CN114306226A - Compound nanometer eye drops and preparation method thereof - Google Patents
Compound nanometer eye drops and preparation method thereof Download PDFInfo
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- CN114306226A CN114306226A CN202210070618.XA CN202210070618A CN114306226A CN 114306226 A CN114306226 A CN 114306226A CN 202210070618 A CN202210070618 A CN 202210070618A CN 114306226 A CN114306226 A CN 114306226A
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- brinzolamide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 claims abstract description 45
- 229960000722 brinzolamide Drugs 0.000 claims abstract description 44
- IWEGDQUCWQFKHS-UHFFFAOYSA-N 1-(1,3-dioxolan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(CC2OCCO2)N=C1 IWEGDQUCWQFKHS-UHFFFAOYSA-N 0.000 claims abstract description 37
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides compound nanometer eye drops and a preparation method thereof, belonging to the technical field of eye drops. The compound nanometer eye drops provided by the invention simultaneously contain two medicines, namely the brinzolamide and the brimonidine tartrate, and are matched with an adhesive, a stabilizer and an osmotic pressure regulator, so that the complexity and the administration frequency of combined administration can be reduced; the particle size of solid particles in the eye drops is nano-scale, the specific surface area of the drug is large, the residence time before the cornea can improve the stimulation effect of the large-particle drug on the eyes, and the compliance of patients is improved. The adhesive increases the specific surface area of the brinzolamide drug, increases the residence time of the hydrophobic drug before the cornea, reduces the loss of the drug in the eyes, reduces the systemic side effect caused by the loss of the nasolacrimal duct, improves the bioavailability, prolongs the medication period of the eye drops by slow release, and improves the antibacterial and anti-inflammatory effects; does not contain preservative, avoids secondary damage to eyes of patients.
Description
Technical Field
The invention relates to the technical field of eye drops, in particular to compound nanometer eye drops and a preparation method thereof.
Background
Since most patients with ocular hypertension (e.g., glaucoma) require long-term or even lifelong topical administration of anti-ocular hypertension drugs, the systemic adverse effects caused by such drugs are of great concern. At present, the clinically applied ocular hypotensive drugs mainly include eye drops, eye ointments and oral tablets. Among them, the eye drops do not cause blurring and irritation, and have the characteristics of low price, easy acceptance by patients, easy preparation, and the most extensive application.
For example, chinese patent CN103142462A discloses a brinzolamide nanosuspension, which contains the following components by weight in 100mL of nanosuspension: the dosage of the brinzolamide or the brinzolamide salt is 0.1-10.0 g, the dosage of the stabilizer is 0.01-30.0 g, and other pharmaceutically acceptable ophthalmic components are as follows: 0.01-8.0 g of osmotic pressure regulator, 0.01-2.0 g of pH regulator, or other pharmaceutically acceptable ophthalmic components such as preservative, metal ion complexing agent and the like, or 1.0-20.0 g of freeze-drying protective agent and water for supplementing 100 mL. The brinzolamide medicine is solid nano-particles existing in a certain crystal form or an amorphous state, has a large surface area, has certain adhesiveness in eyes, and prolongs the action time. However, the above-mentioned eye drops have a retention time of about 40 minutes in the eye region, and the retention time is not long enough.
Disclosure of Invention
In view of the above, the present invention provides a compound nano eye drop and a preparation method thereof, and the compound nano eye drop provided by the present invention has a long retention time in the eye.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides compound nanometer eye drops which comprise the following components in mass concentration: 0.5-1.5% of brinzolamide, 0.5-1.5% of brimonidine tartrate, 0.1-2% of adhesive, 1-30% of stabilizer, 0.2-3% of osmotic pressure regulator and 62-98.2% of water.
Preferably, the adhesive comprises one or more of chitosan, hyaluronic acid, heparin and acrylic acid polymer.
Preferably, the stabilizer comprises a polysorbate and/or a poloxamer.
Preferably, the osmotic pressure regulator comprises one or more of sodium chloride, potassium chloride and mannitol.
