High-stability and low-irritation composition for eye diseases as well as preparation method and application of high-stability and low-irritation composition

Abstract

The invention relates to a high-stability and low-irritation composition for eye diseases as well as a preparation method and application of the high-stability and low-irritation composition. The composition comprises the following components in percentage by weight: 0.01%-0.2% of cyclosporin, 0.5%-10% of an oil phase, 0.05%-0.5% of cationic lipid, 0.1%-3.0% of an emulsifier, 0.1%-5.0% of a stability enhancer, 0.3%-3.0% of an osmotic pressure regulator and the balance of water. The innovation points are as follows: 1, the cyclosporin is embedded into an oil phase by adopting the oil-in-water nano emulsion, so that hydrolysis is avoided; meanwhile, trehalose or sodium mannose phosphate is added to inhibit drug degradation. 2, net positive charges are given to the emulsion through stearylamine or oleylamine, electrostatic adsorption with ocular surface anionic mucosa is enhanced, and the dwell time of a tear film is prolonged; and 3, poloxamer 188 is used for replacing a traditional preservative and is combined with natural anti-inflammatory components, so that the risk of corneal epithelium injury is reduced. Experiments show that the six-month drug retention rate of the composition in an acceleration test at 40 DEG C is greater than 95%, the irritation score of rabbit eyes is less than or equal to level 1, and the effective rate of treating xerophthalmia is increased by 25% compared with that of commercially available cyclosporin emulsion.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a highly stable, low-irritant composition for eye diseases, its preparation method, and its uses. Background Technology

[0002] Dry eye syndrome (xeorphobia), also known as keratoconjunctivitis sicca, is a common ophthalmic disease that primarily affects women aged 40-50. It is caused by various ocular and / or systemic factors (such as ocular surface dysfunction, eye trauma, diabetes, inflammation, etc.) leading to insufficient lacrimal secretion, resulting in abnormal tear film and dry ocular epithelial changes. Initial clinical manifestations of dry eye syndrome include a foreign body sensation, dryness, itching, burning, photophobia, blurred vision, eye strain, indescribable discomfort, and intolerance to smoky or dusty environments. These symptoms worsen as the disease progresses, eventually leading to corneal ulcers and even blindness.

[0003] The main treatments for dry eye syndrome currently available are medication and surgery. Medication treatment primarily includes tear replacement drugs, tear secretion stimulants, and drugs that address the underlying cause.

[0004] Cyclosporine is a novel, potent immunosuppressant characterized by its high efficacy and low toxicity. It inhibits the proliferation of T and B lymphocytes and selectively affects the immune system, achieving immunosuppression. Furthermore, cyclosporine possesses various physiological activities, including anti-inflammatory, anti-infective, and antifungal effects. Restasis (0.05% cyclosporine), a product using cyclosporine to treat dry eye, is the world's first drug to treat dry eye at its pathogenesis. It reduces ocular inflammation through its anti-inflammatory effects, thus achieving a therapeutic effect. However, Restasis has several side effects, the most common being a burning sensation in the eyes, occurring in 17% of cases. Other adverse reactions occur in 1% to 5% of cases, including conjunctival hyperemia, discharge, tearing, eye pain, foreign body sensation, itching, stinging, and visual disturbances.

[0005] Dry eye syndrome has a high incidence rate in my country, ranging from 21% to 52.4% in the general population. Sjögren's syndrome-associated dry eye (SSDE) is a particularly severe and progressive subtype of dry eye. As a chronic autoimmune disease, it is characterized by a higher incidence in women and progressive lacrimal gland atrophy, with patients experiencing far greater tear secretion dysfunction than other types of dry eye. Currently, the commonly used cyclosporine eye drops suffer from limited ocular absorption due to the tear film and corneal barrier, with even less reaching the lacrimal gland. Furthermore, persistent inflammation can lead to glandular atrophy, complicating drug accumulation within the lacrimal gland.

