Brimonidine tartrate eye drops and preparation method thereof

Abstract

The invention discloses brimonidine tartrate eye drops and a preparation method thereof.The brimonidine tartrate eye drops are prepared from brimonidine tartrate, soybean lecithin, cholesterol, a surfactant, a tackifier, a plant extract, a penetration enhancer, a pH regulator, an osmotic pressure regulator and deionized water. The preparation method comprises the steps that 1, raw materials are prepared; step 2, preparing nanoparticles; step 3, preparing eye drops; step 4, adjusting pH and osmotic pressure; step five, degerming and sub-packaging; brimonib tartrate is customized into nanoparticles, and the tackifier is added, so that the adhesion of the medicine on the cornea can be enhanced, the adhesion time can be prolonged, and the loss of medicine components is reduced; plant extracts which are free of toxic and side effects and have anti-inflammatory and repairing functions are adopted as natural preservatives, so that eyes are prevented from being damaged; the penetration enhancer is added, the pH value is optimized to be close to the physiological value of eyes, the osmotic pressure is adjusted to be close to tears, the corneal permeability of the medicine can be improved, tear secretion and medicine outflow are reduced, penetration and absorption are promoted, and the curative effect is ensured.

Description

Technical Field

[0001] The invention relates to the technical field of eye drops, in particular to brimonidine tartrate eye drops and a preparation method thereof. Background Art

[0002] Brimonidine tartrate eye drops are an alpha-adrenergic receptor agonist. This drug lowers intraocular pressure primarily by reducing aqueous humor production, but it also increases uveoscleral outflow, thus playing a dual role in lowering intraocular pressure. Increased intraocular pressure is a major risk factor for glaucomatous optic neuropathy, and brimonidine tartrate eye drops help prevent further damage to the optic nerve and protect vision by lowering intraocular pressure. The existing brimonidine tartrate eye drops have the following disadvantages when used: 1. After using the eye drops, the patient may easily cause the eye drops to flow out due to blinking reaction and tear secretion, resulting in inaccurate actual dosage, which affects the accuracy and effectiveness of the treatment; 2. In order to extend the shelf life, preservatives are generally added to the eye drops, and most glaucoma patients need to use local anti-glaucoma drugs for a long time or even for life. Under the background of such long-term medication, the continuous accumulation of preservatives in the eye will gradually cause a series of serious problems, such as damage to corneal epithelial cells and dysfunction of conjunctival goblet cells. These damages are often irreversible and can lead to adverse consequences such as dryness of the ocular surface, aggravated inflammation, and further impairment of vision in the long term; 3. The active ingredients in the eye drops need to stay in front of the cornea for a certain period of time before they can fully penetrate into the intraocular tissues to exert their effects. However, due to the patient's physiological actions such as blinking and rubbing the eyes, the residence time of the eye drops in front of the cornea is greatly shortened, and the active ingredients are cleared in large quantities before they can be fully absorbed. This situation greatly reduces the bioavailability of the drug, and ultimately has a significant negative impact on the overall treatment effect, delaying the improvement of the disease. Summary of the invention

[0003] The object of the present invention is to provide a brimonidine tartrate eye drops and a preparation method thereof, so as to solve the problems raised in the above background technology.

[0004] To achieve the above-mentioned purpose, the present invention provides the following technical scheme: a brimonidine tartrate eye drop, the formula of which includes: brimonidine tartrate, soybean lecithin, cholesterol, surfactant, thickener, plant extract, penetration enhancer, pH regulator, osmotic pressure regulator and deionized water, the mass percentage content of each component is: 0.2-0.6% of brimonidine tartrate, 1.3-1.7% of soybean lecithin, 0.3-0.7% of cholesterol, 0.05-0.15% of surfactant, 0.1-0.3% of thickener, 0.03-0.1% of plant extract, 0.4-0.7% of penetration enhancer, 0.05-0.2% of pH regulator and 0.05-0.2% of osmotic pressure regulator, and the balance is deionized water.

[0005] Preferably, the mass percentage contents of the components are: 0.4% brimonidine tartrate, 1.5% soybean lecithin, 0.5% cholesterol, 0.1% surfactant, 0.2% viscosity enhancer, 0.05% plant extract, 0.5% penetration enhancer, 0.1% pH regulator and 0.1% osmotic pressure regulator, and the balance is deionized water.