Preferably, the pH regulator further comprises one or more of sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate and disodium hydrogen phosphate.
Preferably, the pH value of the compound nanometer eye drops is 6-8.
The invention provides a preparation method of compound nanometer eye drops, which comprises the following steps:
mixing brinzolamide, adhesive, stabilizer, brimonidine tartrate, osmotic pressure regulator and water, homogenizing, and grinding to obtain compound nanometer eye drop.
Preferably, the pressure of the homogenization treatment is 10-20 MPa, the rotating speed is 5000-10000 r/min, and the time is 20-30 min.
Preferably, the grinding further comprises: and adding a pH regulator into the grinding liquid obtained by grinding to regulate the pH value to 6-8.
The invention also provides the application of the compound nanometer eye drops in the technical scheme in preparing the medicine for treating the ocular hypertension.
The invention provides compound nanometer eye drops which comprise the following components in mass concentration: 0.5-1.5% of brinzolamide, 0.5-1.5% of brimonidine tartrate, 0.1-2% of adhesive, 1-30% of stabilizer, 0.2-3% of osmotic pressure regulator and 62-98.2% of water. The effect of the brinzolamide is low when the brinzolamide is used alone, and the brinzolamide is generally usedThe eye drops need to be combined with eye drops containing other medicines. The compound nanometer eye drops provided by the invention simultaneously contain two medicines, namely brinzolamide and brimonidine tartrate, wherein the brinzolamide is a latest local carbonic anhydrase inhibitor, and HCO is reduced by inhibiting the activity of carbonic anhydrase3The generation of the sodium and water reduces the transport of sodium and water, so that the osmotic pressure in the aqueous humor is reduced, the aqueous humor generation is reduced, and the intraocular pressure is finally reduced; brimonidine tartrate is a highly selective alpha2Receptor agonists by activating alpha in ciliary body2The receptor inhibits the generation of cyclic adenosine monophosphate (cAMP) to reduce the generation of aqueous humor, and meanwhile, the grape membrane can be increased to the sclera aqueous humor outflow to reduce the intraocular pressure. The particle size of solid particles in the compound nanometer eye drops provided by the invention is nanometer, the specific surface area of the medicine is large, the detention time of brinzolamide and brimonidine tartrate before the cornea is long, the irritation effect of the large-particle medicine on eyes can be improved, and the compliance of patients is improved. In the compound nanometer eye drops provided by the invention, the adhesive agent increases the specific surface area of the brinzolamide and the brimonidine tartrate, increases the retention time of the hydrophobic drug before the cornea, reduces the loss of the drug in the eyes, reduces the systemic side effect caused by the loss of the nasolacrimal duct, improves the bioavailability and prolongs the medication period of the compound nanometer eye drops. The compound nanometer eye drops provided by the invention do not contain preservatives, thereby avoiding secondary damage to eyes of patients and filling up the defect of clinically containing preservatives. Compared with the eye drops without the adhesive, the compound nanometer eye drops with the adhesive have longer medicine concentration maintaining time on the cornea.
The invention provides a preparation method of the compound nanometer eye drops. The preparation method provided by the invention can be used for preparing the nano-scale eye drops, is simple to operate, has wide raw material source and low cost, and is suitable for large-scale production.
Detailed Description
The invention provides compound nanometer eye drops which comprise the following components in mass concentration: 0.5-1.5% of brinzolamide, 0.5-1.5% of brimonidine tartrate, 0.1-2% of adhesive, 1-30% of stabilizer, 0.2-3% of osmotic pressure regulator and 62-98.2% of water.
In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
The compound nanometer eye drops provided by the invention comprise 0.5-1.5% of brinzolamide, preferably 0.6-1.4%, more preferably 0.7-1.3%, further preferably 0.8-1.2%, and most preferably 0.9-1.0% by mass concentration.
Based on the mass concentration of the brinzolamide, the compound nanometer eye drops provided by the invention comprise 0.5-1.5% of brimonidine tartrate, preferably 0.6-1.4%, more preferably 0.7-1.3%, further preferably 0.8-1.2%, and most preferably 0.9-1.0%.