[0006] Clinical needs and limitations of dry eye treatment: The incidence of dry eye (DED) in my country is 21%-30%, with more than 300 million patients, of which 90% are related to meibomian gland dysfunction (MGD). There are three major bottlenecks in existing treatment methods: (1) Poor stability: mainstream drugs such as cyclosporine and diquafosol sodium are easily hydrolyzed. For example, the bioavailability of aqueous cyclosporine preparations is <5%, and it needs to be refrigerated (shelf life ≤12 months); low concentration atropine eye drops need to be adjusted to pH 5.0 to delay degradation due to ester hydrolysis, but it is significantly irritating. (2) Short retention time on the ocular surface: traditional eye drops have a retention time of only 2-5 minutes due to tear flushing and blink reflex. Although the retention time can be extended by adding adhesives (such as polycarboxamide), the high viscosity leads to blurred vision and low patient compliance. (3) Irritation and side effects: Long-term use of eye drops containing preservatives (such as benzalkonium chloride) can damage the corneal epithelium; combined use of drugs (such as cyclosporine + glucocorticoids) increases the risk of infection and increased intraocular pressure.

[0007] Invention patent CN116672310A embeds easily hydrolyzable drugs into the oil phase (olive oil / castor oil) to form an oil-in-water nanoemulsion, significantly improving the stability of drugs such as atropine. However, this technology does not solve the problem of drug retention on the ocular surface, and olive oil may induce corneal epithelial keratosis.

[0008] There is an urgent need for a dry eye treatment composition that combines high stability (especially for hydrolyzable drugs), low irritation (avoiding damage from preservatives), and long-lasting retention (improving bioavailability). Summary of the Invention

[0009] To address the aforementioned problems, this invention proposes a highly stable, low-irritant composition for ocular diseases, its preparation method, and its uses. This invention overcomes the limitations of existing dry eye treatments by integrating nanoemulsion stabilization with cationic charge technology and introducing novel stabilizers and low-irritant components.

[0010] This invention first provides a highly stable, low-irritant composition for eye diseases, comprising the following components by weight percentage: cyclosporine 0.01-0.2%, oil phase 0.5-10%, cationic lipid 0.05-0.5%, emulsifier 0.1-3.0%, stabilizer 0.1-5.0%, osmotic pressure regulator 0.3-3.0%, natural anti-inflammatory agent 0.1%-0.5%, with the balance being deionized water;

[0011] The oil phase is castor oil or medium-chain triglycerides; the aqueous phase is a mixture of stabilizer, osmotic pressure regulator, natural anti-inflammatory agent, and deionized water, stirred and dissolved at 65°C.

[0012] The cationic lipid is stearylamine or oleylamine; the emulsifier is poloxamer 188; and the stabilizing agent is trehalose or sodium mannose phosphate.

[0013] Furthermore, the composition is an oil-in-water nanoemulsion with a particle size ≤200nm.

[0014] Furthermore, the weight ratio of the oil phase to the cationic lipid is (10-20):1.

[0015] Furthermore, the natural anti-inflammatory agent is aloe vera extract or grape seed oil.

[0016] Furthermore, the osmotic pressure regulator is a mixture of glycerol and mannitol in a 1:1 weight ratio.

[0017] The present invention also provides a method for preparing the composition, comprising the following steps:

[0018] (1) Dissolve the emulsifier and cationic lipid in the oil phase at 70-80℃;

[0019] (2) Dissolve the stability enhancer and osmotic pressure regulator in an aqueous phase at 60-70℃;

[0020] (3) Slowly add the oil phase to the aqueous phase and emulsify by high-speed shearing at a speed of 10,000-15,000 rpm for 5-10 minutes.

[0021] (4) The final material obtained in step (3) above is homogenized by high pressure microjets at a pressure ≥1500 bar and the pH is adjusted to 6.8-7.2.

[0022] (5) The composition homogenized by high pressure microfluidic jet in step (4) above is sterilized by 0.22 μm filter membrane and then packaged with nitrogen.

[0023] Furthermore, cyclosporine is added during emulsification in step (3), and the temperature is controlled to be ≤80℃.

[0024] Furthermore, after homogenization in step (4), the emulsion is rapidly cooled to 2-8°C to solidify the charge structure.

