pharmaceutical preparations, and in particular to an aqueous ophthalmic thermosensitive gel for treating myopia and its preparation method. Background Technology
[0002] Myopia, especially pediatric myopia, has become an increasingly serious global public health problem. Its pathological characteristics mainly include excessive elongation of the eye axis, causing light to focus in front of the retina, resulting in blurred vision. Without effective intervention, moderate to high myopia significantly increases the risk of developing blinding eye diseases such as retinal diseases, glaucoma, and macular degeneration.
[0003] In the field of drug therapy, muscarinic receptor antagonists have been proven to effectively slow the progression of myopia. Among them, pirenzepine, as a relatively selective M1 receptor antagonist, has shown an effect comparable to atropine in inhibiting axial elongation, but avoids the serious side effects inherent in atropine, such as pupil dilation and accommodation paralysis. Therefore, it is considered a more promising pediatric myopia treatment drug for clinical application.
[0004] However, successfully transforming pirenzepine into an ideal medication for patients, especially children, still faces significant challenges. First, current pirenzepine aqueous solution eye drops have a very short residence time on the ocular surface, resulting in low bioavailability and requiring multiple daily doses. This leads to poor medication adherence in children requiring long-term treatment, severely impacting efficacy. Second, studies have indicated that pirenzepine slowly degrades in aqueous solutions, particularly under its most stable pH conditions, producing insoluble impurities. Even trace accumulations can affect the clarity and appearance of the solution, reducing patient acceptance.
[0005] To improve retention time, existing technologies attempt to formulate pirenzepine into a gel form. For example, some formulations use water-soluble cellulose derivatives (such as hydroxypropyl methylcellulose) as the gel matrix, using high viscosity to prolong drug contact time. However, such conventional gels are highly viscous before administration, making instillation difficult and causing high resistance in children; after instillation, they may cause persistent blurred vision and foreign body sensation, affecting learning and activities. In addition, to meet the need for multiple doses, these formulations usually require the addition of preservatives (such as benzalkonium chloride), and long-term use of preservatives can damage the delicate ocular surface of children, causing drug toxicity reactions such as dry eye.
[0006] On the other hand, although thermosensitive in-situ gel technology has been explored in other ophthalmic medication fields, its application in pirenzepine for pediatric myopia treatment has not been reported, and there are technical barriers. An ideal thermosensitive gel for children needs to have a sufficiently low viscosity (e.g., <1000 mPa·s) at room temperature (approximately 25°C) to ensure smooth instillation and accurate dosage; and at ocular surface temperature (approximately 34°C), it should rapidly transform into a gel of sufficient strength (viscosity >10000 mPa·s) to achieve long-lasting retention. Existing technologies struggle to achieve this significant "liquid-gel" transformation while ensuring the sterility, stability, and ultimate safety and comfort for pediatric use.
[0007] Therefore, there is an urgent need in this field to develop a novel ophthalmic formulation of pirenzepine to address issues of medication adherence, safety, and comfort. Summary of the Invention
[0008] To improve the convenience, long-lasting release, safety, and comfort of long-term treatment of myopia in children, this application provides an aqueous ophthalmic thermosensitive gel for treating myopia and its preparation method.
[0009] Firstly, this application provides a water-based, temperature-sensitive ophthalmic gel for treating myopia, employing the following technical solution: A water-based ophthalmic thermosensitive gel for treating myopia comprises pirenzepine, a thermosensitive gel matrix, an osmotic pressure regulator, a pH regulator, and an aqueous solvent; the water-based ophthalmic thermosensitive gel for treating myopia has a viscosity of less than 1000 mPa·s at 25°C and a viscosity of greater than 10000 mPa·s at 34°C.
[0010] In one specific feasible implementation, the concentration of pirenzepine is 1-5% (w / v) based on the total weight of the aqueous ophthalmic thermosensitive gel used to treat myopia.
[0011] In one specific feasible implementation, the concentration of pirenzepine is 2% (w / v) based on the total weight of the aqueous ophthalmic thermosensitive gel used to treat myopia.
[0012] In one specific implementation, the thermosensitive gel matrix is poloxamer.
[0013] In one specific implementation, the thermosensitive gel matrix comprises poloxamer 407 and poloxamer 188, wherein, based on the total weight of the aqueous ophthalmic thermosensitive gel for treating myopia, the concentration of poloxamer 407 is 15-20% (w / v) and the concentration of poloxamer 188 is 0-10% (w / v).
[0014] In one specific implementation, the gelation temperature of the thermosensitive gel matrix is 25-34°C.