The compound nanometer eye drops provided by the invention comprise 0.1-2% of adhesive agent, preferably 0.2-1.8%, more preferably 0.5-1.5%, further preferably 0.7-1.3%, and most preferably 1.0-1.2% by mass concentration of brinzolamide. In the present invention, the adhesive preferably includes one or more of chitosan, hyaluronic acid, heparin, and an acrylic polymer, and more preferably chitosan. In the present invention, when the adhesive is a mixture of two or more kinds, the amount ratio of the different adhesives is not particularly limited, and may be any ratio. The adhesive provided by the invention also has certain antibacterial and anti-inflammatory effects, and further improves the treatment effect on the ocular hypertension disease.
The compound nanometer eye drops comprise 1-30% of a stabilizer, preferably 3-27%, more preferably 5-25%, further preferably 10-20%, and most preferably 15-18% by mass concentration of brinzolamide. In the present invention, the stabilizer preferably includes polysorbate and/or poloxamer. In the present invention, the polysorbate preferably includes one or more of 20, polysorbate 60 and polysorbate 80. In the present invention, the polysorbate loxamer preferably includes one or more of poloxamer 407 and poloxamer 188. In the present invention, when the stabilizer is a mixture of two or more kinds, the amount ratio of the different stabilizers in the present invention is not particularly limited, and may be any ratio.
The compound nanometer eye drops provided by the invention comprise 0.2-3% of osmotic pressure regulator, preferably 0.2-1.8%, more preferably 0.5-1.5%, further preferably 0.7-1.3%, and most preferably 1.0-1.2% by mass concentration of brinzolamide. In the invention, the osmotic pressure regulator comprises one or more of sodium chloride, potassium chloride and mannitol. In the present invention, when the osmotic pressure regulator is a mixture of two or more kinds, the ratio of the different osmotic pressure regulators used in the present invention is not particularly limited, and may be any ratio.
According to the mass concentration of the brinzolamide, the compound nanometer eye drop provided by the invention comprises 62-98.2% of water, preferably 70-95%, more preferably 75-90%, further preferably 80-88%, and most preferably 83-85%. In the present invention, the water is preferably sterilized water for injection.
In the invention, the pH value of the compound nanometer eye drops is preferably 6-8, more preferably 6.5-7.5, and further preferably 7-7.2. In the compound nanometer eye drop, the particle size of solid particles in the compound nanometer eye drop is preferably nanometer, more preferably 130-350 nm, and further preferably 132-240 nm.
In the invention, the compound nanometer eye drops preferably also comprise a pH regulator. The dosage of the pH regulator is not specially limited, and the pH value of the compound nanometer eye drops can be controlled to be 6-8. In the invention, the pH regulator comprises one or more of sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate and disodium hydrogen phosphate. In the invention, when the pH regulator is a mixture of more than two pH regulators, the dosage ratio of different pH regulators is not particularly limited, and the pH value of the compound nanometer eye drops can be controlled to be 6-8.
The invention provides a preparation method of compound nanometer eye drops, which comprises the following steps:
mixing brinzolamide, adhesive, stabilizer, brimonidine tartrate, osmotic pressure regulator and water, homogenizing, and grinding to obtain compound nanometer eye drop.
The mixing mode of the invention is not particularly limited, and the mixing mode known to those skilled in the art can be adopted, such as stirring and mixing; the stirring and mixing speed and time are not particularly limited, and the raw materials can be uniformly mixed.
In the invention, the pressure of the homogenization treatment is preferably 10-20 MPa, more preferably 12-18 MPa, and further preferably 14-15 MPa, the rotation speed of the homogenization treatment is preferably 5000-10000 r/min, more preferably 6000-9000 r/min, and further preferably 7000-8000 r/min, and the time of the homogenization treatment is preferably 20-30 min, more preferably 12-18 min, and further preferably 14-15 min. In the present invention, the homogenization treatment is preferably performed in a high-pressure homogenizer.
