阅读说明：本技术 一种眼用制剂及其制备方法和应用 (Eye preparation and preparation method and application thereof ) 是由 高子彬 张福云 张国刚 孟思 臧香环 付玉飞 黄德胜 李玲玲 霍月香 李硕 张惠 于 2019-12-23 设计创作，主要内容包括：本发明涉及药物制剂技术领域,具体公开一种眼用制剂及其制备方法和应用。本发明提供的眼用制剂的活性组分为可溶性环氧化物水解酶抑制剂t-AUCB,其可有效抑制可溶性环氧化物水解酶(sEH)的表达,降低视网膜中周细胞的丧失,改善微血管病变程度,从而达到防治糖尿病视网膜病变的目的。本发明提供的眼用制剂可将t-AUCB与药学上可接受的辅料制备成临床上所用的药物制剂,如滴眼剂、眼用膏剂或眼用凝胶剂等,实现眼部局部给药,有利于提高患者的用药顺应性,且本发明提供的眼用制剂的制备方法简单、可控性强,有利于实现工业化生产,在防治糖尿病视网膜病变领域具有广阔的应用前景。(The invention relates to the technical field of medicinal preparations, and particularly discloses an ophthalmic preparation as well as a preparation method and application thereof. The active component of the ophthalmic preparation provided by the invention is a soluble epoxide hydrolase inhibitor t-AUCB, which can effectively inhibit the expression of soluble epoxide hydrolase (sEH), reduce the loss of pericytes in retina and improve the degree of microvascular disease, thereby achieving the purpose of preventing and treating diabetic retinopathy. The ophthalmic preparation provided by the invention can be prepared into a clinically used pharmaceutical preparation such as eye drops, ophthalmic ointment or ophthalmic gel by using the t-AUCB and pharmaceutically acceptable auxiliary materials, realizes local administration to eyes, is favorable for improving the medication compliance of patients, has a simple preparation method and strong controllability, is favorable for realizing industrial production, and has wide application prospects in the field of preventing and treating diabetic retinopathy.)

1. An ophthalmic preparation, characterized in that the active ingredient of the ophthalmic preparation is a soluble epoxide hydrolase inhibitor t-AUCB.

2. The ophthalmic formulation of claim 1, further comprising a pharmaceutically acceptable excipient.

3. The ophthalmic formulation of claim 2, wherein the excipient comprises a surfactant or an inclusion material, and an osmotic pressure regulator and a pH regulator.

4. The ophthalmic formulation of claim 3, wherein the surfactant is at least one of Tween 80, span 80, polyoxyethylated castor oil, Poloxamer 122, Poloxamer 188, Poloxamer 237, Poloxamer 338, or Poloxamer 407, polyethylene glycol, or polyethylene glycol-12-hydroxystearate; and/or

The inclusion material is at least one of β -cyclodextrin, gamma-cyclodextrin, methyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, hydroxypropyl-gamma-cyclodextrin or sulfobutyl- β -cyclodextrin, and/or

The osmotic pressure regulator is at least one of sodium chloride, potassium chloride, sodium bisulfate or sodium citrate; and/or

The pH regulator is at least one of sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium citrate or citric acid.

5. The ophthalmic formulation according to any one of claims 1 to 4, wherein the dosage form of the ophthalmic formulation is an eye drop, an eye ointment or an ophthalmic gel.

6. The ophthalmic formulation of claim 5, wherein the dosage form of the ophthalmic formulation is an eye drop.

7. The ophthalmic formulation of claim 5, wherein the soluble epoxide hydrolase inhibitor t-AUCB is present in the ophthalmic formulation in an amount of 0.01 to 10 wt%.

8. The ophthalmic formulation of claim 7, wherein the soluble epoxide hydrolase inhibitor t-AUCB is present in the ophthalmic formulation in an amount of 0.05 to 1 wt%.

9. A process for the preparation of an ophthalmic formulation according to claim 6, characterized in that it comprises the following steps:

dissolving a surfactant or an inclusion material in water, uniformly mixing, adding an osmotic pressure regulator, regulating the osmotic pressure to be 280-330mOsm/Kg, adding a soluble epoxide hydrolase inhibitor t-AUCB, uniformly mixing, adding a pH regulator, and regulating the pH to be 5.0-9.0 to obtain the ophthalmic preparation.

10. An ophthalmic formulation according to any one of claims 1 to 8 for use in the treatment of diabetic retinopathy.

Technical Field

The invention relates to the technical field of medicinal preparations, in particular to an ophthalmic preparation and a preparation method and application thereof.

Background

Diabetic Retinopathy (DR) belongs to microangiopathy, is one of the most common and serious chronic complications of diabetes, and has become an important cause of blindness in the world at present. The basic pathological changes are destruction of the retinal blood-retinal barrier and formation of retinal neovessels, macular edema, and finally retinal detachment, leading to blindness. Currently, the clinical means for treating diabetic retinopathy are mainly: intravitreal injection of angiogenic growth factor inhibitors and laser photocoagulation. Intraocular injection of the angiogenesis factor inhibitor is inconvenient, and frequent intravitreal injection of the drug can cause local complications such as uveitis, cataract, retinal detachment and intraocular infection; laser photocoagulation may damage a part of normal retinal tissue during the operation, thereby causing visual field defects, and also easily causing local damage during the operation, resulting in retinal edema or iatrogenic retinal holes, with certain risks. Therefore, the treatment of diabetic retinopathy remains challenging, and exploring entirely new treatment modalities becomes a new direction of research.