[0015] In one specific implementation, the osmotic pressure regulator is selected from one or more of sodium chloride, boric acid, sodium acetate, and sodium borate.
[0016] In one specific implementation, the pH adjuster is selected from one or more of hydrochloric acid, boric acid, and sodium hydroxide; the pH of the aqueous ophthalmic thermosensitive gel for treating myopia is 5.0-7.0.
[0017] Secondly, this application provides a method for preparing an aqueous ophthalmic thermosensitive gel for treating myopia, which adopts the following technical solution: A method for preparing the above-mentioned aqueous ophthalmic thermosensitive gel for the prevention or treatment of myopia in children includes the following steps: mixing the pirenzepine, thermosensitive gel matrix, osmotic pressure regulator and water evenly, performing aseptic treatment and filling, thereby obtaining the aqueous ophthalmic thermosensitive gel for the prevention or treatment of myopia in children.
[0018] In summary, this application has the following beneficial effects: 1. Improve medication adherence: Through thermosensitive gel technology, the formulation is a low-viscosity liquid when instilled into the eye at room temperature, making it easy to instill accurately. It can also quickly form a gel on the ocular surface (at body temperature), realizing a smart "liquid-gel" phase transition. This not only greatly facilitates drug administration, but more importantly, it significantly prolongs the drug's residence time in the eye, achieving long-acting sustained release. It is expected to reduce the frequency of administration from several times a day to once or twice a day, thus reducing the daily dosing frequency and greatly improving the feasibility of long-term medication in children.
[0019] 2. Enhanced efficacy and safety: By prolonging the retention time on the ocular surface, the bioavailability of the drug is improved, which is expected to enhance the effect of controlling myopia progression. At the same time, the formulation can be designed as a single-dose sterile package, eliminating the need for preservatives and fundamentally avoiding the potential toxicity of preservatives to the ocular surface in children.
[0020] 3. Improved medication comfort: The liquid is low-viscosity before instillation, ensuring smooth and accurate dosage; after instillation, it forms a gel, resulting in minimal foreign body sensation and high acceptance by children. This solves the problems of difficulty in administering traditional high-viscosity gel eye drops and initial blurred vision, providing a better medication experience. Detailed Implementation
[0021] The present application will be further described in detail below with reference to the embodiments.
[0022] Example Example 1
[0023] This embodiment provides an aqueous ophthalmic thermosensitive gel for treating myopia, the components of which per 100g are shown in Table 1.
[0024] This embodiment also provides a method for preparing an aqueous ophthalmic thermosensitive gel for treating myopia, comprising the following steps: Cool 60g of water for injection to 4°C, add poloxamer 407 and poloxamer 188 sequentially while stirring at 500rpm, and continue stirring for 30 minutes to obtain a milky white dispersion. Let it stand at a constant temperature of 4°C for more than 12 hours to obtain a clear and viscous poloxamer stock solution.
[0025] Take 20g of water for injection, add sodium chloride and pirenzepine, and stir continuously until completely dissolved. Then, add poloxamer stock solution while stirring at 400rpm, mix well, adjust the pH to 6.0±0.1 with 1M hydrochloric acid solution and 1M sodium hydroxide solution, add water for injection to a total weight of 100g, and continue stirring for 1 hour until the system is completely homogeneous. Then, after pressure sterile filtration through a PES membrane with a pore size of 0.22μm, fill the filtrate into single-dose ophthalmic ampoules under Class A sterile conditions, with each ampoule containing 0.4mL, and heat-seal to obtain an aqueous ophthalmic thermosensitive gel for the treatment of myopia.
[0026] Table 1 Example 2
[0027] The only difference between this embodiment and Embodiment 1 is that the aqueous ophthalmic thermosensitive gel for treating myopia in this embodiment contains the components shown in Table 2 per 100g.
[0028] Table 2 Example 3
[0029] The only difference between this embodiment and Embodiment 1 is that the aqueous ophthalmic thermosensitive gel for treating myopia in this embodiment comprises the components shown in Table 3 per 100g. In the preparation method, the pH is adjusted to 5.8 ± 0.1 using a 1M hydrochloric acid solution and a 1M sodium hydroxide solution.
[0030] Table 3 Example 4
[0031] The only difference between this embodiment and Example 1 is that the aqueous ophthalmic thermosensitive gel for treating myopia in this embodiment comprises the components shown in Table 4 per 100g. In the preparation method, 20g of water for injection is taken, and boric acid, sodium borate, and pirenzepine are added. After continuous stirring until completely dissolved, the solution is added to poloxamer stock solution while stirring at 400rpm. The mixture is then stirred until homogeneous, and the pH is adjusted to 7.0±0.1 using 1M hydrochloric acid solution and 1M sodium hydroxide solution. Water for injection is added to a total weight of 100g, and stirring is continued for 1 hour until the system is completely homogeneous.