In the present invention, the grinding media used for the grinding preferably include zirconia, alumina; the particle size of the grinding medium is preferably 0.2-0.4 mm, more preferably 0.2mm, and the rotation speed of the grinding is preferably 200-500 r/min, more preferably 350-450 r/min. In the present invention, the grinding is preferably carried out in a high energy mill. In the present invention, the mass ratio of the homogenized liquid obtained by the homogenization treatment to the grinding medium is preferably 1: 5-10, more preferably 1: 6-9, and more preferably 1: 7 to 8. In the present invention, the grinding is preferably carried out in a high energy mill. In the present invention, the filling volume of the grinding media is preferably 40 to 60%, more preferably 45 to 55%, and still more preferably 50% of the capacity of the high-energy grinding mill.
In a specific embodiment of the present invention, the preparation method of the compound nanometer eye drops preferably comprises the following steps: first mixing brinzolamide, an adhesive, a stabilizer and first part of water to obtain brinzolamide mixed solution; dissolving brimonidine tartrate in the second part of water to obtain brimonidine tartrate solution; and (3) carrying out second mixing on the brimonidine tartrate solution, the mixed solution and the osmotic pressure regulator, then carrying out homogenization treatment, adding the residual water, and carrying out third mixing to obtain the compound nanometer eye drops. In the invention, the mass ratio of the brinzolamide to the first part of water is preferably 0.01-0.05: 1, more preferably 0.01 to 0.02: 1. in the invention, the mass ratio of the brimonidine tartrate to the second part of water is preferably 0.02-0.1: 1, more preferably 0.025 to 0.05: 1. in the present invention, the second mixing mode is preferably to add the brimonidine tartrate solution to the brinzolamide mixed solution under stirring.
The method further comprises the following steps after grinding: and adding a pH regulator into the grinding liquid obtained by grinding to regulate the pH value to 6-8, and then adding the rest water for mixing to obtain the compound nano eye drops. The dosage of the pH regulator is not specially limited, and the pH value of the compound nanometer eye drops can be controlled to be 6-8. In the present invention, the pH adjuster is preferably used in the form of a pH adjuster aqueous solution, and the concentration of the pH adjuster aqueous solution is preferably 0.01 to 0.6 wt%, more preferably 0.03 to 0.1 wt%, and further preferably 0.05 to 0.07 wt%.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Mixing 1g of brinzolamide, 2g of chitosan, 10g of polysorbate 80 and 50g of water for injection to obtain a brinzolamide mixed solution;
adding 1g of brimonidine tartrate into 20g of water for injection, and fully stirring until the brimonidine tartrate is dissolved to obtain a brimonidine tartrate solution;
under the condition of stirring, adding the brimonidine tartrate solution into the brinzolamide mixed solution, adding 0.5g of sodium chloride, and carrying out high-pressure homogenization treatment for 30min by using a high-pressure homogenizer under the conditions of 20MPa and 10000r/min to obtain a homogenized solution;
grinding the homogeneous liquid for 30min at 2000r/min by using a high-energy grinder and using 0.2mm zirconium oxide grinding beads as grinding media, adding 10 wt% of sodium hydroxide aqueous solution to adjust the pH value to 6.8, adding water for injection to fix the volume to 100mL, and obtaining the compound nano eye drops with the particle size of 132nm, wherein the mass ratio of the homogeneous liquid to the zirconium oxide is 1:5, and the filling volume fraction of the zirconium oxide is 50%.
Example 2
Mixing 1g of brinzolamide, 0.5g of chitosan, 20g of polysorbate 60 and 50g of water for injection to obtain a brinzolamide mixed solution;
adding 1g of brimonidine tartrate into 20g of water for injection, and fully stirring until the brimonidine tartrate is dissolved to obtain a brimonidine tartrate solution;
under the condition of stirring, adding the brimonidine tartrate solution into the brinzolamide mixed solution, adding 0.5g of sodium chloride, and carrying out high-pressure homogenization treatment for 20min by using a high-pressure homogenizer under the conditions of 15MPa and 8000r/min to obtain a homogenized solution.