[0006] Preferably, the viscosity increasing agent is one or more combinations of chondroitin sulfate, chitosan, carbomer, sodium carboxymethyl cellulose, polyaspartic acid, polyglutamic acid, and dextran sulfate.

[0007] Preferably, the surfactant is one or more combinations of Tween 80, egg yolk lecithin, and poloxamer 188.

[0008] Preferably, the plant extract is one or more combinations of rosemary extract, grapefruit seed extract, calendula extract, green tea extract, blueberry extract, and elderberry extract.

[0009] Preferably, the penetration enhancer is one or more combinations of laurocapram, menthol, capric glyceride, and N-acetyl-L-cysteine.

[0010] Preferably, the pH adjuster is one of a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, a citric acid-sodium citrate buffer pair, and a boric acid-borax buffer pair.

[0011] Preferably, the osmotic pressure regulator is one or more combinations of glucose, glycerol, mannitol and xylitol.

[0012] A method for preparing brimonidine tartrate eye drops, comprising step 1, preparing raw materials; step 2, preparing nanoparticles; step 3, preparing eye drops; step 4, adjusting pH and osmotic pressure; step 5, sterilizing and packaging;

[0013] Wherein in the above step 1, taking the sum of the mass percentages of each component as 1, weighing brimonidine tartrate, soybean lecithin, cholesterol, surfactant, viscosity enhancer, plant extract, penetration enhancer, pH adjuster, osmotic pressure regulator and deionized water;

[0014] In the above step 2, soybean lecithin, cholesterol and surfactant are placed in a stirred tank, anhydrous ethanol is added, and the mixture is stirred for 20-40 minutes under heating in a water bath at 50-70° C. to form a uniform organic phase, brimonidine tartrate is dissolved in deionized water, and then the brimonidine tartrate solution is added to the organic phase under stirring to form colostrum, and the colostrum is placed in a high-pressure homogenizer and circulated and homogenized for 3-5 times under a pressure of 1000-1500 bar to obtain a brimonidine tartrate lipid nanoparticle dispersion;

[0015] In the above step 3, the viscosity enhancer is dissolved in deionized water and stirred until completely dissolved, the lipid nanoparticle dispersion prepared in the above step 2 is added to the sodium hyaluronate solution, stirred at 30-40°C for 20-30 minutes to fully mix, and then the plant extract and the penetration enhancer are added, stirred at 25-30°C for 20-30 minutes to fully mix to obtain a mixed solution;

[0016] In the above step 4, the pH of the mixed solution is adjusted to 7.3 with a pH adjuster, and then the osmotic pressure is adjusted to 300 mOsm / L with an osmotic pressure adjuster to obtain eye drops;

[0017] In the above step 5, the eye drops obtained in step 4 are sterilized and then dispensed into sterile eye drop bottles.

[0018] Preferably, in the step 2, the amount of anhydrous ethanol used is 5-10 times the total mass of soybean lecithin and cholesterol, and the amount of ionized water used is 3-6 times the mass of brimonidine tartrate.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention prepares brimonidine tartrate into nanoparticles and adds a viscosity enhancer, which can enhance the adhesion and adhesion time of the drug on the cornea and reduce the loss of drug components; adopts plant extracts with no toxic side effects and anti-inflammatory and repair functions as natural preservatives to avoid eye damage; adds a penetration enhancer, optimizes the pH value to be close to the physiological value of the eye, and adjusts the osmotic pressure to be close to that of tears, which can improve the corneal permeability of the drug, reduce tear secretion and drug outflow, and promote osmotic absorption to ensure the efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The present invention is a flow chart of the method. DETAILED DESCRIPTION

[0021] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0022] Please see attached Figure 1 , a technical solution provided by the present invention:

[0023] Embodiment 1:

[0024] The invention discloses brimonidine tartrate eye drops, which comprises: brimonidine tartrate, soybean lecithin, cholesterol, surfactant, viscosity enhancer, plant extract, permeation enhancer, pH adjuster, osmotic pressure adjuster and deionized water, wherein the mass percentage content of each component is: 0.4% of brimonidine tartrate, 1.5% of soybean lecithin, 0.5% of cholesterol, 0.1% of surfactant, 0.2% of viscosity enhancer, 0.05% of plant extract, 0.5% of permeation enhancer, 0.1% of pH adjuster and 0.1% of osmotic pressure adjuster, and the balance is deionized water, the viscosity enhancer is chitosan, the surfactant is Tween 80, the plant extract is rosemary extract, the permeation enhancer is menthol, the pH adjuster is disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, and the osmotic pressure adjuster is glycerol.

