A brimonidine tartrate eye drop and a preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a brimonidine tartrate eye drop and a preparation method thereof. The brimonidine tartrate eye drop disclosed by the application comprises brimonidine tartrate, a thickening agent, an osmotic pressure regulator, a pH regulator and an antioxidant. Single-dose brimonidine tartrate eye drops are prepared by optimizing the types and proportions of the auxiliary materials, the adverse reactions caused by preservatives in the eye drops and the problems of poor ocular bioavailability of the brimonidine tartrate eye drops in the prior art are solved, and the brimonidine tartrate eye drops with small adverse reactions and high permeability are provided.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a bromonidine tartrate eye drop and its preparation method. Background Technology

[0002] Glaucoma is a group of diseases characterized by pathologically elevated intraocular pressure, leading to characteristic optic nerve damage and visual field defects. It ranks among the leading causes of irreversible visual impairment worldwide, severely affecting patients' daily lives and socio-psychological function, resulting in a significant decline in their quality of life. The disease develops due to disruption of the aqueous humor circulation; drug treatment primarily aims to lower intraocular pressure by inhibiting aqueous humor secretion and increasing its outflow.

[0003] Brimonidine tartrate (BRT) is currently the main clinically used selective α2-adrenergic receptor agonist. Its intraocular pressure-lowering effect reaches its peak two hours after administration, with minimal impact on cardiovascular and pulmonary function. Brimonidine tartrate has a dual mechanism of action: it reduces aqueous humor formation while increasing glucose efflux from the sclera.

[0004] The molecular formula of brimonidine tartrate is C 11 H 10 BrN5·C4H6O6, with a molecular weight of 442.24, has the chemical name 5-bromo-6-(2-imidazolidineammonia)quinoxaline-L-tartaric acid, and its structural formula is as follows:

[0005]

[0006] Because of BRT's significant effect in lowering blood pressure, Allergan, an American company, developed 0.2% brimonidine tartrate eye drops (Chinese name: Alphagan, trade name: Alphagan), which was first launched in the United States in 1996. It was subsequently launched in Argentina, Australia, Brazil, Canada, China, France, Germany, and other countries, and was approved for import into my country in 1999. Another commonly used clinical product is 0.15% brimonidine tartrate eye drops (Alphagan), but both strengths contain preservatives.

[0007] Because most glaucoma patients require long-term or even lifelong topical use of anti-glaucoma medications, close monitoring of any toxic reactions is necessary. Studies have found that continuous use of eye drops for more than one month, containing antibacterial agents, can lead to corneal epithelial keratinization, limbal keratinization, conjunctival stroma, and epithelial inflammatory cell infiltration in brown rats. Multicenter studies in several European countries compared the ocular surface toxicity of preservative-containing and preservative-free eye drops on open-angle glaucoma; all recorded symptoms and eyelid, conjunctival, and corneal signs were significantly increased in the preservative group (refer to patent CN 108261390 A).

[0008] BRT eye drops are typically administered 2-3 times daily, one drop each time. However, due to physiological reasons in most patients (such as blinking reflex, tear secretion, and nasolacrimal duct drainage), the medication is easily and rapidly eliminated, resulting in a short residence time in the cornea, limited drug absorption, poor ocular bioavailability, and difficulty in controlling the dosage. This makes overdose or frequent use easy. Furthermore, nasolacrimal duct drainage can easily lead to medication entering other non-target areas, causing side effects. While low-concentration BRT eye drops can reduce adverse reactions to some extent, the effect is limited. Domestic and international scholars have studied a series of novel drug delivery systems such as nano-suspensions, ointments, and intraocular inserts. Compared to traditional eye drops, these formulations can prolong the retention time of the drug in the eye, but due to poor patient tolerance (e.g., intraocular inserts) and high cost, they have not been widely accepted.