Grinding the homogeneous liquid for 30min at 2000r/min by using a high-energy grinder and using 0.2mm zirconium oxide grinding beads as grinding media, adding 10 wt% of sodium hydroxide aqueous solution to adjust the pH value to 6.8, adding water for injection to fix the volume to 100mL, and obtaining the compound nanometer eye drops with the particle size of 240nm, wherein the mass ratio of the homogeneous liquid to the zirconium oxide is 1:5, and the filling volume fraction of the zirconium oxide is 50%.
Example 3
Mixing 0.5g of brinzolamide, 0.5g of chitosan, 20g of polysorbate 60 and 50g of water for injection to obtain a brinzolamide mixed solution;
adding 0.5g of brimonidine tartrate into 20g of water for injection, and fully stirring until the brimonidine tartrate is dissolved to obtain a brimonidine tartrate solution;
under the condition of stirring, adding the brimonidine tartrate solution into the brinzolamide mixed solution, adding 0.5g of sodium chloride, and carrying out high-pressure homogenization treatment for 30min by using a high-pressure homogenizer under the conditions of 15MPa and 6000r/min to obtain a homogenized solution.
Grinding the homogeneous liquid for 30min at 2000r/min by using a high-energy grinder and using 0.2mm zirconium oxide grinding beads as grinding media, adding 10 wt% of sodium hydroxide aqueous solution to adjust the pH value to 7.5, adding water for injection to fix the volume to 100mL, and obtaining the compound nanometer eye drops with the particle size of 350nm, wherein the mass ratio of the homogeneous liquid to the zirconium oxide is 1:5, and the filling volume fraction of the zirconium oxide is 50%.
Example 4
Mixing 1g of brinzolamide, 1.5g of chitosan, 15g of poloxamer 407 and 50g of water for injection to obtain a brinzolamide mixed solution;
adding 1g of brimonidine tartrate into 20g of water for injection, and fully stirring until the brimonidine tartrate is dissolved to obtain a brimonidine tartrate solution;
under the condition of stirring, adding the brimonidine tartrate solution into the brinzolamide mixed solution, adding 0.5g of sodium chloride, and carrying out high-pressure homogenization treatment for 30min by using a high-pressure homogenizer under the conditions of 10MPa and 10000r/min to obtain a homogenized solution.
Grinding the homogeneous liquid for 30min at 2000r/min by using a high-energy grinder and using 0.2mm zirconium oxide grinding beads as grinding media, adding 10 wt% of sodium hydroxide aqueous solution to adjust the pH value to 6.8, adding water for injection to fix the volume to 100mL, and obtaining the compound nanometer eye drops with the particle size of 260nm, wherein the mass ratio of the homogeneous liquid to the zirconium oxide is 1:5, and the filling volume fraction of the zirconium oxide is 50%.
Comparative example 1
Alcon laboratories (UK) Ltd 1% brinzolamide eye drops are commercially available.
Comparative example 2
Commercially available Allergan Sales LLC 0.15% brimonidine tartrate eye drops.
Comparative example 3
Compound nanometer eye drops are prepared according to the method of the embodiment 1, which is different from the embodiment 1 in that chitosan is not added.
Comparative example 4
Compound nano eye drops are prepared according to the method of example 1, and the difference from example 1 is that the mass of chitosan is 0.05 g.
Comparative example 5
Compound nano eye drops are prepared according to the method of example 1, and the difference from example 1 is that the mass of chitosan is 2.5 g.
Test example 1
Eye irritation test
Purpose of the experiment: the animals were observed for the stimulus response after ocular administration of the samples.
Experimental animals: new Zealand rabbits weigh 2.0-2.5 kg, can be used for both male and female, and do not have any inflammatory reaction and eye injury to tested animals.
The tested drugs are: the compound nanometer eye drops prepared in the examples 1-3 and the eye drops prepared in the comparative examples 1-5.
The experimental method comprises the following steps: the same-body left-right measurement self-comparison method is adopted, 4 rabbits (2 female rabbits and 2 male rabbits) are selected for each group, the eyes of each animal are inspected within 24 hours before the experiment, and animals with eye irritation symptoms, corneal defects and conjunctival loss cannot be used for the experiment.
