TW201417818A - Triamcinolone acetonide ophthalmic preparation and preparation method thereof - Google Patents

Abstract

A triamcinolone acetonide ophthalmic preparation and preparation method thereof. The main components of the preparation in percentage by weight are: 0.05% to 0.5% of triamcinolone acetonide, 0.1% to 0.9% of sodium chloride, 1.0% to 5.0% of hydroxypropyl methyl cellulose, 0.05% to 0.2% of polysorbate 80, and an appropriate amount of buffer solution and sterile purified water. The preparation can also comprise preservative and/or boric acid. The preparation method is as follows: sterilized triamcinolone acetonide and polysorbate 80 are mixed evenly, and an appropriate amount of sterile purified water is added to produce a suspension; all components except hydroxypropyl methyl cellulose are added to sterile purified water to obtain a solution after an appropriate amount of dissolution; the produced suspension and solution are mixed evenly and sterilized, and then mixed evenly with a hydroxypropyl methyl cellulose solution; sterile purified water is added such that sterile purified water accounts for 90% of the liquid volume; pH value is adjusted; sterile purified water is used to dilute and fix the volume of the solution.

Description

Triamcinolone acetonide ophthalmic preparation and preparation method thereof

The present invention relates to an ophthalmic preparation, in particular to an ophthalmic preparation containing triamcinolone acetonide for treating ophthalmic diseases, and to a preparation method of the ophthalmic preparation.

The eyes are the windows of the human mind and are extremely sensitive organs. Vision is not only related to everyone's study, work and life, but has also become a topic of particular concern to modern society and families. According to relevant information, the high incidence of ophthalmic diseases in China is mainly myopia, trachoma, conjunctivitis, keratitis, cataract, retinopathy, etc. The use rate of ophthalmic drugs has reached 32%, and the number of visual fatigue has reached 150 million. The pharmaceutical market accounts for more than 70% of the market. A study from the United States indicates that the global ophthalmic drug market in 2010 is expected to reach more than $15 billion, driven by new formulations. In the past three years, the incidence rate of eye diseases in China in the past two years was about 2.5%. Every half month, there were nearly 3 million eye disease patients seeking medical treatment in the country. With the growth of population, the popularization of modernization tools and the arrival of an aging society. The sensory drug market has developed rapidly.

Ophthalmology is an independent system formed naturally in medicine. The therapeutic drugs also have certain special characteristics. In terms of dosage form, the basic drugs mainly consist of eye drops and eye ointments. Statistics show that: up to now, there are more than 150 kinds of ophthalmic drugs approved by China for research and development, and more than 90 kinds of drugs have entered the hospital market with the main pipeline, accounting for more than 80%; the production approval issued by SFDA has been With more than 1,400, these products have become the mainstay of the ophthalmology market.

Triamcinolone acetonide (TA) is a long-acting adrenal glucocorticoid, also known as triamcinolone acetonide, acetonide, and Corning ketone-A. It is mainly used in various allergic diseases of the respiratory tract and skin system. Rheumatoid arthritis, rheumatoid arthritis, etc. from It was applied to ophthalmology in the 1980s and has since been widely used in vitreoretinal diseases. As a class of hormones, TA has the following main pharmacological effects: it can inhibit cellular immunity, reduce the expansion of cancer and early capillary, maintain capillary permeability, stabilize the blood-water barrier, and limit fibrin exudation and inhibition. Fibroblast differentiation, proliferation of pigment epithelial cells; at the same time, induces vascular epithelial cell function changes or death by inhibiting the transformation of extravascular matrix, or indirectly promotes the formation of anti-angiogenic stimulation factors for cancer cells, and prevents macrophages and hypertrophy The migration of cells inhibits heparin, growth factors, etc., and promotes the activity of angiogenesis-related factors, thereby preventing the formation of new blood vessels. Due to these characteristics of triamcinolone acetonide, intravitreal injection of triamcinolone acetonide is often used clinically to control inflammation of the retina, uvea and optic nerve, inhibit proliferative vitreoretinopathy and neovascularization of the optic membrane, choroid, and iris. Treatment of macular edema caused by various lesions.

