CN116473918A - Brimonidine tartrate eye drops and preparation method thereof - Google Patents

Brimonidine tartrate eye drops and preparation method thereof Download PDF

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CN116473918A
CN116473918A CN202210038962.0A CN202210038962A CN116473918A CN 116473918 A CN116473918 A CN 116473918A CN 202210038962 A CN202210038962 A CN 202210038962A CN 116473918 A CN116473918 A CN 116473918A
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eye drops
brimonidine tartrate
sodium
regulator
stirring
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张孝娜
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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Abstract

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to brimonidine tartrate eye drops and a preparation method thereof. The brimonidine tartrate eye drops disclosed by the invention comprise brimonidine tartrate, a thickening agent, an osmotic pressure regulator, a pH regulator and an antioxidant. The single-dose brimonidine tartrate eye drops are prepared by optimizing the types and the proportions of auxiliary materials, so that the problems of adverse reaction caused by preservatives in the eye drops, poor bioavailability of brimonidine tartrate eye drops in the prior art and the like are solved, and the brimonidine tartrate eye drops with small adverse reaction and high permeability are provided.

Description

Brimonidine tartrate eye drops and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to brimonidine tartrate eye drops and a preparation method thereof.
Background
Glaucoma is a group of diseases with pathological elevated intraocular pressure, which causes characteristic optic nerve damage and visual field defect, and is the leading position in the eye disease with irreversible visual damage in the world, and the visual disorder caused by the disease seriously affects the daily life and the social psychological function of a patient, so that the life quality of the patient is greatly reduced. The disease develops as a result of disrupted aqueous humor circulation, and drug therapy is primarily aimed at lowering intraocular pressure by inhibiting aqueous humor secretion and increasing aqueous humor removal.
Brimonidine tartrate (Brimonidine Tartrate, BRT) is a selective alpha 2 adrenergic receptor agonist currently used clinically primarily, and the ocular hypotensive effect peaks two hours after administration with little effect on cardiovascular and pulmonary function. Brimonidine tartrate has a dual mechanism of action: not only reduces the formation of aqueous humor, but also increases the outflow of the glucose membrane sclera.
Brimonidine tartrate has the formula C 11 H 10 BrN 5 ·C 4 H 6 O 6 The molecular weight is 442.24, the chemical name is 5-bromo-6- (2-imidazole dienoamine) quinoxaline-L-tartaric acid, and the structural formula is as follows:
just because BRT has a remarkable effect on blood pressure reduction, the American Allergan company developed 0.2% brimonidine tartrate eye drops (Chinese name: alfagen, trade name: alphagan), which were first marketed in the United states in 1996, and later marketed in Argentina, australia, brazil, canada, china, french, germany, etc., and approved for import in China in 1999. Brimonidine tartrate eye drops (alfasin) at 0.15% are also commonly used clinically, but both specifications contain preservatives.
Since most glaucoma patients need to use anti-glaucoma drugs locally for a long period of time or even throughout the life, close attention is required to the toxic response after administration. It was found that continuous use of the eye drops for more than one month, the antibacterial agent contained therein resulted in keratinization of the corneal epithelium of the palm rats, and infiltration of limbus, conjunctival stroma, and epithelial dermatitis cells. The European multi-national multi-center study compares the ocular surface toxic effects of ophthalmic drugs with or without preservatives on open angle glaucoma, with all recorded symptoms and signs of eyelid, conjunctiva, cornea significantly increased in the preservative group (see patent CN 108261390A).
The frequency of administration of BRT eye drops is typically 2-3 times per day, 1 drop each time. However, most eye drops are easy to eliminate rapidly due to physiological reasons (such as blink reaction, tear secretion, nasolacrimal duct drainage, etc.), so that the pre-cornea residence time is short, the drug absorption is limited, the ocular bioavailability is poor, the administration dosage is not easy to control, and thus, excessive or frequent use is easy, and other non-target areas are easy to enter due to nasolacrimal duct drainage, so that side effects are generated. The low-concentration BRT eye drops have limited effects although the adverse reaction of BRT can be reduced to a certain extent. The scholars at home and abroad research a series of novel drug delivery systems such as nano suspension, ointment, intraocular inserts and the like, compared with the traditional eye drops, the dosage forms can prolong the retention time of the drug in eyes, but are not widely accepted due to the influences of poor tolerance (such as intraocular inserts) of patients, high price and the like.
The amino polysaccharide substance is also called as mucopolysaccharide, the basic unit is two pond subunits, and the amino polysaccharide substance comprises the following four types: hyaluronic acid; chondroitin sulfate; a chitosan; heparan sulfate and heparin, which are important components of the cornea stroma, have higher viscosity and affinity, remain on the cornea surface for a longer time, wet the ocular surface, promote the expansion of cornea epithelium and wound healing, prevent bacteria and viruses from invading cells, have a protective effect on cornea epithelium cells, and can reduce adverse effects brought by preservatives in ophthalmic preparations.