Single dose eye irritation test: 1 drop of the tested medicine is dripped into the conjunctival sac of the right eye of the rabbit, and the same amount of gel matrix is dripped into the left eye to serve as a control. After the administration, the rabbit eyes were allowed to slightly and passively close for 10 seconds, then 2% fluorescein sodium was dropped, and local stimulation responses were observed with a slit lamp for 1, 2, 4, 24, 48, 72h to 7 days after the administration.
Multiple dose eye irritation test: 1 drop of the tested medicine is dripped into the conjunctival sac of the right eye of the rabbit, and the same amount of gel matrix is dripped into the left eye to serve as a control. After the administration, the rabbit eyes were allowed to slightly and passively close for 10 seconds, and then 2% fluorescein sodium was dropped and observed with a slit lamp. The administration is 1 time per day for 14 days. Eye irritation responses were observed before each day and 1, 2, 4, 24, 48, 72h to 7 days after the last dose.
And (4) judging the standard: the eye corneal, iris and conjunctival irritation response values for each animal at each observation time were summed to give a total score, and the total of the integrals for each group was divided by the number of animals to give the final score, based on the eye irritation response scores in table 1. The degree of irritation was judged according to the evaluation criteria for ocular irritation in Table 2. The results of the rabbit eye irritation scoring experiments in the single and multiple post-dose groups are shown in table 3.
TABLE 1 eye irritation response score
TABLE 2 evaluation criteria for eye irritation
TABLE 3 Ocular irritation test result scores
As can be seen from Table 3, at each time point, no obvious irritation of the compound nanometer eye drops prepared in examples 1-3 and comparative examples 3-4 to the eyes of the tested animals is found, and the average value of the comprehensive eye irritation score is 0. The 1% brinzolamide ophthalmic solution of comparative example 1 had slight irritation to the eyes of the test animals, and the average value of the eye irritation after a single administration was 6 minutes, and the average value of the eye irritation after multiple administrations was 8 minutes. The 0.15% brimonidine tartrate eye drops of comparative example 2 were slightly irritating to the eyes of the test animals, and the average mean value of eye irritation after a single administration was 4 points and the average mean value of eye irritation after multiple administrations was 7 points. Comparative example 5 had mild irritation to the eyes of the test animals, and the average mean value of eye irritation after a single administration was 4 points and the average mean value of eye irritation after multiple administrations was 6 points. The administration and observation periods of the animals in each group are abnormal behavior activities such as dysphoria and somnolence. The compound nanometer eye drops have mild irritation to the tested rabbit eyes after single and multiple administration, while the compound nanometer eye drops prepared by the invention have no obvious irritation to the rabbit eyes after single and multiple administration.
Test example 2
Examination of eye residence time
Purpose of the experiment: the residence time of the drug in the eye after ocular administration of the sample to the animal is examined.
Experimental animals: new Zealand rabbits weigh 2.0-2.5 kg, can be used for both male and female, and do not have any inflammatory reaction and eye injury to tested animals.
The tested drugs are: the compound nanometer eye drops prepared in the example 1 and the eye drops prepared in the comparative examples 1-5.
The experimental method comprises the following steps: slightly pulling the eye conjunctival sac of the rabbit open, dripping 1 drop of the tested medicine into the right eye conjunctival sac of the rabbit, slightly and passively closing the eye of the rabbit for 10 seconds after administration, then dripping 2% fluorescein sodium, and observing the fluorescence intensity of the eye of the rabbit by using a slit lamp 15, 30, 60, 90, 130, 180 and 240 minutes after administration by using a slit lamp.
And (4) judging the standard: the three grades of strong (2), weak (1-2) and no (1) are respectively graded according to the fluorescence intensity, each tested group uses 4 rabbit eyes (2 female rabbit eyes and 2 male rabbit eyes) respectively, the experiment is repeated, and the average value is taken, wherein, when the fluorescence intensity is strong, the suspension eye drops are regarded as being retained in the eyes. The test results are shown in table 4.