[0025] The application of a highly stable, low-irritant composition for eye diseases prepared in this invention in the preparation of drugs for treating dry eye syndrome.

[0026] Furthermore, the dry eye syndrome is either meibomian gland dysfunction (MGD) related type or Sjögren's syndrome related type (SSDE).

[0027] Furthermore, the drug is an eye drop or a microneedle patch carrier.

[0028] Technical effects of the present invention:

[0029] This invention significantly improves the safety and effectiveness of dry eye treatment through a triple synergistic mechanism:

[0030] 1. High stability: Cyclosporine is embedded in the oil phase (castor oil / medium-chain triglycerides) to avoid hydrolysis. Combined with the molecular shielding effect of trehalose / mannose phosphate sodium, the drug retention rate is >95% after 6 months of accelerated testing at 40℃, and the shelf life is extended to 24 months.

[0031] 2. Long-lasting retention: Cationic lipids (oleylamine / stearylamine) impart a net positive charge to the emulsion, with a particle size ≤200nm, enhancing electrostatic adsorption. The tear film retention time reaches 10-12 minutes, significantly increasing the amount of corneal drug penetration.

[0032] 3. Low irritation: Poloxamer 188 replaces benzalkonium chloride as a preservative, combined with natural anti-inflammatory agents (aloe vera / grape seed oil), achieving a Draize score ≤1 (ISO standard), reducing the clinical burning sensation incidence to 3%. It has an efficacy rate of over 90% in treating MGD-type dry eye syndrome. Attached Figure Description

[0033] Figure 1 This is a flowchart illustrating a method for preparing a highly stable, low-irritation composition for eye diseases, according to an embodiment of the present invention. Detailed Implementation

[0034] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the respective manufacturers.

[0035] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in this invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of those skilled in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or identical to those described in the embodiments of this invention may be used to implement this invention.

[0036] Unless otherwise stated, the test methods, detection methods and preparation methods disclosed in this invention all adopt conventional techniques in this technical field.

[0037] Example 1

[0038] A highly stable, low-irritant composition for eye diseases comprises the following components in weight percentage: cyclosporine 0.05%, castor oil 2.5%, cationic lipid oleamine 0.2%, poloxamer 188 0.5%, trehalose (stabilizing agent) 1.0%, glycerol / mannitol (1:1) (osmotic pressure regulator) 1.5%, aloe vera extract (natural anti-inflammatory agent) 0.2%, and deionized water as the balance.

[0039] Preparation method:

[0040] (1) Oil phase: Take 2.5g of castor oil and heat it in a water bath at 70℃;

[0041] (2) Add 0.2g of oleylamine and 0.5g of poloxamer 188 to the oil phase and stir to dissolve;

[0042] (3) Aqueous phase: 1.0 g of trehalose, 0.75 g of glycerol, 0.75 g of mannitol, and 0.2 g of aloe vera extract were dissolved in deionized water at 60 °C;

[0043] (4) Slowly inject the oil phase into the aqueous phase and shear at 12,000 rpm for 8 minutes;

[0044] (5) Add 0.05g of cyclosporine and homogenize under high pressure at 1600 bar;

[0045] (6) Adjust the pH to 7.0, cool rapidly to 5°C, and sterilize with a 0.22μm filter membrane.

[0046] The preparation method process is as follows: Figure 1 As shown.

[0047] Example 2

[0048] A highly stable, low-irritant composition for eye diseases comprises the following components in weight percentage: cyclosporine 0.2%, medium-chain triglycerides 5.0%, stearamide 0.4%, poloxamer 188 1.0%, sodium mannophosphate 2.5%, glycerol / mannitol (1:1) 2.0%, grape seed oil 0.3%, and deionized water as balance; the preparation steps are the same as in Example 1, and the homogenization pressure is 1800 bar.

[0049] Comparative Example 1

[0050] The main characteristic difference between Comparative Example 1 and Example 1 is the absence of natural anti-inflammatory agents.