Brimonidine has a pKa of 7.4 and will ionize at pH values below 6.6. For example, brimonidine has been ionized by about 90% at a pH of 6.4. Ionized ophthalmic drugs greatly reduce ocular permeability, and brimonidine is expected to not penetrate ocular tissue well at pH values below 6.6 or 6.5, thus decreasing efficacy compared to higher pH products. To overcome this disadvantage, nonionic cellulose derivatives such as hydroxypropyl methylcellulose (HPMC E4M grade), sodium carboxymethylcellulose (CMC) are used, which lower the surface tension of the eye drops from about 0.072N/M to 0.045N/M, thereby helping to allow the eye drops to spread more effectively around the eyes. In addition, the viscosity of HPMC can extend the residence time of eye drops in the eye, both of which are believed to contribute to increased drug penetration.
Disclosure of Invention
Based on the adverse reaction caused by the preservative in the eye drops and the problems of poor bioavailability of the brimonidine tartrate eye drops in the prior art, the invention provides a single-dose brimonidine tartrate eye drop without the preservative. The technical scheme is as follows:
brimonidine tartrate eye drops comprising the following components in 100 mL: brimonidine tartrate 0.05-0.5 g, osmotic pressure regulator 0.3-0.8 g, thickener 1-2 g, antioxidant 5-10 mg, pH regulator and water for injection in balance, wherein the pH regulator is added to make the pH of eye drops 5.6-6.6.
Preferably, the osmotic pressure of the eye drops is 270-320 mOsmol/Kg.
Preferably, the osmotic pressure is one or more selected from sodium chloride, potassium chloride, glucose and glycerol
Preferably, the thickener is selected from one or more of polyvinyl alcohol, chitosan, hydroxypropyl methylcellulose sodium and carboxymethyl cellulose sodium.
Preferably, the viscosity of the eye drops is 3.0 to 5.0mpa·s.
Preferably, the pH regulator is one or more selected from citric acid and sodium citrate, phosphate buffer solution, sodium hydroxide and hydrochloric acid
Preferably, the antioxidant is selected from one or more of sodium thiosulfate, sodium sulfite, potassium sulfite and butyl hydroxy anisole
A preparation method of brimonidine tartrate eye drops, which comprises the following steps:
taking 50-80 wt% of water for injection, adding the thickener into a container, stirring and dissolving;
adding an osmotic pressure regulator, a pH regulator and an antioxidant into a container, stirring, mixing and dissolving;
cooling to 30-60 deg.c, adding brimonidine tartrate and stirring to dissolve;
the rest water for injection is added, evenly mixed, filtered and sterilized by a filter membrane of 0.22-0.45 mu m, and the aseptic filling adopts the scheme, so that the invention has the following advantages:
the single-dose eye drop is prepared by taking brimonidine tartrate as a main component and adding the thickener, the pH regulator and the osmotic pressure regulator, does not contain the preservative, can prolong the acting time of the eye drop on a medicine application part to a certain extent by adding the thickener, can effectively reduce the intraocular pressure, has no secondary injury of the preservative to eyes, has the effects of moisturizing, promoting cornea epithelium repair and the like, and increases the comfort level of patients.
Detailed Description
Example 1
Brimonidine tartrate eye drops comprising the following components in 100 mL:
the preparation method of the brimonidine tartrate eye drops comprises the following steps:
(1) Taking 70wt% of water for injection, adding sodium chloride, sodium sulfite, citric acid and sodium citrate into a container at 35 ℃, stirring, mixing and dissolving;
(2) Adding brimonidine tartrate into a container, stirring, mixing, dissolving, and filtering and sterilizing by using a filter membrane with the diameter of 0.45 mu m;
(3) Adding chitosan into the filtrate, stirring at 200rpm for 2 hours at 30 ℃ until the chitosan is dissolved;
(4) Adding the rest water for injection, shaking, adjusting pH to 6.0 with sodium hydroxide or hydrochloric acid, filtering with 0.2 μm filter membrane, sterilizing, and packaging under aseptic condition.
Example 2
Brimonidine tartrate eye drops comprising the following components in 100 mL:
composition of the components Content (g/100 mL)
Brimonidine tartrate 0.45
Potassium chloride 0.7
HPMC 1.5
Sodium thiosulfate 0.005
Sodium dihydrogen phosphate 0.05
Disodium hydrogen phosphate 0.45
Sodium hydroxide or hydrochloric acid 6.5
Water for injection To 100mL
A method for preparing brimonidine tartrate eye drops, comprising the following steps:
(1) Taking 60wt% of water for injection, slowly adding HPMC into a container under the condition of continuously stirring at 60-70 ℃, stirring at 150rpm, and stirring and dissolving for 30-60 min;
(2) The solution was cooled to room temperature (25 ℃) with stirring until the HPMC was completely dissolved;
(3) Adding potassium chloride, sodium thiosulfate, sodium dihydrogen phosphate and disodium hydrogen phosphate under stirring, and stirring for dissolution;
(4) Adding brimonidine tartrate under stirring, stirring and dissolving;
(5) Adding the rest water for injection, shaking, adjusting pH to 6.5,0.25 μm with sodium hydroxide or hydrochloric acid, filtering, sterilizing, and packaging under aseptic condition.
Example 3
Brimonidine tartrate eye drops comprising the following components in 100 mL:
composition of the components Content (g/100 mL)
Brimonidine 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 Adjusting pH to 5.8
Water for injection To 100mL
A preparation method of brimonidine tartrate eye drops, which comprises the following steps:
(1) Taking 60wt% of water for injection, slowly adding CMC into a container under the condition of continuously stirring at 90-100 ℃, stirring at 150rpm, and stirring and dissolving for 30-60 min;
(2) Cooling the solution to room temperature under stirring until CMC is completely dissolved;
(3) Adding potassium chloride, sodium thiosulfate, sodium dihydrogen phosphate and disodium hydrogen phosphate under stirring, and stirring for dissolution;
(4) Adding brimonidine tartrate under stirring, stirring and dissolving;
(5) Adding the rest water for injection, shaking, adjusting pH to 5.8 with sodium hydroxide or hydrochloric acid, filtering with 0.2 μm filter membrane, sterilizing, and packaging under aseptic condition.