Proliferative vitreoretinopathy (PVR) is the main reason for the failure of rhegmatogenous retinal detachment surgery. The pathogenesis is retinal detachment caused by contraction and stretching of extensive fibrous proliferative membrane on the surface of the retina and vitreous. According to clinical data, the incidence rate is about 10%. Macular edema is a well-recognized refractory disease in the ophthalmology field. It refers to the inflammatory reaction, fluid infiltration, and edema of the macular area of the retina of the fundus, which causes the vision to be seriously degraded. It is an ocular manifestation of various eye diseases such as central retinal vein occlusion, diabetic retinopathy, central serous chorioretinopathy, and uveitis. Usually caused by diabetes, retinal vein occlusion, uveitis, cataract surgery and other reasons, it is one of the important causes of vision loss. Triamcinolone acetonide is its main therapeutic drug.

Through the patent library data search, there is a patent "Triamcinolone acetonide and anecoxime acetate injection preparation", the patent number is: CN200480026439.6, which discloses injectable triamcinolone acetonide or anacetamide acetate composition. The composition is particularly suitable for injection into the posterior segment of the eye To treat eye diseases. Patent "Local treatment for the eye, and preferably comprising a combination of triamcinolone acetonide and hyaluronic acid", patent number CN200580002777.0, provides a composition and a method of using the same for injection into a human Or the posterior section of the animal's eye. The composition includes small particles of a less soluble therapeutic agent that promotes the formation of a therapeutic agent that is more concentrated in the retinal pigment epithelium of the eye. The particles are formed by combining a therapeutic agent with an ophthalmic polymer component. The size of the particles is less than about 3000 nanometers, and in some cases, less than about 200 nanometers. One example of a composition includes particles of triamcinolone acetonide and hyaluronic acid having a size of less than about 3000 nanometers. The formulation methods of these invention patents are all injected into the posterior segment of the eye.

The invention provides an ophthalmic preparation which can be administered topically according to the clinical use such as triamcinolone acetonide, and the ophthalmic preparation has the characteristics of suitable viscosity, high bioavailability and less irritation, and can be used for treating ocular diseases and diseases. Such as proliferative vitreoretinopathy, macular edema and so on.

It is an object of the present invention to provide an eye drop composition containing triamcinolone acetonide which has an advantage of having a suitable viscosity, high bioavailability, and less irritation to the eye.

The main composition of the triamcinolone acetonide-containing eye drops of the present invention is: (a) triamcinolone acetonide (TA) 0.05-0.5% (b) sodium chloride (Sodium chloride; NaCl) 0.1-0.9% (c) hydroxy Hydroxypropyl methyl cellulose (HPMC) 1.0~5.0% (d) polysorbate 80 (polysorbate 80) 0.05~0.2% (e) acetic acid / sodium acetate buffer amount, the balance is sterile pure water.

The preferred composition of the triamcinolone acetonide-containing eye drops of the present invention is: (a) triamcinolone acetonide (TA) 0.1 to 0.2% (b) sodium chloride (NaCl) 0.4~0.5% (c) hydroxypropyl methyl cellulose (HPMC) 2.0~3.0% (d) polysorbate 80 (polysorbate 80) 0.1~ 0.12% (e) acetic acid / sodium acetate buffered the appropriate amount, the balance is sterile pure water.

The pH of the eye drops is 4.5±0.5.

The active ingredient in the eye drop of the present invention is triamcinolone acetonide (TA), and the triamcinolone acetonide (TA) component accounts for 0.05-0.5% in the eye drop of the present invention, and the amount is 0.1-0.2. % is preferred.