[0051] A highly stable, low-irritant composition for eye diseases comprises the following components in weight percentages: cyclosporine 0.1%, castor oil 3.0%, oleylamine 0.3%, poloxamer 188 0.8%, trehalose 1.5%, glycerol / mannitol (1:1) 1.8%, and deionized water as balance. Natural anti-inflammatory agents are omitted; the remainder is the same as in Example 1.

[0052] Comparative Example 2

[0053] Compared with Example 1, the main characteristic difference of Comparative Example 2 is that it is free of cationic lipids.

[0054] Comparative Example 3

[0055] Compared with Example 1, the main characteristic difference of Comparative Example 3 is that it does not contain trehalose and is replaced by sucrose.

[0056] Comparative Example 4

[0057] Compared with Example 1, the main characteristic difference of Comparative Example 4 is that it contains 0.01% benzalkonium chloride (BAC), which removes the antibacterial function of poloxamer 188.

[0058] Comparative Example 5

[0059] Compared with Example 1, the main characteristic difference of Comparative Example 5 is that the commercially available product directly uses commercially available... (0.05% cyclosporine emulsion, containing castor oil and 0.005% BAC).

[0060] Test items and results

[0061] Testing standards:

[0062] Stability: Accelerated test at 40℃ / 75% RH for 6 months (ICH Q1A);

[0063] Retention time: Determination of the tear film half-life in rabbits by fluorescence tracer method (ISO 11978);

[0064] Irritation: Rabbit corneal Draize score (0-4, ISO 10993-10);

[0065] Efficacy: Tear film breakup time (TBUT) and corneal staining score (Oxford scale) in a rabbit model of dry eye.

[0066] Test items: Tests of relevant indicators of the compositions for ocular diseases prepared in the above embodiments and comparative examples.

[0067] Table 1. Drug retention rate, tear film retention time (min), Draize score, TBUT (s), and efficacy test results of the above-mentioned pharmaceutical compositions for treating ocular diseases in the examples and comparative examples.

[0068]

[0069] Analysis of Table 1 shows that, comparing Example 1 and Example 2, Example 1 is superior to Example 2. The possible reasons are: 1. Drug concentration and oil phase type: The cyclosporine concentration in Example 2 (0.2%) is four times that in Example 1 (0.05%). Higher drug concentrations may increase the density of drug molecules on the surface of the droplets, slightly reduce charge uniformity, and weaken electrostatic adsorption. The cyclosporine concentration in Example 2 (0.2%) is also four times that in Example 1 (0.05%), which may promote drug molecule aggregation, increase particle size, and reduce the contact area with the ocular surface. MCT replaces castor oil: Medium-chain triglycerides (MCT) have lower viscosity than castor oil, shortening the tear film lipid layer maintenance time. The hydroxyl groups in castor oil can enhance hydrogen bonding with ocular surface mucins. 2. Differences in anti-inflammatory agents: Example 1 used aloe vera extract (mucopolysaccharide for corneal repair), while Example 2 used grape seed oil (proanthocyanidins for anti-inflammation but without adhesiveness), leading to differences in corneal repair efficiency. 3. Process parameters: The homogenization pressure in Example 2 is higher (1800 bar), which may damage a small amount of the emulsion droplet interface membrane structure and slightly increase irritation.

[0070] Compared with Comparative Example 2, the tear film retention time was shortened by 62.8%, proving that charge adsorption is the key long-acting mechanism. The possible reasons are: (1) loss of charge mechanism: Comparative Example 1 lacks oleamine (cationic lipid), and the electrostatic adsorption force disappears, resulting in the tear film being cleared by blink reflex. (2) reduced drug penetration: cationic lipids can promote the transcorneal transport of cyclosporine.

[0071] Comparing Example 1 with Comparative Example 3, it is shown that the lack of trehalose increases the drug degradation rate by 14.4%; the advantage of no preservative (Comparative Example 3): BAC makes the Draize score reach 3.2 (unacceptable irritation); the possible reasons are: (1) failure of molecular shielding: sucrose cannot form a glassy protective layer of trehalose, which leads to the exposure of cyclosporine ester bonds to the aqueous phase, and the hydrolysis rate is accelerated; (2) oxidation risk: the lack of antioxidant effect of trehalose increases the peroxide value of castor oil, which exacerbates irritation.