[0025] A method for preparing brimonidine tartrate eye drops, comprising step 1, preparing raw materials; step 2, preparing nanoparticles; step 3, preparing eye drops; step 4, adjusting pH and osmotic pressure; step 5, sterilizing and packaging;

[0026] Wherein in the above step 1, taking the sum of the mass percentages of each component as 1, weighing brimonidine tartrate, soybean lecithin, cholesterol, surfactant, viscosity enhancer, plant extract, penetration enhancer, pH adjuster, osmotic pressure regulator and deionized water;

[0027] In the above step 2, soybean lecithin, cholesterol and surfactant are placed in a stirred tank, anhydrous ethanol is added in an amount of 5-10 times the total mass of soybean lecithin and cholesterol, and stirred for 20-40 minutes under heating in a water bath at 50-70° C. to form a uniform organic phase, brimonidine tartrate is dissolved in deionized water in an amount of 3-6 times the mass of brimonidine tartrate, and then the brimonidine tartrate solution is added to the organic phase under stirring to form colostrum, and the colostrum is placed in a high-pressure homogenizer and circulated and homogenized for 3-5 times under a pressure of 1000-1500 bar to obtain a brimonidine tartrate lipid nanoparticle dispersion;

[0028] In the above step 3, the viscosity enhancer is dissolved in deionized water and stirred until completely dissolved, the lipid nanoparticle dispersion prepared in the above step 2 is added to the sodium hyaluronate solution, stirred at 30-40°C for 20-30 minutes to fully mix, and then the plant extract and the penetration enhancer are added, stirred at 25-30°C for 20-30 minutes to fully mix to obtain a mixed solution;

[0029] In the above step 4, the pH of the mixed solution is adjusted to 7.3 with a pH adjuster, and then the osmotic pressure is adjusted to 300 mOsm / L with an osmotic pressure adjuster to obtain eye drops;

[0030] In the above step 5, the eye drops obtained in step 4 are sterilized and then dispensed into sterile eye drop bottles.

[0031] Embodiment 2:

[0032] Referring to the formula and preparation method of Example 1, only the mass percentage content of each component was changed to: 0.2% brimonidine tartrate, 1.3% soybean lecithin, 0.4% cholesterol, 0.1% surfactant, 0.1% viscosity enhancer, 0.1% plant extract, 0.4% penetration enhancer, 0.1% pH adjuster and 0.15% osmotic pressure regulator, and the balance was deionized water.

[0033] Embodiment 3:

[0034] Referring to the formula and preparation method of Example 1, only the mass percentage content of each component was changed to: 0.6% brimonidine tartrate, 1.7% soybean lecithin, 0.7% cholesterol, 0.15% surfactant, 0.1% viscosity enhancer, 0.03% plant extract, 0.4% penetration enhancer, 0.08% pH adjuster and 0.1% osmotic pressure regulator, and the balance was deionized water.

[0035] Embodiment 4:

[0036] Referring to the formula and preparation method of Example 1, only the viscosity enhancer was changed to sodium carboxymethyl cellulose, the surfactant was changed to egg yolk lecithin, the plant extract was changed to green tea extract, the penetration enhancer was changed to capric glyceride, the pH adjuster was changed to citric acid-sodium citrate buffer pair, and the osmotic pressure regulator was changed to mannitol.

[0037] Embodiment 5:

[0038] Referring to the formula and preparation method of Example 1, only the viscosity enhancer was changed to carbomer, the surfactant was changed to poloxamer 188, the plant extract was changed to elderberry extract, the penetration enhancer was changed to laurocapram, the pH adjuster was changed to boric acid-borax buffer pair, and the osmotic pressure regulator was changed to xylitol.