In addition to the active ingredient, the eye drop of the present invention further contains sodium chloride (Sodium chloride; NaCl) as an ionic reinforcing agent, and the eye drop of the present invention is provided so that the eye drop has an osmolality of about 250 to 350 mOsm. The suitable amount of sodium chloride (Sodium chloride; NaCl) is 0.1 to 0.9%, and preferably 0.4 to 0.5%.

The invention adopts hydroxypropyl methyl cellulose (HPMC) as a nonionic polymer for adjusting the viscosity of the eye drop, and the amount thereof accounts for 1.0 to 5.0% of the total amount of the eye drops. The dosage is preferably 2.0~3.0%, and the concentration can ensure the viscosity of the eye drops reaches about 5.0 cPa. s or so, can make eye drops achieve better results.

Polysorbate 80 is used as the nonionic surfactant of the present invention in an amount of 0.05 to 0.2%, preferably 0.1 to 0.12%.

The eye drop of the present invention may further comprise a preservative, and the preservative may be Benzalkonium Bromide, Benzalkonium Chloride or disodium edetate, ethylene diammonium. Sodium calcium tetraacetate, or other ophthalmic preservatives, and combinations of the above preservatives. For example, a suitable concentration of benzalkonium bromide is selected from 0.001 to 0.1%, preferably from 0.01 to 0.02%.

The preparation of the present invention further contains 0.1 to 1.5% of boric acid.

The pH of the eye drop of the invention is 5-7, and the best is 6±0.5. The pH value can be adjusted by NaOH/HCl and buffered with a buffer solution, and the buffer solution for the eye drops of the present invention is Acetic acid/sodium acetate combination. The concentration of acetic acid in the present invention is 0.02 to 0.08%, and the concentration of sodium acetate is 0.015 to 0.06%.

The active ingredient triamcinolone acetonide (TA) in the preparation of the present invention is extremely soluble in water, and can be pulverized by techniques such as ball milling, microfluidization and sonication classification, so that the fineness range is ≦10 μm, which can be avoided. Irritating or uncomfortable to the eyes.

In the eye drop of the present invention, the remainder is made up to 100% with sterile pure water, except for the active ingredient and the auxiliary preparation contained in the above-mentioned contents.

The present invention also includes a method for preparing an eye drop containing triamcinolone acetonide (TA) as follows:

(1) Mixing the ratio of triamcinolone acetonide (TA) and polysorbate 80 (sterilized at 180 ° C for 2 hours), adding appropriate amount of sterile pure water to prepare a suspension .

(2) Take the ratio of sodium chloride (Sodium chloride; NaCl), sodium edetate, sodium benzalkonium bromide, acetic acid, sodium acetate, boric acid, and dissolve in sterile water.

(3) Take a ratio of hydroxypropyl methyl cellulose (HPMC), add appropriate amount of sterile pure water, and dissolve by heating.

(4) Mix (1) and (2), sterilize at 100 °C, and mix with (3), add sterile pure water to 90% of the required volume.

(5) Detect the pH value of the suspension, adjust the pH value to 5~7 with sterile NaOH or HCl solution as needed, and dilute it to the established volume with sterile pure water.

The invention has the advantages that the eye drop agent has suitable viscosity, high bioavailability, less irritation to the eye, and can be directly used for the eye and the like.

The invention is further illustrated by the following examples, which are intended to illustrate the invention and not to limit the scope of the invention.

Example 1

(1) sterilized (180 ° C for 2 hours) triamcinolone acetonide (TA) 10g and polysorbate 80 (polysorbate 80) 10g mixed, add 800ml of sterile pure water, to make a suspension a; (2) Take 40 g of sodium chloride (Sodium chloride; NaCl), 1 g of sodium edetate, 1 g of benzalkonium bromide, 4.5 g of acetic acid, 4.2 g of sodium acetate, 60 g of boric acid, and add 3500 ml of sterile pure water. Dissolved solution b; (3) taken hydroxypropyl methyl cellulose (HPMC) 200g, added to sterile pure water 4000ml, heated to dissolve solution c; (4) Mix a and b, sterilize at 100 °C, mix with c, add sterile pure water to 9000ml; (5) adjust pH to 5~7 with sterile NaOH or HCl solution as needed, and finally use sterile Dilute to 10,000ml of pure water and dispense into 1000 vials to get the product.