[0072] Compared to Comparative Example 4, Example 1 scored higher on the Draize test. The incidence of burning sensation was 3% in Example 1 and 21% in Comparative Example 4. Therefore, the composition prepared in Example 1 is gentler and less irritating to the skin around the eyes. This may be because benzalkonium chloride (BAC) dissolves phospholipids in the corneal epithelial cell membrane (disrupting tight junctions), leading to abnormally increased corneal permeability; exposure of nerve endings triggers the burning sensation.

[0073] Compared with Comparative Example 1 and Comparative Example 5, the present invention comprehensively surpasses commercially available products in terms of stability, safety, and efficacy. The possible reasons are: Restasis is a conventional emulsion (particle size > 500 nm), which cannot effectively embed into the microfolds of the ocular surface; it contains castor oil but has no cationic lipids, resulting in a neutral charge (ζ potential ≈ 0) and no electrostatic adsorption; and it uses benzalkonium chloride as a preservative (0.005%), which accumulates toxicity and leads to chronic inflammation.

[0074] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention and not to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A highly stable, low-irritation composition for eye diseases, characterized in that, The composition comprises the following components by weight percentage: cyclosporine 0.01-0.2%, oil phase 0.5-10%, cationic lipids 0.05-0.5%, emulsifier 0.1-3.0%, stabilizer 0.1-5.0%, osmotic pressure regulator 0.3-3.0%, natural anti-inflammatory agent 0.1%-0.5%, with the balance being deionized water; the composition is an oil-in-water nanoemulsion with a particle size ≤200nm.

2. The highly stable, low-irritation composition for eye diseases according to claim 1, characterized in that: The weight ratio of the oil phase to the cationic lipid is (10-20):1; the oil phase is castor oil medium-chain triglycerides; the aqueous phase is a mixture of stabilizer, osmotic pressure regulator, natural anti-inflammatory agent, and deionized water.

3. The highly stable, low-irritation composition for eye diseases according to claim 1, characterized in that: The cationic lipid is stearylamine or oleylamine; the emulsifier is poloxamer 188; the stabilizer is trehalose or sodium mannose phosphate; and the natural anti-inflammatory agent is aloe vera extract or grape seed oil.

4. The highly stable, low-irritation composition for eye diseases according to claim 1, characterized in that: The osmotic pressure regulator is a mixture of glycerol and mannitol in a 1:1 weight ratio.

5. A highly stable, low-irritation composition for eye diseases according to any one of claims 1-4, characterized in that, The method for preparing the composition includes the following steps: (1) Dissolve the emulsifier and cationic lipid in the oil phase at 70-80℃; (2) Dissolve the stability enhancer and osmotic pressure regulator in an aqueous phase at 60-70℃; (3) Slowly add the oil phase to the aqueous phase and emulsify by high-speed shearing at a speed of 10,000-15,000 rpm for 5-10 minutes to form a crude emulsion; (4) The crude emulsion obtained in step (3) above is homogenized by high pressure microjet, with a pressure ≥1500 bar, and the pH is adjusted to 6.8-7.2; (5) The composition homogenized by high pressure microjet in step (4) above is sterilized by a 0.22μm filter membrane and then packaged with nitrogen.

6. The method for preparing a highly stable, low-irritation composition for eye diseases according to claim 5, characterized in that: In step (3), cyclosporine is added during emulsification, and the temperature is controlled to be ≤80℃.

7. The method for preparing a highly stable, low-irritation composition for eye diseases according to claim 5, characterized in that: After homogenization in step (4), the emulsion is rapidly cooled to 2-8°C to solidify the charge structure.

8. The use of the highly stable, low-irritant composition for eye diseases according to any one of claims 1-4 in the preparation of a medicament for treating dry eye syndrome.

9. The application according to claim 8, characterized in that, The dry eye syndrome is either meibomian gland dysfunction (MGD) related type or Sjögren's syndrome related type (SSDE).

10. The application according to claim 8, characterized in that: The drug is an eye drop or a microneedle patch carrier.

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