TABLE 4 eye residence time of the compound nano eye drops prepared in example 1 and the eye drops of comparative examples 1 to 5
As can be seen from Table 4, the compound nano eye drops prepared by the invention have a retention time of 60min in the eye, which is significantly longer than common commercially available brinzolamide eye drops (retention time of 30min) and brimonidine tartrate eye drops (retention time of 15 min). The compound nanometer eye drops added with chitosan provided by the invention can prolong the detention time of the drug in the eyes, overcomes the defect that the eye drops are rapidly lost in the eyes, and continuously releases the drug, thereby improving the local drug effect of the drug, and further reducing and lowering the risk of systemic adverse reaction of the drug.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. The compound nanometer eye drops are characterized by comprising the following components in mass concentration: 0.5-1.5% of brinzolamide, 0.5-1.5% of brimonidine tartrate, 0.1-2% of adhesive, 1-30% of stabilizer, 0.2-3% of osmotic pressure regulator and 62-98.2% of water.
2. The compound nano eye drops according to claim 1, wherein the adhesive comprises one or more of chitosan, hyaluronic acid, heparin and acrylic acid polymer.
3. The compound nano eye drop according to claim 1, wherein the stabilizer comprises polysorbate and/or poloxamer.
4. The compound nanometer eye drop according to claim 1, wherein the osmotic pressure regulator comprises one or more of sodium chloride, potassium chloride and mannitol.
5. The compound nanometer eye drop according to any one of claims 1 to 4, further comprising a pH regulator, wherein the pH regulator comprises one or more of sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate and disodium hydrogen phosphate.
6. The compound nanometer eye drop according to claim 5, wherein the pH value of the compound nanometer eye drop is 6-8.
7. The preparation method of the compound nanometer eye drops as claimed in any one of claims 1 to 6, which is characterized by comprising the following steps:
mixing brinzolamide, adhesive, stabilizer, brimonidine tartrate, osmotic pressure regulator and water, homogenizing, and grinding to obtain compound nanometer eye drop.
8. The method according to claim 7, wherein the homogenization treatment is performed at a pressure of 10 to 20MPa, a rotation speed of 5000 to 10000r/min, and a time of 20 to 30 min.
9. The method of claim 7 or 8, further comprising, after the grinding: and adding a pH regulator into the grinding liquid obtained by grinding to regulate the pH value to 6-8.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115068416A (en) * | 2022-06-30 | 2022-09-20 | 北京新领先医药科技发展有限公司 | Brimonidine tartrate eye drops and preparation method thereof |
| CN116421555A (en) * | 2023-04-27 | 2023-07-14 | 亚邦医药股份有限公司 | Brimonidine tartrate eye drops and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142462A (en) * | 2012-02-23 | 2013-06-12 | 四川大学 | Brinzolamide eye preparations, and preparation method and use thereof |
| CN104721145A (en) * | 2013-02-21 | 2015-06-24 | 四川大学 | Brinzolamide nanoparticle preparation used for eyes and preparation method thereof |
| CN108261390A (en) * | 2017-06-12 | 2018-07-10 | 上海昊海生物科技股份有限公司 | A kind of brinzolamide Brimonidine eye drops and preparation method thereof |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142462A (en) * | 2012-02-23 | 2013-06-12 | 四川大学 | Brinzolamide eye preparations, and preparation method and use thereof |
| CN104721145A (en) * | 2013-02-21 | 2015-06-24 | 四川大学 | Brinzolamide nanoparticle preparation used for eyes and preparation method thereof |
| CN108261390A (en) * | 2017-06-12 | 2018-07-10 | 上海昊海生物科技股份有限公司 | A kind of brinzolamide Brimonidine eye drops and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115068416A (en) * | 2022-06-30 | 2022-09-20 | 北京新领先医药科技发展有限公司 | Brimonidine tartrate eye drops and preparation method thereof |
| CN116421555A (en) * | 2023-04-27 | 2023-07-14 | 亚邦医药股份有限公司 | Brimonidine tartrate eye drops and preparation method thereof |
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