[0009] Aminopolysaccharides, also known as mucopolysaccharides, are based on the dipeptide subunit and include the following four categories: hyaluronic acid; chondroitin sulfate; chitosan; heparan sulfate; and heparin. They are important components of the corneal stroma, possessing high viscosity and affinity, and can remain on the corneal surface for a long time. They moisten the ocular surface, promote corneal epithelial stretching and wound healing, prevent bacteria and viruses from invading cells, protect corneal epithelial cells, and reduce the adverse effects of preservatives in ophthalmic preparations.

[0010] Brimonidine has a pKa of 7.4 and will ionize at pH values ​​below 6.6. For example, at pH 6.4, approximately 90% of brimonidine is ionized. Ionization of ophthalmic drugs significantly reduces ocular permeability, and it is expected that brimonidine will not penetrate ocular tissues well at pH values ​​below 6.6 or 6.5, thus reducing its efficacy compared to products with higher pH values. To overcome this drawback, non-ionic cellulose derivatives such as hydroxypropyl methylcellulose (HPMC E4M grade) and sodium carboxymethyl cellulose (CMC) are used. These polymers reduce the surface tension of eye drops from approximately 0.072 N / m to 0.045 N / m, thereby helping the eye drops spread more effectively around the eye. Furthermore, the viscosity of HPMC prolongs the residence time of the eye drops in the eye; both of these effects are considered to contribute to increased drug penetration. Summary of the Invention

[0011] Based on the adverse reactions caused by preservatives in eye drops and the poor ocular bioavailability of brimonidine tartrate eye drops in existing technologies, this invention provides a preservative-free, single-dose brimonidine tartrate eye drop. The technical solution is as follows:

[0012] A brimonidine tartrate eye drop, per 100 mL, comprises the following components: 0.05–0.5 g brimonidine tartrate, 0.3–0.8 g osmotic pressure regulator, 1–2 g thickener, 5–10 mg antioxidant, pH adjuster, and the remainder being water for injection. The amount of pH adjuster added is such that the pH of the eye drop is 5.6–6.6.

[0013] Preferably, the osmotic pressure of the eye drops is 270–320 mOsmol / Kg.

[0014] Preferably, the osmotic pressure is selected from one or more of sodium chloride, potassium chloride, glucose, and glycerol.

[0015] Preferably, the thickener is selected from one or more of polyvinyl alcohol, chitosan, sodium hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose.

[0016] Preferably, the viscosity of the eye drops is 3.0 to 5.0 mPa·s.

[0017] Preferably, the pH adjuster is selected from one or more of citric acid and sodium citrate, phosphate buffer, sodium hydroxide, and hydrochloric acid.

[0018] Preferably, the antioxidant is selected from one or more of sodium thiosulfate, sodium sulfite, potassium sulfite, and butylated hydroxyanisole.

[0019] A method for preparing brimonidine tartrate eye drops includes the following steps:

[0020] Take 50-80 wt% of the prescribed amount of water for injection, add the thickener to the container, and stir to dissolve;

[0021] Add the osmotic pressure regulator, pH regulator, and antioxidant to the container and stir to mix and dissolve.

[0022] Lower the temperature to 30–60°C, add brimonidine tartrate and stir to dissolve;

[0023] Add the remaining water for injection, mix well, filter through a 0.22-0.45μm filter membrane for sterilization, and perform aseptic filling using the above method. This invention has the following advantages:

[0024] This invention is a single-dose eye drop prepared with brimonidine tartrate as the main ingredient, and thickeners, pH adjusters, and osmotic pressure adjusters added. It contains no preservatives, and the addition of thickeners can prolong the action time of the eye drops at the application site to a certain extent, which can effectively reduce intraocular pressure. It does not cause secondary damage to the eyes due to the absence of preservatives, and also has moisturizing and corneal epithelial repair effects, increasing patient comfort. Detailed Implementation

[0025] Example 1

[0026] 1. A brimonidine tartrate eye drop, comprising the following components per 100 mL:

[0027]

[0028]

[0029] The preparation method of brimonidine tartrate eye drops is as follows:

[0030] (1) Take 70wt% of the prescribed amount of water for injection at a temperature of 35℃, add sodium chloride, sodium sulfite, citric acid and sodium citrate to the container, stir and mix to dissolve;

[0031] (2) Add bromonidin tartrate to the container, stir and mix to dissolve, and filter with a 0.45 μm filter membrane for sterilization;

[0032] (3) Add chitosan to the filtrate and stir at a speed of 200 rpm for 2 hours at a temperature of 30°C until the chitosan dissolves.