Disclosure of Invention

Aiming at the problems of more complications and inconvenient treatment and medication in the existing treatment method of diabetic retinopathy, the invention provides an ophthalmic preparation, a preparation method and application thereof.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

an ophthalmic preparation contains soluble epoxide hydrolase inhibitor t-AUCB as active ingredient.

The soluble epoxide hydrolase inhibitor t-AUCB is collectively referred to as trans-4- [4- (3-adaman-1-yl-ureido) -cyclohexyloxy ] -benzoic-acid.

Preferably, the ophthalmic preparation further comprises pharmaceutically acceptable excipients.

Preferably, the auxiliary materials comprise a surfactant or an inclusion material, an osmotic pressure regulator and a pH regulator.

Preferably, the surfactant is at least one of tween 80, span 80, polyoxyethylene castor oil, poloxamer 122, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407, polyethylene glycol or polyethylene glycol-12-hydroxystearate.

Preferably, the inclusion material is at least one of β -cyclodextrin, gamma-cyclodextrin, methyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, hydroxypropyl-gamma-cyclodextrin or sulfobutyl- β -cyclodextrin.

the t-AUCB has low solubility, and the effective content of the t-AUCB is difficult to achieve when the t-AUCB is used as an external preparation.

Preferably, the osmotic pressure regulator is at least one of sodium chloride, potassium chloride, sodium bisulfate or sodium citrate.

The dosage of the osmotic pressure regulator is based on regulating the osmotic pressure to 280-330 mOsm/Kg.

Preferably, the pH adjuster is at least one of sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium citrate, or citric acid.

The dosage of the pH regulator is based on the regulation of pH to 5.0-9.0.

The pharmaceutically acceptable auxiliary materials can be the conventional medicinal auxiliary materials in the field, and the specific types of the selected surfactant, inclusion material, osmotic pressure regulator or pH regulator do not have obvious influence on the treatment effect of the eye preparation.

Preferably, the dosage form of the ophthalmic preparation is eye drops, eye ointment or ophthalmic gel.

More preferably, the dosage form of the ophthalmic preparation is eye drops.

Preferably, the soluble epoxide hydrolase inhibitor t-AUCB is present in the ophthalmic formulation in an amount of 0.01 to 10% by weight.

More preferably, the ophthalmic formulation has a soluble epoxide hydrolase inhibitor t-AUCB content of 0.05 to 1 wt%.

The treatment effect and the cost are comprehensively considered, and the content of the soluble epoxide hydrolase inhibitor is selected to be 0.05-1 wt%, so that the better treatment effect can be achieved, and the production cost can be reduced.

The invention also provides a preparation method of the ophthalmic preparation, which comprises the following steps:

dissolving a surfactant or an inclusion material in water, uniformly mixing, adding an osmotic pressure regulator, regulating the osmotic pressure to be 280-330mOsm/Kg, adding a soluble epoxide hydrolase inhibitor t-AUCB, uniformly mixing, adding a pH regulator, and regulating the pH to be 5.0-9.0 to obtain the ophthalmic preparation. The ophthalmic preparation obtained by the preparation was placed in an eye drop bottle and stored at 4 ℃.

The invention also provides the application of the ophthalmic preparation in treating diabetic retinopathy.

The active component of the ophthalmic preparation provided by the invention is a soluble epoxide hydrolase inhibitor (t-AUCB), which can effectively inhibit the expression of soluble epoxide hydrolase (sEH), reduce the loss of pericytes in retina and improve the degree of microvascular disease, thereby achieving the purpose of preventing and treating diabetic retinopathy. The ophthalmic preparation provided by the invention can be prepared into a clinically used pharmaceutical preparation such as eye drops, ophthalmic ointment or ophthalmic gel by using the t-AUCB and pharmaceutically acceptable auxiliary materials, realizes local administration to eyes, is favorable for improving the medication compliance of patients, has a simple preparation method and strong controllability, is favorable for realizing industrial production, and has wide application prospects in the field of preventing and treating diabetic retinopathy.

Drawings

FIG. 1 is a graph comparing sEH activity in retinas of various groups of rats in a pharmacodynamic study of the invention;

FIG. 2 is a photomicrograph of a retinal vessel digest replicate of rats of the model group in the pharmacodynamic study of the present invention;

FIG. 3 is a graph comparing the number of retinal capillary free pericytes/total pericytes in various groups of rats in the pharmacodynamic study of the present invention;

FIG. 4 is a graph comparing the total pericyte count ^ 10^ 5/capillary area of retinal capillaries in various groups of rats in the pharmacodynamic study of the invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

In order to better illustrate the invention, the following examples are given by way of further illustration.