[0032] Table 4 Example 5
[0033] The only difference between this embodiment and Embodiment 1 is that the aqueous ophthalmic thermosensitive gel for treating myopia in this embodiment contains the components shown in Table 5 per 100g.
[0034] Table 5 Performance testing For Examples 1-5, the following performance tests were performed: Gelation temperature: Using a rheometer (Harker MARS series), at a heating rate of 1℃ / min and a shear rate of 10s, the gelation temperature was determined. -1 The gelation temperature (G) of the aqueous ophthalmic thermosensitive gels for treating myopia prepared in each embodiment was determined under the specified conditions. ‘ =G ’’ (Points). The test results are shown in Table 6.
[0035] Viscosity: The viscosity (mPa·s) of the aqueous ophthalmic thermosensitive gels prepared in each example for treating myopia was measured at 25°C and 34°C using a cone-plate viscometer. The test results are shown in Table 6.
[0036] Osmotic molar concentration: The osmotic molar concentration (mOsm / kg) of the aqueous ophthalmic thermosensitive gels prepared in each example for treating myopia was measured using an osmotic molar concentration meter (FPOSM-V2.0). The test results are shown in Table 6.
[0037] In vitro release: The Franz diffusion cell method was used, with phosphate buffer solution at pH 7.4 as the release medium. The release of the aqueous ophthalmic thermosensitive gels prepared in each example for treating myopia was detected in vitro at 4 h and 8 h. The test results are shown in Table 6.
[0038] Accelerated stability testing: Three batches of samples prepared in Example 1 (batch numbers: FMS-240301, FMS-240302, FMS-240303) were used. Following ICH guidelines, the samples were placed in a stability test chamber at 40℃±2℃ / 75%RH±5%RH, and samples were taken for testing at the end of month 0 and month 3. The test results are shown in Table 7.
[0039] Table 6 Table 7 This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.
Claims
1. A water-based thermosensitive ophthalmic gel for treating myopia, characterized in that, It contains pirenzepine, a thermosensitive gel matrix, an osmotic pressure regulator, a pH regulator, and an aqueous solvent; the aqueous ophthalmic thermosensitive gel for treating myopia has a viscosity of less than 1000 mPa·s at 25°C and a viscosity of greater than 10,000 mPa·s at 34°C.
2. The aqueous ophthalmic thermosensitive gel for treating myopia according to claim 1, characterized in that: The concentration of pirenzepine is 1-5% (w / v) based on the total weight of the aqueous ophthalmic thermosensitive gel used to treat myopia.
3. The aqueous ophthalmic thermosensitive gel for treating myopia according to claim 2, characterized in that: The concentration of pirenzepine is 2% (w / v) based on the total weight of the aqueous ophthalmic thermosensitive gel used to treat myopia.
4. The aqueous ophthalmic thermosensitive gel for treating myopia according to claim 1, characterized in that: The thermosensitive gel matrix is poloxamer.
5. The aqueous ophthalmic thermosensitive gel for treating myopia according to claim 4, characterized in that: The thermosensitive gel matrix includes poloxamer 407 and poloxamer 188, wherein, based on the total weight of the aqueous ophthalmic thermosensitive gel used to treat myopia, the concentration of poloxamer 407 is 15-20% (w / v) and the concentration of poloxamer 188 is 0-10% (w / v).
6. The aqueous ophthalmic thermosensitive gel for treating myopia according to claim 4, characterized in that: The gelation temperature of the thermosensitive gel matrix is 25-34℃.
7. The aqueous ophthalmic thermosensitive gel for treating myopia according to claim 1, characterized in that: The osmotic pressure regulator is selected from one or more of sodium chloride, boric acid, sodium acetate, and sodium borate.
8. The aqueous ophthalmic thermosensitive gel for treating myopia according to claim 1, characterized in that: The pH adjuster is selected from one or more of hydrochloric acid, boric acid, and sodium hydroxide; the pH value of the aqueous ophthalmic thermosensitive gel for treating myopia is 5.0-7.
0.
9. A method for preparing an aqueous ophthalmic thermosensitive gel for preventing or treating myopia in children as described in any one of 1-8 above, characterized in that, Includes the following steps: The pirenzepine, thermosensitive gel matrix, osmotic pressure regulator and water are mixed evenly, and then sterilely processed and filled to obtain an aqueous ophthalmic thermosensitive gel for the prevention or treatment of myopia in children.