[0033] (4) Add the remaining water for injection, shake well, adjust the pH to 6.0 with sodium hydroxide or hydrochloric acid, filter with a 0.2μm filter membrane for sterilization, and then fill aseptically.

[0034] Example 2

[0035] A brimonidine tartrate eye drop solution comprises the following components per 100 mL:

[0036] Element Content (g / 100mL) bromonidin tartrate 0.45 Potassium chloride 0.7 HPMC 1.5 Sodium thiosulfate 0.005 Sodium dihydrogen phosphate 0.05 Sodium hydrogen phosphate 0.45 Sodium hydroxide or hydrochloric acid 6.5 Water for Injection Add to 100mL

[0037] 2. A method for preparing brimonidine tartrate eye drops, comprising the following steps:

[0038] (1) Take 60wt% of the prescribed amount of water for injection, and slowly add HPMC into the container under the condition of continuous stirring at 60-70℃, stirring at 150rpm for 30-60min.

[0039] (2) Cool the solution to room temperature (25°C) with stirring until HPMC is completely dissolved;

[0040] (3) Add potassium chloride, sodium thiosulfate, sodium dihydrogen phosphate and disodium hydrogen phosphate while stirring, and stir to dissolve;

[0041] (4) Add brimonidine tartrate while stirring and stir to dissolve;

[0042] (5) Add the remaining water for injection, shake well, adjust the pH to 6.5 with sodium hydroxide or hydrochloric acid, filter with a 0.25μm filter membrane for sterilization, and then fill aseptically.

[0043] Example 3

[0044] A brimonidine tartrate eye drop solution comprises the following components per 100 mL:

[0045] Element Content (g / 100mL) bromonidin tartrate 0.2 Sodium chloride 0.6 Sodium carboxymethyl cellulose 1.8 Sodium sulfite 0.009 Citric acid 0.05 Sodium citrate 0.45 Sodium hydroxide or hydrochloric acid Adjust the pH to 5.8. Water for Injection Add to 100mL

[0046] A method for preparing brimonidine tartrate eye drops includes the following steps:

[0047] (1) Take 60wt% of the prescribed amount of water for injection, and slowly add CMC into the container under the condition of continuous stirring at 90-100℃, stirring at 150rpm for 30-60min.

[0048] (2) Cool the solution to room temperature with stirring until the CMC is completely dissolved;

[0049] (3) Add potassium chloride, sodium thiosulfate, sodium dihydrogen phosphate and disodium hydrogen phosphate while stirring, and stir to dissolve;

[0050] (4) Add brimonidine tartrate while stirring and stir to dissolve;

[0051] (5) Add the remaining water for injection, shake well, adjust the pH to 5.8 with sodium hydroxide or hydrochloric acid, filter with a 0.2μm filter membrane for sterilization, and then fill aseptically.

[0052] Comparative Example 1

[0053] A brimonidine tartrate eye drop solution comprises the following components per 100 mL:

[0054] Element Content (g / 100mL) bromonidin tartrate 1.5 Sodium chloride 1.2 Polyvinyl alcohol 0.8 Sodium thiosulfate 0.015 Citric acid 0.05 Sodium citrate 0.45 Sodium hydroxide or hydrochloric acid Adjust the pH to 5.5. Water for Injection Add to 100mL

[0055] A method for preparing brimonidine tartrate eye drops includes the following steps:

[0056] (1) Take 60wt% of the prescribed amount of room temperature water for injection, slowly add polyvinyl alcohol to the container, stir at 200 rpm for 10-30 min to disperse evenly, add sodium chloride, sodium thiosulfate and citrate buffer to the container, heat to 95℃ and stir for 40-60 min to dissolve.