Example 2

The preparation method was the same as in Example 1.

Example 3

The preparation method was the same as in Example 1.

Example 4

The preparation method was the same as in Example 1.

Example 5

The preparation method was the same as in Example 1.

Experimental Example 1 Topical irritation test

Experimental animals: New Zealand rabbits weighing about 2.5 kg, half male and half female.

1. Single eye administration of the present invention for eye irritation test of rabbits

Eight rabbits weighing 2.0-2.5 kg were selected and divided into two groups, namely, the eye drop group of the present invention and the blank control group, 4 in each group. Rabbits were examined within 24 hours prior to the test, and animals with eye irritation, corneal defects, and conjunctival lesions could not be used for the test. Each rabbit was administered to both the left and right eyes of each rabbit. In the eye drops of the present invention, the left and right eyes of the animal were dropped into 0.1 ml of the test eye drops, and then the eyelids were lightly closed for 10 seconds; in the blank control group, the left and right eyes of each rabbit were instilled into 0.1 ml of the physiological saline for injection. . At 1, 2, 4, 24, 48 and 72 hours after the administration, the eyes of the rabbits were examined with fissures to observe whether the cornea and the iris were abnormal; whether the conjunctiva was congested or edema.

The results showed that: in a single administration, no conjunctiva, cornea, eye congestion, edema, etc. were observed in the rabbits, indicating that the eye drops of the present invention were administered once, and no irritating reaction was observed in the rabbit eyes.

2. Eye irritation test of rabbit eye drops by multiple administrations of the present invention

Eight rabbits weighing 2.0-2.5 kg were selected and divided into two groups, namely, the eye drop group of the present invention and the blank control group, 4 in each group. Rabbits were examined within 24 hours prior to the test, and animals with eye irritation, corneal defects, and conjunctival lesions could not be used for the test. Each rabbit was administered to both the left and right eyes of each rabbit. In the eye drop group of the present invention, 0.1 ml of the test drug was instilled into the left and right eyes, and then the eyelids were lightly closed for 10 seconds; in the blank control group, 0.1 ml of each of the physiological saline for injection was dropped into the left and right eyes of each rabbit. The drug was administered 4 times a day for 14 days. Rabbit eyes were examined with fissures before and after the first dose every day, and the cornea and iris were observed for abnormalities; the conjunctiva was congested or edema.

The results showed that the eye drops of the present invention were administered multiple times without irritating reaction, indicating that the clinical method was safe.

Experimental Example 2 Therapeutic effect on bacterial ocular conjunctivitis and keratitis in rabbits Experimental animals: New Zealand rabbits weighing about 2.5 kg, half male and half female.

Bacterial culture: Staphylococcus aureus and pneumococci are provided by the Experimental Teaching Center of Zhongshan Medical University. The above bacteria were inoculated on agar medium 3 days before the experiment, and cultured at 37 ° C for 18 hours, then an appropriate amount of bacteria was inoculated into a common liquid medium, and culture was continued for 24 hours at 37 ° C. The bacterial solution was diluted with physiological saline to a certain concentration before the experiment. spare.

Animal models and methods of administration: Rabbit models of bacterial conjunctivitis and keratitis were established by reference to literature methods. 3. To the eyes of the white rabbit, 3 × 10 CFU of Staphylococcus aureus and pneumococci. Ml ^-1 , the amount of bacteria instilled was 30 μl/eye, and 2 drops were continuously dropped. After 5 days, the white rabbit eye secretions were taken for bacterial culture, and the numbered records were taken. The rabbits with positive bacterial infection were randomly divided into 3 groups, and the number of rabbit eyes infected with bacteria was not less than 10 eyes, respectively. Eye drops (test group) and levofloxacin hydrochloride eye drops (control group), 4 times a day, 2 drops each time, for 7 consecutive days, continued to observe for 5 days after stopping the drug, and no liquid was given to the blank group.