[0039] Experimental Example 1:

[0040] Sodium fluorescein was selected as the color developing material, and the corneal retention time of the eye drops prepared in the above embodiments was studied. The experiment was divided into three groups, each group had 10 rabbits, and 100 μL of the eye drops of Embodiment 1 and Embodiment 5 containing 0.10% sodium fluorescein solution was respectively dripped into the conjunctival sac of the right eyes of the rabbits in two groups, and 100 μL of the existing brimonidine tartrate eye drops containing 0.10% sodium fluorescein solution was dripped into the conjunctival sac of the right eyes of the rabbits in the third group. As a comparative example, the same volume of citrate buffer with a pH of 6.30 was dripped into the left eyes of all rabbits as a control. After the administration, the rabbits' eyes were passively closed for 30 seconds, and the fluorescence fading time of sodium fluorescein in the cornea and conjunctival sac after the administration was observed and recorded with a slit lamp. The test results are shown in Table 1.

[0041] Experimental Example 2:

[0042] Rabbits were divided into three groups, 5 in each group, and 1% methylcellulose was injected into the anterior chamber of the rabbits in small amounts and multiple times to establish a high intraocular pressure model. The rabbits were housed in separate cages. The first group was given water for injection as a control group, the second group was given the eye drops prepared in Example 1, and the third group was given the existing brimonidine tartrate eye drops as a comparative example. The drug was administered 3 times / d, 1 drop / time, starting from 12 hours after modeling for a period of 10 days, and the intraocular pressure was detected every day with an indentation tonometer. The results are shown in Table 2.

[0043] Experimental Example 3:

[0044] The rabbit was killed, the intact cornea was separated, and the cornea was fixed on the diffusion cell, with the inner side of the cornea (aqueous humor test) facing the receiving cell and the outer side of the cornea facing the supply cell. 2 g of the eye drops prepared in Example 1 were placed in the supply cell, and 2 g of the existing brimonidine tartrate eye drops were placed in the supply cell. As a comparative example, a corneal penetration test was performed at 37° C., and the receiving solution was completely taken out from the receiving cell at different times, and the same volume of receiving solution was supplemented. The concentration of brimonidine tartrate in the receiving solution was determined by HPLC. The test results are shown in Table 3.

[0045] Table 1 Fluorescence fading time of fluorescein sodium in cornea and conjunctival sac after administration

[0046] Retention time in cornea (min±SD) Retention time in conjunctival sac (min±SD) Example 1 67±6 69±6 Example 5 60±7 63±8 Comparative Example 20±4 22±7

[0047] Table 2 Intraocular pressure data within 10 days

[0048]

[0049] Table 3 Concentration of brimonidine tartrate in receiving solution

[0050] <![CDATA[Papp×10 6 (cm / s)±SD]]> Example 1 4.02±0.35 Comparative Example 3.11±0.32

[0051] Based on the above, the present invention wraps brimonidine tartrate in nanoparticles to enhance the adhesion ability of the drug on the corneal surface, and increases the adhesion time of the drug on the ocular surface by adding a viscosity enhancer to the formula, thereby reducing the loss of the drug caused by blinking and tear flushing; by using plant extracts as natural preservatives, there are no toxic side effects on ocular surface cells, and the anti-inflammatory and cell repair functions are also provided; the permeation enhancer is added to improve the permeability of corneal epithelial cells, and by optimizing the pH value of the eye drops to make it close to the physiological pH value of the eye, the stimulation to the ocular surface is reduced, the corneal permeability of the drug is improved, and the osmotic pressure is adjusted to make it close to the osmotic pressure of tears, which can reduce the tear secretion and drug outflow caused by the difference in osmotic pressure, and create good conditions for the penetration and absorption of the drug.