[0057] (2) Cool the solution temperature to below 40°C, add brimonidine tartrate raw material, and stir to dissolve;

[0058] (3) Add the remaining water for injection, stir well, adjust the pH to 5.5 with sodium hydroxide or hydrochloric acid, filter with 0.45μm or 0.22μm filter membranes for sterilization, and then fill aseptically.

[0059] Comparative Example 2: Brimonidine Tartrate Eye Drops (per 100 mL)

[0060]

[0061]

[0062] A method for preparing brimonidine tartrate eye drops includes the following steps:

[0063] (1) Take 60wt% of the prescribed amount of room temperature water for injection, slowly add polyvinyl alcohol to the container, stir at 200 rpm for 10-30 min to disperse evenly, add sodium chloride, sodium thiosulfate, benzalkonium chloride and citrate buffer to the container, heat to 95℃ and stir for 40-60 min to dissolve;

[0064] (2) Cool the solution temperature to below 40°C, add brimonidine tartrate raw material, and stir to dissolve;

[0065] (3) Add the remaining water for injection, stir well, adjust the pH to 5.6-6.6 with sodium hydroxide or hydrochloric acid, filter with 0.45μm or 0.22μm filter membranes for sterilization, and then fill aseptically.

[0066] Testing and Evaluation

[0067] Test results of various indicators of eye drops

[0068]

[0069] The results showed that, compared with the comparative examples, the various indicators of the samples in Examples 1, 2, and 3 were basically unchanged.

[0070] animal testing

[0071] corneal retention time

[0072] Using sodium fluorescein as the chromogenic material, the in vivo corneal retention time of the eye drops was studied using Comparative Examples 1, 2, 1, 2, and 3 as examples. The experiment was divided into five groups, with six rabbits in each group. In four groups, 100 μL of eye drops containing 0.10% sodium fluorescein solution (Comparative Examples 1, 2, and 3) were instilled into the conjunctival sac of the right eye, respectively. In the fifth group, 100 μL of eye drops containing 0.20% sodium fluorescein solution (Comparative Example 2) were instilled into the conjunctival sac of the right eye. All rabbits received an equal volume of pH 6.30 citrate buffer solution in their left eye as a control. After administration, the rabbits' eyes were passively closed for 30 seconds. The fluorescence fading time of sodium fluorescein in the cornea and conjunctival sac was observed and recorded using a slit lamp. The experimental results are shown in the table below.

[0073] Group corneal residence time (min±SD) Conjunctival sac retention time (min±SD) Comparative Example 1 23±3 21±9 Comparative Example 2 26±5 23±4 Example 1 48±6 51±8 Example 2 69±9 71±8 Example 3 59±6 65±5

[0074] The results showed that the retention time of the eye drops in the rabbit cornea and conjunctival sac of Comparative Example 1 was approximately 23 min and 21 min, respectively, while the retention time of the eye drops in the rabbit cornea and conjunctival sac of Comparative Example 2 was approximately 26 min and 23 min, respectively. Compared with Examples 1, 2, and 3, the retention time in the conjunctival sac and the retention time on the cornea were significantly increased, with Example 2 having the longest retention time.

[0075] (2) Effect on lowering intraocular pressure

[0076] Rabbits were divided into 5 groups: a blank control group, comparative examples 2, 1, 2, and 3, with 5 rabbits in each group. A high intraocular pressure model was established by injecting small amounts of 1% methylcellulose into the anterior chamber of each rabbit multiple times. The rabbits were housed individually. The blank control group was given sterile water for injection, administered 3 times daily, 1 drop per dose, starting 12 hours after model establishment and continuing for 10 days. Intraocular pressure was measured daily using a tonometer. The results are shown in the table below.