Comparative example 1
Brimonidine tartrate eye drops comprising the following components in 100 mL:
composition of the components Content (g/100 mL)
Brimonidine 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 Adjusting pH to 5.5
Water for injection To 100mL
A preparation method of brimonidine tartrate eye drops, which comprises the following steps:
(1) Taking 60wt% of normal-temperature water for injection, slowly adding polyvinyl alcohol into a container, stirring at 200rpm for 10-30 min to uniformly disperse, adding sodium chloride, sodium thiosulfate and citrate buffer into the container, heating to 95 ℃, stirring for 40-60 min, and stirring for dissolution;
(2) The temperature of the solution is reduced to below 40 ℃, and the brimonidine tartrate raw material is added and stirred for dissolution;
(3) The rest water for injection is filled up, stirred evenly, pH is regulated to 5.5 by sodium hydroxide or hydrochloric acid, and the mixture is filtered and sterilized by a filter membrane with 0.45 mu m and 0.22 mu m, and then the mixture is filled in a sterile way.
Comparative example 2 brimonidine tartrate eye drops (100 mL)
A preparation method of brimonidine tartrate eye drops, which comprises the following steps:
(1) Taking 60wt% of normal-temperature water for injection, slowly adding polyvinyl alcohol into a container, stirring at 200rpm for 10-30 min to uniformly disperse, adding sodium chloride, sodium thiosulfate, benzalkonium chloride and citrate buffer into the container, heating to 95 ℃, stirring for 40-60 min, and stirring for dissolution;
(2) The temperature of the solution is reduced to below 40 ℃, and the brimonidine tartrate raw material is added and stirred for dissolution;
(3) The rest water for injection is filled up, stirred evenly, pH is regulated to 5.6-6.6 by sodium hydroxide or hydrochloric acid, and the mixture is filtered and sterilized by a filter membrane with 0.45 mu m and 0.22 mu m, and then the mixture is filled in a sterile way.
Testing and evaluation
Detection results of various indexes of eye drops
The results show that: in examples 1, 2 and 3, there was substantially no significant change in the respective indices of the samples as compared with the comparative examples.
Animal test
Cornea residence time
The in vivo cornea residence time of the eye drops was studied using sodium fluorescein as the chromogenic material, in comparative examples 1, 2, and 3, respectively. The test was divided into five groups of 6 rabbits, wherein four groups of rabbits were instilled with 100. Mu.L of the eye drops of comparative example 1, example 2 and example 3 containing 0.10% sodium fluorescein solution in the conjunctival sac of the right eye, and the fifth group was instilled with 100. Mu.L of the eye drops of comparative example 2 containing 0.20% sodium fluorescein solution in the conjunctival sac of the right eye, and all rabbits were instilled with the same volume of citrate buffer solution of pH6.30 in the left eye as a control. The eyes of the rabbits were passively closed for 30 seconds after administration. Fluorescence decay times of corneal and conjunctival sac fluorescein sodium after administration were observed and recorded with a slit lamp, and the test results are shown in the following table.
Group of Time of residence in cornea (min.+ -. SD) Residence time in conjunctival sac (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
The results showed that the retention time of the eye drops of comparative example 1 in the cornea and conjunctival sac of rabbit eye was about 23min and 21min, the retention time of the eye drops of comparative example 2 in the cornea and conjunctival sac of rabbit eye was about 26min and 23min, and the retention time in conjunctival sac and the retention time on cornea were significantly increased as compared with examples 1, 2, 3, wherein the retention time of example 2 was the longest.
(2) Ocular hypotensive effect
Rabbits were divided into 5 groups, namely, a blank control group, a comparative example 2, an example 1, an example 2 and an example 3, and 5 rabbits in each group were injected into the anterior chamber of the rabbits for a plurality of times with 1% methyl cellulose to establish an ocular hypertension model, and were fed in single cages. Wherein the blank group was administered 3 times/d, 1 drop/time with water for injection, and the administration was started 12 hours after molding, and the intraocular pressure was measured with a indentation tonometer every day for 10 days, and the results are shown in the following table.
Group/time Before molding (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
The results show that after the administration for 10 days, compared with a control group, the intraocular pressure of the rabbits in each group in the example is reduced to be normal, which indicates that the eye drops have better antihypertensive effect on the ocular hypertension of the rabbits.
(3) In vitro corneal penetration test
Rabbits were sacrificed, intact corneas were isolated, corneas were fixed on diffusion cells, the inner side of corneas (aqueous humor) was facing the receiving cell, the outer side of corneas was facing the supply cell, and 2g of eye drops of comparative examples 2, 1, 2 and 3 were placed in the supply cell, and corneal penetration test was performed at 37 ℃. All the receiving liquid is taken out of the receiving pool in different time, and the receiving liquid with the same volume is replenished. The concentration of brimonidine tartrate in the receiving solution was determined by HPLC and the test results are shown in the following table.
Group of 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
The results show that the permeability of examples 1, 2, and 3 is increased compared to the comparative examples, indicating that the adhesive selected has a good effect in promoting penetration of the drug into the cornea.
It will be apparent to those skilled in the art from this disclosure that various other changes and modifications can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (9)