Observation index and results: On the 5th and 7th day after drug administration, the secretion of rabbit eyes was taken for identification and bacterial culture identification on the 3rd day after drug withdrawal, thereby calculating the bacterial clearance rate, clearance rate = clearance rate 1 / infection eye number. The clearing effect of the eye drops of the present invention on the bacterial infection of rabbit eyes is comparable to that of levofloxacin hydrochloride eye drops. After statistical analysis (test), the results show that there is no statistical difference in the total clearance rate between the test group and the positive control group.

Claims (10)

A triamcinolone acetonide ophthalmic preparation, wherein the ophthalmic preparation has a main component weight percentage: triamcinolone acetonide (TA) 0.05-0.5% sodium chloride (Sodium chloride; NaCl) 0.1-0.9% hydroxypropyl Hydroxypropyl methyl cellulose (HPMC) 1.0~5.0% polysorbate 80 (polysorbate 80) 0.05-0.2% buffer solution The appropriate amount of sterile pure water. A triamcinolone acetonide ophthalmic preparation according to claim 1, wherein the weight percentage of the main component is preferably: triamcinolone acetonide (TA) 0.1 to 0.2% sodium chloride (Sodium chloride) ;NaCl) 0.4~0.5% hydroxypropyl methyl cellulose (HPMC) 2.0~3.0% polysorbate 80 (0.1) 0.1-0.12% buffer solution The appropriate amount is sterile pure water. A triamcinolone acetonide ophthalmic preparation according to claim 1, wherein the ophthalmic preparation further contains a preservative. The triamcinolone acetonide ophthalmic preparation according to claim 1 or 3, wherein the preservative is Benzalkonium Bromide, Benzalkonium Chloride, ethylenediaminetetraacetic acid Sodium, sodium calcium edetate or other ophthalmic preservatives, and combinations of these preservatives. The triamcinolone acetonide ophthalmic preparation according to claim 3, wherein the preservative Benzalkonium Bromide has a concentration of 0.001 to 0.1%, preferably 0.01 to 0.02%. The triamcinolone acetonide ophthalmic preparation according to claim 1, wherein the ophthalmic use The formulation also contains 0.1 to 1.5% boric acid. The triamcinolone acetonide ophthalmic preparation according to claim 1, wherein the ophthalmic preparation has a pH of 5 to 7, preferably 6 ± 0.5, and the pH is adjusted by NaOH/HCl, and buffered with a buffer solution. The triamcinolone acetonide ophthalmic preparation according to claim 1 or 7, wherein the buffer solution is an acetic acid/sodium acetate combination, the concentration of acetic acid is 0.02-0.08%, and the concentration of sodium acetate is 0.015-0.06%. . The triamcinolone acetonide (TA) according to claim 1, wherein the triamcinolone acetonide (TA) is pulverized by ball milling, microfluidization and sonication classification, and has a fineness of 10 m or less. A method for preparing the triamcinolone acetonide ophthalmic preparation according to claim 1, wherein the steps are as follows: (1) taking the above-mentioned ratio and sterilizing triamcinolone acetonide (TA) and polysorbate 80 (polysorbate) 80) Mix, add appropriate amount of sterile pure water to make a suspension a; (2) take the ratio of sodium chloride (Sodium chloride; NaCl), sodium edetate, sodium benzalkonium bromide, acetic acid , sodium acetate, boric acid, add sterile water to dissolve the solution b; (3) take the ratio of hydroxypropyl methyl cellulose (HPMC), add sterile pure water, heat to dissolve the solution c (4) Mix a and b, sterilize at 100 ° C, mix with c, add sterile pure water to the required volume of 90%; (5) check the pH of the suspension, adjust the pH with sterile NaOH or HCl solution The value is 5~7, and it is diluted with sterile pure water to the volume.