[0077] Group / Time Before modeling (kPa) 1d(kPa) 3d(kPa) 5d(kPa) 7d(kPa) 10d(kPa) Blank control group 2.5±0.4 3.0±0.4 3.1±0.4 2.9±0.4 3.3±0.4 2.9±0.4 Comparative Example 2 2.6±0.4 6.6±0.4 5.9±0.4 5.1±0.4 4.4±0.4 3.5±0.4 Example 1 2.5±0.4 6.9±0.4 5.7±0.4 4.6±0.4 4.0±0.4 2.9±0.4 Example 2 2.6±0.4 6.7±0.4 5.8±0.4 4.3±0.4 3.9±0.4 2.9±0.4 Example 3 2.7±0.4 6.5±0.4 6.0±0.4 4.9±0.4 3.8±0.4 2.8±0.4

[0078] The results showed that after 10 days of medication, compared with the control group, the intraocular pressure of rabbits in each group of the examples all dropped to normal, indicating that the eye drops of the present invention have a good antihypertensive effect on high intraocular pressure in rabbits.

[0079] (3) In vitro corneal permeability test

[0080] Rabbits were euthanized, and their intact corneas were separated. The corneas were fixed to a diffusion cell, with the inner corneal side (aqueous humor side) facing the receiving cell and the outer cornea facing the supply cell. 2g of the eye drops from Comparative Examples 2, 1, 2, and 3 were placed in the supply cell, and a corneal permeability test was performed at 37°C. The receiving solution was completely removed from the receiving cell at different time points, and the same volume of receiving solution was replenished. The concentration of brimonidine tartrate in the receiving solution was determined by HPLC. The results are shown in the table below.

[0081] Group <![CDATA[Papp×10 6 (cm / s)±SD]]> Comparative Example 2 3.10±0.45 Example 1 3.86±0.67 Example 2 4.01±0.35 Example 3 3.89±0.23

[0082] The results showed that, compared with the comparative examples, the permeability of Examples 1, 2, and 3 increased, indicating that the selected adhesive can effectively promote drug penetration in the cornea.

[0083] For those skilled in the art, various other corresponding changes and modifications can be made based on the technical solutions and concepts described above, and all such changes and modifications should fall within the protection scope of the claims of this invention.

Claims

1. A brimonidine tartrate eye drop, characterized in that, The formulation of the brimonidine tartrate eye drops comprises brimonidine tartrate, sodium chloride (osmotic pressure regulator), chitosan (thickening agent), sodium sulfite (antioxidant), citric acid (pH regulator), sodium citrate (pH regulator), sodium hydroxide or hydrochloric acid (pH regulator), and water for injection; or brimonidine tartrate, potassium chloride (osmotic pressure regulator), HPMC (thickening agent), sodium thiosulfate (antioxidant), sodium dihydrogen phosphate (pH regulator), disodium hydrogen phosphate (pH regulator), sodium hydroxide or hydrochloric acid (pH regulator), and water for injection; or brimonidine tartrate... The solution comprises sodium chloride (osmotic pressure regulator), sodium carboxymethyl cellulose (thickener), sodium sulfite (antioxidant), citric acid (pH regulator), sodium citrate (pH regulator), sodium hydroxide or hydrochloric acid (pH regulator), and water for injection. The formulation content per 100 mL is as follows: 0.05–0.5 g brimonidine tartrate, 0.3–0.8 g osmotic pressure regulator, 1–2 g thickener, 5–10 mg antioxidant, pH regulator, and the remainder is water for injection. The amount of pH regulator added is to adjust the pH of the eye drops to 5.6–6.

6.

2. The brimonidine tartrate ophthalmic solution of claim 1, wherein, The viscosity of the eye drops is 3.0–5.0 mPa·s.

3. The brimonidine tartrate ophthalmic solution of claim 1, wherein, The osmotic pressure of the eye drops is 270–320 mOsmol / Kg.

4. A method for preparing brimonidine tartrate eye drops as described in claim 1, characterized in that, Includes the following steps: (1) Take 50-80 wt% of the prescribed amount of water for injection, add the thickener to the container, and stir to dissolve; (2) Add the osmotic pressure regulator, pH regulator, and antioxidant to the container and stir to mix and dissolve; (3) Lower the temperature to 30-60℃, add brimonidine tartrate and stir to dissolve; (4) Add the remaining water for injection, mix well, filter through a 0.22-0.45μm filter membrane for sterilization, and aseptically fill.

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