1. The brimonidine tartrate eye drops are characterized by comprising brimonidine tartrate and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise a thickening agent, an osmotic pressure regulator, a pH regulator and an antioxidant.
2. Brimonidine tartrate eye drops according to claim 1, wherein said raw and auxiliary materials comprise, based on 100 mL: brimonidine tartrate 0.05-0.5 g osmotic pressure regulator 0.3-0.8 g, thickener 1-2 g, antioxidant 5-10 mg, pH regulator and water for injection, wherein the pH regulator is added to make the pH of eye drops 5.6-6.6.
3. Brimonidine tartrate eye drops according to claim 1, wherein said osmolality adjusting agent is selected from one or more of sodium chloride, potassium chloride, glucose and glycerol.
4. Brimonidine tartrate eye drops according to claim 1, wherein said thickener is selected from one or more of polyvinyl alcohol, chitosan, sodium hypromellose, sodium carboxymethyl cellulose.
5. Brimonidine tartrate eye drops according to claim 1, wherein said pH adjusting agent is selected from one or more of citric acid and sodium citrate, phosphate buffer, sodium hydroxide and hydrochloric acid.
6. Brimonidine tartrate eye drops according to claim 1, wherein said antioxidant is selected from one or more of sodium thiosulfate, sodium sulfite, potassium sulfite and butyl hydroxy anisole.
7. Brimonidine tartrate eye drops according to claim 1, wherein said eye drops have a viscosity of 3.0-5.0 mPa-s.
8. Brimonidine tartrate eye drops according to claim 1, wherein said eye drops have an osmotic pressure of 270-320 mOsmol/Kg.
9. A process for the preparation of brimonidine tartrate eye drops as defined in any one of claims 1 to 6, comprising the steps of:
(1) Taking 50-80 wt% of water for injection, adding the thickener into a container, stirring and dissolving;
(2) Adding an osmotic pressure regulator, a pH regulator and an antioxidant into a container, stirring, mixing and dissolving;
(3) Cooling to 30-60 deg.c, adding brimonidine tartrate and stirring to dissolve;
(4) Adding the rest water for injection, mixing, filtering with 0.22-0.45 μm filter membrane, sterilizing, and packaging under aseptic condition.
CN202210038962.0A 2022-01-13 2022-01-13 Brimonidine tartrate eye drops and preparation method thereof Pending CN116473918A (en)

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