[0052] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

Claims

1. A brimonidine tartrate eye drops, the formula comprising: The invention relates to brimonidine tartrate, soybean lecithin, cholesterol, surfactant, thickener, plant extract, penetration enhancer, pH regulator, osmotic pressure regulator and deionized water, wherein the mass percentage contents of the components are respectively: 0.2-0.6% of brimonidine tartrate, 1.3-1.7% of soybean lecithin, 0.3-0.7% of cholesterol, 0.05-0.15% of surfactant, 0.1-0.3% of thickener, 0.03-0.1% of plant extract, 0.4-0.7% of penetration enhancer, 0.05-0.2% of pH regulator and 0.05-0.2% of osmotic pressure regulator, and the balance is deionized water.

2. A brimonidine tartrate eye drops according to claim 1, characterized in that: The mass percentage contents of the components are: 0.4% brimonidine tartrate, 1.5% soybean lecithin, 0.5% cholesterol, 0.1% surfactant, 0.2% viscosity enhancer, 0.05% plant extract, 0.5% penetration enhancer, 0.1% pH regulator and 0.1% osmotic pressure regulator, and the balance is deionized water.

3. A brimonidine tartrate eye drops according to claim 2, characterized in that: The viscosity enhancer is one or more combinations of chondroitin sulfate, chitosan, carbomer, sodium carboxymethyl cellulose, polyaspartic acid, polyglutamic acid, and dextran sulfate.

4. A brimonidine tartrate eye drops according to claim 2, characterized in that: The surfactant is one or more combinations of Tween 80, egg yolk lecithin, and poloxamer 188.

5. A brimonidine tartrate eye drops according to claim 2, characterized in that: The plant extract is one or more combinations of rosemary extract, grapefruit seed extract, calendula extract, green tea extract, blueberry extract and elderberry extract.

6. A brimonidine tartrate eye drops according to claim 2, characterized in that: The penetration enhancer is one or more combinations of laurocapram, menthol, capric glyceride, and N-acetyl-L-cysteine.

7. A brimonidine tartrate eye drops according to claim 2, characterized in that: The pH adjuster is one of a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, a citric acid-sodium citrate buffer pair, and a boric acid-borax buffer pair.

8. A brimonidine tartrate eye drops according to claim 2, characterized in that: The osmotic pressure regulator is one or more combinations of glucose, glycerol, mannitol and xylitol.

9. A method for preparing brimonidine tartrate eye drops, comprising step 1, preparing raw materials; step 2, preparing nanoparticles; step 3, preparing eye drops; step 4, adjusting pH and osmotic pressure; step 5, sterilizing and packaging; characterized in that: Wherein in the above step 1, taking the sum of the mass percentages of each component as 1, weighing brimonidine tartrate, soybean lecithin, cholesterol, surfactant, viscosity enhancer, plant extract, penetration enhancer, pH adjuster, osmotic pressure regulator and deionized water; In the above step 2, soybean lecithin, cholesterol and surfactant are placed in a stirred tank, anhydrous ethanol is added, and the mixture is stirred for 20-40 minutes under heating in a water bath at 50-70° C. to form a uniform organic phase, brimonidine tartrate is dissolved in deionized water, and then the brimonidine tartrate solution is added to the organic phase under stirring to form colostrum, and the colostrum is placed in a high-pressure homogenizer and circulated and homogenized for 3-5 times under a pressure of 1000-1500 bar to obtain a brimonidine tartrate lipid nanoparticle dispersion; In the above step 3, the viscosity enhancer is dissolved in deionized water and stirred until completely dissolved, the lipid nanoparticle dispersion prepared in the above step 2 is added to the sodium hyaluronate solution, stirred at 30-40°C for 20-30 minutes to fully mix, and then the plant extract and the penetration enhancer are added, stirred at 25-30°C for 20-30 minutes to fully mix to obtain a mixed solution; In the above step 4, the pH of the mixed solution is adjusted to 7.3 with a pH adjuster, and then the osmotic pressure is adjusted to 300 mOsm / L with an osmotic pressure adjuster to obtain eye drops; In the above step 5, the eye drops obtained in step 4 are sterilized and then dispensed into sterile eye drop bottles.

10. A method for preparing brimonidine tartrate eye drops according to claim 9, characterized in that: In the step 2, the amount of anhydrous ethanol used is 5-10 times the total mass of soybean lecithin and cholesterol, and the amount of ionized water used is 3-6 times the mass of brimonidine tartrate.

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